Compositions and methods for antioxidant and anti-inflammatory treatment - Patents.com

Abstract

The present invention relates to compositions and methods for antioxidant and anti-inflammatory treatment.

Description

[Technical Field]

[0001] Federal Grant Statement This invention was made with government support under Grant No. 1R43AG063560-01 and Grant No. R44AG056181 awarded by the National Institute on Aging. The U.S. Government has certain rights in this invention. [Background technology]

[0002] DYRK1A is a member of the DYRK family, which influences tau phosphorylation and the formation of tau neurofibrillary tangles. In addition, DYRK1A alters APP phosphorylation and induces amyloid beta (Aβ) production, and DYRK1A expression in the hippocampus is increased in neurodegenerative diseases. Furthermore, DYRK1A is strongly associated with neuroinflammation. These findings support DYRK1A as a potential target for the prevention or treatment of various diseases. Summary of the Invention

[0003] In one aspect, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, halogen, -NO2, -CN, C1-C 10 Alkyl, C1-C 10 Haloalkyl, -NH2, -NH(C1-C 10 alkyl), -N(C1-C 10 alkyl)2, -OH, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy, -SH, hydroxy(C1-C 10 alkyl), alkoxy (C1-C 10 alkyl), amino (C1-C 10alkyl), -CONH2, -CONH(C1-C 10 alkyl), -CON(C1-C 10 alkyl)2, -OC(O)NH2, -OC(O)NH(C1-C 10 alkyl), -OC(O)N(C1-C 10 alkyl), -CO2H, -CO2(C1-C 10 alkyl), -CHO, -CO(C1-C 10 alkyl), -OC(O)(C1-C 10 alkyl), -S(O) 0-2 (C1-C 10 alkyl), or -NH(S(O) 0-2 (C1-C 10 alkyl); R 5 and R 9 are each independently hydrogen, halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or —SH; R 7 are hydrogen, halogens, -NO2, -CN, C1-C 10 Alkyl, C1-C 10 Haloalkyl, -NH2, -NH(C1-C 10 alkyl), -N(C1-C 10 alkyl)2, -OH, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy, -SH, hydroxy(C1-C 10 alkyl), alkoxy (C1-C 10 alkyl), amino (C1-C 10 alkyl), -CONH2, -CONH(C1-C 10 alkyl), -CON(C1-C 10 alkyl), -CO2H, -CO2(C1-C 10 alkyl), -CHO, -CO(C1-C 10 alkyl), -S(O) 0-2 (C1-C 10 alkyl), or -NH(S(O) 0-2 (C1-C10 alkyl); R 6 and R 8 are each independently hydrogen, halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or —SH; X is O or C; Y is O or NH; and Z is [ka] wherein: R 10 and R 14 are each independently hydrogen, halogen, —NO2, —CN, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or —SH; R 12 are hydrogen, halogens, -NO2, -CN, C1-C 10 Alkyl, C1-C 10 Haloalkyl, -NH2, -NH(C1-C 10 alkyl), -N(C1-C 10 alkyl)2, -OH, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy, -SH, hydroxy(C1-C 10 alkyl), alkoxy (C1-C 10 alkyl), amino (C1-C 10 alkyl), -CONH2, -CONH(C1-C 10 alkyl), -CON(C1-C 10 alkyl), -CO2H, -CO2(C1-C 10 alkyl), -CHO, -CO(C1-C 10 alkyl), -S(O) 0-2 (C1-C 10 alkyl), or -NH(S(O) 0-2 (C1-C 10alkyl); R 11 and R 13 are each independently hydrogen, halogen, —NO, —CN, C-C alkyl, C-C haloalkyl, —NH, —NH(C-C alkyl), —N(C-C alkyl), —OH, C-C alkoxy, C-C haloalkoxy, or —SH; or Z is [ka] wherein: n is 0 to 4, and Each R 15 are independently C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; or Z is [ka] wherein: R 16 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, C1-C6 alkoxy, or C1-C6 haloalkoxy; or Z is [ka] wherein: R 17 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0004] In one embodiment, the compound of formula I is (2R,3R)-2-(3,5-dihydroxy-4-methoxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,5-dihydroxy-4-methoxybenzoate, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5-trihydroxybenzoate, (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5-trihydroxybenzoate, (2R,3S)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl Not 3,4,5-trihydroxybenzoate, (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate, (2S,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4-dihydroxy-5-methoxybenzoate; (2R,3S)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4-difluorobenzoate; or (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,3,4-trihydroxybenzoate.

[0005] In another aspect, the present disclosure provides pharmaceutical compositions comprising one or more compounds of the present disclosure described herein and a pharmaceutically acceptable carrier, excipient, adjuvant, and / or diluent.

[0006] In another aspect, the present disclosure provides a composition comprising one or more compounds of the present disclosure described herein present in a total amount of 1 to 40% by weight; and a penetration enhancer, present in an amount of 0.1 to 20% by weight; a chelating agent / antioxidant, present in an amount of 0.1 to 20% by weight; a water retention agent, present in an amount of 1 to 30% by weight; and a preservative present in an amount of 0.03 to 2% by weight; An intranasal pharmaceutical composition is provided, which has a pH of 4.0 to 6.5.

[0007] In another aspect, the present disclosure provides methods for treating or inhibiting oxidative stress and / or inflammation, including but not limited to, oxidative stress and / or inflammation associated with neurological disorders or viral infections, comprising administering to a subject in need thereof one or more compounds of the present disclosure described herein or a pharmaceutical composition of the present disclosure described herein.

[0008] In another aspect, the present disclosure provides a method for inhibiting DYRK1A, the method comprising administering to a subject in need thereof one or more compounds of the present disclosure described herein or a pharmaceutical composition of the present disclosure described herein.

[0009] Additional aspects of the present disclosure will become apparent from the disclosure herein. The accompanying drawings are included to provide a further understanding of the compositions and methods of the present disclosure, and are incorporated in and constitute a part of this specification. The drawings illustrate one or more embodiments of the present disclosure and, together with the description, serve to explain the principles and operation of the present disclosure. [Brief explanation of the drawings]

[0010] [Figure 1] 1 is a graph showing the efficacy of compound 40 described herein in the MOG35-55 induced mouse model of chronic progressive experimental autoimmune encephalomyelitis (EAE). [Figure 2] 1 is a graph comparing the effects of compound 40 described herein on tissue markers in a chronic progressive experimental autoimmune encephalomyelitis (EAE) treatment model. [Figure 3]1 is a graph showing the effect of compound 68 described herein on hippocampal levels of TNFα in a lipopolysaccharide-induced TNFα inflammation model. (*P<0.05; **P<0.01; ***P<0.001 vs. G2 vehicle) [Figure 4] 1 is a graph showing the effect of compound 68 described herein on plasma levels of TNFα in a lipopolysaccharide-induced TNFα inflammation model. (*P<0.05; **P<0.01; ***P<0.001 vs. G2 vehicle) [Figure 5] 1 is a graph showing the effect of compound 68 described herein on p-tau levels in hippocampal tissue in a lipopolysaccharide-induced TNFα inflammation model. DETAILED DESCRIPTION OF THE INVENTION

[0011] Before describing the disclosed methods and materials, it is to be understood that the aspects described herein are not limited to particular embodiments. As such, they may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting, unless otherwise specified.

[0012] As disclosed herein, compounds of Formula I effectively treat or suppress oxidative stress and / or inflammation in vivo (e.g., at significantly lower doses with increased overall safety and greatly reduced toxicity). Furthermore, the inventors have demonstrated that the highly bioavailable compounds described herein may be advantageously useful for indications other than the central nervous system. Thus, compounds of the present disclosure are particularly useful for treating or suppressing diseases associated with oxidative stress and / or inflammation, including, but not limited to, neurological disorders and viral infections.

[0013] therapeutic application Accordingly, one aspect of the present disclosure provides a method for treating or suppressing oxidative stress and / or inflammation, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula I or pharmaceutically acceptable salts thereof (i.e., as described elsewhere herein); or a pharmaceutical composition comprising one or more compounds of formula I or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient, adjuvant, and / or diluent (i.e., as described elsewhere herein); or an intranasal pharmaceutical composition comprising one or more compounds of formula I (i.e., as described elsewhere herein).

[0014] One aspect of the present disclosure provides a method of treating or inhibiting a central nervous system disorder, tumor, diabetes, obesity, or systemic disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula I or pharmaceutically acceptable salts thereof (i.e., as described elsewhere herein); or a pharmaceutical composition comprising one or more compounds of formula I or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient, adjuvant, and / or diluent (i.e., as described elsewhere herein); or an intranasal pharmaceutical composition comprising one or more compounds of formula I (i.e., as described elsewhere herein).

