Effective inhibitors of D-amino acid oxidase (DAAO) and their uses

Abstract

Provided herein are effective compounds of formula (I), and their use for inhibiting the activity of D-amino acid oxidase (DAAO) or treating diseases or disorders associated with DAAO, such as central nervous system (CNS) disorders, pain, obesity, diabetes or hyperlipidemia. Also provided in the present disclosure are methods for synthesizing compounds of formula (I) described herein. (I)

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Patent Application No. 15 / 991,710, entitled “Inhibitors of D-Amino Acid Oxidase (DAAO) and Uses Thereof” and filed on May 29, 2018, the entire contents of which are incorporated herein by reference. Background Art

[0003] The central nervous system (CNS) includes the brain and spinal cord. The CNS is susceptible to a variety of disorders, which may be caused by a variety of factors, including heredity, trauma, infection, degeneration, structural defects and / or injury, tumors, interrupted blood flow, and autoimmune disorders. The symptoms of CNS disorders depend on the area of ​​the nervous system involved and the cause of the disorder.

[0004] Due to the complexity of CNS disorders and the lack of effective technologies for delivering therapeutic agents across the blood-brain barrier, the development of effective treatments for CNS disorders has lagged behind other therapeutic areas. Given this, there is great interest in developing new treatments for CNS disorders.

[0005] The N-methyl-D-aspartate (NMDA) receptor is a subtype of glutamate receptor that plays a key role in cognition, memory, and neurotoxicity. It is shown that the regulation of NMDA receptors is beneficial for the treatment of diseases of the central nervous system. D-amino acid oxidase (DAAO) is a peroxisomal enzyme that oxidizes D-amino acids to the corresponding imino acids. It is reported that DAAO is involved in the metabolism of brain D-amino acids (including D-serine) and the regulation of glutamatergic neurotransmission. In view of this, DAAO is a target for the treatment of central nervous system (CNS) disorders related to D-serine and / or glutamatergic neurotransmission. In addition, DAAO also degrades D-serine to 3-hydroxypyruvate, a potential mediator of type II diabetes (Zhang, 2015). This suggests that DAAO inhibitors can be used to treat obesity, diabetes, and hyperlipidemia. Summary of the invention

[0006] The present disclosure is based, at least in part, on the development of compounds of formula (I) described herein as potent DAAO inhibitors. Such compounds are expected to be beneficial in treating diseases and disorders associated with DAAO and / or glutamatergic neurotransmission (e.g., obesity, diabetes, hyperlipidemia, pain, or CNS disorders).

[0007] Therefore, one aspect of the present disclosure provides a compound of formula (I):

[0008] or a pharmaceutically acceptable salt thereof, wherein:

[0009] Ring A is a 5- to 8-membered monocyclic ring system, which optionally includes at least one heteroatom selected from the group consisting of N, O, P and S;

[0010] Each of R1, R2, R3, R4, R5, R6, R7 and R8 is independently absent or has the formula:

[0011]

[0012] It is optionally substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of: C 1-3 Alkyl, halogen, –CN, –NO2, –SH, –S(C 1-3 alkyl), –NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2 and -O(C 1-3 alkyl); wherein

[0013] n is 0 or 1;

[0014] m is 1, 2, 3, 4 or 5; and

[0015] The total number of galloyl moieties is an integer from 4 to 35, inclusive, and wherein when the compound of formula (I) is When , the total number of galloyl moieties is an integer from 15 to 35, inclusive.

[0016] In some embodiments, one, two, three, four, five, or six of R1, R2, R3, R4, R5, R6, R7, and R8 are absent.

[0017] In another aspect, the present disclosure provides a composition comprising a compound described herein and a carrier, which composition can be a pharmaceutical composition.

[0018] Also provided herein is a method for preparing a compound of formula (I) as described herein. Such a method may comprise the following steps:

[0019] (a) providing a compound of formula (Ia)

[0020]

[0021] wherein R1′, R2′, R3′, R4′, R5′, R6′, R7′ and R8′ are each independently -OH, -NH2 or absent;

[0022] Ring A is a 5- to 8-membered monocyclic ring system, which optionally includes at least one heteroatom selected from the group consisting of N, O, P and S;

[0023] (b) reacting the compound of formula (Ia) with 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride to conjugate 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride with one or more of R1′, R2′, R3′, R4′, R5′, R6′, R7′ and R8′ of the compound of formula (Ia) to produce a first intermediate; and

[0024] (c) deprotecting the allyl group and the cyclic acetal group in 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride conjugated with the compound of formula (Ia) to obtain the compound of formula (I).

[0025] In some embodiments, one, two, three, four, five, or six of R1′, R2′, R3′, R4′, R5′, R6′, R7′, and R8′ are absent.

[0026] In yet another aspect, the disclosure features a method for treating a disease or condition associated with DAAO, the method comprising administering to a subject in need thereof an effective amount of a composition (e.g., a pharmaceutical composition) comprising a compound described herein and (ii) a pharmaceutically acceptable carrier.

[0027] In some embodiments, the subject can be a human having, suspected of having, or at risk of having a central nervous system (CNS) disorder, metabolic disorder, or pain.

[0028] 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 disorders, childhood learning disabilities, premenstrual syndrome, depression, major depressive disorder, anhedonia, suicidal ideation and / or behavior, bipolar disorder, anxiety disorders, panic disorder, post-traumatic stress disorder, chronic mild and unpredictable stress, eating disorders, addictive disorders, personality disorders, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, ataxia, Friedreich's ataxia, Tourette's syndrome, nocturnal enuresis, nonepileptic seizures, blepharospasm, Duchenne muscular dystrophy, or stroke.

[0029] Exemplary metabolic disorders include, but are not limited to, obesity, hyperlipidemia, hypercholesterolemia, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetes.

[0030] Exemplary pain disorders include, but are not limited to, psychogenic pain, acute pain, chronic pain, chronic pain syndrome, neuropathic pain, nociceptive pain, and hyperalgesia. In some cases, the pain disorder is psychogenic pain, which can be headache, muscle pain, back pain, and stomach pain. In other cases, the pain disorder can be neuropathic pain, which can be sciatica, carpal tunnel syndrome, diabetic neuropathy, post-herpetic neuralgia, or central pain syndrome. In yet other cases, the pain disorder is nociceptive pain, which can be radicular pain, somatic pain, and visceral pain.

[0031] In any of the methods disclosed herein, the compound or a composition comprising the compound may be administered to the subject (e.g., a human patient) at a frequency of four times a day to once every three months. In some embodiments, the subject may be treated simultaneously with, before, or after one or more additional agents for treating and / or reducing the risk of a CNS disorder.

[0032] Also within the scope of the present disclosure is any of the compounds of formula (I) described herein or compositions comprising the compounds for use in treating any of the target diseases and disorders as disclosed herein, and the use of such compounds or compositions in the manufacture of a medicament for treating any of the target diseases / disorders.

[0033] The details of one or more embodiments of the invention are set forth in the following description. Other features or advantages of the invention will become apparent from the following drawings and detailed description of several embodiments, and also from the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The following drawings constitute part of this specification and are included to further illustrate certain aspects of the present disclosure, which may be better understood by referring to the drawings in combination with the detailed description of specific embodiments presented herein.

[0035] Figure 1 The human DAAO (hDAAO) inhibitory activity (IC) of compounds of formula (I) with different numbers of galloyl moieties is shown. 50 , μM).

[0036] Figure 2 is a graph showing the prepulse inhibition in MK-801-treated mice by compound 24. **P<0.01; ***P<0.001 compared with the MK-801 group. DETAILED DESCRIPTION

[0037] Thus, the present disclosure provides compounds of formula (I) having 4 to 35 galloyl moieties (e.g., glucose moieties) attached to a ring system; compositions comprising any of the compounds of formula (I) and a carrier; kits comprising any of the compounds of formula (I); methods for preparing the compounds of formula (I) described herein; and methods of using them for inhibiting DAAO, thereby improving basic function, weight, hyperactivity, anxiety, depression, suicidal ideation and / or behavior, sensorimotor gating, pain thresholds, memory and cognitive behavior in subjects in need of treatment, and / or for treating diseases and disorders associated with DAAO, such as obesity disorders, hyperlipidemia, hypercholesterolemia, hyperglycemia, diabetes, and CNS disorders. It has been reported herein that compounds of formula (I) having a large number of galloyl moieties (e.g., ≥15) show a trend toward excellent therapeutic effects. Further, relative to naturally occurring tannic acid, the compounds of formula (I) disclosed herein show high levels of activity to cross the BBB and accumulate in the brain. Therefore, compounds of formula (I) are expected to have better therapeutic effects for treating CNS disorders such as those disclosed herein.

[0038] The details of one or more embodiments of the present disclosure are set forth herein. Other features, objects and advantages of the present disclosure will be apparent from the detailed description, examples and claims.

[0039] definition

[0040] 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 version, Handbook of Chemistry and Physics, 75th Edition, inside cover, and specific functional groups are generally defined as described herein. Additionally, general principles of organic chemistry as well as specific functional moieties and reactivities are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th ed., 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, 3rd ed., Cambridge University Press, Cambridge, 1987. The present disclosure is not intended to be limited in any way by the exemplary list of substituents described herein.

[0041] The compounds described herein may include one or more asymmetric centers, and therefore may exist in various isomeric forms, such as 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 a mixture of stereoisomers, including a racemic mixture and a mixture of one or more stereoisomers enriched. Isomers may be separated from the mixture 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 may be prepared by asymmetric synthesis. See, e.g., 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, New York, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively as mixtures of various isomers.

[0042] When a range of values ​​is listed, it is intended to include every value and subrange within that range. For example, “C 1–6 "Aims to cover 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 , C 4–5 and C 5–6 .

[0043] The term "aliphatic" includes saturated and unsaturated, straight-chain (i.e., unbranched), branched, acyclic, cyclic or polycyclic aliphatic hydrocarbons, which are optionally substituted by one or more functional groups. As will be appreciated by those of ordinary skill in the art, "aliphatic" is intended to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and cycloalkynyl moieties in this article. Therefore, the term "alkyl" includes straight-chain, branched and cyclic alkyl groups. Similar conventions apply to other general terms, such as "alkenyl", "alkynyl" etc. In addition, the terms "alkyl", "alkenyl", "alkynyl" etc. cover substituted and unsubstituted groups. In some embodiments, "low alkyl" is used to represent those alkyl groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) with 1-6 carbon atoms.

[0044] In certain embodiments, the alkyl, alkenyl and alkynyl groups used in the present disclosure include 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl and alkynyl groups used in the present disclosure include 1-10 aliphatic carbon atoms. In other embodiments, the alkyl, alkenyl and alkynyl groups used in the present disclosure include 1-8 aliphatic carbon atoms. In other embodiments, the alkyl, alkenyl and alkynyl groups used in the present disclosure include 1-6 aliphatic carbon atoms. In other embodiments, the alkyl, alkenyl and alkynyl groups used in the present disclosure include 1-4 carbon atoms. Thus, exemplary aliphatic groups include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH2-cyclopropyl, vinyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH2-cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, -CH2-cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH2-cyclohexyl moiety, etc., which may again carry one or more substituents. Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-butene-1-yl, etc. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, etc.

[0045] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 10 carbon atoms ("C 1–10 In some embodiments, the alkyl group has 1 to 9 carbon atoms (“C 1-9 In some embodiments, the alkyl group has 1 to 8 carbon atoms (“C 1-8 In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C 1-7 In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1-5In some embodiments, the 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 ("C1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 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, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl) and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise specified, each example of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., halogen, such as F or -OH). In certain embodiments, an alkyl group is an unsubstituted C 1-10 Alkyl (such as unsubstituted C 1-6 In some embodiments, the alkyl group is a substituted C 1-10 Alkyl (such as substituted C 1-6 Alkyl or substituted C 1-3 Alkyl, e.g., -CF3 or -CH2OH).

[0046] "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C 2-20 In some embodiments, the 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, the alkenyl group has 2 to 8 carbon atoms (“C 2-8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C 2-7 In some embodiments, the 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 2-4In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 In some embodiments, an alkenyl group has 2 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). 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 above-mentioned C 2-4 In some embodiments, the alkenyl group is an unsubstituted C 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1, 1-1 2-10 In certain embodiments, the alkenyl group is a substituted C 2-10 In an alkenyl group, there is no C=C double bond with a specified stereochemistry (e.g., -CH=CHCH3 or ) can be an (E)- or (Z)-double bond.

[0047] "Alkynyl" refers to a straight or branched chain hydrocarbon radical 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, the alkynyl group has 2 to 10 carbon atoms (“C 2-10 In some embodiments, the alkynyl group has 2 to 9 carbon atoms (“C 2-9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms (“C 2-8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms (“C 2-7 In some embodiments, the 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, the alkynyl group has 2 to 4 carbon atoms (“C 2-4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C 2-3In some embodiments, an alkynyl group has 2 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 above-mentioned C 2-4 In some embodiments, the alkynyl group is an unsubstituted C alkynyl group, and pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl groups 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 (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 Alkynyl.

[0048] "Carbocyclyl" or "carbocyclic" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, the 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 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3-8 Carbocyclyl groups include but are not limited to the above mentioned C 3-6 Carbocyclyl groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3-10 Carbocyclyl groups include but are not limited to the above mentioned C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) and the like. As shown in the foregoing examples, in certain embodiments, the carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or comprises a fused, bridged or spirocyclic system, such as a bicyclic system ("bicyclic carbocyclyl"), and may be saturated or may be partially unsaturated. "Carbocyclyl" also includes a ring system in which the carbocycle as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocycle, and in such a case, the number of carbons continues to specify the number of carbons in the carbocyclic system. Unless otherwise indicated, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C 3-10 In certain embodiments, the carbocyclyl group is a substituted C 3-10 Carbocyclic group.

[0049] In some embodiments, "carbocyclyl" is a monocyclic saturated carbocyclyl group ("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 Cycloalkyl”) C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the above-mentioned C 5-6 Cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of cycloalkyl groups include the above-mentioned C 3-6 Cycloalkyl groups and cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, a cycloalkyl group is an unsubstituted C 3-10 In certain embodiments, the cycloalkyl group is a substituted C 3-10 Cycloalkyl.

[0050] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-10 membered heterocyclyl"). In heterocyclyl radicals containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom when valence permits. Heterocyclyl radicals may be monocyclic ("monocyclic heterocyclyl") or fused, bridged or spiro ring systems, such as bicyclic ring systems ("bicyclic heterocyclyl"), and may be saturated or may be partially unsaturated. Heterocyclyl bicyclic ring systems may include 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, where the point of attachment is on the carbocyclyl or heterocycle, or in which a heterocycle as defined above is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocycle, and in such cases, the number of ring members continues to specify the number of ring members in the heterocycle system. Unless otherwise specified, each instance of a heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") with one or more substituents. In certain embodiments, a heterocyclyl group is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3-10 membered heterocyclyl.

[0051] In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("5-10 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-8 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0052] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thiranyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 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 heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepane, and thiacycloheptane. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocyclooctanyl, oxepane, and thiacyclooctanyl. Exemplary 5-membered heterocyclic groups fused to C6 aryl rings (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolyl, 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, and the like.

[0053] "Aryl" refers to a group having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10 or 14 π electrons shared in the cyclic array) ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 In some embodiments, the aryl group has fourteen ring carbon atoms ("C 14"Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the radical or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms continues to specify the number of carbon atoms in the aromatic ring system. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 Aryl.

[0054] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups as divalent bridging groups are further referred to using the suffix -ene, for example, alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene and heteroarylene.

[0055] "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, the aralkyl is an optionally substituted benzyl. In certain embodiments, the aralkyl is benzyl. In certain embodiments, the aralkyl is an optionally substituted phenethyl. In certain embodiments, the aralkyl is phenethyl.

[0056] "Heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in the cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom when valence permits. Heteroaryl bicyclic ring systems can include 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, wherein the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to specify the number of ring members in 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, wherein the point of attachment is on the aryl or heteroaryl ring, and in such cases, the number of ring members specifies the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on the ring, i.e., the ring with the heteroatom (e.g., 2-indolyl) or the ring without the heteroatom (e.g., 5-indolyl).

[0057] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen and sulfur. Unless otherwise indicated, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.

[0058] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. 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, aza Oxalic acid thia Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0059] "Unsaturated" or "partially unsaturated" refers to a group that includes at least one double or triple bond. "Partially unsaturated" ring systems are further intended to encompass rings with multiple sites of unsaturation, but are not intended to include aromatic groups (e.g., aryl or heteroaryl groups). Likewise, "saturated" refers to a group that does not contain double or triple bonds, i.e., contains all single bonds.

[0060] Unless specifically stated otherwise, atoms, moieties or groups described herein may be unsubstituted or substituted when valency permits. The term "optionally substituted" means substituted or unsubstituted.

[0061] Unless otherwise expressly provided, a group is optionally substituted. The term "optionally substituted" refers to substituted or unsubstituted. In some embodiments, alkyl, alkenyl, alkynyl, carbocyclic radical, heterocyclic radical, aryl and heteroaryl groups are optionally substituted (for example, "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclic radical, "substituted" or "unsubstituted" heterocyclic radical, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl groups). Usually, the term "substituted", whether or not there is a term "optionally" before, means that at least one hydrogen present on a group (such as a carbon or nitrogen atom) is allowed to be substituted, such as after substitution, a stable compound is produced, such as a substituent of a compound that will not spontaneously undergo transformation (such as by rearrangement, cyclization, elimination or other reactions) is substituted. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is the same or different at each position. It is contemplated that the term "substituted" includes substitution with all permissible substituents of an organic compound, any substituent described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations to obtain a stable compound. For the purposes of the present disclosure, a heteroatom such as nitrogen may have a hydrogen substituent and / or any suitable substituent that satisfies the valence of the heteroatom as described herein and results in the formation of a stable portion. 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 substituent is a sulfur atom substituent.

[0062] Exemplary carbon atom substituents include, but are not limited to, 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 Carbocyclic group, 3-14 membered heterocyclic group, C 6–14 Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution; wherein X- is the counter ion;

[0063] Or the two geminal hydrogen atoms on the carbon atom are replaced by 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 replace;

[0064] R aa Each instance of is independently selected from C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R aa The groups are connected to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0065] R bb Each instance of is independently selected from 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、C1-10 Alkyl, C 1-10 Perhaloalkyl, C 2–10 Alkenyl, C 2–10 Alkynyl, C 3–10 Carbocyclic group, 3-14 membered heterocyclic group, C 6–14 Aryl and 5-14 membered heteroaryl, or two R bb The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution; wherein X - is the counter ion;

[0066] R cc Each instance of is independently selected from hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R cc The groups are connected to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0067] R dd Each instance of is independently selected from halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OR ee ,–ON(R ff )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 ,–NRff 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 S02R 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)(OR ee 2. C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may be linked to form =O or =S; where X - is the counter ion;

[0068] R ee Each instance of is independently selected from C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution;

[0069] R ff Each instance of is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, or two R ff The groups are connected to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution; and

[0070] R gg Each instance of is independently 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 1–6Alkyl)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(C 1–6 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 Perhaloalkane, C 2–6 Alkenyl, C 2–6 Alkynyl, C 3–10Carbocyclic group, C 6–10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R gg Substituents may be linked to form =O or =S, where X – It is a counter ion.

[0071] R gg Each instance of is independently 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(C1–6 alkyl), –C(=NH)NH2, –OC(=NH)N(C 1–6 Alkyl)2, –OC(NH)NH(C 1–6 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 Carbocyclic group, C 6–10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R gg Substituents may be linked to form =O or =S; where X – It is a counter ion.