[0015] One aspect of the present disclosure provides a method of treating or suppressing a neurological disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula I or pharmaceutically acceptable salts thereof (i.e., as described elsewhere herein); or a pharmaceutical composition comprising one or more compounds of formula I or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient, adjuvant, and / or diluent (i.e., as described elsewhere herein); or an intranasal pharmaceutical composition comprising one or more compounds of formula I (i.e., as described elsewhere herein). In certain embodiments, the neurological disorder is selected from multiple sclerosis, central pontine myelinolysis, acute disseminated encephalomyelitis, progressive multifocal leukoencephalopathy, subacute sclerosing panencephalitis, post-infectious encephalomyelitis, chronic inflammatory demyelinating polyneuropathy, Devic's disease, Baro concentric sclerosis, leukodystrophy, optic neuritis, transverse myelitis, cerebral palsy, spinal cord injury, age-associated myelin loss, Down's syndrome, Alzheimer's disease, Parkinson's disorders, Charlevoix-Saguet spastic ataxia (ARSACS), and acquired and inherited neurological disorders of the peripheral nervous system, as described elsewhere herein.

[0016] One aspect of the present disclosure provides a method for treating or suppressing uveitis, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula I or pharmaceutically acceptable salts thereof (i.e., as described elsewhere herein); or a pharmaceutical composition comprising one or more compounds of Formula I or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier, excipient, adjuvant, and / or diluent (i.e., as described elsewhere herein); or an intranasal pharmaceutical composition comprising one or more compounds of Formula I (i.e., as described elsewhere herein). Uveitis refers to a variety of intraocular inflammatory diseases occurring in the uvea (i.e., the iris, ciliary body, and choroid) and its adjacent structures (including the cornea, vitreous body, retina, and optic nerve). If chronic ocular inflammation is not diagnosed and treated in a timely manner, it can lead to cataracts, glaucoma, corneal lesions, macular edema, or even permanent vision loss. Based on inflammatory involvement of the anatomical skeleton, the International Uveitis Study Group (IUSG) has classified uveitis as anterior uveitis, intermediate uveitis, posterior uveitis, or panuveitis. Despite efforts to find a treatment for uveitis, no new drug has been able to demonstrate complete monotherapy due to its specific side effects. Research is still needed to improve the efficacy and safety of treatments for uveitis. Due to its etiology, the use of anti-inflammatory agents has been seen as a viable path to curing uveitis. Anti-inflammatory agents targeting novel pathways would provide another much-needed treatment option for patients with uveitis.

[0017] DYRK1A is an enzyme that has been implicated as an important drug target in various therapeutic areas, including neurological disorders (e.g., Down syndrome, Alzheimer's disease), oncology, and type 2 diabetes (e.g., pancreatic beta cell proliferation). Extensive and growing evidence suggests a role for DYRK1A in inflammation. Recently, it has been shown that DYRK1A phosphorylates cyclin D1, leading to a decrease in p21 in cells, ultimately reducing the expression of nuclear transcription factor erythroid 2-related factor 2 (Nrf2), a transcription factor that induces the expression of genes involved in antioxidant pathways and reduces ROS levels. DYRK1A inhibitors can contribute to neuronal survival by enhancing the neuroprotective p21-Nrf2 pathway and suppressing pro-inflammatory cytokine production caused by neuroinflammation. DYRK1A inhibitors can also reduce inflammation by targeting other essential proteins, such as GFAP and STATs. Without intending to be bound by theory, it is currently hypothesized that reducing DYRK1A activity may reduce ocular inflammation and cure uveitis. Advantageously, the compounds disclosed herein have enhanced efficacy compared to conventional therapies due to their multiple mechanisms of action combined with a superior safety profile.

[0018] One aspect of the present disclosure provides a method for treating or suppressing non-alcoholic fatty liver disease (NAFLD) (for example, treating or suppressing non-alcoholic steatohepatitis), the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula I or pharmaceutically acceptable salts thereof (i.e., as described elsewhere herein); or a pharmaceutical composition comprising one or more compounds of formula I or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient, adjuvant, and / or diluent (i.e., as described elsewhere herein); or an intranasal pharmaceutical composition comprising one or more compounds of formula I (i.e., as described elsewhere herein).Non-alcoholic fatty liver disease (NAFLD) is the most widespread liver disease worldwide, and there is no approved drug therapy for it. The antioxidant vitamin E and the type II antidiabetic drug pioglitazone have shown benefit in nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD, but formulation issues limit their usefulness. GLP-1RA and SGLT2 inhibitors, approved for use in type II diabetes (T2D), have similarly shown some efficacy in NASH. Without intending to be bound by theory, it is currently believed that the compounds described herein may function as potent and selective negative allosteric modulators of dual-specificity tyrosine-(Y)-phosphorylation-regulated kinases (DYRKs).

[0019] DYRK1A has been implicated as an important drug target in various therapeutic areas, including neurological disorders (e.g., Down syndrome, Alzheimer's disease), oncology, and T2D (e.g., pancreatic beta cell proliferation). Extensive and growing evidence suggests a role for DYRK1A and its related family member, DYRK1B, in NAFLD pathogenesis. In particular, DYRK1A phosphorylates nuclear factor of activated T cells (NFAT), and thus DYRK1A inhibitors can induce beta cell proliferation and lower blood glucose levels. Furthermore, DYRK1A phosphorylates cyclin D1, reduces p21, and ultimately reduces the expression of the nuclear transcription factor erythroid 2-related factor 2 (Nrf2), a transcription factor that induces the expression of genes involved in antioxidant pathways and consequently reduces ROS levels. DYRK1A inhibitors contribute to neuronal survival by enhancing the neuroprotective p21-Nrf2 pathway and suppressing pro-inflammatory cytokine production caused by neuroinflammation. DYRK1A inhibitors also reduce inflammation by targeting other essential proteins, such as GFAP and STATs. Diabetes, oxidative stress, and inflammation are all pathological hallmarks of NAFLD. Recently, DYRK1B has also emerged as an important target for liver disease. DYRK1B is highly expressed in NASH, activates mTORC2, and causes hypertriglyceridemia, hepatic steatosis, and hepatic insulin resistance (IR). Furthermore, DYRK1B is a potential therapeutic target for liver fibrosis by suppressing collagen production in hepatic stellate cells (HSCs). Avanti Biosciences claims that reducing DYRK1A / B activity may intervene in NAFLD pathogenesis and slow or halt disease progression. The predicted advantages of DYRK1A / B inhibitors over current therapies are based on their multiple mechanisms of action combined with a favorable safety profile.

[0020] One aspect of the present disclosure provides a method for inhibiting or treating a viral infection, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of Formula I or pharmaceutically acceptable salts thereof (i.e., as described elsewhere herein); or a pharmaceutical composition comprising one or more compounds of Formula I or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier, excipient, adjuvant, and / or diluent (i.e., as described elsewhere herein); or an intranasal pharmaceutical composition comprising one or more compounds of Formula I (i.e., as described elsewhere herein). In certain embodiments described elsewhere herein, the viral infection is a coronavirus infection. In another embodiment, the viral infection is a β-coronavirus infection. In one such embodiment, the β-coronavirus is selected from the group consisting of human coronavirus HKU1, SARS-CoV (including, but not limited to, SARS-CoV-2), and MERS-CoV. In another embodiment, the viral infection is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In certain embodiments described elsewhere herein, the subject has or is "at risk" for a viral infection. In certain embodiments, a subject "at risk" is immunocompromised (e.g., nutritional deficiencies, drug addiction, alcoholism, and certain disease states such as diabetes and AIDS) or at increased risk of exposure to a virus (e.g., health care workers, emergency first responders, patients otherwise exposed to a virus, etc.).

[0021] In certain embodiments, the methods described herein can treat or suppress inflammation due to oxidative stress and / or specific receptor antagonism. For example, in certain embodiments, the methods described herein can inhibit COX (e.g., COX-2). The inventors note that COX-2 has broad anti-inflammatory activity in the brain. In another example, in certain embodiments, the methods described herein can inhibit DYRK1A. The inventors note that inhibition of DYRK1A can lead to increased expression of the nuclear transcription factor erythroid 2-related factor 2 (Nrf2), which regulates virus-induced oxidative stress, ROS generation, and pathogenesis, which are essential in the viral life cycle. Furthermore, Nrf2 can reduce the expression of the angiotensin-converting enzyme 2 (ACE2) receptor, which can function as a receptor for the coronavirus surface spike glycoprotein.

[0022] Accordingly, one aspect of the present disclosure provides a method of inhibiting COX-2, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula I or pharmaceutically acceptable salts thereof (i.e., as described elsewhere herein); or a pharmaceutical composition comprising one or more compounds of formula I or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient, adjuvant, and / or diluent (i.e., as described elsewhere herein); or an intranasal pharmaceutical composition comprising one or more compounds of formula I (i.e., as described elsewhere herein).

[0023] Another aspect of the present disclosure provides a method for inhibiting DYRK1A, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula I or pharmaceutically acceptable salts thereof (i.e., as described elsewhere herein); or a pharmaceutical composition comprising one or more compounds of formula I or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient, adjuvant, and / or diluent (i.e., as described elsewhere herein); or an intranasal pharmaceutical composition comprising one or more compounds of formula I (i.e., as described elsewhere herein).

[0024] Advantageously, the inventors note that the methods described herein can inhibit overexpressed DYRK1A in subjects with Down syndrome. The methods can improve synaptic plasticity and / or delay the onset of Alzheimer's disease symptoms, including tau hyperphosphorylation. Thus, in certain embodiments, the methods described herein can treat or suppress Down syndrome and / or Alzheimer's disease. In certain desirable embodiments, the methods described herein can treat or suppress Alzheimer's disease (e.g., Down syndrome-associated Alzheimer's disease) in subjects with Down syndrome.

[0025] In certain embodiments described elsewhere herein, administration includes oral administration or intranasal administration (e.g., of a pharmaceutical composition described elsewhere herein). For example, in certain embodiments described elsewhere herein, administration is of an intranasal pharmaceutical composition (i.e., as described elsewhere herein) comprising one or more compounds of Formula I.

[0026] In certain embodiments described elsewhere herein, the compound of formula I is a compound in Table 1 below. In certain embodiments described elsewhere herein, the compound of formula I is selected from compounds 9-23, 25-37, and 39-81 in Table 1 below.In certain embodiments described elsewhere herein, the compound of formula I is (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,3,4-trihydroxybenzoate; (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate; (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-4,5-dihydroxybenzoate; (2S,3R)-2-(2-fluoro-3,4,5-trihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-Trihydroxybenzoate;(2S,3R)-2-(2-Fluoro-3,4,5-trihydroxyphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate;(2S,3R)-2-(2-Fluoro-4,5-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate;(2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-4,5-dihydroxy-3-methoxybenzoate;(2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,6-difluoro-3,4,5-trihydroxybenzoate; (2S,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate; (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,6-difluoro-3,4-dihydroxy-5-methoxybenzoate; (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4-dihydroxy-5-methoxybenzoate; or (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate.In certain desirable embodiments described elsewhere herein, the compound of formula I is (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4-dihydroxy-5-methoxybenzoate. In certain desirable embodiments described elsewhere herein, the compound of formula I is (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate.

[0027] compound As noted above, one aspect of the disclosure provides compounds of Formula I: In certain embodiments described elsewhere herein, the compound of formula I is (2R,3R)-2-(3,5-dihydroxy-4-methoxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,5-dihydroxy-4-methoxybenzoate, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5-trihydroxybenzoate, (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5-trihydroxybenzoate, (2R,3S)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl Not 3,4,5-trihydroxybenzoate, (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate, (2S,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4-dihydroxy-5-methoxybenzoate; (2R,3S)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4-difluorobenzoate; or (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,3,4-trihydroxybenzoate.

[0028] In certain embodiments described elsewhere herein, the compound has formula IA or formula IB: [ka] is.

[0029] In certain embodiments described elsewhere herein, X is O. In certain embodiments described elsewhere herein, Y is O. For example, in certain desirable embodiments described elsewhere herein, X and Y are each O.

[0030] In certain embodiments described elsewhere herein, R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, -OH, C1-C 10 Alkoxy, -OC(O)(C1-C 10 alkyl), or -OC(O)NH(C1-C 10 For example, in certain embodiments described elsewhere herein, R 1 and R 3 are each independently hydrogen, -OH, C1-C 10 Alkoxy, -OC(O)(C1-C 10 alkyl) (e.g., —OC(O)(C1-C6 alkyl)), or —OC(O)NH(C1-C 10 alkyl) (e.g., —OC(O)NH(C1-C6 alkyl)); and R 2 and R 4 are each hydrogen. In certain such embodiments, R 1 is -OH and R 3 is -OC(O)(C1-C 10 alkyl) (e.g., —OC(O)(C1-C6 alkyl)), or —OC(O)NH(C1-C 10 alkyl) (e.g., —OC(O)NH(C1-C6 alkyl)); and R 2 and R 4 are each hydrogen. In certain desirable embodiments described elsewhere herein, R 1 and R 3 are each independently —OH; R 2 and R 4 are each hydrogen. In certain such embodiments, the compound is of formula IA or formula IB.

[0031] In certain embodiments described elsewhere herein, R 5 and R 9 are each independently hydrogen, —F, or —OH. For example, in certain embodiments described elsewhere herein, R 5 and R 9 are each independently hydrogen or -F; and R 5 and R 9 At least one of R is hydrogen. In certain such embodiments, R 5 is -F and R 9 is hydrogen. In certain such embodiments, R 5 and R 9 are hydrogen atoms.

[0032] In certain embodiments described elsewhere herein, R 7 -OH, C1-C 10 Alkoxy, -CONH2, -CONH(C1-C 10 alkyl), -CO(C1-C 10 alkyl), or -NH(S(O) 0-2 (C1-C 10 For example, in certain embodiments described elsewhere herein, R 7 -OH, C1-C 10 Alkoxy (e.g., C1-C4 alkoxy), or -CONH(C1-C 10 alkyl) (e.g., —CONH(C1-C4 alkyl)). In certain such embodiments, R 7 is C1-C4 alkoxy (e.g., methoxy) or -CONH(C1-C4 alkyl). In certain desirable embodiments described elsewhere herein, R 7 is -OH.

[0033] In certain embodiments described elsewhere herein, R 6 and R 8 are each independently hydrogen, —OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. For example, in certain embodiments described elsewhere herein, R 6 and R 8are each independently hydrogen or —OH; and R 6 and R 8 At least one of R is —OH. In certain desirable embodiments described elsewhere herein, 6 is hydrogen, and R 8 is —OH. In certain desirable embodiments described elsewhere herein, R 6 and R 8 are each —OH. In certain such embodiments, R 7 is -OH.

[0034] For example, in certain embodiments described elsewhere herein, R 5 and R 9 are each independently hydrogen or -F; R 7 is -OH; R 6 and R 8 are each independently hydrogen or —OH; R 5 and R 9 at least one of is hydrogen; and R 6 and R 8 At least one of R is —OH. In certain such embodiments, R 5 is -F and R 9 is hydrogen. In certain such embodiments, R 5 and R 9 are each hydrogen. In certain such embodiments, R 6 is hydrogen and R 8 is —OH. In certain such embodiments, R 6 and R 8 are each —OH. In certain such embodiments, R 1 and R 3 are each independently —OH; R 2 and R 4 are each hydrogen. In certain such embodiments, the compound is of formula IA.

[0035] In certain embodiments described elsewhere herein, Z is [ka] and R 10 and R 14 are each independently hydrogen, -F, or -OH; R 12 -OH, C1-C 10 Alkoxy, -CONH2, -CONH(C1-C 10 alkyl), -CO(C1-C 10 alkyl), or -NH(S(O) 0-2 (C1-C 10 alkyl); R 11 and R 13 are each independently hydrogen, —OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. In certain embodiments described elsewhere herein, R 10 and R 14 At least one of R is -F. In certain embodiments described elsewhere herein, 12 is —OH. In certain embodiments described elsewhere herein, R 11 and R 13 At least one of R is —OH, C-C alkoxy, or C-C haloalkoxy. In certain embodiments described elsewhere herein, R 10 , R 11 , and R 12 and each is —OH. In certain embodiments described elsewhere herein, R 13 , R 14 are each hydrogen. In certain embodiments described elsewhere herein, R 13 and R 14 are -OH, respectively.

[0036] For example, in certain embodiments described elsewhere herein, the compound has Formula II: [ka] is.

[0037] In certain desirable embodiments, as described elsewhere herein, the compound has formula II-A or II-B: [ka] is.

[0038] In certain embodiments described elsewhere herein, R 1 and R 3 are -OH; R 2 and R 4 are each hydrogen. Thus, in certain embodiments described elsewhere herein, the compound has Formula III, Formula III-A, or Formula III-B: [ka] is.

[0039] Surprisingly, the inventors have discovered that in certain such embodiments (e.g., compounds of formula II, II-A, II-B, III, III-A, and III-B), the substituent R 5 ~R 9 and R 10 ~R 14 The inventors concluded that the presence of R identified below may be interchangeable with respect to the inhibitory properties of compounds against DYRK1A. 10 ~R 14 In certain embodiments, a particular desirable arrangement of R 5 ~R 10 It is noted that the corresponding arrangement of

[0040] Thus, in certain embodiments described elsewhere herein, R 5 , R 9 , R 10 , and R 14 At least one (e.g., one or two) of R is not hydrogen. In certain embodiments described elsewhere herein, R 5 , R 9 , R 10 , and R 14 are each independently hydrogen, halogen, or —OH.

[0041] Advantageously, we have found that R5 , R 9 , R 10 , and R 14 The present inventors have concluded that compounds of Formula II (e.g., Formula II-A, Formula III, Formula III-A) substituted with fluorine atoms at one or more positions of R may have greatly improved inhibitory properties (e.g., a 2- to 3-fold improvement in activity against DYRK1A compared to the corresponding compound lacking fluorine substitution). Accordingly, in certain embodiments described elsewhere herein, R 5 , R 9 , R 10 , and R 14 At least one (e.g., one or two) of R is -F. In certain desirable embodiments described elsewhere herein, R 5 , R 9 , R 10 , and R 14 are each independently hydrogen or -F; and R 5 , R 9 , R 10 , and R 14 One or two of the groups are -F.