[0072] To maintain electron neutrality, a "counterion" or "anionic counterion" is a negatively charged group associated with a positively charged group. Anionic counterions can be monovalent (i.e., include one formal negative charge). Anionic counterions can also be multivalent (i.e., include more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F – , Cl – Br – ,I – )、NO3– 、ClO4 – OH – 、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, propionate, 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 that 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 carborane.

[0073] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) or iodine (iodo, -I).

[0074] "Acyl" refers to a moiety selected from the group consisting of: -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 S02R aa , –C(=S)N(R bb )2, –C(=O)SR aa or –C(=S)SR aa , where R aa and R bb As defined herein.

[0075] The nitrogen atoms may be substituted or unsubstituted where valence permits, and 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 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R attached to the nitrogen atom cc The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein R aa , R bb , R cc , and R ddAs defined above.

[0076] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also known as 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(R cc 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 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein R aa , R bb , R cc and R dd As defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd ed., John Wiley & Sons, 1999, which is incorporated herein by reference.

[0077] For example, a nitrogen protecting group such as an amide group (eg, -C(=O)R aa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, picolinamide, 3-pyridylformamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0078] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)OR aa) include but are not limited to methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthenyl)]methyl carbamate (DBD-Tmoc), 4-methoxybenzoyl carbamate methyl ester (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl 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-biphenyl)ethyl carbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarbamylamino)ethyl carbamate, tert-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolinyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate (alkyldithio carbamate), benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl 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-methylthiophene carbamate Ester (Mtpc), 2,4-dimethylthiophene carbamate (Bmpc), 2-phosphoethyl carbamate (Peoc), 2-triphenylphosphinoisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonomethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl ester, phenyl (o-nitrophenyl) methyl carbamate, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylformamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylformamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furylmethyl carbamate, 2-iodoethyl carbamate, isoboryl carbamate , isobutyl carbamate, isonicotinoyl carbamate, p-(p-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 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-tert-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate. ,

[0079] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)2R aa ) include, but are not limited to, 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), 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 phenacylmethylsulfonamide.

[0080] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N′-toluenesulfonylaminoacyl derivatives, N′-phenylaminosulfonyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiosuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilaziridine adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5- Substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-ones, 1-substituted 3,5-dinitro-4-pyridones, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrroline-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 (Ph F), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-pyridylmethylamino N′-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylamine, N-(5,5-dimethyl-3-oxo-1-cyclohexyl)amine yl)amine, N-borane derivatives, N-diphenylboronic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosoamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylphosphinothioamide (Mpt), diphenylphosphinothioamide (Ppt), dialkylphosphoramidates, dibenzylphosphoramidates, diphenylphosphoramidates, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

[0081] 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

[0082] –P(=O)(N(R bb )2)2, where X - , R aa , R bb and R ccAs defined herein. In certain embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxy protecting group). Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, which are incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, methyl, tert-butyloxycarbonyl (BOC or Boc), methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy) methyl (p-AOM), guaiacol methyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), silyloxymethyl, 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-methoxytetrahydrothiopyranyl 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-methylenebenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenyloxyseleno)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxy benzyl, 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-dinitrodiphenylmethyl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tri(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(acetylpropyloxyphenyl)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, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (I PDMS), diethylisopropylsilyl (DEIPS), dimethylethylsilyl (dimethylthexylsilyl), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formates, benzoylformates, acetates, chloroacetates, dichloroacetates, trichloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, phenoxyacetates, p-chlorophenoxyacetates, 3-phenylpropionates, 4-oxopentanoate (ethyl 4,4-(ethylene dithio) pentanoate (levulinyl dithioacetal), pivaloate, adamantate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenyl methyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl) ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphino) ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl ethyl carbonate Alkenyl esters, alkyl allyl carbonates, alkyl p-nitrophenyl carbonates, alkyl benzyl carbonates, alkyl p-methoxybenzyl carbonates, alkyl 3,4-dimethoxybenzyl carbonates, alkyl o-nitrobenzyl carbonates, alkyl p-nitrobenzyl carbonates, alkyl S-benzyl thiocarbonates, 4-ethoxy-1-naphthyl carbonates, methyl dithiocarbonates, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, 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, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioate, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzyl sulfonate, and tosylate (Ts). ,

[0083] The term "pharmaceutically acceptable salt" refers to those salts which are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and are commensurate with a reasonable benefit / risk ratio. 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.

[0084] 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 with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by ion exchange using other methods known in the art. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 Alkyl)4 -Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate.

[0085] The term "solvate" refers to a form of a compound that is associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), diethyl ether, etc. The compounds described herein can be prepared, for example, in a crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric solvates and non-stoichiometric solvates. In some cases, for example, when one or more solvent molecules are incorporated into the lattice of a crystalline solid, the solvate will be able to separate. "Solvate" includes both solution phases and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0086] It is also understood that compounds that have the same molecular formula but 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."

[0087] Stereoisomers that are not mirror images of each other 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, it is bonded to four different groups, then a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center, and are described by the R- and S-sequential rules of Cahn and Prelog, or by the way in which the molecule rotates the plane of polarized light and is designated as right- or left-handed (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0088] The term "prodrug" refers to a compound with a cleavable group and becomes a compound described herein by solvent decomposition or under physiological conditions, which has pharmaceutical activity in vivo. Such examples include, but are not limited to, choline ester derivatives, N-alkyl morpholine esters, etc. Other derivatives of the compounds described herein are active in their acid and acid derivative forms, but generally provide advantages of solubility, tissue compatibility or delayed release in an acid-sensitive form in mammalian organisms (see, Bundgard, H., Design of Prodrugs, pp. 7-9, pp. 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives known to those skilled in the art, such as, for example, esters prepared by reacting parent acids with suitable alcohols, or amides prepared by reacting parent acid compounds with substituted or unsubstituted amines or anhydrides or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups suspended on compounds described herein are specific prodrugs. In some cases, it is desirable to prepare a double ester type prodrug, such as an (acyloxy)alkyl ester or a ((alkoxycarbonyl)oxy)alkyl ester. The C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C8 12 Substituted aryl and C7-C 12 Aryl alkyl esters may be preferred.

[0089] The terms "inhibition," "inhibiting," "inhibit," 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 the medium.

[0090] When a compound, pharmaceutical composition, method, use, or kit is referred to as "selectively," "specifically," or "competitively" binding to a first protein, the compound binds to the first protein with a higher binding affinity (e.g., not less than about 2-fold, not less than about 5-fold, not less than about 10-fold, not less than about 30-fold, not less than about 100-fold, not less than about 1,000-fold, or not less than about 10,000-fold) than it binds to a second protein or a protein different from the first protein. When a compound is referred to as "selectively," "specifically," or "competitively" modulating (e.g., increasing or inhibiting) the activity of a protein, the compound modulates the activity of the protein to a greater extent than the activity of at least one protein different from the first protein (e.g., not less than about 2-fold, not less than about 5-fold, not less than about 10-fold, not less than about 30-fold, not less than about 100-fold, not less than about 1,000-fold, or not less than about 10,000-fold).

[0091] The term "abnormal activity" refers to an activity that deviates from normal activity. The term "increased activity" refers to an activity that is higher than normal activity.

[0092] The terms "composition" and "formulation" are used interchangeably.

[0093] A "subject" contemplated for administration 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, a middle-aged adult, or an older adult) or a non-human animal. A "patient" refers to a human subject in need of treatment for a disease. In certain embodiments, the subject is a human suffering from or at risk of a central nervous system (CNS) disorder, obesity, diabetes, or hyperlipidemia.

[0094] 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.

[0095] The terms "treatment", "treat" and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease have developed or have 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., based on a history of symptoms and / or based on exposure to a pathogen) to delay or prevent the onset of the disease. Treatment may also be continued after symptoms subside, e.g., to delay or prevent recurrence.

[0096] The terms "disorder," "disease," and "condition" are used interchangeably.

[0097] An "effective amount" of a compound as described herein refers to an amount sufficient to elicit a desired biological response, i.e., to treat a condition. As will be appreciated by those of ordinary skill in the art, an effective amount of a compound as described herein may vary according to 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, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a preventive treatment. In certain embodiments, an effective amount is the amount of a compound as described herein in a single dose. In certain embodiments, an effective amount is the combined amount of a compound as described herein in multiple doses.

[0098] 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 sufficient to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can include an amount that improves the overall treatment of a condition, reduces or avoids symptoms, signs, or causes, and / or enhances the therapeutic efficacy of another therapeutic agent.

[0099] A "prophylactically effective amount" of a compound described herein is an amount sufficient to prevent a disorder or one or more symptoms associated with a disorder or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disorder. The term "prophylactically effective amount" can encompass an amount that improves overall prevention or enhances the prophylactic efficacy of another prophylactic agent.

[0100] The term "blood-brain barrier" (BBB) ​​refers to the interface between the blood and the brain. The BBB and its penetration by neurotherapeutics is a major topic in how central nervous system drugs are effective. From a medicinal chemistry perspective, the ability to design drugs that can penetrate the BBB and achieve the desired biological response is a huge challenge. On the other hand, peripherally acting drugs need to have specific physicochemical properties to prevent them from crossing the BBB. Moderately lipophilic drugs (logP = 0-7) cross the BBB by passive diffusion, and the hydrogen bonding properties of the drug can significantly improve its CNS uptake characteristics in the brain.

[0101] Lipophilicity is an important factor in determining whether a drug can cross the blood-brain barrier (BBB). The logarithm of the n-octanol / water partition coefficient, also known as "logP", has been designed to determine lipophilicity. Compounds with higher positive values ​​of logP generally refer to higher lipophilicity, which is expected to have higher permeability to cell membranes.

[0102] The term "neuropsychiatric disorder" includes neurological diseases or mental disorders or CNS (central nervous system) disorders, or refers to disorders involving behavioral or psychiatric symptoms or syndromes caused by nervous system degeneration or organic brain disorders. The main features of neuropsychiatric symptoms include various psychiatric symptoms, cognitive impairment, the occurrence of neurological symptoms or the possibility of early brain development symptoms. For example, neuropsychiatric disorders can 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 amnesia, closed head injury, autism spectrum disorder, Asperger's disorder, fragile X syndrome, attention deficit hyperactivity disorder, combined attention deficit hyperactivity disorder and tic disorder, obsessive-compulsive disorder, tic disorder, Tourette syndrome, childhood learning disabilities, premenstrual syndrome, depression, bipolar disorder, anxiety disorders, panic disorder, post-traumatic stress disorder, chronic pain, eating disorders, addiction disorders, personality disorders, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, nocturnal enuresis, stroke, Duchenne muscular dystrophy, blepharospasm, and non-epileptic seizures.

[0103] The term "neurological disease" refers to any disease of the nervous system, including diseases involving the central nervous system (brain, brainstem, spinal cord and cerebellum), peripheral nervous system (including cranial nerves) and autonomic nervous system (parts of which are located in the central nervous system and peripheral nervous system). Neurodegenerative diseases refer to a type of neurological disease characterized by loss of nerve cells, including but not limited to Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, tauopathy (including frontotemporal dementia), multiple system atrophy and Huntington's disease. Examples of neurological diseases include but are not limited to headaches, stupor and coma, dementia, seizures, sleep disorders, trauma, infection, vegetation, neuro-ophthalmopathy, movement disorders, demyelinating lesions, spinal cord disorders and peripheral nerve disorders, muscles and neuromuscular junctions. Further examples of neurological diseases include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; corpus callosum dysgenesis; agnosia; Aicardi syndrome; Alexander disease; Alpers disease; alternating hemiplegia; Alzheimer's disease; amyotrophic lateral sclerosis; anencephaly; happy puppet syndrome; angiomatosis; hypoxia; aphasia; apraxia; arachnoid cyst; arachnoiditis; cerebellar tonsillar herniation; arteriovenous malformation; Asperger's syndrome; ataxia-telangiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; chronic pain; Battendisease; red eyes; Bell's palsy; benign essential blepharospasm. essentialblepharospasm; 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 tumor; Brown-Segar syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; brain aneurysm; cerebral arteriosclerosis; brain atrophy; cerebral gigantism; cerebral palsy; progressive 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 syndrome); coma, including persistent vegetative state; Moebius syndrome; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; strain dysfunction; Cushing syndrome; cytomegalovirus infection; cytomegalovirus inclusion disease (CIBD);Dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier'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; cerebral trigeminal angiomatosis; epilepsy; Erb's palsy palsy; essential tremor; Fabry disease; Fall's syndrome; syncope; familial spastic palsy; febrile seizures; Fisher syndrome; Friedreich's ataxia; frontotemporal dementia and other "tauopathy-related diseases"; Gaucher disease; Gerstmann syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barré syndrome; HTLV-related myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; hereditary ataxia of polyneuritis type (heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (see also Neurological Manifestations of AIDS); holoprosencephaly; Huntington disease and other polyglutamine-relapsing disorders; hydrocephalus; hydrocortisonephrosis; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinence pigmenti; infantile phytanic acidstorage disease; infantile Refsum disease; infantile spasms; inflammatory myopathy; intracranial cysts; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome syndrome; Klippel-Feil syndrome; Krabbe disease; Kugelberg-Weiland disease; Kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kloefner syndrome; Lateral medullary (Wallenberg) syndrome; Learning disabilities; Leigh disease; Lennox-Gastaut syndrome; Lesch-Nyne syndrome; Leukodystrophy; Dementia with Lewy bodies; Lissencephaly; Locked-in syndrome; Lou Gehrig's disease (also called motor neuron disease or amyotrophic lateral sclerosis); Lumbar disc disease; Lyme disease-neurological sequelae; Machado-Joseph disease; Macrocephaly; Megalencephaly; May-Row syndrome;Meniere's disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller-Fisher syndrome; mini-strokes; mitochondrial myopathy; Mobius syndrome; monomelic amyotrophy; motor neuron disease; moyamoya disease; mucopolysaccharidosis; multi-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with orthostatic hypotension; muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis sclerosis; infantile myoclonic encephalopathy; myoclonus; myopathy; myotonia congenita; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurologic manifestations of AIDS; neurologic sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorder; Niemann-Pick disease; O'Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus-myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesias; Parkinson's disease; paramyotonia congenita; paraneoplastic diseases; paroxysmal seizures attacks; Parry-Romberg syndrome; Pelitzeau-Merzbacher disease; periodic paralysis; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; generalized developmental disorder; photic sneeze reflex; phytanic acid storage disease; Pick's disease; pinched nerve; pituitary tumor; polymyositis; cerebral punctum; Post-Polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion disease; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri cerebri); Ramsay-Hunt syndrome (types I and II); Rasmussen encephalitis; reflex sympathetic dystrophy syndrome; Refsum's disease;repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retroviral myelopathy; Rett syndrome; Reye's syndrome; Saint Vitus Dance; Sandhoff disease; Schilder's disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; herpes zoster; Shy-Decker syndrome; Sjogren's syndrome; sleep apnea; Soto's syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumor; spinal muscular atrophy; stiff-person syndrome; stroke; Stitch-Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy; chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome syndrome; myotonic cataract; thoracic outlet syndrome; trigeminal neuralgia (tic douloureux); Todd's palsy; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathy; transverse myelitis; head injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis complex; vascular dementia (multi-infarct dementia); vasculitis, including temporal arteritis; von Hippel-Lindau syndrome (VHL); Wallenberg syndrome; Werdnig-Hoffmann disease; Wester syndrome; whiplash; Williams syndrome; Wilson's disease; and Zellweger syndrome.

[0104] The term "pain" encompasses psychogenic pain, acute pain, chronic pain, chronic pain syndromes, neuropathic pain, nociceptive pain, hyperalgesia and allodynia.

[0105] 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

[0106] Neuropathic pain is pain caused by damage or disease that affects the somatic sensory nervous system. Neuropathic pain may be due to disorders of the peripheral nervous system or the central nervous system (brain and spinal cord). Therefore, neuropathic pain can be divided into 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, post-herpetic neuralgia and central pain syndrome.

[0107] Nociceptive pain is the most common type of pain people experience. It develops 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.

[0108] The term "mental disorder" refers to mental illness and includes diseases and disorders listed in the Diagnostic and Statistical Manual of Mental Disorders - Fourth and Fifth Editions (DSM-IV, DSM-V), published by the American Psychiatric Association, Washington, D.C. (1994, 2015). Mental illnesses include, but are not limited to, 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 oppositional defiant disorder), eating disorders (e.g., anorexia nervosa and bulimia nervosa), mood disorders (e.g., depression, bipolar I and II disorders, cyclothymia, dysthymia, and major depressive disorder), suicidal ideation and / or behavior, personality disorders (e.g., antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, narcissistic personality disorder, obsessive-compulsive disorder, paranoid personality disorder, personality disorder, schizoid personality disorder, and schizotypal personality disorder), psychotic disorders (e.g., brief psychotic disorder, delusional disorder, schizoaffective 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 disorder, autism spectrum disorder, delirium, dementia, multi-infarct dementia, learning and memory disorders (e.g., amnesia and age-related memory loss), and Tourette disorder.

[0109] The term "metabolic disorder" refers to any disease involving a change in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids or a combination thereof. Metabolic disorders are associated with a lack or excess of metabolic pathways, resulting in an imbalance in the metabolism of nucleic acids, proteins, lipids and / or carbohydrates. Factors affecting metabolism include, but are not limited to, endocrine (hormone) control systems (e.g., insulin pathways, enteroendocrine hormones, including GLP-1, PYY, etc.), neural control systems (e.g., GLP-1 in the brain), etc. 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.

[0110] Compounds of formula (I)

[0111] One aspect of the present disclosure relates to compounds of formula (I):

[0112]

[0113] or a pharmaceutically acceptable salt thereof, wherein:

[0114] Ring A is a 5- to 8-membered monocyclic ring system, which optionally includes at least one heteroatom selected from the group consisting of N, O, P and S; each of R1, R2, R3, R4, R5, R6, R7 and R8 is independently absent or has the following formula:

[0115]

[0116] It is optionally substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of: C 1-3 Alkyl, halogen, –CN, –NO2, –SH, –S(C 1-3 alkyl), –NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2 and -O(C 1-3 alkyl); wherein

[0117] n is 0 or 1;

[0118] m is 1, 2, 3, 4 or 5; and

[0119] The total number of galloyl moieties is an integer from 4 to 35, inclusive, and wherein when the compound of formula (I) is When , the total number of galloyl moieties is an integer from 15 to 35, inclusive.

[0120] In some embodiments, one of R1, R2, R3, R4, R5, R6, R7 and R8 does not exist. In some embodiments, two of R1, R2, R3, R4, R5, R6, R7 and R8 do not exist. In some embodiments, three of R1, R2, R3, R4, R5, R6, R7 and R8 do not exist. In some embodiments, four of R1, R2, R3, R4, R5, R6, R7 and R8 do not exist. In some embodiments, five of R1, R2, R3, R4, R5, R6, R7 and R8 do not exist. In some embodiments, six of R1, R2, R3, R4, R5, R6, R7 and R8 do not exist. In some embodiments, seven of R1, R2, R3, R4, R5, R6, R7 and R8 do not exist.