[0042] In certain embodiments described elsewhere herein, R 7 and R 12 are each independently -OH, C1-C 10 Alkoxy, -CONH2, -CONH(C1-C 10 alkyl), -CO(C1-C 10 alkyl), or -NH(S(O) 0-2 (C1-C 10 For example, in certain embodiments described elsewhere herein, R 7 is -OH or C1-C 10 alkoxy (e.g., C1-C4 alkoxy). In certain such embodiments, R 7 is —OH. In other such embodiments, R 7 is C1-C4 alkoxy (e.g., methoxy). In certain desirable embodiments described elsewhere herein, R 7 and R 12 are each independently -OH or C1-C10 Alkoxy (e.g., C1-C4 alkoxy).

[0043] In certain embodiments described elsewhere herein, R 6 , R 8 , R 11 , and R 13 are each independently hydrogen, —OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. For example, in certain embodiments described elsewhere herein, R 6 , R 8 , R 11 , and R 13 At least one (e.g., one or two) of R is C-C alkoxy (e.g., C-C alkoxy) or C-C haloalkoxy (e.g., C-C haloalkoxy). In certain such embodiments, R 6 , R 8 , R 11 , and R 13 One or two of are C1-C4 alkoxy (eg, methoxy).

[0044] In certain embodiments described elsewhere herein, R 7 , R 8 , R 11 , and R 12 are -OH, and R 13 is —OH, C1-C6 alkoxy (e.g., C1-C4 alkoxy), or C1-C6 haloalkoxy (e.g., C1-C4 haloalkoxy). In certain such embodiments, R 13 is —OH. In other such embodiments, R 13 is C1-C4 alkoxy (e.g., methoxy).

[0045] Advantageously, we have found that R 5 ~R 9 and R 10 ~R 14The inventors have concluded that the inhibitory potency of the compounds described herein (e.g., compounds of Formula II, II-A, III, or III-A) for inhibiting DYRK1A is surprisingly high when at least one of R contains a fluorine substituent para to the oxy substituent, e.g., —OH, alkoxy, or haloalkoxy. Thus, in certain desirable embodiments described elsewhere herein, R 5 , R 9 , R 10 , and R 14 is -F located para to a substituent selected from -OH, C1-C6 alkoxy, or C1-C6 haloalkoxy. 5 , R 9 , R 10 , and R 14 is —F in the para position to a substituent selected from —OH, or C1-C6 alkoxy (e.g., C1-C4 alkoxy). For example, in certain embodiments described elsewhere herein, R 13 is —OH, C1-C6 alkoxy (e.g., C1-C4 alkoxy), or C1-C6 haloalkoxy (e.g., C1-C4 haloalkoxy), and R 10 is -F. In certain such embodiments, R 13 is —OH. In other such embodiments, R 13 is C1-C4 alkoxy (e.g., methoxy).

[0046] In certain embodiments described elsewhere herein, R 1 , R 3 , R 7 , R 8 , R 11 , and R 12 are -OH; R 2 , R 4 , and R 9 are hydrogen; R 6 and R 13are each —OH, C1-C6 alkoxy (e.g., C1-C4 alkoxy), or C1-C6 haloalkoxy (e.g., C1-C4 haloalkoxy), and R 5 , R 10 , and R 14 At least one of R is -F. In certain such embodiments, R 6 and R 13 are each —OH or C1-C4 alkoxy (e.g., methoxy). In certain such embodiments, R 6 is -OH and R 13 is C1-C4 alkoxy (e.g., methoxy). In certain embodiments described elsewhere herein, R 5 and R 14 are hydrogen, and R 10 is -F. In certain such embodiments, the compound is of Formula III-A or Formula III-B.

[0047] In certain embodiments described elsewhere herein, R 1 , R 3 , R 7 , and R 12 are -OH; R 2 , R 4 , and R 9 are hydrogen; R 5 , R 13 , and R 14 are each independently hydrogen or -F; R 6 and R 8 are each independently hydrogen or —OH; and R 10 and R 11 are each independently hydrogen, OH, C1-C6 alkoxy (e.g., C1-C4 alkoxy), or C1-C6 haloalkoxy (e.g., C1-C4 haloalkoxy). In certain such embodiments, R 5 is hydrogen, and R 14 is -F. In certain such embodiments, R 5 and R 14 are each hydrogen. In certain such embodiments, R 6is hydrogen and R 8 is —OH. In other such embodiments, R 6 and R 8 are each —OH. In certain such embodiments, R 13 is hydrogen and R 10 and R 11 are each independently -OH or C1-C4 alkoxy (e.g., methoxy). In certain such embodiments, the compound is of Formula III-A or Formula III-B.

[0048] In certain embodiments described elsewhere herein, R 1 , R 3 , R 6 , R 7 , R 8 , R 10 , R 11 , and R 12 are each —OH; and R 2 , R 4 , R 5 , R 9 , R 13 , and R 14 is independently hydrogen or -F. In certain such embodiments, R 2 , R 4 , R 5 , R 9 , R 13 and R 14 are hydrogen atoms.

[0049] In certain embodiments described elsewhere herein, Z is [ka] n is 0 to 2; each R 15 is independently -NH, -OH, or C-C alkoxy. For example, in certain embodiments described elsewhere herein, Z is [ka] is. In another example, in certain embodiments described elsewhere herein, Z is [ka] and each R 15 is independently -NH or -OH. In another example, in certain embodiments described elsewhere herein, Z is [ka] and each R 15 is independently —NH or —OH. In certain such embodiments, R 1 and R 3 are each —OH; and R 2 and R 4 are each hydrogen. In certain such embodiments, R 5 and R 9 are each independently hydrogen or -F; R 7 is -OH; R 6 and R 8 are each independently hydrogen or —OH; R 5 and R 9 at least one of is hydrogen; and R 6 and R 8 At least one of is -OH. In certain such embodiments, the compound is of formula IA.

[0050] In certain embodiments described elsewhere herein, Z is [ka] and;R 16 is hydrogen or —OH. In certain such embodiments, R 1 and R 3 are each —OH; and R 2 and R 4 are each hydrogen. In certain such embodiments, R 5 and R 9 are each independently hydrogen or -F; R 7 is -OH; R 6 and R 8are each independently hydrogen or —OH; R 5 and R 9 at least one of is hydrogen; and R 6 and R 8 At least one of is -OH. In certain such embodiments, the compound is of formula IA.

[0051] In certain embodiments described elsewhere herein, Z is [ka] or [ka] is. In certain such embodiments, R 1 and R 3 are each —OH; and R 2 and R 4 are each hydrogen. In certain such embodiments, R 5 and R 9 are each independently hydrogen or -F; R 7 is -OH; R 6 and R 8 are each independently hydrogen or —OH; R 5 and R 9 at least one of is hydrogen; and R 6 and R 8 At least one of is -OH. In certain such embodiments, the compound is of formula IA.

[0052] Specific compounds of Formula I are provided in Table 1. [Table 1] TIFF2024525746000019.tif182159TIFF2024525746000020.tif186159TIFF20245257460000 21.tif188159TIFF2024525746000022.tif190159TIFF2024525746000023.tif164159TIFF202 4525746000024.tif195159TIFF2024525746000025.tif199159TIFF2024525746000026.tif2 05159TIFF2024525746000027.tif200159TIFF2024525746000028.tif173159TIFF2024525746 000029.tif183159TIFF2024525746000030.tif183159TIFF2024525746000031.tif187159TI FF2024525746000032.tif184159TIFF2024525746000033.tif199159TIFF2024525746000034. tif188159TIFF2024525746000035.tif192159TIFF2024525746000036.tif161159TIFF202452 5746000037.tif165159TIFF2024525746000038.tif159159TIFF2024525746000039.tif55159

[0053] In certain embodiments described elsewhere herein, the compound of formula I is selected from compounds 9-23, 25-37, and 39-81 of Table 1.

[0054] In certain embodiments described elsewhere herein, the compound of Formula I is compound 40, 41, 46, 47, 48, 50, 51, 55, 59, 68, or 81. For example, in certain embodiments described elsewhere herein, the compound of Formula I is compound 68. In another example, in certain embodiments described elsewhere herein, the compound of Formula I is compound 81.

[0055] Pharmaceutical Composition In another aspect, the present disclosure provides pharmaceutical compositions comprising one or more compounds described herein and a pharmaceutically acceptable carrier, excipient, adjuvant, and / or diluent. The precise nature of the carrier, excipient, adjuvant, and / or diluent will depend on the intended use of the composition.

[0056] In certain embodiments, a pharmaceutical composition comprises one or more compounds of Formula I or a pharmaceutically acceptable salt thereof (i.e., as described elsewhere herein), and a pharmaceutically acceptable carrier, excipient, adjuvant, and / or diluent. For example, in certain such embodiments, a pharmaceutical composition comprises one or more compounds of Formula II (e.g., Formula II-A or Formula II-B) or Formula III (e.g., Formula III-A or Formula III-B), or a pharmaceutically acceptable salt thereof (i.e., as described elsewhere herein), and a pharmaceutically acceptable carrier, excipient, adjuvant, and / or diluent.