[0121] In some embodiments, the total number of galloyl moieties of the compounds of Formula (I) described herein is an integer from 4 to 35, inclusive. In some embodiments, the total number of galloyl moieties of the compounds of Formula (I) described herein is an integer from 15 to 35, inclusive. In some embodiments, when the compound of Formula (I) is In some embodiments, the total number of galloyl moieties of the compounds of formula (I) described herein is an integer from 15 to 35, including end values. In some embodiments, the total number of galloyl moieties of the compounds of formula (I) described herein is an integer from 15 to 25, including end values. In some embodiments, the total number of galloyl moieties of the compounds of formula (I) described herein is an integer from 20 to 25, including end values. In some embodiments, the total number of galloyl moieties of the compounds of formula (I) described herein is an integer from 15 to 20, including end values. In some embodiments, the total number of galloyl moieties of the compounds of formula (I) described herein is an integer from 25 to 35, including end values. In some embodiments, the total number of galloyl moieties of the compounds of formula (I) described herein is an integer from 20 to 30, including end values. In some embodiments, the total number of galloyl moieties of the compounds of formula (I) described herein is an integer from 30 to 35, including end values. In some embodiments, the total number of galloyl moieties of the compounds of Formula (I) described herein is 30. In some embodiments, the total number of galloyl moieties of the compounds of Formula (I) described herein is 35. In some embodiments, the total number of galloyl moieties of the compounds of Formula (I) described herein is 15, 20, 25, or 30.

[0122] In some embodiments, ring A is a 5-8 membered monocyclic ring system (e.g., having 6 π electrons shared in the cyclic array), which optionally includes at least one ring heteroatom provided in the ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus and sulfur ("5-8 membered heterocycle"). In some embodiments, ring A is a 5-8 membered ring system without heteroatoms. In some embodiments, ring A is a 5-8 membered ring system having ring carbon atoms and at least one ring heteroatom provided in the ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur ("5-8 membered heterocycle"). In some embodiments, ring A is a 5-6 membered heterocycle having ring carbon atoms and at least one ring heteroatom provided in the ring system, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur ("5-6 membered heterocycle"). In some embodiments, ring A is a 5-6 membered heterocycle having 1 ring heteroatom selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur. In some embodiments, Ring A is a 5-8 membered heterocyclic ring having at least one oxygen. In some embodiments, Ring A is a 5-6 membered heterocyclic ring having at least one oxygen.

[0123] In some embodiments, Ring A is In some embodiments, Ring A is

[0124] In some embodiments, each of R1, R2, R3, R4, R5, R6, R7 and R8 can be one of the following:

[0125] and does not exist.

[0126] In some embodiments, at least one instance of R1, R2, R3, R4, R5, R6, R7 or R8 is independently

[0127]

[0128] In some embodiments, at least one instance of R1, R2, R3, R4, R5, R6, R7 or R8 is independently

[0129] In some embodiments, at least one instance of R1, R2, R3, R4, R5, R6, R7 or R8 is independently

[0130] In some embodiments, at least one instance of R1, R2, R3, R4, R5, R6, R7 or R8 is independently

[0131]

[0132] In some embodiments, at least one instance of R1, R2, R3, R4, R5, R6, R7 or R8 is independently

[0133] In some embodiments, at least one instance of R1, R2, R3, R4, R5, R6, R7, or R8 is independently absent.

[0134] In some embodiments, each of R1, R2, R3, R4, R5, R6, R7, and R8 is independently or has the following formula:

[0135]

[0136] Or does not exist.

[0137] In some embodiments, at least one instance of R1, R2, R3, R4, R5, R6, R7 or R8 is

[0138] In some embodiments, at least one instance of R1, R2, R3, R4, R5, R6, R7 or R8 is

[0139] In some embodiments, at least one instance of R1, R2, R3, R4, R5, R6, R7, or R8 is absent.

[0140] In some embodiments, each of R1, R2, R3, R4, R5, R6, R7 and R8 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of: C 1-3 Alkyl, halogen, –CN, –NO2, –SH, –S(C 1-3 alkyl), –NH2, NH(C 1-3 Alkyl), N(C 1-3 Alkyl)2 and -O(C 1-3 In some embodiments, at least one of R1, R2, R3, R4, R5, R6, R7 and R8 is replaced by C 1-3 Alkyl (e.g., unsubstituted methyl, unsubstituted ethyl, or unsubstituted n-propyl) is optionally substituted. In some embodiments, at least one of R1, R2, R3, R4, R5, R6, R7, and R8 is optionally substituted with halogen (e.g., F, Cl, or Br). In some embodiments, at least one of R1, R2, R3, R4, R5, R6, R7, and R8 is optionally substituted with –CN, –NO2, –SH, –S (C1-3 alkyl), –NH2, NH(C 1-3 Alkyl), N(C 1-3 alkyl)2 or -O(C 1-3 In some embodiments, C 1-3 Alkyl is unsubstituted methyl, unsubstituted ethyl or unsubstituted n-propyl. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, m is 1, 2, 3, 4 or 5. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

[0141] In some embodiments, the compound of formula (I) has the following formula:

[0142]

[0143] In some cases, each of R1, R2, R3, R4 and R5 can independently be:

[0144]

[0145] In some embodiments, the compound of formula (I) has the following formula:

[0146]

[0147] In some cases, each of R1, R2, R3, R4 and R5 can independently be:

[0148]

[0149] In some embodiments, the compound of formula (I) is: Compound 24, Compound 27, Compound 37 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is not Compound 10. In some embodiments, the compound of formula (I) is: Compound 37 or a pharmaceutically acceptable salt thereof. The structures of the above exemplary compounds are shown in Table 1 below.

[0150] In some embodiments, the compound of formula (I) is compound 101, compound 102, compound 103, compound 24 (compound product of Example 3), compound 27 (compound product of Example 4), compound 37 (compound product of Example 5), compound 25 (compound product of Example 8), compound 15 (compound product of Example 9), compound 40 (compound product of Example 10), compound 43 (compound product of Example 11), compound 46 (compound product of Example 12), compound 48 (compound product of Example 13), compound 51 (compound product of Example 14), compound 53 (compound product of Example 15), compound 56 (compound product of Example 16) or compound 58 (compound product of Example 17). In some embodiments, the compound of formula (I) is a compound in Table 1 below. Any intermediate disclosed herein, such as in any of the following examples, is also within the scope of the present disclosure.

[0151] In some embodiments, the compound of formula (I) has the following formula:

[0152] Wherein each of R1, R2 and R3 independently can be one of the following formulae (which can be optionally substituted):

[0153]

[0154]

[0155] In some embodiments, at least one of R1, R2, and R3 is substituted.

[0156] Any of the compounds of formula (I) described herein (e.g., those disclosed in any of the following examples) or pharmaceutically acceptable salts thereof are within the scope of the present disclosure. The term "pharmaceutically acceptable salt" refers to a relatively nontoxic inorganic or organic base addition salt of a compound of formula (I). These salts can be prepared in situ during the administration of a vehicle or dosage form manufacturing process, or by the following preparation: reacting one or more compounds of formula (I) described herein with a suitable organic or inorganic base alone, and separating the salts thus formed during subsequent purification. Suitable inorganic bases include, but are not limited to, 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. Suitable organic bases include, but are not limited to, pyridine, methylamine, imidazole, benzimidazole, histidine, phosphazene, or hydroxides of organic cations, such as quaternary ammonium hydroxide and phosphorus hydroxide. See, for example, Berge et al. (1977) Journal of Pharmaceutical Sciences (J.Pharm.Sci.) 66: 1-19.

[0157] The compounds of formula (I) described herein may be subjected to one or more purification procedures, such as recrystallization and chromatography (eg, flash column chromatography), or a combination thereof. See, for example, the Examples below.

[0158] Compositions of compounds of formula (I) and kits containing the compounds

[0159] Any of the compounds described herein can be formulated to form a pharmaceutical composition. Other aspects of the present disclosure relate to compositions including one or more compounds of formula (I) described herein and carriers (e.g., pharmaceutically acceptable carriers), such as pharmaceutical compositions. Such naturally occurring or non-naturally occurring (synthetic) carriers can confer various benefits to the compounds of formula (I) in the composition, for example, improving the in vitro and / or in vivo stability of the compounds of formula (I), improving the bioavailability of the compounds of formula (I), increasing the biological activity of the compounds of formula (I), and / or reducing side effects. In some embodiments, compositions including compounds of formula (I) and carriers are provided herein. In some embodiments, the composition is a pharmaceutical composition. Suitable carriers include, but are not limited to, diluents, fillers, salts, buffers, stabilizers, solubilizers, buffers, preservatives, or combinations thereof. In some instances, the carrier may include benzoates such as sodium benzoate.

[0160] Pharmaceutical composition

[0161] In some embodiments, one or more compounds of Formula (I) described herein may be mixed with a pharmaceutically acceptable carrier (excipient) to form a pharmaceutical composition, which may be used to treat any target disease as described herein. "Acceptable" means that the carrier must be compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and harmless to the subject to be treated. Pharmaceutically acceptable excipients (carriers), including buffers, are well known in the art. See, e.g., Remington: The Science and Practice of Pharmacy, 20th edition (2000) Lippincott Williams and Wilkins, KE Hoover, eds.

[0162] Pharmaceutically acceptable carriers include diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials known in the art. Exemplary pharmaceutically acceptable carriers of compounds of formula (I) or their salts are particularly described in US Pharmacopeia 5,211,657. Such preparations can conventionally include salts, buffers, preservatives, compatible carriers and optionally other therapeutic agents. When used in medicine, these salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts can be conveniently used to prepare their 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 by 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 base, or hydroxides of organic cations, such as quaternary ammonium hydroxide and phosphorus hydroxide). Likewise, pharmaceutically acceptable salts may be prepared as alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium or calcium salts.

[0163] Compositions comprising the compounds described herein may include a pharmaceutically acceptable carrier, excipient or stabilizer in the form of a lyophilized formulation or an aqueous solution. Remington: The Science and Practice of Pharmacy 20th Edition (2000) Lippincott Williams and Wilkins, KE Hoover eds. Such carriers, excipients or stabilizers may enhance one or more properties of the active ingredient (e.g., a compound of formula (I) in the compositions described herein), such as biological activity, stability, bioavailability and other pharmacokinetic and / or biological activities.

[0164] Acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations used, and may include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl alcohol or benzyl alcohol; alkyl parabens such as methyl paraben or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; benzoate, sorbate and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or 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 nonionic surfactants such as TWEEN TM (Polysorbate), PLURONICS TM (nonionic surfactant) or polyethylene glycol (PEG).

[0165] In other examples, the pharmaceutical compositions described herein can be formulated into sustained release forms. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers comprising compounds of formula (I) described herein, with matrices in the form of molded 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)), polylactides (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT TM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0166] In some embodiments, the pharmaceutical composition for in vivo administration is sterile. This is easily accomplished by, for example, filtration through a sterile filtration membrane. The therapeutic composition is typically placed in a container with a sterile access port, for example, an intravenous solution bag or vial with a stopper pierceable by a hypodermic injection needle.

[0167] The pharmaceutical compositions described herein may be in unit dosage form such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories for oral, parenteral or rectal administration, or administration by inhalation or insufflation, or intrathecal or intracerebral routes.

[0168] In order to prepare solid compositions such as tablets, the main active ingredient can be mixed with a pharmaceutical carrier, such as conventional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talcum, stearic acid, magnesium stearate, dicalcium phosphate or gum, and other drug diluents, such as water, to form a solid preformulation composition comprising a uniform mixture of the compound of the present invention or its non-toxic pharmaceutically acceptable salt. When these preformulation compositions are referred to as uniform, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily subdivided into equivalent unit dosage forms, such as tablets, pills and capsules. This solid preformulation composition is then subdivided into a unit dosage form of the type described above comprising 0.1 to about 1000mg of the active ingredient of the present invention. The tablet or pill of the composition can be coated or otherwise mixed to provide a dosage form that provides the advantage of prolonged action. For example, a tablet or pill can include an internal dose and an external dose component, the latter being in the form of a coating on the former. These two components can be separated by an enteric layer, which is used to resist disintegration in the stomach and allow the internal component to enter the duodenum intact or delay release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0169] Suitable surfactants include, among others, non-ionic agents such as polyoxyethylene sorbitan (e.g., Tween TM 20, 40, 60, 80 or 85) and other sorbitans (e.g., Span TM 20, 40, 60, 80 or 85). Compositions with surfactant will conveniently include between 0.05% and 5% surfactant, and may be between 0.1% and 2.5%. It will be appreciated that other ingredients may be added if desired, such as mannitol or other pharmaceutically acceptable vehicles.

[0170] Use commercially available fat emulsions such as Intralipid TM , Liposyn TM Infonutrol TM 、Lipofundin TM Lipiphysan TMPrepare a suitable emulsion. The active ingredient can be dissolved in a premixed emulsion composition, or alternatively it can be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and in an emulsion formed after mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soybean lecithin) and water. It should be understood that other ingredients, such as glycerol or glucose, can be added to adjust the tension of the emulsion. Suitable emulsions will typically contain up to 20%, such as between 5% and 20% oil. Fat emulsions can include fat droplets between 0.1 and 1.0 μm, particularly between 0.1 and 0.5 μm and have a pH in the range of 5.5 to 8.0.

[0171] Pharmaceutical compositions for inhalation or insufflation include pharmaceutically acceptable solutions or suspensions, aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered by oral or nasal respiratory route for local or systemic effect.

[0172] Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by the use of a gas. Nebulized solutions may be breathed directly from the nebulizing device, or the nebulizing device may be attached to a mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally, preferably from a device that delivers the formulation in an appropriate manner.

[0173] In some embodiments, any of the compositions comprising a compound described herein may further comprise a second therapeutic agent, based on the intended therapeutic use of the composition.

[0174] In some embodiments, the second therapeutic agent is an anti-obesity agent, including but not limited to orlistat, lorcaserin, sibutramine, rimonabant, metformin, exenatide, pralintide, phentermine, fenfluramine, dexfenfluramine, topiramate, dinitrophenol, bupropion, and zonisamide.

[0175] In some embodiments, the second therapeutic agent is an agent for treating a CNS disease / disorder. In some embodiments, the second therapeutic agent can be an antidepressant, an antipsychotic, a psychostimulant, a mood stabilizer, an antianxiety agent, an agent for treating attention deficit hyperactivity disorder (ADHD), or an agent for treating Alzheimer's disease (AD).

[0176] Exemplary antipsychotic drugs include, but are not limited to, butyrophenones (e.g., haloperidol (HALDOL TM ), phenothiazines (e.g., chlorpromazineTM ), fluphenazine (PROLIXIN TM ), perphenazine (TRILAFON TM ), prochlorperazine (COMPAZINE TM ), thioridazine (MELLARIL TM ), trifluoperazine (STELAZINE TM ), mesoridazine, promazine, triflupromazine (VESPRIN TM ), levomepromazine (NOZINAN TM ), promethazine TM ), thioxanthenes (e.g., chlorprothixene, trifluthixene (DEPIXOL TM 、FLUANXOL TM )), NAVANE TM ), CLOPIXOL TM 、ACUPHASE TM ), clozapine (CLOZARIL TM ), olanzapine (ZYPREXA TM RISPERDAL TM RISPERDAL CONSTA TM ), quetiapine (SEROQUEL TM ), Ziprasidone (GEODON TM ), amisulpride (SOLIAN TM ), asenapine, paliperidone Aripiprazole (ABILIFY TM ), dopamine partial agonists (BIFEPRUNOX TM 、NORCLOZAPINE TM (ACP-104)), lamotrigine (LAMICTAL TM ), cannabidiol, LY2140023, droperidol, pimozide, butaperazine, carphenazine, remoxipride, piperacetazine, sulpiride, acamprosate, tetrabenazine (NITOMAN TM 、XENAZINE TM )wait.

[0177] Alternatively, the second therapeutic agent may be an antidepressant and / or a mood stabilizer. In certain embodiments, antidepressants include monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), selective serotonin reuptake inhibitors (SSRIs), noradrenergic and specific serotonergic antidepressants (NASSAs), norepinephrine (noradrenaline) reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), mood stabilizers and / or monoamine oxidase inhibitors (MAOIs). Exemplary SSRIs include fluoxetine (PROZAC TM ), paroxetine (PAXIL TM SEROXAT TM ), escitalopram (LEXAPRO TM ESIPRAM TM ), CELEXA TM ), sertraline (ZOLOFT TM ), Fluvoxamine (LUVOX TM )). Exemplary SNRIs include venlafaxine (EFFEXOR TM ), milnacipram, and duloxetine (CYMBALTA TM Additional antidepressants include noradrenergic and specific serotonergic antidepressants (NASSA) (eg, mirtazapine (AVANZA TM 、ZISPIN TM 、REMERON TM ) or mianserin, norepinephrine (epinephrine) reuptake inhibitors (NRIs) (eg, reboxetine (EDRONAX TM )), norepinephrine-dopamine reuptake inhibitors (eg, bupropion (WELLBUTRIN TM 、ZYBAN TM )), amitriptyline, nortriptiline, protriptyline, desipramine, imipramine, trimipramine, amoxapine, bupropion, bupropion SR, clomipramine, doxepin, isocarboxazid, venlafaxine XR, tranylcypromine, trazodone, nefazodone, phenelzine, lamatrogine, lithium, topiramate, gabapentin, carbamazepine, oxacarbazepine, valproate, maprotiline, mirtazapine, bromofaromine, gepirone, moclobemide, isoniazid, iproniazid, etc.

[0178] In some embodiments, the second therapeutic agent can be an agent for treating ADD and / or ADHD. Suitable ADHD drugs include, but are not limited to, amphetamine, modafinil, desoxyn, methamphetamine, cocaine, arecoline, dexmethylphenidate (focalin, XR), dextroamphetamine (dexedrine, dexedrine spansules, dextroamphetamine ER, dextrostat), methylphenidate (concerta, daytrana, metadate CD, methylphenidate ER, methylin, methylphenidate ER, ritalin, ritalin-LA, ritalin-SR), lisdexamfetamine dimesylate (lisdexamfetamine dimesylate (Vyvanse), mixed amphetamine salts (Adderall, Adderall XR), atomoxetine (Strattera), clonidine hydrochloride (Catapres), guanfacine hydrochloride (Tenex), arecoline, and pemoline.

[0179] In addition, in some embodiments, the second therapeutic agent can be an agent used to treat cognitive impairment and / or a condition characterized by neurodegeneration (e.g., Alzheimer's disease or Parkinson's disease). Such therapeutic agents include, but are not limited to, tacrine, rivastigmine, donepezil, TM ), physostigmine, nicotine, arecoline, huperzine α, selegiline, rilutek TM (riluzole), memantine (AXURA TM AKATINOL TM NAMENDA TM EBIXA TM ABIXA TM ), vitamin C, vitamin E, carotenoids, ginkgo biloba, etc.

[0180] Reagent test kit

[0181] The disclosure also provides a kit for treating any of the target disorders described herein. In some embodiments, the kit is used to improve basic behavioral functions, hyperactivity, anxiety, depression, suicidal ideation and / or behavior, sensory motor gating, pain threshold, memory and / or cognitive function, and / or for treating target diseases as described herein, (e.g., obesity disorders, hyperlipidemia, hyperglycemia, diabetes or CNS disorders). Such a kit may include one or more containers, the container including the following composition, the composition including a compound of formula (I) as described herein and optionally one or more second therapeutic agents as described herein.

[0182] In some embodiments, the kit may include instructions for use according to any of the methods described herein. The instructions included may include, for example, a description of the composition of the compound of formula (I) and optionally a description of the second therapeutic agent, to improve basic behavioral function, hyperactivity, anxiety, depression, suicidal ideation and / or behavior, sensory motor gating, pain threshold, memory and / or cognitive function, or to treat a target disease as described herein. The kit may further include a description of selecting an individual suitable for treatment based on identifying whether the individual suffers from the disease or is at risk of the disease. In yet other embodiments, the instructions include a description of applying one or more agents of the present disclosure to an individual at risk of the disease or an individual who needs to improve basic behavioral function, hyperactivity, anxiety, depression, suicidal ideation and / or behavior, sensory motor gating, pain threshold, memory and / or cognitive function.

[0183] Instructions for use of a composition comprising a compound of formula (I) to achieve a desired therapeutic effect typically include information about the dosage, dosage regimen, and route of administration for the intended treatment. The container may be a unit dose, bulk package (e.g., multi-dose package), or subunit dose. The instructions provided in the kit of the present invention are typically written instructions on a label or package insert (e.g., paper included in the kit), but machine-readable instructions (e.g., instructions on a magnetic disk or optical storage disk) are also acceptable.

[0184] The label or package insert may specify that the composition is used for the intended therapeutic utility.Instructions for practicing any of the methods described herein may be provided.

[0185] The kit of the present invention is in a suitable package. Suitable packages include, but are not limited to, vials, bottles, jars, flexible packages (e.g., sealed Mylar bags or plastic bags), etc. It is also contemplated that the package is used in combination with a specific device such as an inhaler, a nasal application device (e.g., a nebulizer), or an infusion device such as a miniature pump. The kit can have a sterile access end (e.g., the container can be an intravenous solution bag or a vial with a stopper that can be pierced by a hypodermic needle). The container can also have a sterile access end (e.g., the container can be an intravenous solution bag or a vial with a stopper that can be pierced by a hypodermic needle).

[0186] The kit may optionally provide additional components such as buffer and interpretative information. Typically, the kit comprises a container and a label or one or more package inserts on or associated with the container. In some embodiments, the invention provides an article comprising the contents of the above-described kit.

[0187] Treatment

[0188] Any of the compounds described herein (e.g., compounds of formula (I)) can be used to treat a disease or illness. In certain embodiments, provided herein are methods for improving basic behavioral function, weight loss, hyperactivity, anxiety, depression, suicidal ideation and / or behavior, sensory motor 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 illnesses associated with DAAO, such as central nervous system disorders (e.g., those described herein). These compounds can also be used to treat obesity disorders.

[0189] As used herein, the term "treating" refers to applying or administering a composition comprising one or more active agents to a subject in need of treatment, e.g., suffering from a target disease or disorder, symptoms of a disease / disorder, or susceptibility to a disease / disorder, with the purpose of curing, rehabilitating, alleviating, alleviating, altering, remedying, improving, ameliorging, or affecting the disorder, symptoms of a disease, or susceptibility to a disease or disorder.

[0190] Relieve target disease / illness and include delaying the development or progress of disease, or reducing the severity of disease. Relieve disease and not necessarily need the result of cure. As used herein, "delaying" the development of target disease or illness means to postpone, hinder, slow down, hinder, stabilize and / or delay the progress of disease. This delay can have different time lengths, depending on the history of disease and / or the individual treated. "Delay" or a method for alleviating disease development or delaying the onset of disease is a method for reducing the possibility of one or more symptoms of disease development within a given time frame and / or reducing the degree of symptoms within a given time frame when compared with not using the method. Such comparisons are usually based on clinical studies using a large number of subjects sufficient to give statistically significant results.

[0191] "Development" or "progression" of a disease means the initial manifestation of the disease and / or the subsequent progression. The progression of a disease can be detectable and assessed using standard clinical techniques as known in the art. However, progression also refers to progression that may not be detectable. For the purposes of this disclosure, development or progression refers to the biological course of symptoms. "Development" includes occurrence, recurrence, and onset. As used herein, "onset" or "occurrence" of a target disease or disorder includes initial onset and / or recurrence.

[0192] In order to achieve any of the desired therapeutic effects described herein, an effective amount of a compound described herein (eg, a compound of Formula (I)) can be administered to a subject in need of treatment via an appropriate route.

[0193] The terms "subject", "individual" and "patient" are used interchangeably herein and refer to a mammal being evaluated for treatment and / or being treated. The subject can be a human, but also includes other mammals, especially those that can be used as laboratory models of human disease, such as mice, rats, rabbits, dogs, etc.

[0194] The human subject in need of treatment can be suffering from target disease / illness, in target disease / illness risk or suspected to suffer from target disease / illness, such as CNS disease or the disease relevant to obesity, for example, the human patient of diabetes, hyperglycemia, hypercholesterolemia or hyperlipidemia. The subject suffering from target disease or illness can be identified by routine medical examination, for example, laboratory test, organ function test and / or behavior test. The subject suspected of suffering from any such target disease / illness may show one or more symptoms of the disease / illness. The subject in disease / illness risk can be one or more risk factors with the disease / illness, for example, the subject of genetic factors. In some cases, the human subject is a child suffering from, suspected to suffer from or in the following risk: obesity or the CNS disease relevant to children, for example, attention deficit / hyperactivity disorder (ADHD), autism, Asperger's disorder, obsessive-compulsive disorder, depression, suicidal ideation and / or behavior, mental illness, chronic pain and learning disability.

[0195] 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, Lewy body dementia, 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 disabilities, premenstrual syndrome, depression, major depressive disorder, anhedonia, suicidal ideation and / or Behavior, bipolar disorder, anxiety disorders, panic disorder, post-traumatic stress disorder, chronic mild and unpredictable stress, eating disorders, addiction disorders, personality disorders, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, ataxia, Friedreich's ataxia, Tourette 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.

[0196] Diseases related to obesity include diseases and conditions that lead to obesity, as well as diseases and conditions that occur at high rates in obese people. Obesity is a medical condition characterized by the accumulation of excess body fat to an extent that may have a negative impact on health. Obesity can be determined by body mass index (BMI), a measure of a person's weight divided by the square of their height. For example, a BMI of more than 30 kg / m 2 May indicate obesity. 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, 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.

[0197] In some embodiments, the compounds described herein (e.g., compounds of Formula (I)) are administered to human subjects at a frequency of four times a day to once every three months, including end values. In some embodiments, the compounds described herein (e.g., compounds of Formula (I)) are administered to human subjects at a frequency of four times a day, three doses a day, two doses a day, one dose a day, one dose every other day, one dose every three days, one dose a week, one dose every other week, one dose a month, one dose every other month, or once every three months. In some embodiments, the compounds described herein (e.g., compounds of Formula (I)) are administered to human subjects at a frequency of 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, the compounds described herein (e.g., compounds of Formula (I)) are administered to human subjects at a frequency of four times a day. In some embodiments, the compounds described herein (e.g., compounds of Formula (I)) are administered to human subjects at a frequency of once every three months. In some embodiments, a compound described herein (e.g., a compound of Formula (I)) is administered to a human subject once a 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 simultaneously with, before, or after one or more additional agents for treating a CNS disorder and a disease associated with obesity and / or reducing the risk of a CNS disorder or a disease associated with obesity.

[0198] As used herein, "effective amount" refers to the amount of each active agent (e.g., a compound of Formula (I) as described herein) required to impart a therapeutic effect to a subject, alone or in combination with one or more other active agents, such as one or more second therapeutic agents described herein. In some embodiments, the therapeutic effect is inhibition of DAAO activity in a subject (e.g., at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more). In some embodiments, the therapeutic effect is improvement in basic behavioral function, weight loss, hyperactivity, anxiety, depression, suicidal ideation and / or behavior, sensorimotor gating, pain threshold, memory, and / or cognitive function. In some embodiments, the therapeutic effect is relief of one or more symptoms associated with any of the CNS disorders described herein. Alternatively or additionally, the therapeutic effect is maintenance or reduction of the subject's weight.

[0199] It will be apparent to one skilled in the art to determine whether an amount of a composition as described herein achieves a therapeutic effect. As will be appreciated by those skilled in the art, an effective amount varies depending on the specific condition being treated, the severity of the condition, individual patient parameters including age, physical condition, size, sex and weight, duration of treatment, nature of concurrent therapy (if any), specific route of administration, genetic factors and the like within the knowledge and expertise of the health care practitioner. These factors are well known to those of ordinary skill in the art and can be addressed only by routine experimentation. It is generally preferred to use the maximum dose of a single component or a combination thereof, i.e., the highest safe dose according to sound medical judgment.

[0200] Empirical considerations, such as half-life, will generally help determine dosage. The frequency of administration can be determined and adjusted during treatment, and is generally, but not necessarily, based on the treatment and / or inhibition and / or improvement and / or delay of the target disease / disorder. Alternatively, sustained continuous release formulations of the compositions as described herein may be appropriate. Various formulations and devices for achieving sustained release are known in the art.

[0201] Typically, for the administration of any composition, depending on the factors mentioned above, an exemplary daily dose may range from about 0.1 μg / kg to 3 μg / kg to 30 μg / kg to 300 μg / kg to 3 mg / kg, to any one of 30 mg / kg to 100 mg / kg or higher. For repeated administration for several days or longer, depending on the condition, continued treatment occurs until the desired symptom suppression or until sufficient therapeutic levels are reached to alleviate the target disease or illness or its symptoms. An exemplary dosing regimen includes administering one or more initial doses at suitable intervals over a suitable period. If desired, multiple maintenance doses may be administered to the subject at suitable intervals over a suitable time period. However, other dosage regimens may be useful, depending on the pattern of pharmacokinetic attenuation that the practitioner wishes to achieve. For example, one to four administrations are envisioned for one day or one week. In some embodiments, a range of about 3 μg / mg to about 2 mg / kg (such as about 3 μg / mg, about 10 μg / mg, about 30 μg / mg, about 100 μg / mg, about 300 μg / mg, about 1 mg / kg, and about 2 mg / kg) can be used. In some embodiments, the dosing frequency can be three times a day, twice a day, once a day, once every other day, once a week, once every 2 weeks, once every 4 weeks, once every 2 months, or once every 3 months. The dosing regimen can change over time.

[0202] In some embodiments, for normal weight adult patients, a dosage range of about 0.3 to 100 mg / kg / day (e.g., 0.5 to 90 mg / kg / day, 1-50 mg / kg / day, 5-30 mg / kg / day, or 10-20 mg / kg / day) may be administered. The specific dosage regimen (i.e., dosage, timing, and repetition) will depend on the specific individual and the individual's medical history, as well as the characteristics of the individual agents (such as the half-life of the agent) and other considerations known in the art).

[0203] For purposes of this disclosure, suitable dosages of the compounds described herein will depend on the specific compounds described herein and / or other active ingredients employed, the type and severity of the disease / disorder, whether the composition is administered for preventive or therapeutic purposes, previous treatments, the patient's clinical history and response to DAAO inhibitors, and the discretion of the attending physician. Typically, the clinician will administer the composition until a dosage is reached that achieves the desired result.

[0204] Depending on the disease type to be treated or the disease site, conventional methods known to those of ordinary skill in the field of medicine can be used to apply compositions (for example, pharmaceutical compositions) to the subject. The composition can also be applied via other conventional routes, for example, oral, parenteral, by inhalation spray, local, rectal, nasal, oral, vaginal or via implanted reservoirs. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. In addition, it can be applied to the subject via injectable long-acting administration routes, such as using 1 week, half a month (or two weeks), 1 month, 3 months or 6 months of long-acting injectable or biodegradable materials and methods. In some instances, pharmaceutical compositions are applied intraocularly or intravitreally.

[0205] Injectable compositions can include various carriers, such as vegetable oils, dimethylacetamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol and polyols (glycerol, propylene glycol, liquid polyethylene glycol, etc.). For intravenous injection, water-soluble antibodies can be administered by drip infusion, whereby a pharmaceutical preparation containing a compound of formula (I) and a physiologically acceptable excipient is infused. Physiologically acceptable excipients can include, for example, 5% dextrose, 0.9% saline, Ringer's solution or other suitable excipients. Intramuscular preparations, such as sterile preparations of suitable soluble salt forms of compounds of formula (I), can be dissolved in pharmaceutical excipients such as water for injection, 0.9% saline or 5% glucose solution and administered therein.

[0206] In one embodiment, the compounds described herein are administered via localized or targeted local delivery techniques. Examples of localized or targeted local delivery techniques include various implantable long-acting sources or local delivery catheters of the compounds described herein, such as infusion catheters, indwelling catheters or needle catheters, synthetic grafts, adventitial wraps, shunts and stents or other implantable devices, localized carriers, direct injection or direct application. See, for example, PCT Publication No. WO 00 / 53211 and U.S. Patent No. 5,981,568.

[0207] The efficacy of treatment against a target disease / disorder can be assessed by methods well known in the art.

[0208] Also provided herein is a conjoint therapy using any of the compounds described herein and a second therapeutic agent, such as those described herein. As used herein, the term "conjoint therapy" includes the administration of these medicaments (e.g., compounds of formula (I) as described herein and anti-CNS disorders or anti-obesity agents) in a sequential manner, that is, wherein each therapeutic agent is administered at different times, and at least two of these therapeutic agents or medicaments are administered in a substantially simultaneous manner. The order or substantially simultaneous administration of each medicament can be subject to any appropriate route, including but not limited to oral routes, intravenous routes, intramuscular, subcutaneous routes, and the effects of direct absorption by mucosal tissue. Medicaments can be administered by the same route or by different routes. For example, a first medicament (e.g., a compound of formula (I) as described herein) can be administered orally, and a second medicament (e.g., anti-CNS disorders or anti-obesity agents) can be administered intravenously.

[0209] As used herein, unless otherwise indicated, the term "sequential" means characterized by a regular sequence or order, for example, if a dosage regimen includes the administration of a compound as described herein and an anti-CNS disorder agent or an anti-obesity agent, a sequential dosage regimen may include administering a compound as described herein before, simultaneously, substantially simultaneously, or after the administration of an anti-CNS disorder agent or an anti-obesity agent, but the two agents will be administered in a regular sequence or order. Unless otherwise indicated, the term "separate" means separated from each other. Unless otherwise indicated, the term "simultaneous" means occurring or completed at the same time, that is, administering the agents of the present invention simultaneously. The term "substantially simultaneously" means that the agents are administered within a few minutes of each other (e.g., within 10 minutes of each other), and is intended to include combined administration and continuous administration, but if the administration is continuous, it is only separated in time within a short period of time (e.g., the time required for a practitioner to administer two compounds separately). As used herein, simultaneous administration and substantially simultaneous administration are used interchangeably. Sequential administration refers to the administration of agents described herein separated in time.

[0210] Combination therapy can also include administration of the agents described herein (e.g., compounds of Formula (I) and anti-CNS disorder agents or anti-obesity agents) in further combination with other biologically active ingredients (e.g., different anti-CNS disorder agents) and non-drug therapies (e.g., surgery).

[0211] It should be understood that any combination of the compounds described herein and a second therapeutic agent (e.g., an anti-CNS disorder agent or an anti-obesity agent) can be used in any order to treat the target disease. The combinations described herein can be selected based on many factors, including but not limited to inhibiting DAAO, improving basic behavioral function, weight loss, hyperactivity, anxiety, depression, suicidal ideation and / or behavior, sensory motor gating, pain threshold, memory, or enhancing cognitive function, and / or relieving the efficacy of at least one symptom associated with the target disease, or for reducing the efficacy of the side effects of another agent in the combination. For example, the combination therapy described herein can reduce any side effects associated with each individual member of the combination, for example, side effects associated with the second therapeutic agent.

[0212] Process for preparing compounds of formula (I)

[0213] The present disclosure provides methods for preparing compounds described herein. In one aspect, the present disclosure provides methods for preparing compounds of formula (I). In one aspect, provided herein are methods for synthesizing (e.g., preparing) compounds described herein (e.g., compounds of formula (I)). In some embodiments, provided are methods for preparing compounds of formula (I), comprising:

[0214] (a) providing a compound of formula (Ia)

[0215]

[0216] wherein R1′, R2′, R3′, R4′, R5′, R6′, R7′ and R8′ are each independently -OH, -NH2 or absent;

[0217] Ring A is a 5- to 8-membered monocyclic ring system, which optionally includes at least one heteroatom selected from the group consisting of N, O, P and S;

[0218] (b) reacting a compound of formula (Ia) with 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride to conjugate the compound of 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride with one or more of R1′, R2′, R3′, R4′, R5′, R6′, R7′ and R8′ of the compound of formula (Ia) to produce a first intermediate; and

[0219] (c) deprotecting the allyl group and the cyclic acetal group in 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride conjugated with the compound of formula (Ia) to obtain the compound of formula (I).

[0220] In some embodiments, ring A is a 5- to 8-membered monocyclic ring system, which optionally includes at least one heteroatom selected from the group consisting of N, O, P, and S. In some embodiments, ring A is a 5- to 8-membered monocyclic ring system, which includes at least one N. In some embodiments, ring A is a 5- to 8-membered monocyclic ring system, which includes at least one O. In some embodiments, ring A includes at least one heteroatom selected from the group consisting of N, O, P, and S. In some embodiments, ring A is a heterocycle including at least one O. In some embodiments, ring A is a 5-8-membered heterocycle including at least one O. In some embodiments, ring A is

[0221]

[0222] In some embodiments, Ring A is:

[0223] In some embodiments, the compound of Formula (Ia) is glucose.

[0224] In some embodiments, the compound of formula (Ia) is glucose in the alpha form or in the beta form.

[0225] In some embodiments, the compound of Formula (Ia) is glucose in the alpha form.

[0226] In some embodiments, the compound of Formula (Ia) is glucose in the beta form.

[0227] In some embodiments, in step (a), the compound of formula (Ia) is

[0228] In some embodiments, in step (a), the compound of formula is

[0229] In some embodiments, R1', R2', R3', R4', R5', R6', R7' and R8' are each independently selected from the group consisting of -OH, -NH2 and are absent. In some embodiments, at least one of R1', R2', R3', R4', R5', R6', R7' or R8' is -OH. In some embodiments, all of R1', R2', R3', R4', R5', R6', R7' or R8' are -OH. In some embodiments, at least one of R1', R2', R3', R4', R5', R6', R7' or R8' is -NH2. In some embodiments, at least one of R1', R2', R3', R4', R5', R6', R7' or R8' is absent.

[0230] In some embodiments, step (b) comprises reacting a compound of formula (Ia) with (7-(Allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride reaction.

[0231] In some embodiments, step (b) comprises reacting a compound of formula (Ia) with 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride in the presence of a base (e.g., N-methylmorpholine (NMM)) and 4-dimethylaminopyridine (DMAP).

[0232] In some embodiments, step (b) comprises reacting a compound of formula (Ia) with 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride and a base.

[0233] In some embodiments, the base is trimethylamine (TEA), pyridine, or N-methylmorpholine (NMM).

[0234] In some embodiments, step (c) comprises deprotecting the allyl group and the cyclic acetal group in 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride conjugated to the compound of formula (Ia) to obtain the compound of formula (I).

[0235] In some embodiments, step (c) is performed by: step (c1) deprotecting the allyl group in 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride conjugated to a compound of formula (Ia); and step (c2) deprotecting the cyclic acetal group in 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride conjugated to a compound of formula (Ia).

[0236] In some embodiments, step (c) is performed by: (c1) deprotecting the allyl group in 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride conjugated to the compound of formula (Ia).

[0237] In some embodiments, step (c) is performed by: (c1) deprotecting the allyl group using a palladium catalyst and an amine base.

[0238] In some embodiments, the amine base is a tertiary amine.

[0239] In some embodiments, the amine base is a bulky tertiary amine.

[0240] In some embodiments, the amine base is tert-butylamine.

[0241] In some embodiments, the amine base is an aromatic amine.

[0242] In some embodiments, step (c) is performed by: (c1) deprotecting the allyl group, which comprises removing (allyl) group.