[0057] Pharmaceutical compositions containing the compounds can be prepared by conventional mixing, dissolving, granulating, sugar-coating, pulverizing, emulsifying, encapsulating, encapsulating or lyophilizing methods. The compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries that facilitate the processing of the compounds into pharmaceutically usable preparations.

[0058] The compounds may be formulated in pharmaceutical compositions per se or in the form of a hydrate, solvate, or N-oxide or pharmaceutically acceptable salt as previously described. Typically, such salts are more soluble in aqueous solution than the corresponding free acids and bases, although salts having lower solubility than the corresponding free acids and bases can also be formed.

[0059] Pharmaceutical compositions may be in a form suitable for virtually any mode of administration, including, for example, a form suitable for administration topically, ophthalmically, orally, bucally, systemically, intranasally (e.g., as described in more detail below), by injection, transdermally, rectally, vaginally, etc., or by inhalation or insufflation.

[0060] For topical administration, the compounds may be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art. Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal administration, as well as those designed for transdermal, transmucosal oral, or pulmonary administration.

[0061] Useful administrable formulations include sterile suspensions, solutions, or emulsions of the active compound in aqueous or oily vehicles. The compositions may contain formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents. Injectable preparations may be provided in unit dosage form, for example, in ampoules or multi-dose containers, and may contain added preservatives. Alternatively, injectable preparations may be provided in powder form for reconstitution with a suitable vehicle, such as, but not limited to, sterile, pyrogen-free water, buffer, dextrose solution, etc., before use. For this purpose, the active compound may be dried by any art-known technique, such as lyophilization, and reconstituted before use.

[0062] For oral administration, the pharmaceutical compositions can take the form of lozenges, tablets, or capsules prepared by conventional methods using pharmaceutically acceptable excipients such as binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose), fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc, or silica), disintegrants (e.g., potato starch or sodium starch glycolate), or wetting agents (e.g., sodium lauryl sulfate). Tablets can be coated, for example, with sugars, membranes, or enteric coatings by methods well known in the art.

[0063] Liquid preparations for oral administration can be in the form of, for example, elixirs, solutions, syrups, or suspensions, or they can be provided as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional methods using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats and oils), emulsifiers (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, Cremophor™, or fractionated vegetable oils), and preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid). Preparations can also contain buffer salts, preservatives, flavoring agents, coloring agents, and sweeteners, as needed.

[0064] As is well known, the preparation for oral administration can be formulated appropriately to obtain controlled release of compound.For buccal administration, composition can take the form of tablets or lozenges formulated in conventional manner.For rectal and vaginal administration, compound can be formulated as solution (retention enema) suppository or ointment, for example, containing conventional suppository base such as cocoa butter or other glycerides.

[0065] For nasal administration or administration by inhalation or insufflation, the compounds can be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gases. In the case of a pressurized aerosol, the dosage unit can be metered by providing a valve to deliver a metered amount. Capsules and cartridges (e.g., capsules and cartridges made of gelatin) for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base, for example, lactose or starch.

[0066] For ocular administration, the compounds may be formulated as solutions, emulsions, suspensions, etc., suitable for administration to the eye. A variety of vehicles suitable for administering compounds to the eye are known in the art.

[0067] For long-term delivery, the compound can be formulated as a depot preparation for administration by implantation or intramuscular injection.The compound can be formulated with suitable polymers or hydrophobic materials (for example, as an emulsion in an acceptable oil), or ion exchange resins, or as a poorly soluble derivative, for example, a poorly soluble salt.Alternatively, for transdermal absorption, a transdermal delivery system can be used, which is manufactured as an adhesive disk or patch that slowly releases the compound.For this purpose, a penetration enhancer can be used to promote the percutaneous penetration of the compound.

[0068] Alternatively, other drug delivery systems may be used. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver compounds. Certain organic solvents, such as dimethyl sulfoxide (DMSO), may also be used, although usually at the cost of greater toxicity.

[0069] The pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the compound. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

[0070] The compounds described herein, or compositions thereof, are typically used in an amount effective to achieve the desired result, e.g., an amount effective to treat or inhibit the particular disease being treated.

[0071] The amount of compound administered will depend on a variety of factors, including, for example, the particular indication being treated, the method of administration, whether the desired effect is prophylactic or therapeutic, the severity of the indication being treated, and the age and weight of the patient, the bioavailability of the particular compound, the rate and efficiency of conversion to the active drug compound under the selected route of administration, etc.

[0072] Determining effective dosages and methods of administration of a compound for a particular use is well within the capabilities of one of ordinary skill in the art. Effective dosages may be initially estimated from in vitro activity and metabolism assays. For example, initial dosages of a compound for use in animals may be determined from in vitro assays to determine the IC value of a particular compound. 50 The compound may be formulated to achieve a circulating blood or serum concentration of the metabolically active compound at or above that of the target compound. Calculating the dosage to achieve such a circulating blood or serum concentration, taking into account the bioavailability of a particular compound via the desired route of administration, is well within the capabilities of one skilled in the art. The dosage of the initial compound can also be estimated from in vivo data, such as animal models. Animal models useful for testing the effectiveness of active metabolites to treat or suppress the various diseases mentioned above are well known in the art. Animal models suitable for testing the bioavailability and / or metabolism of a compound to active metabolites are also well known. Those skilled in the art can routinely adapt such information to determine the dosage of a particular compound suitable for human administration.

[0073] Dosages typically range from about 0.0001 mg / kg / day, 0.001 mg / kg / day, or 0.01 mg / kg / day to about 100 mg / kg / day, but may be higher or lower depending, inter alia, on the activity of the active compound, the bioavailability of the compound, its metabolic kinetics and other pharmacokinetic properties, the method of administration, and various other factors, as discussed above. Dosage amounts and administration intervals may be individually adjusted to provide plasma concentrations of the compound and / or active metabolite compound sufficient to maintain therapeutic or prophylactic efficacy. For example, the compound may be administered once a week, several times a week (e.g., every other day), once a day, or multiple times a day, depending, inter alia, on the method of administration, the particular indication being treated, and the judgment of the prescribing physician. In cases of local administration, such as topical administration, or selective uptake, the effective local concentration of the compound and / or active metabolite compound may not be related to plasma concentration. Those skilled in the art will be able to optimize effective dosages without undue experimentation.

[0074] In some embodiments, the pharmaceutical compositions are formulated for once-daily or QD oral administration, and some such formulations are units in which the effective amount of the active ingredient ranges from 50 mg to 5000 mg. Alternatively, oral solutions may be provided in concentrations ranging from 1 mg / ml to 50 mg / ml or greater.

[0075] One embodiment of the present disclosure includes administering a compound of the present disclosure to provide a serum concentration in the range of 0.1 μM to 50 μM. One embodiment of the present disclosure includes administering a compound of the present disclosure to provide a serum concentration in the range of 1 μM to 20 μM. One embodiment of the present disclosure includes administering a compound of the present disclosure to provide a serum concentration in the range of 5 μM to 20 μM. One embodiment of the present disclosure includes administering a compound of the present disclosure to provide a serum concentration of 10 μM, 20 μM, 5 μM, 1 μM, 15 μM, or 40 μM.

[0076] One embodiment of the present disclosure includes administering a compound of the present disclosure at a dosage of 1-100 mg / kg / day, 5-40 mg / kg / day, 10-20 mg / kg / day, 1-2 mg / kg / day, 20-40 mg / kg / day, 45-50 mg / kg / day, 50-60 mg / kg / day, 55-65 mg / kg / day, 60-70 mg / kg / day, or 65-75 mg / kg / day.

[0077] The compositions described herein can be administered once, but are not limited to a single administration. Thus, administration can be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more times. When more than two administrations are used in the method, the administrations can be spaced apart by 1 minute, 2 minutes, 3, 4, 5, 6, 7, 8, 9, 10 minutes, or more, and can be spaced apart by about 1 hour, 2 hours, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 hours, etc. In the case of time, the term "about" refers to any time interval within ±30 minutes. Administrations can also be spaced apart by 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, and combinations thereof. The present disclosure is not limited to evenly spaced administration intervals, but encompasses unequal intervals of administration, such as a stimulation schedule consisting of administration at 1 day, 4 days, 7 days, and 25 days (which is an example only for purposes of providing a non-limiting example).

[0078] For example, dosing schedules of once per week, twice per week, three times per week, four times per week, five times per week, six times per week, seven times per week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, etc. Dosing schedules include, for example, administration over a total period of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, and 12 months.

[0079] Provided is the repetition of the above-mentioned administration schedule.Repetition can be, for example, every 7 days; every 14 days; every 21 days; every 28 days; every 35 days; every 42 days; every 49 days; every 56 days; every 63 days; every 70 days etc.An interval without administration can occur during the repetition, and the interval can be, for example, about 7 days; 14 days; 21 days; 28 days; 35 days; 42 days; 49 days; 56 days; 63 days; 70 days etc.In this context, the term "about" means ±1 day, ±2 days, ±3 days, ±4 days, ±5 days, ±6 days or ±7 days.