[0243] In some embodiments, step (c) is performed by: (c1) deprotecting the allyl group using a palladium catalyst and aniline.

[0244] In some embodiments, step (c) is performed by: (c1) deprotecting the allyl group using Pd(PPh3)4 and aniline.

[0245] In some embodiments, step (c) is performed by: (c2) deprotecting the cyclic acetal group in 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride conjugated to the compound of formula (Ia).

[0246] In some embodiments, step (c) is performed by: (c2) deprotecting the cyclic acetal group, which comprises Convert to Among them l a Specify the attachment of the cyclic acetal to the rest of the cyclic intermediate.

[0247] In some embodiments, step (c) is performed by: (c2) deprotecting the cyclic acetal group using a palladium catalyst.

[0248] In some embodiments, step (c) is performed by: (c2) deprotecting the cyclic acetal group using Pd / C under H2 gas.

[0249] In some embodiments, the method for preparing the compound of formula (I) comprises: before step (c2), repeating the process consisting of steps (b) and (c1) 3-7 times.

[0250] In some embodiments, the method for preparing a compound of formula (I) comprises: before step (c2), repeating the process consisting of steps (b) and (c1) 3-4 times, 3-5 times, 3-6 times, 3-7 times, 4-5 times, 4-6 times, 4-7 times, 5-6 times, 5-7 times or 6-7 times.

[0251] In some embodiments, the method for preparing the compound of formula (I) comprises: before step (c2), repeating the process consisting of steps (b) and (c1) 3 times, 4 times, 5 times, 6 times or 7 times.

[0252] In some embodiments, the method for preparing the compound of formula (I) comprises: before step (c2), repeating the process consisting of steps (b) and (c1) three times.

[0253] In some embodiments, the method for preparing the compound of formula (I) comprises: before step (c2), repeating the process consisting of steps (b) and (c1) 4 times.

[0254] In some embodiments, the method for preparing the compound of formula (I) comprises: before step (c2), repeating the process consisting of steps (b) and (c1) 5 times.

[0255] In some embodiments, the method for preparing the compound of formula (I) comprises: before step (c2), repeating the process consisting of steps (b) and (c1) 6 times.

[0256] In some embodiments, the method for preparing the compound of formula (I) comprises: before step (c2), repeating the process consisting of steps (b) and (c1) 7 times.

[0257] In some embodiments, the method for preparing the compound of formula (I) comprises: before step (c2), repeating the process consisting of steps (b) and (c1) 3-7 times.

[0258] In some embodiments, the method for preparing the compound of formula (I) comprises (c3) deprotecting the cyclic acetal group and the benzyl group.

[0259] In some embodiments, the method for preparing the compound of formula (I) further comprises purifying the compound of formula (I) produced after step (c).

[0260] In some embodiments, the method for preparing the compound of formula (I) further comprises purifying the intermediate produced after step (c).

[0261] In some embodiments, purification comprises one or more purification procedures.

[0262] In some embodiments, purification comprises recrystallization and chromatography (eg, flash column chromatography), or a combination thereof.

[0263] In some embodiments, purification comprises recrystallization. In some embodiments, purification comprises chromatography.

[0264] The present disclosure provides methods for synthesizing compounds described herein. In view of the embodiments and disclosures provided herein, those of ordinary skill in the art will appreciate the synthetic techniques for synthesizing compounds described herein. Based on the embodiments and disclosures provided herein, those of ordinary skill in the art will recognize the synthetic techniques (e.g., standard organic synthesis reactions) for synthesizing compounds described herein.

[0265] General Technology

[0266] Unless otherwise indicated, the practice of the present invention will adopt the conventional techniques of neuroscience, molecular biology (including recombinant technology), microbiology, cell biology, biochemistry and immunology within the skill of the art. Such techniques are fully explained in the literature, such as the current scheme (Current protocol in Neuroscience) in neuroscience (development editor: Eric Prager, online ISBN: 9780471142300, DOI: 10.1002 / 0471142301). Molecular Cloning: A Laboratory Manual, 2nd 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 (JE Cellis, ed., 1998), Academic Press; Animal Cell Culture (RI Freshney, ed., 1987); Introduction to Cell and Tissue Culture (JP Mather and PE Roberts, 1998), Plenum Press; Cell and Tissue Culture: Laboratory Procedures (JPMather and PE Roberts, 1998), Plenum Press; Procedures (A. Doyle, JB Griffiths and DG Newell, eds., 1993-8), John 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 (JM Miller and MPCalos, 1987; Current Protocols in Molecular Biology (F.M. Ausubeld et al., 1987); PCR: The Polymerase Chain Reaction (Mullis et al., 1994); Current Protocols in Immunology (J.E. Coligan et al., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (CA Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: a practical approach (D. Catty, 1988-1989); Monoclonal antibodies: a practical approach (Wiley and Sons, 1999); 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 JD Capra, eds., Harwood Academic Publishers, 1995).

[0267] Without further elaboration, it is believed that one skilled in the art will be able to utilize the present invention to its fullest extent based on the above description. Therefore, the specific embodiments provided herein should be interpreted as merely illustrative and not limiting the remainder of the present disclosure in any way. All publications cited herein are incorporated by reference for the purposes or subject matter cited herein.

[0268] Example 1. Synthesis of 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride (5)

[0269]

[0270] Preparation of 3,4,5-trihydroxybenzoic acid methyl ester (1)

[0271] At RT, sulfuric acid (3.1 mL, 58.8 mmol) was added to a solution of 3,4,5-trihydroxybenzoic acid (10.0 g, 58.8 mmol) in methanol (118.0 mL). The resulting mixture was heated to reflux for 6 h. After the reaction was complete, the reaction mixture was concentrated under vacuum. The residue was diluted with ethyl acetate, extracted with water, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to provide methyl 3,4,5-trihydroxybenzoate (1) (9.6 g, 89%) as a white solid. 1 H NMR (MeOD, 400MHz) δ7.03 (s, 2H), 3.81 (s, 3H).

[0272] Preparation of 7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid methyl ester (2)

[0273] To a solution of 3,4,5-trihydroxybenzoate (1,10.0 g, 54.3 mmol) in acetonitrile (543.0 mL), potassium carbonate (15.0 g, 108.6 mmol) and α,α-dichlorodiphenylmethane (9.9 mL, 51.6 mmol) were added. The mixture was stirred at 40 ° C for 6 h. After the reaction was completed, the mixture was concentrated under vacuum. 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 column chromatography with silica gel and ethyl acetate / hexane (1: 3) to provide 7-hydroxy-2,2-diphenylbenzo [d] [1,3] dioxole-5-methyl formate (2) (10.5 g, 55%) as a white solid. 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).

[0274] Preparation of methyl 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (3)

[0275] Potassium carbonate (7.9 g, 57.4 mmol) and allyl bromide (8.7 mL, 100.5 mmol) were added to a solution of 7-hydroxy-2,2-diphenylbenzo [d] [1,3] dioxole-5-methyl carboxylate (2, 10.0 g, 28.7 mmol) in methyl ethyl ketone (144.0 mL). The mixture was stirred at 40 ° C for 6 h. After the reaction was completed, 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 stripped in vacuo. The residue was purified by flash column chromatography with silica gel and ethyl acetate / hexane (1: 4) to provide 7- (allyloxy) -2,2-diphenylbenzo [d] [1,3] dioxole -5-methyl carboxylate (3) (10.4 g, 93%) as a white solid. 1 HNMR(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).

[0276] Preparation of 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (4)

[0277] 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 under vacuum. The residue was purified by dropwise addition of 10% HCl. (水性) , making the resulting residue acidic (pH = 5). The solid was collected and purified by recrystallization from ethyl acetate / hexane (1:4) to provide 7-(allyloxy)-2,2-diphenylbenzo[d]1,3]dioxole-5-carboxylic acid (4) (9.0 g, 93%) as a white solid.

[0278] 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).

[0279] Preparation of 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride (5)

[0280] 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) at 0°C was added oxalyl chloride (6.2 mL, 72.1 mmol) and DMF (0.1 mL). The mixture was stirred at RT for 16 h. The mixture was concentrated under vacuum to provide 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).

[0281] 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)

[0282]

[0283] Preparation of tert-butyl 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (6)

[0284] Under N2 at 0 ° C, 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 (100 mL) was added potassium tert-butoxide (10.3 g, 91.8 mmol) solution. The mixture was stirred at RT for 2 h. After the reaction was complete, the residue was diluted with ethyl acetate, extracted with water, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was stripped in vacuo. The residue was purified by flash column chromatography with silica gel and ethyl acetate / hexane (1: 8) to provide compound (6) (32 g, 97%) as a white solid. 1HNMR(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).

[0285] Preparation of tert-butyl 7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylate (7)

[0286] To the stirring solution of 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid tert-butyl ester (6, 32.0g, 74.3mmol) in anhydrous tetrahydrofuran (766.0mL), aniline (5.2mL, 37.2mmol) and tetrakis(triphenylphosphine)palladium (8.6g, 7.43mmol) are added. The mixture is stirred at RT under N2 for 16h. The mixture is filtered through a diatomaceous earth bed, and the filtrate is concentrated in vacuo. The residue is purified by flash column chromatography with silica gel and ethyl acetate / hexane (1:4) to provide compound (7) (27g, 93%) as a white solid. 1 H 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).

[0287] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carboxylate (8)

[0288] 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-dimethyl-aminopropyl)carbodiimide (14.6 g, 76.1 mmol) was added thereto, and the mixture was stirred at 0 ° C for 10 min, and then returned to RT. After the reaction was completed, 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 column chromatography with silica gel and ethyl acetate / hexane (1:9) to provide 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).

[0289] 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)

[0290] At 0 ° C, formic acid (377.6 mL) was added to a stirred solution of compound (8, 28.2 g, 37.8 mmol) in anhydrous dichloromethane (377.6 mL). After 10 min, it was stirred for 4 h at RT. The mixture was extracted with water 3 times, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash column chromatography with silica gel and ethyl acetate / dichloromethane (3:7) to provide compound (9) (16.0 g, 61%) as a white solid. 1H 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,12 H),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).

[0291] Example 3. Synthesis of 7-((7-(Benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (12)

[0292]

[0293] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxol-5-carboxylate (10)

[0294] 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 RT under N2 for 16 h. The mixture was filtered through a diatomaceous earth bed, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with silica gel and ethyl acetate / hexane (1:5) to provide compound (10) (17.5 g, 92%) as a white solid. 1 H NMR(CDCl3,400MHz)δ7.62-7.58(m,4H),7.58-7.54(m,4H),7.52-7.51(d,J=1.4H z,1H),7.46(s,1H),7.45(s,1H),7.43-7.36(m,13H),5.67(br,1H),1.56(s,9H).

[0295] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carboxylate (11)

[0296] Potassium carbonate (1.5 g, 10.6 mmol) and benzyl bromide (1.3 mL, 10.6 mmol) were added to a solution of compound (10, 2.5 g, 3.5 mmol) in methyl ethyl ketone (35.4 mL). The mixture was stirred at 40 ° C for 6 h. After the reaction was completed, 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 stripped in vacuo. The residue was purified by flash column chromatography with silica gel and ethyl acetate / hexane (1: 8) to provide compound (11) (2.6 g, 92%) as a white solid. 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).

[0297] 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 (12)

[0298] At 0 ° C, formic acid (31.4 mL) was added to a stirred solution of compound (11, 2.5 g, 3.1 mmol) in anhydrous dichloromethane (31.4 mL). After 10 min, it was stirred at RT for 4 h. The mixture was extracted with water 3 times, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash column chromatography with silica gel and ethyl acetate / dichloromethane (1: 10) to provide compound (12) (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).

[0299] Example 4. Synthesis 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 (16)

[0300] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carboxylate (13)

[0301] 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 thereto, and the mixture was stirred at 0 ° C for 10 min, and then returned to RT. After the reaction was completed, 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 column chromatography with silica gel and ethyl acetate / hexane (1: 8) to provide compound (13) (25.0 g, 95%) as a white solid. 1 H 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=1.4 Hz,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).

[0302] Preparation of 6-(tert-butoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxol-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carboxylate (14)

[0303] To the stirred solution of compound (13, 25.0 g, 23.5 mmol) in anhydrous tetrahydrofuran (235.2 mL), aniline (1.6 mL, 11.8 mmol) and tetrakis (triphenylphosphine) palladium (2.7 g, 2.4 mmol) were added. The mixture was stirred for 16 h at RT under N2. The mixture was filtered through a diatomaceous earth bed, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with silica gel and ethyl acetate / hexane (1: 4) to provide compound (14) (22.2 g, 91%) as a white solid. 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).

[0304] 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]dioxol-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carboxylate (15)

[0305] A mixture of compound (14, 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 thereto, and the mixture was stirred at 0 ° C for 10 min, and then returned to RT. After the reaction was completed, 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 column chromatography with silica gel and dichloromethane / hexane (3:2) to provide 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,2 0H),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).

[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-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid (16)

[0307] At 0 ° C, formic acid (88.5 mL) was added to a stirred solution of compound (15, 30.0 g, 17.7 mmol) in anhydrous dichloromethane (176.9 mL). After 10 min, it was stirred for 4 h at RT. The mixture was extracted with water 3 times, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash column chromatography with silica gel and ethyl acetate / dichloromethane (1: 8) to provide compound (16) (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,21 H),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,1H),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).

[0308] Example 5. Synthesis of the α-form of tetrakis(3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoic acid)(2R,3R,4S,5R,6R)-6-(((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (21)

[0309]

[0310] Preparation of the α-form of tetrakis(7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid)(2R,3R,4S,5R,6R)-6-(((7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (17)

[0311] -D-(+)-glucose (1.5 g, 8.3 mmol), pyridine (9.4 mL, 116.6 mmol) and 7-(allyloxy)-2,2-diphenylbenzo [d] [1,3] dioxole-5-carbonyl chloride (5, 28.9 g, 58.3 mmol) in anhydrous acetonitrile (43.0 mL) were stirred at RT for 12 h. After the reaction was complete, the mixture was evaporated 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 residue was purified by flash column chromatography with silica gel and ethyl acetate / hexane (1: 3) to provide compound (17) (10.2 g, 62%) as a white solid. 1H NMR(CDCl3,600MHz)δ7.62-7.58(m,8H),7.55-7.47(m,12H),7.40-7.29(m,34H),7.21(s,1H),7.19(s,1H),7.16(s,1H), 7.14(s,1H),7.11(s,2H),6.70(d,J=3.7Hz,1H),6.10(t,J=10.0Hz,1H),6.07-5.92(m,4H),5.88-5.81(m,1H),5.67(t,J =10.0Hz,1H),5.46(dd,J=10.3,3.7Hz,1H),5.43(s,1H),5.40(s,1H),5.37-5.31(m,2H),5.27-5.17(m,5H),5.10(d,J=1 0.6Hz, 1H), 4.71-4.69 (m, 4H), 4.62 (d, J = 5.5Hz, 2H), 4.57-4.54 (m, 3H), 4.46-4.44 (m, 3H), 4.29 (dd, J = 12.5, 4.6Hz, 1H). Preparation of the α-form of tetrakis(7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid)(2R,3R,4S,5R,6R)-6-(((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (18)

[0312] To a solution of compound (17, 10.0 g, 5.1 mmol) in anhydrous tetrahydrofuran (51.0 mL) was added aniline (1.9 mL, 20.4 mmol) and tetrakis (triphenylphosphine) palladium (3.0 g, 2.6 mmol). The mixture was stirred at RT for 16 h. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with silica gel and ethyl acetate / hexane (1: 1) to provide compound (18) (7.4 g, 82%) as a white solid. 1H NMR (CDCl3, 600MHz) δ7.55-6.97 (m, 60H), 6.59 (d, J = 3.4Hz, 1H), 6.07 (t, J = 10.0Hz, 1H), 5.69 (t, J = 10.0Hz, 1H), 5.42 (dd, J = 10.1, 3.5Hz, 1H), 4.53 (d, J = 11.0Hz, 1H), 4.42-4.40 (m, 1H), 4.25 (dd, J = 12.4, 4.4Hz, 1H). Tris(7-((7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid)(2R,3R,4S,5R,6R)-2-((7-((7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid) Preparation of the α-form of 2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-6-(((7-((7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl ester (19)

[0313] The mixture of compound (18, 7.4 g, 4.2 mmol), triethylamine (17.6 mL, 126.2 mmol), 4-dimethylaminopyridine (0.3 g, 2.1 mmol) and compound (5, 16.5 g, 42.1 mmol) in dichloromethane (84.0 mL) was stirred at RT for 12 h. After the reaction was completed, 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 column chromatography with silica gel and ethyl acetate / hexane (1: 2) to provide compound (19) (12.7 g, 85%) as a white solid. 1 H NMR(CDCl3,400MHz)δ7.61-7.28(m,120H),6.76(d,J=4.0Hz,1H),6.12(t,J=10.0Hz,1H),6.08-5.96(m,5H),5.68(t,J=10.0Hz,1H) ,5.51(dd,J=10.0,3.2Hz,1H),5.43-5.35(m,5H),5.29-5.23(m,5H),4.72-4.64(m,10H),4.47(d,J=10.8Hz,2H),4.42-4.38(m,1H).

[0314] Preparation of the α-form of tetrakis(7-((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid)(2R,3R,4S,5R,6R)-6-(((7-((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (20)

[0315] A mixture of compound (19, 12.7 g, 3.6 mmol), aniline (1.3 mL, 14.3 mmol), tetrakis (triphenylphosphine) palladium (2.1 g, 1.8 mmol) in anhydrous tetrahydrofuran (70.0 mL) was stirred at RT for 16 h. The mixture was filtered through a celite bed, and the filtrate was concentrated in vacuo. The crude product was purified by flash column chromatography with silica gel and ethyl acetate / hexane (1: 1) to provide compound (20) (10.7 g, 89%) as a white solid. 1 H NMR (CDCl3, 400MHz) δ7.59-7.12 (m, 120H), 6.74 (d, J = 3.3Hz, 1H), 6.08 (t, J = 9.6Hz ,1H),5.59-5.52(m,2H),4.59-4.56(m,1H),4.52-4.50(m,1H),4.39-4.37(m,1H).

[0316] Preparation of the α-form of tetrakis(3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoic acid)(2R,3R,4S,5R,6R)-6-(((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (21)

[0317] To the stirring solution of compound (20,100.0mg, 0.02mmol) in anhydrous tetrahydrofuran (3.0mL), 10wt% Pd / C (100mg) is added. The mixture is stirred for 24h under H2(8atm) at RT. The mixture is then filtered through diatomite and washed with acetone (10mL), and the combined filtrate is evaporated in vacuo. The residue is precipitated with ethyl acetate / hexane (1:25) to give compound (21) (37.0mg, 64%) as off-white solid. 1H NMR (MeOD, 400MHz) δ7.59-6.96 (m, 20H), 6.80 (s, 1H), 6.19 (t, J = 9.6Hz, 1H), 5.79 (t, J = 9.2Hz, 1H), 5.62-5.61 (m, 1H), 4.68 (s, 1H), 4.52 (s, 2H). ESI-MS,m / z 1699[MH] - .

[0318] Example 6. Synthesis of the α-form of tetrakis(3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoic acid)(2R,3R,4S,5R,6R)-6-(((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (24)

[0319]

[0320] Tetrakis(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-carboxylic acid)(2R,3R,4S,5R,6R)-6-(((7-((7- Preparation of the α-form of ((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)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (22)

[0321] The mixture of compound (20, 10.7 g, 3.2 mmol), N-methylmorpholine (10.6 mL, 96.0 mmol), 4-dimethylaminopyridine (0.2 g, 1.6 mmol) and compound (5, 12.6 g, 32.0 mmol) in dichloromethane (64.0 mL) was stirred at RT for 16 h. After the reaction was completed, 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 column chromatography with silica gel and ethyl acetate / hexane (1: 2) to provide compound (22) (15.0 g, 91%) as a white solid. 1H NMR(CDCl3,400MHz)δ7.66-7.26(m,180H),6.79(d,J=3.2Hz,1H),6.16(t,J=9.8Hz,1H),6.13-6.02(m,5H),5.71(t,J=10.0Hz,1H ),5.55(dd,J=10.4,3.4Hz,1H),5.47-5.40(m,5H),5.33-5.28(m,5H),4.77-4.64(m,10H),4.52-4.49(m,2H),4.43-4.41(m,1H).

[0322] Tetrakis(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)(2R,3R,4S,5R,6R)-6-(((7-((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid)(2R,3R,4S,5R,6R)- Preparation of the α-form of ((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)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (23)

[0323] To the stirred solution of compound (22,15.0g, 3.6mmol) in anhydrous tetrahydrofuran (60.0mL), aniline (1.1mL, 11.7mmol) and tetrakis (triphenylphosphine) palladium (1.7g, 1.5mmol) are added. The mixture is stirred for 24h under N2 at RT. The mixture is filtered through a diatomaceous earth bed, and the filtrate is concentrated in vacuo. The residue is purified by flash column chromatography with silica gel and ethyl acetate / hexane (1: 1) to provide compound (23) (12.3g, 85%) as a white solid. 1 H NMR (CDCl3, 400MHz) δ7.58-7.22 (m, 180H), 6.73 (d, J = 3.5Hz, 1H), 6.09 (t, J = 9.2Hz, 1H), 5.62(t,J=9.2Hz,1H), 5.51(dd,J=9.7,2.9Hz,1H), 4.48-4.46(m,2H), 4.39-4.37(m,1H).

[0324] Preparation of the α-form of tetrakis(3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoic acid)(2R,3R,4S,5R,6R)-6-(((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (24)

[0325] To the stirred solution of compound (23, 100.0mg, 0.02mmol) in anhydrous tetrahydrofuran (3.0mL), 10wt% Pd / C (100mg) is added. The mixture is stirred for 24h under H2 (8atm) at RT. The mixture is then filtered through diatomaceous earth, washed with acetone (10mL) and the combined filtrate is evaporated in vacuo. The residue is precipitated with ethyl acetate / hexane (1:25) to give compound (24) (37.0mg, 64%) as an off-white solid. 1 H NMR (MeOD, 400MHz) δ7.59-7.12 (m, 30H), 6.81 (d, J = 9.2Hz, 1H), 6.19 (s, 1H), 5.80 (s, 1H), 5.62 (s, 1H), 4.69 (s, 1H), 4.53 (s, 2H). MALDI-MS, m / z 2484.2200[M+Na].

[0326] Example 7. Synthesis of the α-form of tetrakis(3-((3,4-dihydroxy-5-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoic acid)(2R,3R,4S,5R,6R)-6-(((3-((3,4-dihydroxy-5-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (27)

[0327]

[0328] Tetrakis(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-carboxylic acid)(2R,3R,4S,5R,6R)-6-(((7-((7- Preparation of the α-form of ((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)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (25)

[0329] N-methylmorpholine (10.6mL, 96.0mmol), 4-dimethylaminopyridine (25.0mg, 0.2mmol) and compound (5, 1.6g, 4.1mmol) are added to the stirred solution of compound (23, 2.0g, 0.4mmol) in dichloromethane (8.0mL). The mixture is stirred for 12h at RT. After the reaction is completed, the mixture is extracted with water, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated in a vacuum. The residue is purified by flash column chromatography with silica gel and ethyl acetate / hexane (1:2) to provide compound (25) (2.5g, 92%) as a white solid. 1 H NMR(CDCl3,600MHz)δ7.65-7.24(m,240H),6.75(d,J=3.6Hz,1H),6.12(t,J=9.6Hz,1H),6.10-6.00(m,5H),5.67(t,J=9.6Hz,1H ),5.51(dd,J=10.2,3.6Hz,1H),5.44-5.38(m,5H),5.32-5.26(m,5H),4.72-4.64(m,10H),4.49-4.47(m,2H),4.38-4.36(m,1H).

[0330] Tetrakis(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-carboxylic acid)(2R,3R,4S,5R,6R)-6-(((7-((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid) Preparation of the α-form of ((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)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (26)

[0331] To the stirred solution of compound (25, 2.5 g, 0.4 mmol) in dry tetrahydrofuran (8.0 mL), aniline (0.2 mL, 1.5 mmol) and tetrakis (triphenylphosphine) palladium (0.2 g, 0.2 mmol) were added. The mixture was stirred for 12 h at RT. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with silica gel and ethyl acetate / hexane (1: 1) to provide compound (26) (2.3 g, 93%) as a white solid. 1 H NMR (CDCl3, 600MHz) δ7.59-7.12 (m, 240H), 6.72 (d, J = 3.7Hz, 1H), 6.09 (t, J = 10.8Hz, 1H), 5. 64(t,J=10.0Hz,1H),5.47(dd,J=10.7Hz,3.7Hz,1H),4.45-4.44(m,2H),4.36-4.35(m,1H).

[0332] Preparation of the α-form of tetrakis(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)(2R,3R,4S,5R,6R)-6-(((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (27)

[0333] To the stirred solution of compound (26, 100.0mg, 0.02mmol) in anhydrous tetrahydrofuran (3.0mL), 10wt% Pd / C (100mg) is added. The mixture is stirred for 24h under H2 (8atm) at RT. The mixture is then filtered through diatomaceous earth, washed with acetone (10mL) and the combined filtrate is evaporated in vacuo. The residue is precipitated with ethyl acetate / hexane (1:25) to give compound (27) (21.5mg, 43%) as an off-white solid. 1 H NMR (MeOD, 600MHz) δ7.60-7.03 (m, 40H), 6.82 (d, J = 11.4Hz, 1H), 6.20 (s, 1H), 5.81 (s, 1H), 5.68-5.63 (m, 1H), 4.70 (s, 2H), 4.54 (s, 1H). MALDI-MS, m / z 3244.2758[M+Na].

[0334] Example 8. Synthesis of the α-Form of Tetrakis(3-((3,4-dihydroxy-5-((3,4-dihydroxy-5-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)benzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoic acid)(2R,3R,4S,5R,6R)-6-(((3-((3,4-dihydroxy-5-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)benzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (30)

[0335]

[0336] Tetrakis(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)(2R,3R,4S,5R,6R)-6-(((7-((7- Preparation of the α-form of ((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-carbonyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (28)

[0337] N-methylmorpholine (0.4mL, 3.6mmol), 4-dimethylaminopyridine (5.0mg, 0.04mmol) and compound (5, 0.5g, 1.3mmol) are added to the stirred solution of compound (26, 0.58g, 0.1mmol) in dichloromethane (4.5mL). The mixture is stirred for 12h at RT. After the reaction is completed, the mixture is extracted with water, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated in a vacuum. The residue is purified by flash column chromatography with silica gel and ethyl acetate / dichloromethane / hexane (5 / 40 / 55) to provide compound (28) (0.63g, 85%) as a white solid. 1 HNMR(CD2Cl2,500MHz)δ7.70-7.18(m,300H),6.70-6.69(d,J=3.7Hz,1H),6.09-5.99(m,6H),5.69-5.66(t,J=10.0Hz,1 H),5.54-5.51(m,1H),5.42-5.36(m,5H),5.28-5.24(m,5H),4.69-4.63(m,10H),4.51-4.47(m,2H),4.37-4.35(m,1H).

[0338] Tetrakis(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)(2R,3R,4S,5R,6R)-6-(((7-((7- Preparation of the α-form 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-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (29)

[0339] To the stirring solution of compound (28,0.63g, 0.08mmol) in dry tetrahydrofuran (1.5mL), aniline (0.03mL, 0.31mmol) and tetrakis (triphenylphosphine) palladium (44g, 0.04mmol) are added. The mixture is stirred for 12h at RT. The mixture is filtered through diatomaceous earth, and the filtrate is concentrated in vacuo. The residue is purified by flash column chromatography with silica gel and ethyl acetate / dichloromethane / hexane (15 / 50 / 35), to provide compound (29) (0.4g, 65%) as a white solid. 1 H NMR (CD2Cl2, 400MHz) δ7.66-7.22 (m, 300H), 6.74-6.73 (d, J=3.7Hz, 1H), 6.15-6.10 (t, J=9.7Hz, 1H), 5. 83-5.79(m,5H),5.73-5.68(t,J=10.0Hz,1H),5.58-5.54(m,1H),4.56-4.51(m,2H),4.41-4.39(m,1H).

[0340] Preparation of the α-form of tetrakis(3-((3,4-dihydroxy-5-((3,4-dihydroxy-5-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)benzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoic acid)(2R,3R,4S,5R,6R)-6-(((3-((3,4-dihydroxy-5-((3,4-dihydroxy-5-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)benzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (30)

[0341] To the stirred solution of compound (29, 0.1 g, 0.012 mmol) in anhydrous tetrahydrofuran (3.0 mL), 10 wt% Pd / C (0.1 g) was added. The mixture was stirred for 24 h at RT under H2 (8 atm). The mixture was then filtered through diatomaceous earth, washed with tetrahydrofuran (10 mL) and the combined filtrate was evaporated in vacuo. The residue was precipitated with ethyl acetate / hexane (1:25) to give compound (30) (18 mg, 36%) as an off-white solid. 1 H NMR (MeOD, 400MHz) δ7.59-7.18 (m, 50H), 6.82 (d, J = 11.4Hz, 1H), 6.20 (s, 1H), 5.80 (s, 1H), 5.64 (s, 1H), 4.66 (s, 2H), 4.53 (s, 1H).

[0342] Example 9. Synthesis of the β-form of tetrakis(3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoic acid)(2S,3R,4S,5R,6R)-6-(((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (37)

[0343]

[0344]

[0345] Preparation of the β-form of tetrakis(7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid)(2S,3R,4S,5R,6R)-6-(((7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (31)

[0346] A mixture of β-D-(+)-glucose (200.0 mg, 1.1 mmol), pyridine (1.3 mL, mmol) and compound (5, 3.1 g, 7.8 mmol) in anhydrous acetonitrile (6.0 mL) was stirred at RT for 12 h. After the reaction was complete, the mixture was concentrated under vacuum. The residue was diluted with dichloromethane, 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 column chromatography with silica gel and ethyl acetate / hexane (1:2) to provide compound (31) (1.1 g, 49%) as a white solid. 1 H NMR(CDCl3,500MHz)δ7.56-7.04(m,60H),6.05-5.89(m,6H),5.82(t,J=9.8Hz,1H),5.63(t,J=9.6Hz,1H),5.56( t,J=9.8Hz,1H),5.40-5.27(m,5H),5.25-5.14(m,5H),4.68-4.52(m,10H),4.27-4.23(m,1H),4.20-4.18(m,1H).

[0347] Preparation of the β-form of tetrakis(7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid)(2S,3R,4S,5R,6R)-6-(((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (32)

[0348] To the stirred solution of compound (31,1.0g, 0.5mmol) in dry tetrahydrofuran (5.0mL), aniline (0.2mL, 2.0mmol) and tetrakis (triphenylphosphine) palladium (0.3g, 0.3mmol) are added. The mixture is stirred for 12h at RT. The mixture is filtered through diatomaceous earth, and the filtrate is concentrated in vacuo. The residue is purified by flash column chromatography with silica gel and ethyl acetate / hexane (1:1) to provide compound (32) (598.0mg, 66%) as a white solid. 1H NMR (CDCl3, 600MHz) δ7.52-6.93 (m, 60H), 6.13 (d, J = 7.8H, 1H), 5.86 (t, J = 9.0Hz, 1H), 5.72-5.71 (m, 2H), 4.57 (d, J = 10.8Hz, 1H), 4.32 (m, 2H).

[0349] Tris(7-((7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid)(2S,3R,4S,5R,6R)-2-((7-((7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2, Preparation of β-form of 2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-6-(((7-((7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl ester (33)

[0350] The mixture of compound (32,573.0mg, 0.3mmol), triethylamine (1.4mL, 9.8mmol) and 4-dimethylaminopyridine (20.0mg, 0.2mmol) and compound (5,1.3g, 3.3mmol) in dichloromethane (6.6mL) was stirred at RT for 12h. After the reaction was completed, the mixture was extracted with water, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in a vacuum. The residue was purified by flash column chromatography with silica gel and ethyl acetate / hexane (1:2) to provide compound (33) (1.1g, 96%) as a white solid. 1 H NMR(CDCl3,600MHz)δ7.58-7.26(m,120H),6.08(d,J=8.4Hz,1H),6.06-5.96(m,5H),5.85(t,J=9.6Hz,1H),5.67(dd,J=9.6,8.5Hz,1H),5.56(t, J=9.7Hz,1H),5.40-5.34(m,5H),5.26-5.22(m,5H),4.68-4.63(m,10H), 4.45(d,J=10.8Hz,1H), 4.34(dd,J=12.0,4.8Hz,1H), 4.20-4.17(m,1H).

[0351] Preparation of the β-form of tetrakis(7-((7-hydroxy-2,2-dimethylbenzo[d][1,3]dioxole-5-carbonyl)oxy-2,2-dimethylbenzo[d][1,3]dioxole-5-carboxylic acid)(2S,3R,4S,5R,6R)-6-(((7-((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (34)

[0352] To the stirred solution of compound (33, 1.1 g, 0.3 mmol) in anhydrous tetrahydrofuran (6.0 mL), aniline (0.1 mL, 1.3 mmol) and tetrakis (triphenylphosphine) palladium (0.2 g, 0.2 mmol) were added. The mixture was stirred for 12 h at RT. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with silica gel and ethyl acetate / hexane (1: 1) to provide compound (34) (0.8 g, 76%) as a white solid. 1 H NMR (CDCl3, 600MHz) δ7.62-7.19 (m, 120H), 6.09 (d, J =8.4Hz,1H),5.85(t,J=9.6Hz,1H),5.64(t,J=9.6Hz,1H),5.51(t,J=9.6H z,1H),4.60(dd,J=12.0,3.6Hz,1H),4.37-4.35(m,1H),4.25-4.23(m,1H).

[0353] Tetrakis(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-carboxylic acid)(2S,3R,4S,5R,6R)-6-(((7-((7- Preparation of the β-form of ((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)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (35)

[0354] The mixture of compound (34, 789.0 mg, 0.2 mmol), N-methylmorpholine (0.8 mL, 7.1 mmol), 4-dimethylaminopyridine (14.0 mg, 0.1 mmol) and compound (5, 927.0 g, 2.4 mmol) in dichloromethane (2.4 mL) was stirred at RT for 12 h. 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 a vacuum. The residue was purified by flash column chromatography with silica gel and ethyl acetate / hexane (1:2) to provide compound (35) (600.0 mg, 50%) as a white solid. 1 H NMR(CDCl3,400MHz)δ7.68-7.22(m,180H),6.08-5.96(m,6H),5.84(t,J=9.5Hz,1H),5.66(t,J=8.9Hz,1H),5.55(t,J=9.6Hz, 1H),5.41-5.36(m,5H),5.26-5.24(m,5H),4.68-4.63(m,10H),4.46(d,J=11.4Hz,1H),4.33-4.31(m,1H),4.21-4.17(m,1H).

[0355] Tetrakis(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)(2S,3R,4S,5R,6R)-6-(((7-((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid) Preparation of the β-form of ((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)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (36)

[0356] To the stirred solution of compound (35, 598.0 mg, 0.1 mmol) in anhydrous tetrahydrofuran (2.5 mL), aniline (0.04 mL, 0.8 mmol) was added and tetrakis (triphenylphosphine) palladium (67.0 mg, 0.1 mmol) was added. The mixture was stirred for 12 h at RT. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with silica gel and ethyl acetate / hexane (1: 1) to provide compound (36) (340.0 mg, 59%) as a white solid. 1H NMR (CDCl3, 600MHz) δ7.67-7.18 (m, 180H), 6.07 (d, J = 7.8Hz, 1H), 5.82 (t, J = 9.6Hz, 1H), 5.64 (t, J =9.0Hz,1H),5.52(t,J=9.6Hz,1H),4.45(d,J=10.2Hz,1H),4.37-4.34(m,1H),4.19-4.17(m,1H).

[0357] Preparation of the β-form of tetrakis(3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoic acid)(2S,3R,4S,5R,6R)-6-(((3-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (37)

[0358] To the stirred solution of compound (36, 100.0 mg, 0.02 mmol) in dry THF (3.0 mL), 10 wt% Pd / C (100 mg) was added. The mixture was stirred for 24 h at RT under H2 (8 atm). The mixture was then filtered through diatomaceous earth, washed with acetone (10 mL) and the combined filtrate was evaporated in vacuo. The residue was precipitated with ethyl acetate / hexane (1:25) to give compound (37) (21.0 mg, 42%) as an off-white solid. 1 H NMR (MeOD, 600MHz) δ7.54-6.97 (m, 30H), 6.32 (s, 1H), 6.01 (s, 1H), 5.68 (s, 2H), 4.59-4.49 (m, 3H). ESI-MS,m / z 1229[M-2H] 2- .

[0359] Example 10. Synthesis of the β-Form of Tetrakis(3-((3,4-dihydroxy-5-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoic acid)(2S,3R,4S,5R,6R)-6-(((3-((3,4-dihydroxy-5-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (40)

[0360]

[0361] Tetrakis(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-carboxylic acid)(2S,3R,4S,5R,6R)-6-(((7-((7- Preparation of the β-form of ((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)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (38)

[0362] To the stirred solution of compound (36, 2.0 g, 0.4 mmol) in dichloromethane (8.0 mL), N-methylmorpholine (10.6 mL, 96.0 mmol), 4-dimethylaminopyridine (25.0 mg, 0.2 mmol) and compound (5) (1.6 g, 4.1 mmol) were added. The mixture was stirred at RT for 12 h. 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 a vacuum. The residue was purified by flash column chromatography with silica gel and ethyl acetate / hexane (1:2) to provide compound (38) (2.5 g, 92%) as a white solid. 1 H NMR(CDCl3,400MHz)δ7.72-7.45(m,120H),7.43-7.31(m,103H),7.30-7.21( m,37H),6.11-6.01(m,6H),5.89-5.84(t,J=9.5Hz,1H),5.71-5.67(t,J=8.9 Hz,1H),5.60-5.55(t,J=9.6Hz,1H),5.45-5.37(m,5H),5.32-5.26(m,5H),4 .72-4.67(m,10H),4.51-4.48(m,1H),4.36-4.34(m,1H),4.23-4.20(m,1H).

[0363] Tetrakis(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-carboxylic acid)(2S,3R,4S,5R,6R)-6-(((7-((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carboxylic acid) Preparation of the β-form of ((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)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (39)

[0364] To the stirred solution of compound (38, 2.5 g, 0.4 mmol) in dry tetrahydrofuran (8.0 mL), aniline (0.2 mL, 1.5 mmol) and tetrakis (triphenylphosphine) palladium (0.2 g, 0.2 mmol) were added. The mixture was stirred for 12 h at RT. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography with silica gel and ethyl acetate / hexane (1: 1) to provide compound (39) (2.3 g, 93%) as a white solid. 1 H NMR(CDCl3,400MHz)δ7.60-7.20(m,240H),6.11-6.09(d,J=8,2Hz,1H),5.98(br,5H),5.88-5.84(t,J=9.5Hz,1H),5.71 -5.66(t,J=8.5Hz,1H),5.60-5.54(t,J=9.8Hz,1H),4.51-4.48(d,J=10.8Hz,1H),4.36-4.34(m,1H),4.23-4.21(m,1H).