[0080] Since one aspect of the present disclosure contemplates treating a disease / condition with a compound of the present disclosure, the present disclosure also relates to pharmaceutical compositions in kit form. When the composition of the present disclosure is part of a combination therapy with a second therapeutic agent, the kit can include two separate pharmaceutical compositions: one for the compound of the present disclosure and one for the second therapeutic agent. The kit includes containers containing the separate compositions, such as divided bottles or divided foil packets. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit includes instructions for use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dosing intervals, or when it is desirable to titrate the individual components of the combination as prescribed by a medical professional.

[0081] The compounds and compositions of the present disclosure described herein may also be administered in combination with one or more secondary therapeutic agents. Thus, in certain embodiments, the method also includes administering an effective amount of one or more compounds of the present disclosure described herein (e.g., compounds of Formula I or Formula II, or those provided in Tables 1 and 2) or pharmaceutical compositions of the present disclosure described herein and one or more secondary therapeutic agents to a subject in need of such treatment.

[0082] Combination therapy, in defining the use of the compounds of the present disclosure and the second therapeutic agent, is intended to encompass administration of each agent in a sequential manner in a dosing regimen that provides the beneficial effect of the drug combination (e.g., the compounds and compositions of the present disclosure and the second therapeutic agent described herein can be formulated as separate compositions administered sequentially), and is also intended to encompass co-administration of these agents in a substantially simultaneous manner, such as in a single pharmaceutical composition having a fixed ratio of these active agents, or in multiple or separate pharmaceutical compositions for each agent. The present disclosure is not limited to sequential administration: the compounds and compositions of the present disclosure can be administered prior to or after (i.e., sequentially), or simultaneously with (i.e., simultaneously) the administration of the second therapeutic agent.

[0083] In certain embodiments, when administered for human treatment, the secondary therapeutic agent can be administered at a previously established clinical dose. In certain embodiments, when administered for treatment, the secondary therapeutic agent can be administered at a dose lower than the established human clinical dose. For example, the secondary therapeutic agent can be administered at an amount less than 1%, for example, less than 10%, or less than 25%, or less than 50%, or less than 75%, or less than 90% of the established human clinical dose.

[0084] Examples of second-line therapeutic agents include, but are not limited to, steroids (e.g., but not limited to, dexamethasone, cortisone, hydrocortisone, hydrocortisone acetate, cortisone acetate, prednisolone, methylprednisolone, prednisone, betamethasone, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone, fluprednidene acetate, hydrocortisone aceponate, hydrocortisone butyrate propionate, hydrocortisone butyrate, hydrocortisone valerate, fluocortolone, halometasone, mometasone, and prednicarbate), nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., but not limited to, indomethacin, sulindac, ibuprofen, aspirin, naproxen, and tolmetin), immunomodulators (e.g., but not limited to, azathioprine, fluprednisolone ... purines, cyclosporine, cyclophosphamide, deoxyspergualin, bredinin, rituximab, tocilizumab, sirolimus, methotrexate, anti-CD3 antibodies, anti-CD19 antibodies, anti-CD22 antibodies, folinic acid, cyclophosphamide, mycophenolate mofetil, and B-cell targeted agents), chemotherapeutic agents (for example, but not limited to, didemnin B, dehydrodidemnin B, and bortezomib), intravenous gamma globulin (IVIG), thalidomide, inebilizumab, vascular health medications (for example, but not limited to, anticoagulants, antiplatelet agents, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, angiotensin receptor neprilysin inhibitors, beta-blockers, calcium channel blockers, cholesterol-lowering drugs, diuretics, and vasodilators), and convalescent plasma.

[0085] Pharmaceutical Composition The inventors have concluded that the compounds described herein, when administered intranasally, may be absorbed (e.g., into the brain) more rapidly after intranasal administration than the corresponding oral administration. The inventors note that rapid absorption may lead to a more rapid onset of action and efficacy at lower doses.

[0086] Accordingly, another aspect of the present disclosure is an intranasal pharmaceutical composition comprising one or more compounds of Formula I or pharmaceutically acceptable salts thereof (i.e., as otherwise described herein) present in a total amount of 1-40% by weight. The intranasal composition further comprises one or more penetration enhancers present in an amount of 0.1-20% by weight; a chelating agent / antioxidant present in an amount of 0.1-20% by weight; a humectant present in an amount of 1-30% by weight; and a preservative present in an amount of 0.03-2% by weight. And, the intranasal composition has a pH of 4.0-6.5.

[0087] In certain embodiments described elsewhere herein, the intranasal composition comprises one or more compounds of Formula II (e.g., Formula II-A or Formula II-B) or Formula III (e.g., Formula III-A or Formula III-B) or a pharmaceutically acceptable salt thereof (i.e., as described elsewhere herein). For example, in certain such embodiments, the intranasal composition comprises one or more compounds of Table 1 (e.g., one or more of compounds 40, 41, 46, 47, 48, 50, 51, 55, 59, 68, and 81).

[0088] In certain embodiments described elsewhere herein, the intranasal composition comprises one or more compounds of Formula I (e.g., Formula IA, II, II-A, III, or Formula III-A, as described elsewhere herein) or a pharmaceutically acceptable salt thereof, present in a total amount of 1-30 w / w%, e.g., 10-25 w / w%, or 1-12 w / w%.

[0089] In certain embodiments described elsewhere herein, the intranasal composition includes a penetration enhancer present in an amount of 1-20% by weight. The inventors note that the use of a penetration enhancer can further improve the aqueous solubility of polyphenolic compounds, such as catechins. Examples of suitable penetration enhancers include HP-β-CD, glycerin, and chitosan, mucosal delivery enhancers, including but not limited to, alkyl saccharides (including but not limited to, tetradecyl maltoside (TDM)), or combinations thereof. In various embodiments, the penetration enhancer is HP-β-CD (e.g., at a concentration of about 1.0 to about 20% w / w, or any of the alternative embodiments generally listed for penetration enhancers), chitosan (e.g., at a concentration of about 0.1% to about 2% w / w, or any of the alternative embodiments generally listed for penetration enhancers), glycerin (e.g., at a concentration of about 1% to about 10% w / w, or any of the alternative embodiments generally listed for penetration enhancers), PEG300 (e.g., at a concentration of about 1% to about 20% w / w, or any of the alternative embodiments generally listed for penetration enhancers), or PEG-300 (e.g., at a concentration of about 1% to about 20% w / w, or any of the alternative embodiments generally listed for penetration enhancers). Examples of suitable penetration enhancers include PEG 400 (e.g., at a concentration of about 1% to about 20% w / w, or any of the alternative embodiments generally listed for penetration enhancers), PEG 600 (e.g., at a concentration of about 1% to about 20% w / w, or any of the related alternative embodiments generally listed for penetration enhancers), and / or transmucosal delivery enhancers (e.g., at a concentration of about 0.1% to about 2% w / w, or any of the related alternative embodiments generally listed for penetration enhancers), including, but not limited to, alkyl saccharides, including, but not limited to, tetradecyl maltoside (TDM). The inventors note that such penetration enhancers increase the solubility in water of one or more compounds of Formula I or pharmaceutically acceptable salts thereof (i.e., as described elsewhere herein) to greater than 10% w / w, preferably allowing for the administration of more concentrated solutions, facilitating rapid onset of action, and reducing irritancy.

[0090] In certain embodiments described elsewhere herein, the penetration enhancer is present in an amount of 1-20%, e.g., 1-18%, 2-18%, 3-17%, 4-16%, 5-15%, 6-14%, 7-13%, 8-12%, 9-11%, 2.3-10%, or 0.1%-2% w / w. In certain such embodiments, the penetration enhancer comprises one or more compounds selected from cyclodextrins or analogs thereof, glycerin, PEG 400, sucrose monolaurate, chitosan, transmucosal delivery enhancers, including but not limited to, alkyl saccharide transmucosal delivery enhancers (including but not limited to, tetradecyl maltoside (TDM)), pharmaceutically acceptable salts thereof, and any combination thereof. In certain such embodiments, the penetration enhancer comprises one or more compounds selected from (2-hydroxypropyl)-β-cyclodextrin (HP-β-cyclodextrin) (also known as HP-β-CD or hydroxypropyl betadex), randomly methylated cyclodextrin (also known as RM-β-CD), sulfobutylether-β-cyclodextrin (also known as SBE-β-CD), sucrose monolaurate, pharmaceutically acceptable salts thereof, and any combination thereof.

[0091] In certain embodiments described elsewhere herein, the intranasal composition includes an antioxidant / chelating agent present in an amount of 0.1-20% by weight. The inventors note that the antioxidant / chelating agent can assist in stabilizing one or more compounds of Formula I or pharmaceutically acceptable salts thereof (i.e., as described elsewhere herein) from autoxidation. In certain such embodiments, the antioxidant / chelating agent is present in an amount of 0.05-15%, 0.8-15%, 0.1-15%, 0.1-10%, 0.1-9%, or 0.1-6% w / w. In certain such embodiments, the antioxidant includes one or more compounds selected from ascorbic acid, sodium metabisulfite, sodium bisulfite, tocopherol, and pharmaceutically acceptable salts thereof. In another embodiment, the antioxidant includes ascorbic acid or a pharmaceutically acceptable salt thereof. The inventors note that additional stabilizers, for example antioxidants such as ascorbic acid, sodium metabisulfite, sodium bisulfite or tocopherol, or metal chelators such as ethylenediaminetetraacetic acid (EDTA), may be used to improve the chemical stability of the formulation.