[0365] Preparation of the β-form of tetrakis(3-((3,4-dihydroxy-5-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoic acid)(2S,3R,4S,5R,6R)-6-(((3-((3,4-dihydroxy-5-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (40)

[0366] To the stirred solution of compound (39, 100.0mg, 0.02mmol) in anhydrous tetrahydrofuran (3.0mL), 10wt% Pd / C (100mg) is added. The mixture is stirred for 24h under H2 (8atm) at RT. The mixture is then filtered through diatomaceous earth, washed with tetrahydrofuran (10mL) and the combined filtrate is evaporated in vacuo. The residue is precipitated with ethyl acetate / hexane (1:25) to give compound (40) (21.5mg, 43%) as an off-white solid. 1 H NMR (MeOD, 500MHz) δ7.41-6.95(m,40H), 6.29(s,1H), 5.97(s,1H), 5.65-5.62(m,2H), 4.49-4.42(m,3H).

[0367] Example 11. Synthesis of the β-Form of Tetrakis(3-((3,4-dihydroxy-5-((3,4-dihydroxy-5-(((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)benzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoic acid)(2S,3R,4S,5R,6R)-6-(((3-((3,4-dihydroxy-5-((3,4-dihydroxy-5-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)benzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (43)

[0368]

[0369] Tetrakis(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)(2S,3R,4S,5R,6R)-6-(((7-((7- Preparation of the β-form of ((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-carbonyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (41)

[0370] N-methylmorpholine (0.4mL, 3.6mmol), 4-dimethylaminopyridine (5mg, 0.04mmol) and compound (5, 0.5g, 1.3mmol) are added to the stirred solution of compound (39, 0.58g, 0.1mmol) in dichloromethane (4.5mL). The mixture is stirred for 12h at RT. After the reaction is completed, the mixture is extracted with water, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated in a vacuum. The residue is purified by flash column chromatography with silica gel and ethyl acetate / dichloromethane / hexane (5 / 40 / 55) to provide compound (41) (0.63g, 85%) as a white solid. 1 H NMR(CD2Cl2,500MHz)δ7.73-7.46(m,140H),7.46-7.24(m,160H),6.17-6.03(m,6H),5.92-5.87(t,J=9.6Hz,1H),5.73-5.68(t,J=8.1Hz,1H),5 .67-5.62(t,J=9.8Hz,1H),5.46-5.40(m,5H),5.32-5.28(m,5H),4.72- 4.68(m,10H),4.55-4.52(m,1H),4.42-4.40(m,1H),4.31-4.29(m,1H).

[0371] Tetrakis(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)(2S,3R,4S,5R,6R)-6-(((7-((7- Preparation of the β-form 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-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (42)

[0372] To the stirring solution of compound (41,0.63g, 0.08mmol) in dry tetrahydrofuran (1.5mL), aniline (0.03mL, 0.31mmol) and tetrakis (triphenylphosphine) palladium (44g, 0.04mmol) are added. The mixture is stirred for 12h at RT. The mixture is filtered through diatomaceous earth, and the filtrate is concentrated in vacuo. The residue is purified by flash column chromatography with silica gel and ethyl acetate / dichloromethane / hexane (15 / 50 / 35), to provide compound (42) (0.4g, 65%) as a white solid. 1 H NMR(CD2Cl2,400MHz)δ7.70-7.43(m,140H),7.43-7.24(m,160H),6.18-6.16(d,J=8.1Hz,1H),5.93-5.88(t,J=9.8Hz,1H),5.74- 5.69(t,J=8.2Hz,1H), 5.68-5.63(t,J=9.5Hz,1H), 4.56-4.53(d,J=11.1Hz,1H), 4.43-4.41(d,J=7.9Hz,1H), 4.32-4.29(m,1H).

[0373] Preparation of the β-form of tetrakis(3-((3,4-dihydroxy-5-((3,4-dihydroxy-5-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)benzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoic acid)(2S,3R,4S,5R,6R)-6-(((3-((3,4-dihydroxy-5-((3,4-dihydroxy-5-((3,4,5-trihydroxybenzoyl)oxy)benzoyl)oxy)benzoyl)oxy)benzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl ester (43)

[0374] To the stirred solution of compound (42, 0.1 g, 0.012 mmol) in anhydrous tetrahydrofuran (3 mL), 10 wt% Pd / C (0.1 g) was added. The mixture was stirred for 24 h at RT under H2 (8 atm). The mixture was then filtered through diatomaceous earth, washed with tetrahydrofuran (10 mL) and the combined filtrate was evaporated in vacuo. The residue was precipitated with ethyl acetate / hexane (1:25) to give compound (43) (18 mg, 36%) as an off-white solid. 1 H NMR (MeOD, 400MHz) δ 7.58-6.98 (m, 50H), 6.33 (s, 1H), 6.01 (s, 1H), 5.69 (s, 1H), 4.64-4.43 (m, 3H). MALDI-MS, m / z4005.3496[M+Na].

[0375] Example 12. Synthesis of 5-((5-((5-((2,3-dihydroxy-5-(phenoxycarbonyl)phenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenyl 3,4,5-trihydroxybenzoate (46)

[0376]

[0377] Preparation of 6-(phenoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-((7-((7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carboxylate (44)

[0378] A mixture of phenol (80 mg, 0.85 mmol), compound (16, 1.46 g, 0.89 mmol) and 4-dimethylaminopyridine (108 mg, 0.89 mmol) in dichloromethane (8.5 mL) was stirred at 0 ° C, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (171 mg, 0.89 mmol) was added thereto, and the mixture was stirred at 0 ° C for 10 min, then returned to RT. After the reaction was completed, 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 column chromatography with silica gel and ethyl acetate / dichloromethane / hexane (3 / 37 / 60) to provide compound (44) (1.16 g, 80%) as a white solid. 1 H NMR (CDCl3, 500MHz) δ7.71-7.70 (m, 3H), 7.66-7.65 (d, J = 1.6Hz, 1H), 7.63-7.62 (m, 3H), 7. 59-7.56(m,5H),7.55-7.51(m,16H),7.48-7.47(d,J=1.4Hz,1H),7.45-7.44(d,J=1.5Hz,1 H),7.38-7.33(m,32H),7.21-7.19(m,1H),7.13-7.12(m,2H),6.07-6.01(m,1H),5.42-5.3 7(dd,J=17.2,1.4Hz,1H), 5.28-5.25(dd,J=10.6,1.3Hz,1H), 4.72-4.70(d,J=5.5Hz,2H).

[0379] Preparation of 6-(phenoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-((7-hydroxy-2,2-diphenylbenzo[d][1,3]dioxol-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carboxylate (45)

[0380] To the stirring solution of compound (44,1.16g, 0.68mmol) in dry tetrahydrofuran (13.5mL), aniline (0.19mL, 2.03mmol) and tetrakis (triphenylphosphine) palladium (78g, 0.07mmol) are added. The mixture is stirred for 12h at RT. The mixture is filtered through diatomaceous earth, and the filtrate is concentrated in vacuo. The residue is purified by flash column chromatography with silica gel and ethyl acetate / dichloromethane / hexane (2 / 50 / 48), to provide compound (45) (978mg, 86%) as a white solid. 1 H NMR(CDCl3,500MHz)δ7.76-7.75(m,3H),7.72-7.71(d,J=1.3Hz,1H),7.68-7.67(m,3H),7.64-7.63(d,J=1.6 Hz, 1H), 7.61-7.57 (m, 21H), 7.52-7.51 (d, J = 1.6Hz, 1H), 7.44-7.39 (m, 35H), 7.26-7.17 (m, 3H), 5.38 (s, 1H). MALDI-MS, m / z 877.0857[M+Na].

[0381] Preparation of 5-((5-((5-((2,3-dihydroxy-5-(phenoxycarbonyl)phenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenyl 3,4,5-trihydroxybenzoate (46)

[0382] To the stirring solution of compound (45,125mg, 0.08mmol) in anhydrous tetrahydrofuran (7.5mL), 10wt% Pd / C (63mg) is added. The mixture is stirred for 24h under H2(8atm) at RT. The mixture is then filtered through diatomite, washed with tetrahydrofuran (10mL) and the combined filtrate is evaporated in vacuo. The residue is precipitated with ethyl acetate / hexane (1:25) to give compound (46) (50mg, 78%) as off-white solid. 1 H NMR (MeOD, 400MHz) δ7.61-7.42(m,8H),7.33-7.19(m,7H).

[0383] Example 13. Synthesis of 5-((5-((5-((5-((2,3-dihydroxy-5-(phenoxycarbonyl)phenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenyl 3,4,5-trihydroxybenzoate (48)

[0384]

[0385] Preparation of 6-(phenoxycarbonyl)-2,2-diphenylbenzo[d][1,3]dioxol-4-yl 7-((7-((7-((7-((7-((7-(benzyloxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carbonyl)oxy)2,2-diphenylbenzo[d][1,3]dioxol-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carbonyl)oxy)-2,2-diphenylbenzo[d][1,3]dioxol-5-carboxylate (47)

[0386] The mixture of compound (45,500mg, 0.30mmol), compound (12,232mg, 0.31mmol) and 4-dimethylaminopyridine (38mg, 0.31mmol) in dichloromethane (3.0mL) is stirred at 0°C, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (60mg, 0.31mmol) is added thereto, and the mixture is stirred at 0°C for 10min, then returned to RT. After the reaction is complete, the mixture is extracted with water, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated in vacuo. The residue is purified by flash column chromatography with silica gel and ethyl acetate / dichloromethane / hexane (4 / 36 / 60) to provide compound (47) (600mg, 84%) as a white solid. 1 H NMR (CDCl3, 400MHz) δ7.73-7.14 (m, 89H), 5.27 (s, 2H).

[0387] Preparation of 5-((5-((5-((5-((2,3-dihydroxy-5-(phenoxycarbonyl)phenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenoxy)carbonyl)-2,3-dihydroxyphenyl 3,4,5-trihydroxybenzoate (48)

[0388] To the stirred solution of compound (47, 200mg, 0.08mmol) in anhydrous tetrahydrofuran (8.3mL), 10wt% Pd / C (100mg) is added. The mixture is stirred for 24h under H2 (8atm) at RT. The mixture is then filtered through diatomaceous earth, washed with tetrahydrofuran (10mL) and the combined filtrate is evaporated in vacuo. The residue is precipitated with ethyl acetate / hexane (1:25) to give compound (48) (40mg, 41%) as off-white solid. 1 H NMR (MeOD, 400MHz) δ7.62-7.38 (m, 11H), 7.34-7.16 (m, 8H). MALDI-MS, m / z 1181.1071[M+Na].

[0389] Example 14. Synthesis of 1,3-phenylene bis(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-dihydroxybenzoic acid) ester (51)

[0390]

[0391] Preparation of 1,3-phenylene bis(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 (49)

[0392] A mixture of benzene-1,3-diol (50 mg, 0.45 mmol), compound (16, 1.53 g, 0.93 mmol) and 4-dimethylaminopyridine (113 mg, 0.93 mmol) in dichloromethane (9 mL) was stirred at 0 ° C, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (178 mg, 0.93 mmol) was added thereto, and the mixture was stirred at 0 ° C for 10 min, then returned to RT. After the reaction was completed, 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 column chromatography with silica gel and ethyl acetate / toluene (2 / 98) to provide compound (49) (1.4 g, 92%) as a white solid. 1H NMR(CDCl3,400MHz)δ7.75-7.74(m,5H),7.68-7.66(m,7H),7.62-7.54(m, 40H),7.52-7.51(d,J=1.2Hz,2H),7.49-7.48(d,J=1.4Hz,2H),7.41-7.36 (m,63H),7.10-7.08(m,3H),6.11-6.03(m,2H),5.45-5.41(dd,J=17.2,1. 3Hz, 2H), 5.31-5.28 (dd, J=10.5, 1.0Hz, 2H), 4.75-4.73 (d, J=5.4Hz, 4H). Preparation of 1,3-phenylene bis(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 (50)

[0393] To the stirring solution of compound (49,1.4g, 0.42mmol) in dry tetrahydrofuran (8.4mL), aniline (0.11mL, 1.25mmol) and tetrakis (triphenylphosphine) palladium (48g, 0.04mmol) are added. The mixture is stirred for 12h at RT. The mixture is filtered through diatomaceous earth, and the filtrate is concentrated in vacuo. The residue is purified by flash column chromatography with silica gel and ethyl acetate / toluene (4 / 96), to provide compound (50) (1.2g, 88%) as a white solid. 1 H NMR(CDCl3,400MHz)δ7.73(s,5H),7.68-7.67(d,J=1.4Hz,2H),7.65(s,5H),7.60-7.59(d,J=1.5Hz,2H) ,7.59-7.53(m,40H),7.48-7.47(d,J=1.4Hz,2H),7.40-7.36(m,65H),7.09-7.07(m,3H),5.54(br,2H). Preparation of 1,3-phenylene bis(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-dihydroxybenzoic acid) ester (51)

[0394] To the stirring solution of compound (50,200mg, 0.06mmol) in anhydrous tetrahydrofuran (4mL), 10wt% Pd / C (100mg) is added. The mixture is stirred for 24h under H2(8atm) at RT. The mixture is then filtered through diatomite, washed with tetrahydrofuran (10mL) and the combined filtrate is evaporated in vacuo. The residue is precipitated with ethyl acetate / hexane (1:25) to give compound (51) (44mg, 44%) as off-white solid. 1 H NMR (MeOD, 400MHz) δ7.59-7.47(m,13H),7.31-7.24(m,8H),7.15(s,3H). MALDI-MS, m / z 2430.2[M+Na].

[0395] Example 15. Synthesis of 1,3-phenylene bis(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-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid) ester (53)

[0396]

[0397] Bis(7-((7-((7-((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 Preparation of 1,3-phenylene 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-carboxylate (52)

[0398] A mixture of compound (50,800 mg, 0.24 mmol), compound (12,371 mg, 0.50 mmol) and 4-dimethylaminopyridine (61 mg, 0.50 mmol) in dichloromethane (2.5 mL) was stirred at 0 ° C, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (96 mg, 0.5 mmol) was added thereto, and the mixture was stirred at 0 ° C for 10 min, then returned to RT. After the reaction was completed, 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 column chromatography with silica gel and ethyl acetate / toluene (2 / 96) to provide compound (52) (919 mg, 80%) as a white solid. 1 H NMR (CDCl3, 400 MHz) δ 7.73 (s, 8H), 7.67-7.65 (m, 10H), 7.59-7.55 (m, 62H), 7.47-7.33 (m, 98H), 7.09-7.07 (m, 4H), 5.26 (s, 4H). Preparation of 1,3-phenylene bis(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-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid) 1,3-phenylene ester (53)

[0399] To the stirring solution of compound (52,200mg, 0.04mmol) in anhydrous tetrahydrofuran (4mL), 10wt% Pd / C (100mg) is added. The mixture is stirred for 24h under H2(8atm) at RT. The mixture is then filtered through diatomite, washed with tetrahydrofuran (10mL) and the combined filtrate is evaporated in vacuo. The residue is precipitated with ethyl acetate / hexane (1:25) to give compound (53) (50mg, 53%) as off-white solid. 1 H NMR (MeOD, 400MHz) δ7.58-7.47 (m, 18H), 7.31-7.24 (m, 10H), 7.15 (s, 4H). MALDI-MS, m / z 2262.1866[M+Na].

[0400] Example 16. Synthesis of tris(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)benzene-1,3,5-triyl ester (56)

[0401]

[0402]

[0403] Preparation of benzene-1,3,5-triyl tris(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 (54)

[0404] A mixture of benzene-1,3,5-triol (150 mg, 1.19 mmol), compound (16, 6.44 g, 3.93 mmol) and 4-dimethylaminopyridine (476 mg, 3.93 mmol) in dichloromethane (40 mL) was stirred at 0 ° C, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (752 mg, 3.93 mmol) was added thereto, and the mixture was stirred at 0 ° C for 10 min, then returned to RT. After the reaction was completed, 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 column chromatography with silica gel and ethyl acetate / dichloromethane / hexane (2 / 50 / 48) to provide compound (54) (5.5 g, 92%) as a white solid. 1 H NMR(CDCl3,400MHz)δ7.78-7.76(m,9H),7.70-7.68(m,12H),7.64-7.57(m,63H),7.54-7.53(d,J=1.5Hz,3H),7.51-7.50(d,J=1.5Hz,3H),7.43-7 .37(m,90H),7.07(s,3H),6.15-6.05(m,3H),5.48-5.42(dd,J=17.2,1.5 Hz, 3H), 5.34-5.30 (dd, J=10.5, 1.4Hz, 3H), 4.77-4.75 (d, J=5.3Hz, 6H).

[0405] Preparation of benzene-1,3,5-triyl tris(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 (55)

[0406] To the stirred solution of compound (54,5.5g, 1.1mmol) in dry tetrahydrofuran (11mL), aniline (0.23mL, 1.64mmol) and tetrakis (triphenylphosphine) palladium (126g, 0.11mmol) are added. The mixture is stirred for 12h at RT. The mixture is filtered through diatomaceous earth, and the filtrate is concentrated in vacuo. The residue is purified by flash column chromatography with silica gel and ethyl acetate / toluene (5 / 95), to provide compound (55) (4.0g, 75%) as a white solid. 1 H NMR(CDCl3,400MHz)δ7.76-7.75(m,9H),7.68-7.66(m,12H),7.61-7.57(m,63H ),7.50-7.49(d,J=1.6Hz,3H),7.42-7.37(m,93H),7.06(s,3H),5.74(br,3H).

[0407] Preparation of benzene-1,3,5-triyl tris(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-dihydroxybenzoic acid) ester (56)

[0408] To the stirring solution of compound (55,500mg, 0.04mmol) in anhydrous tetrahydrofuran (4mL), 10wt% Pd / C (100mg) is added. The mixture is stirred for 24h under H2(8atm) at RT. The mixture is then filtered through diatomite, washed with tetrahydrofuran (10mL) and the combined filtrate is evaporated in vacuo. The residue is precipitated with ethyl acetate / hexane (1:25) to give compound (53) (50mg, 53%) as off-white solid. 1H NMR (MeOD, 400MHz) δ7.59-7.55(m,9H), 7.50-7.46(m,9H), 7.31-7.23(m,12H), 7.13-7.11(m,3H). MALDI-MS, m / z2430.1925[M+Na].

[0409] Example 17. Synthesis of tris(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-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoic acid)benzene-1,3,5-triyl ester (58)

[0410]

[0411]

[0412] Tris(7-((7-((7-((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 Preparation of 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-carboxylic acid)benzene-1,3,5-triyl ester (57)

[0413] A mixture of compound (55, 650 mg, 0.13 mmol), compound (12, 326 mg, 0.44 mmol) and 4-dimethylaminopyridine (53 mg, 0.44 mmol) in dichloromethane (4.5 mL) was stirred at 0 ° C, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (84 mg, 0.44 mmol) was added thereto, and the mixture was stirred at 0 ° C for 10 min, and then returned to RT. After the reaction was completed, 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 column chromatography with silica gel and ethyl acetate / toluene (2 / 96) to provide compound (57) (755 mg, 80%) as a white solid. 1H NMR (CDCl3, 400MHz) δ7.72-7.30 (m, 267H), 7.03 (s, 3H), 5.25 (s, 6H).

[0414] Preparation of tris(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-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzoyl)oxy)-4,5-dihydroxybenzyl)benzene 1,3,5-triyl ester (58)

[0415] To the stirring solution of compound (57,100mg, 0.01mmol) in anhydrous tetrahydrofuran (4mL), 10wt% Pd / C (100mg) is added. The mixture is stirred for 24h under H2(8atm) at RT. The mixture is then filtered through diatomite, washed with tetrahydrofuran (10mL) and the combined filtrate is evaporated in vacuo. The residue is precipitated with ethyl acetate / hexane (1:25) to give compound (58) (30mg, 60%) as off-white solid. 1 H NMR (MeOD, 500MHz) δ7.55-7.43 (m, 27H), 7.27-7.20 (m, 15H), 7.09-7.08 (m, 3H). MALDI-MS, m / z 3343.3317[M+Na].

[0416] Example 18. In vitro measurement of human D-amino acid oxidase (hDAAO) activity

[0417] The hDAAO inhibitory activity of the above-mentioned embodiment is measured by using D-serine as a substrate to produce H2O2. The H2O2 produced will be oxidized by peroxidase, and the free radicals produced will further react with Amplex Red reagent to emit fluorescence. The fluorescence intensity at 590nm will be measured to represent the activity of hDAAO. All compounds are dissolved in DMSO. Each compound is diluted with DMSO in 3-fold serial dilutions to create a 9-point dose-response curve. Each sample is added to a 96-well black plate in triplicate (1 μL / well). 1 μL of DMSO is added to the positive control well. Then, 49 μL of assay buffer (100mM Tris-HCl, pH 8.5) containing 1.2 ng / mL hDAAO, 900nM FAD, 0.2 units / mL HRP and 100 μM Amplex Red is added to each well of the plate using a multichannel pipette. Next, 50 μL of 100mM D-serine is added in the assay buffer. The reaction plate was then incubated in the dark at room temperature. The following settings were used by the Gemini EM fluorescence reader of Molecular Devices, Inc.: excitation filter 530nm and emission filter 590nm at 0 and 20min to detect the fluorescence reading. The percentage of inhibition value for each well was calculated using the following equation:

[0418] Inhibition percentage = (fluorescence sample, 20 min-fluorescence sample, 0 min) / (fluorescence DMSO, 20 min-fluorescence DMSO, 0 min) x 100%

[0419] The IC of each compound was calculated using a nonlinear curve fitting model in GraphPad Prism 5. 50 The results are shown in Table 1 and Figure 1 Shown in.

[0420] Table 1. IC of exemplary compounds of formula (I) 50 value

[0421]

[0422]

[0423]

[0424] As shown in Table 1, the general trend is that the more galloyl moieties there are, the higher the IC 50 The lower the value.

[0425] Example 19. Acute toxicity study of exemplary compound 24

[0426] The objectives of this study were to evaluate adverse effects and determine the maximum tolerated dose (MTD) following a single dose administration by oral gavage (po) followed by a 7-day observation period (using compound 24 presented in Example 6 as an example).

[0427] C57BL / 6J mice were group housed (3-5 mice of the same sex per cage) with food and water available ad libitum in polysulfone ventilated cages in SyneuRx animal rooms (Alternative Design, AR, USA). Colonies were maintained on a 12 / 12-h light / dark cycle at a temperature of 22±2°C, and all experimental treatments and behavioral studies were performed during the dark cycle. All animals used in this study were adult mice (at least 2.5 months old). All animal procedures were performed according to protocols approved by the Institutional Animal Care and Use Committee (IACUC) (IACUC).

[0428] Mice were randomly divided into three groups: Group 1: vehicle control; Group 2: compound 24 (4000mg / kg), and Group 3: compound 24 (4500mg / kg), which were respectively administered orally with 65% PEG400 in ddH2O, compound 24 at 4000mg / kg, and compound 24 at 4500mg / kg. Animals were observed twice a day (morning and afternoon), or frequently observed signs of mortality, morbidity, respiration, secretions, feces, and water and food intake capacity as needed during the study period. Throughout the study, the weight of each mouse was recorded every day as an indicator of its physical development and metabolism. No changes in body weight, food intake, full view, and no mortality or morbidity were observed in all mice in the study. Under the conditions of this study, the maximum tolerated dose (MTD) of compound 24 was determined to be 4500mg / kg.

[0429] Example 20. Therapeutic Effects of Exemplary Compound 24

[0430] C57BL / 6J male mice were group-housed under the same conditions as described in Example 1. The mice were randomly divided into three groups: Group 1: vehicle control; Group 2: MK-801; Group 3: Compound 24 (30 mg / kg) + MK-801. 20 minutes before the prepulse inhibition test, mice in Groups 2-3 received an acute intraperitoneal (ip) injection of 0.3 mg / kg of MK-801 (Sigma-Aldrich, USA), an NMDA receptor antagonist dissolved in saline. 20 minutes before the administration of MK-801, each mouse in Groups 1-2 and 3 received acute oral administration of 65% PEG400 in ddH2O and 30 mg / kg of Compound 24 (dissolved in 65% PEG400 in ddH2O), respectively.

[0431] Prepulse inhibition using the SR-LAB startle device (San Diego Instruments, San Diego, California, the United States) was used to determine the efficacy of compound 24 in alleviating the sensorimotor gating function defects of mice induced by MK-801. Under 65dB background noise, each session consisted of a 5-minute accumulation period, followed by 64 trials in four blocks. The single pulse (PA) test was a 40ms, 120dB white noise burst. In the prepulse (pp) + pulse test, 20ms white noise prepulse stimulations of 71dB (pp6), 75dB (pp10) and 83dB (pp18) were presented 100ms before the 40ms 120dB pulse. The non-stimulation (NS) test only presented background noise. The initial and final blocks were composed of six PA tests, respectively. Two middle blocks consisted of PA, pp + pulse and NS tests. The trials were presented pseudorandomly and separated by an average intertribal interval of 15 s (varied between 10 and 20 s). The percentage of prepulse inhibition was estimated by the following formula: %PPI=100×[(PA score)-(pp-P score)] / (PA score), where PA score is the mean of the PA values ​​in the block.

[0432] Figure 2 The effect of exemplary compound 24 on prepulse inhibition in MK-801 treated mice is shown. Although the MK-801 group showed prepulse inhibition deficits at all prepulse intensities, compound 24 at 30 mg / kg modestly increased the percentage inhibition at 71 and 83 dB prepulse intensities and significantly improved the MK-801-induced prepulse inhibition deficit at 75 dB prepulse intensity.

[0433] Example 21. LogP Values ​​of Exemplary Compounds of Formula I

[0434] Lipophilicity is an important factor in determining whether a drug can cross the blood-brain barrier (BBB) ​​and exert the therapeutic effect of the drug in the brain. The logarithm of the n-octanol / water partition coefficient, also referred to as logP, has been designed to determine lipophilicity. Compounds with a higher positive value of logP generally refer to a higher lipophilicity, which is expected to have a higher permeability to cell membranes.

[0435] Sample compounds tested in the logP experiment included enriched tannic acid (prepared by enrichment method 10 of US10105378), compounds 21, 24, 27, 46 and 56.

[0436] First, n-octanol and water were saturated with each other to achieve distribution equilibrium, and the two phases were separated for further use. The sample compound was dissolved in the water and n-octanol phases, respectively. The two phases were mixed by vertical rotation motion. After the water phase and the n-octanol phase reached equilibrium, the two phases were analyzed to determine the concentration of the sample compound for determination of logP value. All samples were run on a Shimadzu CBM-20A HPLC system. Chromatographic separation was performed on a 5μm, Kinetex C18 The analysis was performed on an LC column (100X 4.6 mm). The mobile phase was 0.1% formic acid in water and acetonitrile / methanol was set as a gradient. The flow rate used was 1.2 mL / min. The column was at room temperature 20±5°C.

[0437] The partition coefficient, abbreviated as P, is calculated based on the concentration in n-octanol divided by the concentration in water. The formula for logP is shown below:

[0438]

[0439] The results are shown in Table 2 below.

[0440] Table 2. LogP values

[0441]

[0442] Example 22. Partitioning and enrichment of compound 24 in mouse brain

[0443] The purpose of this experiment is to compare the concentration of compound 24 and enriched tannic acid in the mouse brain after intraperitoneal (ip) administration. Enriched tannic acid was prepared by enrichment method 10 of US10105378. 14-week-old C57BL / 6J mice were divided into two groups, 3 mice in each group. Once every two days, mice in group I and group II were injected intraperitoneally with 30 mg / kg of compound 24 and 15 mg / kg of enriched tannic acid for three months. At 24 hours after the last intraperitoneal administration, brain samples were collected from each animal and immediately frozen and stored at -70°C until further use.

[0444] After enzymatic hydrolysis to gallic acid, the amount of compound 24 and the enriched tannic acid in mouse brain was analyzed by high performance liquid chromatography-mass spectrometry (HPLC-MS). Each frozen brain sample was homogenized with 4 volumes of deionized water (ddH2O) using a handheld tissue homogenizer (BT Lab Systems). Immediately after homogenization, each sample was fully mixed with 200 μL of tannase (analytical grade, Merck (E.Merck KGaA), Germany) reaction solution (15 mg / mL). The mixture was incubated at 30 ° C for 4 hours to complete the hydrolysis reaction. The hydrolyzate was extracted with 10 volumes of extraction reagent (1.5% (w / w) formic acid in acetonitrile), and the hydrolyzate was centrifuged at 12,000 rpm for 10 min at 2-8 ° C. The supernatant was collected and mixed with 50 μL of internal standard (4-hydroxybenzoic acid, 40 μg / mL), and then evaporated to dryness under N2. The dried extract containing gallic acid was reconstituted in 200 μL 0.1% (v / v) formic acid in ddH2O and filtered through a 0.45 μm membrane filter. The samples were stored at -20°C prior to HPLC-MS analysis.

[0445] Chromatographic analysis was performed using a Phenomenex Kinetex C8 column (150 x 4.6 mm, 5 μm). The mobile phase consisted of (A) 0.1% (v / v) formic acid in ddH2O and (B) acetonitrile / methanol (80 / 20 (v / v)) with the gradient conditions shown in Table 3. The flow rate was 0.3 mL / min. The autosampler temperature was set to 4 ° C, and the injection volume was maintained at 20 μL. The total LC run time was 40 min. Ionization and detection of the analytes were performed in negative ion mode on an electrospray ionization mass spectrometer. Quantification was performed using selected ion monitoring chromatography (SIM) mode to monitor the precursor ions of gallic acid at m / z 169 and 4-hydroxybenzoic acid at m / z 137 as internal standards. The concentrations of compound 24 and enriched tannic acid in mouse brain are shown in Table 4. Compared with the group enriched with tannic acid, the dose level of compound 24 was 2 times higher, and the brain concentration of compound 24 was about 9 times higher than that of enriched tannic acid. This result indicates that compound 24 has better brain distribution or permeability than enriched tannic acid, which is consistent with the results of Examples 20 and 21.

[0446] Table 3: Mobile phases used for LC-MS of brain samples

[0447] Time (min) A(％) B(％) 0.0 98.0 2.0 5.0 98.0 2.0 20.0 66.0 34.0 25.0 0.0 100.0 30.0 0.0 100.0 31.0 98.0 2.0 40.0 98.0 2.0

[0448] Table 4: Concentrations of compound 24 and enriched tannic acid in mouse brain after intraperitoneal injection

[0449]

[0450] In summary, based on the findings of logP values, brain concentrations and therapeutic effects as demonstrated in Examples 20, 21 and 22, compounds of Formula I with higher logP values ​​are expected to cross the BBB to reach higher concentrations in the brain, thereby producing more favorable therapeutic effects than naturally occurring tannic acid.

[0451] Other Implementations

[0452] All features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent or similar purpose. Therefore, unless otherwise expressly stated, each feature disclosed is merely an example of a general series of equivalent or similar features.

[0453] Through the above description, those skilled in the art can easily determine the essential characteristics of the present disclosure, and without departing from its spirit and scope, various modifications and changes can be made to the present disclosure to adapt it to various uses and conditions. Therefore, other embodiments are also within the scope of the claims.

[0454] Equivalent

[0455] Although several inventive embodiments have been described and shown herein, a person of ordinary skill in the art will readily envision a variety of other means and / or structures for performing functions and / or obtaining the results and / or one or more advantages described herein, and each of such variations and / or modifications is considered to be within the scope of the embodiments of the invention described herein. More generally, it will be readily understood by those skilled in the art that all parameters, dimensions, materials, and configurations described herein are intended to be exemplary, and that actual parameters, dimensions, materials, and / or configurations will depend on one or more specific applications for which the teachings of the invention are used. Using only routine experiments, those skilled in the art will recognize or be able to determine many equivalents of the specific embodiments of the invention described herein. Therefore, it should be understood that the foregoing embodiments are presented only by way of example, and within the scope of the appended claims and their equivalents, embodiments of the invention may be practiced in a manner different from that specifically described and claimed. The inventive embodiments of the present disclosure relate to each individual feature, system, article, material, kit, and / or method described herein. In addition, if such features, systems, articles, materials, kits, and / or methods are not inconsistent with each other, any combination of two or more such features, systems, articles, materials, kits, and / or methods is also included within the scope of the invention disclosed herein.

[0456] All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0457] All references, patents, and patent applications disclosed herein are incorporated by reference with respect to the subject matter for which each is cited, which in some cases may be incorporated in its entirety.

[0458] Unless clearly indicated to the contrary, the indefinite articles "a" and "an" as used herein in the specification and claims should be understood to mean "at least one".

[0459] The phrase "and / or" as used herein in the specification and claims should be understood to mean "either or both" of the elements so combined, i.e., elements that are present in combination in some cases and separately in other cases. Multiple elements listed with "and / or" should be interpreted in the same manner, i.e., "one or more" of the elements so combined. In addition to the elements explicitly identified by the "and / or" clause, other elements may optionally be present, whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, when used in conjunction with open language such as "comprising", references to "A and / or B" may, in one embodiment, refer only to A (optionally including elements other than B); in other embodiments, to only B (optionally including elements other than A); in yet other embodiments, to both A and B (optionally including other elements), etc.

[0460] As used herein in the specification and claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating the items in a list, "or" or "and / or" should be interpreted as inclusive, i.e., including at least one of a plurality of elements or a list of elements, but also including more than one, and optionally, additional unlisted items. Only when the opposite terms are clearly specified, such as "only one of ..." or "exactly one of ...", or when used in the claims, "consisting of ..." will refer to including exactly one element in a plurality of elements or a list of elements. In general, the term "or" as used herein is preceded by an exclusive term, such as "one of the two", "one of ...", "only one of ..." or "exactly one of ...", which should only be interpreted as indicating exclusive substitution (i.e. "one or the other but not both"). When used in the claims, "consisting essentially of ..." should have the common meaning as used in the field of patent law.

[0461] As used herein in the specification and claims, the phrase "at least one" with respect to a list of one or more elements should be understood to mean at least one element selected from any one or more elements of the list of elements, but not necessarily including at least one of each and each element explicitly listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows that elements other than the elements specifically identified in the list of elements referenced by the phrase "at least one" may optionally be present, whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B", or equivalently "at least one of A and / or B") may mean, in one embodiment, at least one, optionally including more than one A, wherein B is absent (and optionally including elements other than B); in other embodiments, at least one, optionally including more than one B, wherein A is absent (and optionally including elements other than A); in yet other embodiments, at least one, optionally including more than one A, and at least one, preferably including more than one B (and optionally including other elements), etc.

[0462] It should also be understood that in any method claimed herein that includes more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order of the steps or actions of the method recited therein unless clearly indicated to the contrary.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Ring A is Each of R1, R2, R3, R4, R5, R6, R7 and R8 is independently absent or has the formula: in n is 0 or 1; m is 1, 2, 3, 4 or 5; And the total number of galloyl moieties is an integer from 15 to 35, inclusive.

2. The compound according to claim 1, wherein Each of R1, R2, R3, R4, R5, R6, R7 and R8 independently has the formula: Or does not exist.

3. The compound according to claim 2, wherein The compound of formula (I) has the following formula: and optionally wherein R1, R2, R3, R4 and R5 are each selected from the group consisting of:

4. The compound according to claim 2, wherein The compound of formula (I) has the following formula: and optionally wherein R1, R2, R3, R4 and R5 are each selected from the group consisting of:

5. The compound according to claim 1, wherein The compound is selected from the group consisting of:

6. A composition comprising the compound according to any one of claims 1 to 5 and a carrier.

7. The composition according to claim 6, wherein The composition is a pharmaceutical composition.

8. Use of a compound according to any one of claims 1 to 5 or a composition according to claim 6 or claim 7 in the preparation of a medicament for inhibiting D-amino acid oxidase (DAAO) in a subject.

9. The use according to claim 8, wherein The subject is a human having, suspected of having, or at risk of having a central nervous system (CNS) disorder, metabolic disorder, or pain.

10. The use according to claim 9, wherein 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 disorder, fragile X syndrome, attention deficit hyperactivity disorder, attention deficit disorder, obsessive-compulsive disorder, tic disorder, childhood learning disabilities, premenstrual syndrome, depression, anhedonia, suicidal thoughts and / or behaviors, bipolar disorder, anxiety disorders, panic disorder, post-traumatic stress disorder, chronic mild and unpredictable stress, eating disorders, addiction disorders, personality disorders, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, ataxia, Tourette syndrome, nocturnal enuresis, non-epileptic seizures, blepharospasm, Duchenne muscular dystrophy or stroke.

11. The use according to claim 10, wherein the ataxia is Friedreich's ataxia.

12. The use according to claim 10, wherein the depression is major depressive disorder.

13. The use according to claim 9, wherein The metabolic disorder is selected from the group consisting of obesity, hyperlipidemia, hypercholesterolemia, hyperglycemia, hyperinsulinemia, insulin resistance and diabetes.

14. The use according to claim 9, wherein The pain is selected from the group consisting of psychogenic pain, acute pain, chronic pain, neuropathic pain, nociceptive pain and hyperalgesia.

15. The use according to claim 14, 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, post-herpetic neuralgia and central pain syndrome, and the nociceptive pain is selected from the group consisting of radicular pain, somatic pain and visceral pain.

16. The use according to claim 9, wherein the pain is a chronic pain syndrome.

17. The use according to any one of claims 8 to 16, wherein The compound or a composition comprising the compound is administered to a human subject at a frequency of four times a day to once every three months.

18. The use according to any one of claims 8 to 16, wherein The human subject is treated simultaneously with, before, or after one or more additional agents for treating and / or reducing the risk of a CNS disorder.

19. A method for preparing the compound according to claim 1, comprising: (a) providing a compound of formula (Ia) wherein at least one of R1′, R2′, R3′, R4′, R5′, R6′, R7′ and R8′ is —OH, and the others are each independently —OH or absent; and wherein Ring A is (b) reacting the compound of formula (Ia) with 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride to conjugate 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride with one or more of R1′, R2′, R3′, R4′, R5′, R6′, R7′ and R8′ of the compound of formula (Ia) to produce a first intermediate; and (c) deprotecting the allyl group in 7-(allyloxy)-2,2-diphenylbenzo[d][1,3]dioxole-5-carbonyl chloride conjugated to the compound of formula (Ia), repeating the process consisting of step (b) and deprotecting the allyl group 3-7 times to deprotect the cyclic acetal group to obtain the compound according to claim 1.

20. The method according to claim 19, wherein: The compound of formula (Ia) is glucose.

21. The method according to claim 20, wherein the glucose is in the alpha form or in the beta form.

22. The method of claim 19, further comprising purifying the compound of claim 1 produced after step (c).

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