[0092] In certain embodiments described elsewhere herein, the intranasal composition includes a humectant present in an amount of 1-30% by weight. The inventors note that the humectant can assist in increasing the solubility (e.g., patient acceptability of the nasal formulation) of one or more compounds of Formula I or pharmaceutically acceptable salts thereof (i.e., as described elsewhere herein). In certain such embodiments, the humectant is present in an amount of 1-25%, 1-20%, 1-15%, 1-10%, 1-9%, 2-8%, 3-7%, or 4-6% w / w. In certain such embodiments, the humectant includes one or more compounds selected from glycerin, PEG (including but not limited to PEG300, PEG400, and PEG600), pharmaceutically acceptable salts thereof, and any combination thereof.

[0093] In certain embodiments described elsewhere herein, the intranasal composition includes a preservative present in an amount of 0.03-2% by weight. The inventors note that a preservative can extend the shelf life of the intranasal composition. In certain such embodiments, the preservative is present in an amount of 0.03-2%, e.g., 0.03-1%, 0.03-0.5%, or 0.03-0.1% by weight. In certain such embodiments, the preservative includes one or more compounds selected from benzyl alcohol, parabens, thimerosal, chlorobutanol, and benzalkonium chloride, and any combination thereof.

[0094] In certain embodiments described elsewhere herein, the intranasal composition includes a pH adjuster, such as, for example, citric acid, lactic acid, sodium hydroxide, or a phosphate buffer. The inventors note that the pH adjuster can assist in making the pH of the intranasal composition physiological and non-irritating (e.g., pH 5.0-6.5 for the nasal mucosa). In certain embodiments described elsewhere herein, the intranasal composition includes a pH adjuster present in an amount of 0.1-2% (e.g., 0.5-1.5%) w / w. In certain such embodiments, the pH adjuster is sodium hydroxide or a pharmaceutically acceptable salt thereof. The inventors further note that the intranasal composition can include one or more zymogens (e.g., sodium chloride, mannitol, glucose), for example, to achieve an isotonic formulation. The inventors note that an osmolality of 300 to 700 mOsmol / kg may preferably increase viscosity and therefore increase residence time and improve absorption of one or more compounds of Formula I or pharmaceutically acceptable salts thereof (i.e., as described elsewhere herein).

[0095] The inventors note that the intranasal pharmaceutical composition may comprise any suitable form for intranasal administration. In certain embodiments described elsewhere herein, the intranasal composition is in the form of a liquid, powder, spray, nasal drops, gel, ointment, or any combination thereof. The intranasal composition may be formulated, for example, as an intranasal emulsion, ointment, or gel (which offer advantages for topical application due to their viscosity), or may be, for example, a powder formulation or an intranasal spray. Such sprays typically contain a solution of an active drug in saline or other pharmaceutically suitable carrier liquid. Various intranasal spray compression pumps can be used and calibrated to deliver a predetermined dose of one or more compounds of Formula I or pharmaceutically acceptable salts thereof (i.e., as described elsewhere herein).

[0096] For example, an intranasal formulation may deliver a dose of about 1 mg to about 100 mg, or about 5 mg to about 20 mg, of a compound of Formula I (e.g., one or more compounds of Table 1; e.g., compounds 40, 41, 46, 47, 48, 50, 51, 55, 59, 68, and / or 81) per shot (i.e., per pump of nasal spray), which may be administered as one or more shots per nostril.

[0097] For solution formulations, typical volumes used to deliver about 1 mg to about 100 mg, or about 5 mg to about 20 mg in humans, are 25 to 200 μL, or 75 to 150 μL, per nostril per dose. Intranasal solution formulations can be administered as drops from a nasal dropper bottle, or as an aerosol following application of a squeeze bottle, single unit dose, or metered dose pump spray.

[0098] Administration of a compound of Formula I (e.g., one or more compounds of Table 1; e.g., compounds 40, 41, 46, 47, 48, 50, 51, 55, 59, 68, and / or 81) can be combined with a mucoadhesive to enhance its contact with the olfactory mucosa. In some embodiments, the mucoadhesive is selected from the group consisting of hydrophilic polymers, hydrogels, and thermoplastic polymers. Preferred hydrophilic polymers include cellulose-based polymers (e.g., methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), carbomer chitosan, and vegetable gums. In some embodiments, the mucoadhesive is selected from the group consisting of poly(lactic acid) (“PLA”) and poly(glycolic acid) (“PGA”), and copolymers thereof. In some embodiments, the mucoadhesive formulation comprises a penetration enhancer, such as sodium glycocholate, sodium taurocholate, L-lysophosphatidyl choline, DMSO, and a protease inhibitor. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier, a lipophilic micelle, a liposome, or a combination thereof. For example, the lipophilic micelle or liposome can comprise a ganglioside, a phosphatidylcholine, a phosphatidylserine, or a combination thereof.

[0099] In some embodiments of intranasal delivery, it may be desirable to extend the residence time of the pharmaceutical composition within the nasal cavity (e.g., within the olfactory and / or paranasal sinus regions), e.g., to enhance absorption. Therefore, the pharmaceutical composition can be formulated, if desired, with bioadhesive polymers, gums (e.g., xanthan gum), chitosan (e.g., highly purified cationic polysaccharides), pectin (or any carbohydrate that thickens or emulsifies into a gel upon application to the nasal mucosa), microspheres (e.g., starch, albumin, dextran, cyclodextrin), gelatin, liposomes, carbomers, polyvinyl alcohol, alginate, acacia, chitosan, and / or cellulose (e.g., methyl or propyl; hydroxyl or carboxy; carboxymethyl or hydroxylpropyl), which are agents that enhance residence time within the nasal cavity. As a further approach, increasing the viscosity of the administered formulation can also provide a means of extending contact of the drug with the olfactory epithelium.

[0100] Pharmaceutical formulations can also optionally include absorption enhancers, such as agents that inhibit enzymatic activity, reduce mucus viscosity or elasticity, reduce mucociliary clearance, open tight junctions, and / or solubilize the active compound. Chemical enhancers are known in the art and include chelating agents (e.g., EDTA), fatty acids, bile salts, surfactants, and / or preservatives. Penetration enhancers can be particularly useful when formulating compounds that exhibit poor membrane permeability, lack lipophilicity, and / or are degraded by aminopeptidases. The concentration of absorption enhancers in pharmaceutical compositions will vary depending on the drug selected and the formulation.

[0101] The pharmaceutical formulation can optionally include an odorant to provide the sensation of odor, aid in inhalation of the composition to facilitate delivery to the olfactory epithelium, and / or cause transport by olfactory neurons. The pharmaceutical formulation can also optionally include a viscosity enhancing agent, which can be present in an amount of 1%, 0.5%, 0.2%, 0.1% or less by weight (or not present at all).

[0102] The single unit dose aerosols can be prepared aseptically or terminally sterilized to produce a sterile final product.

[0103] In formulation, effective concentration of one or more compounds or pharmaceutically acceptable derivatives are mixed with suitable pharmaceutical carrier or vehicle.Compound can be derivatized as corresponding salt, ester, enol ether or ester, acid, base, solvate, hydrate or prodrug before formulation.Any suitable carrier or diluent can be used, including but not limited to, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, etc.), suitable mixture thereof and the solvent of dispersion medium, including vegetable oil.

[0104] definition Unless the context requires otherwise, throughout this specification the terms "comprise" and "include", and variations such as "comprises", "comprising", "includes", "including", will be understood to mean the inclusion of the stated component, feature, element or step or group of components, features, elements or steps, but not the exclusion of any other integer or step or group of integers or steps.

[0105] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0106] Terms used herein may be preceded and / or followed by a single dash, "-", or double dash, "=" to indicate the bond order of the bond between the indicated substituent and its parent moiety; a single dash indicates a single bond, and a double dash indicates a double bond. In the absence of a single or double dash, it is understood that a single bond is formed between the substituent and its parent moiety; further, unless the dash indicates otherwise, substituents are intended to be read "left to right" (i.e., the bond is by the last part of the name). For example, C1-C6 alkoxycarbonyloxy and -OC(O)C1-C6 alkyl indicate the same functional group; similarly, arylalkyl and -alkylaryl indicate the same functional group.

[0107] As used herein, unless otherwise specified, the term "alkenyl" refers to a straight or branched chain hydrocarbon having 2 to 10 carbon atoms and containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl, and 3,7-dimethylocta-2,6-dienyl.

[0108] The term "alkoxy," as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0109] As used herein, the term "alkyl," unless otherwise specified, means a straight or branched chain hydrocarbon containing 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. When an "alkyl group" is a linking group between two other moieties, it may be straight or branched; examples include, but are not limited to, -CH-, -CHCH-, -CHCHCHC(CH)-, and -CHCH(CHCH)CH-.

[0110] The term "alkylene" means a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups. The alkylene chain may also be substituted at one or more positions with an aliphatic group or a substituted aliphatic group.

[0111] As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon group containing 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

[0112] As used herein, the term "aryl" refers to a bicyclic ring system containing phenyl (i.e., a monocyclic aryl) or an aromatic bicycle containing only carbon atoms in at least one phenyl ring or aromatic bicyclic ring system. The bicyclic aryl can be an azulenyl, naphthyl, or phenyl fused to a monocyclic cycloalkyl, monocyclic cycloalkenyl, or monocyclic heterocyclyl. The bicyclic aryl is bonded to the parent molecular moiety through any carbon atom contained within the phenyl portion of the bicyclic ring system or any carbon atom bearing the naphthyl or azulenyl ring. The fused monocyclic cycloalkyl or monocyclic heterocyclyl portion of the bicyclic aryl may be optionally substituted with one or two oxo and / or thia groups, as appropriate. Representative examples of bicyclic aryls include, but are not limited to, azulenyl, naphthyl, dihydroinden-1-yl, dihydroinden-2-yl, dihydroinden-3-yl, dihydroinden-4-yl, 2,3-dihydroindol-4-yl, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl, 2,3-dihydroindol-7-yl, inden-1-yl, inden-2-yl, inden-3-yl, inden-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl, dihydronaphthalen-4-yl, dihydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 2,3-dihydrobenzofuran- 4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl, benzo[d][1,3]dioxol-4-yl, benzo[d][1,3]dioxol-5-yl, 2H-chromen-2-one-5-yl, 2H-chromen-2-one-6-yl, 2H-chromen-2-one-7-yl, 2H-chromen-2-one-8-yl, isoindoline-1,3-dione-4-yl, isoindoline-1,3-dione-5-yl, inden-1-one-4-yl, inden-1-one-5-yl, inden-1-one-6-yl, inden-1-one-7-yl, 2,3-dihydrobenzo[b][1,4]dioxan-5-yl, 2,3-dihydrobenzo[b][1,4]dioxan-6-yl, 2H-benzo[b][1,4]oxazin-3(4H)-one-5-yl, 2H-benzo[b][1,4]oxazin-3(4H)-one-6-yl, 2H-benzo[b][1,4]oxazin-3(4H)-one-7-yl, 2H-benzo[b][1,4]oxazin-3(4H)-one-8-yl, benzo[d]oxazin-2(3H)-one-5-yl, benzo[d]oxazin-2(3H)-one-6-yl, benzo[d]oxazin-2(3H)-one-7-yl, benzo[d]oxazin-2(3H)-one-8-yl, quinazolin-4(3H)-one -5-yl, quinazolin-4(3H)-one-6-yl, quinazolin-4(3H)-one-7-yl, quinazolin-4(3H)-one-8-yl, quinoxalin-2(1H)-one-5-yl, quinoxalin-2(1H)-one-6-yl, quinoxalin-2(1H)-one-7-yl, quinoxalin-2(1H)-one-8-yl, benzo[d]thiazol-2(3H)-one-4-yl, benzo[d]thiazol-2(3H)-one-5-yl, benzo[d]thiazol-2(3H)-one-6-yl, and benzo[d]thiazol-2(3H)-one-7-yl. In certain embodiments, the bicyclic aryl is (i) a naphthyl or (ii) a phenyl ring fused to a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, or a 5- or 6-membered monocyclic heterocyclyl, wherein the fused cycloalkyl, fused cycloalkenyl, and fused heterocyclyl groups are optionally substituted with one or two groups that are independently oxo or thia.

[0113] As used herein, the terms "cyano" and "nitrile" refer to a -CN group.

[0114] As used herein, the term "cycloalkyl" refers to a monocyclic or bicyclic cycloalkyl ring system. A monocyclic ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms; such groups may be saturated or unsaturated, but are not aromatic. In certain embodiments, a cycloalkyl group is fully saturated. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A bicyclic cycloalkyl ring system is a bridged monocyclic ring or a fused bicyclic ring. A bridged monocyclic ring includes a monocyclic cycloalkyl ring in which two non-adjacent carbon atoms of the monocyclic ring are joined by one to three additional carbon atoms (i.e., of the form -(CH2) w -, where w is 1, 2, or 3 bridging groups). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems include a monocyclic cycloalkyl ring fused to a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. A bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. The cycloalkyl group may be optionally substituted with one or two groups, independently oxo or thia. In certain embodiments, the fused bicyclic cycloalkyl is a 5- or 6-membered monocyclic cycloalkyl ring fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted with one or two groups that are independently oxo or thia.

[0115] As used herein, the term "halo" or "halogen" means -Cl, -Br, -I or -F.

[0116] The terms "haloalkyl" and "haloalkoxy" mean an alkyl or alkoxy group, as the case may be, substituted with one or more halogen atoms.

[0117] As used herein, the term "heteroaryl" refers to a monocyclic heteroaryl or a bicyclic ring system containing at least one heteroaromatic ring. Monocyclic heteroaryls can be 5- or 6-membered rings. Five-membered rings consist of two double bonds and 1, 2, 3, or 4 nitrogen atoms, and optionally 1 oxygen or sulfur atom. Six-membered rings consist of three double bonds and 1, 2, 3, or 4 nitrogen atoms. Five- or 6-membered heteroaryls are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of monocyclic heteroaryls include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. A bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The heterocyclyl portion of the fused cycloalkyl or bicyclic heteroaryl group may be optionally substituted with one or two groups, independently oxo or thia. When the bicyclic heteroaryl contains a fused cycloalkyl, cycloalkenyl, or heterocyclyl ring, the bicyclic heteroaryl group is attached to the parent molecular moiety through any carbon or nitrogen atom contained within the monocyclic heteroaryl portion of the bicyclic ring system. When the bicyclic heteroaryl is a monocyclic heteroaryl fused to a benzo ring, the bicyclic heteroaryl group is attached to the parent molecular moiety through any carbon or nitrogen atom within the bicyclic ring system.Representative examples of bicyclic heteroaryls include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, 5,6,7,8-tetrahydroquinolin-2-yl , 5,6,7,8-tetrahydroquinolin-3-yl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl, thienopyridinyl, 4,5,6,7-tetrahydrobenzo[c][1,2,5]oxadiazolyl, 2,3-dihydrothieno[3,4-b][1,4]dioxan-5-yl, and 6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-onyl. In certain embodiments, the fused bicyclic heteroaryl is a 5- or 6-membered monocyclic heteroaryl ring fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, wherein the fused cycloalkyl, fused cycloalkenyl, and fused heterocyclyl groups are optionally substituted with one or two groups that are independently oxo or thia.

[0118] As used herein, the terms "heterocyclyl" and "heterocycloalkyl" refer to a monocyclic heterocycle or a bicyclic heterocyclic ring system. A monocyclic heterocycle is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S, and the ring is saturated or unsaturated, but not aromatic. A 3- or 4-membered ring contains one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring can contain zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6- or 7-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, o- ... Examples of heterocyclic rings include oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl. Bicyclic heterocycles are bridged monocyclic or monocyclic heterocycles fused to phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. Bridged monocycles include monocyclic cycloalkyl rings, where two non-adjacent carbon atoms of the monocycle are joined by one to three additional carbon atoms (i.e., of the form -(CH)). w- bridging groups, where w is 1, 2, or 3 bridging groups) are connected by an alkylene bridge between them. Bicyclic heterocycles are attached to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. Heterocyclyl groups may be optionally substituted with one or two groups, independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5- or 6-membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted with one or two groups that are independently oxo or thia.

[0119] As used herein, the term "oxo" means a =O group.

[0120] As used herein, the term "saturated" means that the referenced chemical structure does not contain any multiple carbon-carbon bonds. For example, saturated cycloalkyl groups as defined herein include cyclohexyl, cyclopropyl, and the like.

[0121] As used herein, the term "substituted" means that a hydrogen radical of the specified moiety is replaced with the radical of a specified substituent, provided that such replacement results in a stable or chemically feasible compound. When used in reference to a specified atom, the term "substitutable" means that a hydrogen radical is attached to the atom and that the hydrogen radical can be replaced with the radical of a suitable substituent.

[0122] As used herein, the phrase "one or more" substituents refers to a number of substituents equal to one to the maximum number of possible substituents based on the number of available bonding sites, provided that the above conditions of stability and chemical feasibility are met. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and the substitutions may be the same or different. As used herein, the term "independently selected" means that the same or different values ​​may be selected for multiple occurrences of a given variable in a single compound.

[0123] As used herein, the term "thia" refers to the group ═S.

[0124] As used herein, the term "unsaturated" means that the referenced chemical structure contains at least one multiple carbon-carbon bond, but is not aromatic. For example, unsaturated cycloalkyl groups as defined herein include cyclohexenyl, cyclopentenyl, cyclohexadienyl, etc.

[0125] It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present disclosure. Unless otherwise specified, the structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., R and S configurations for each asymmetric center. Thus, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the present disclosure. Both R and S stereochemical isomers, and all mixtures thereof, are included within the scope of the present disclosure.

[0126] "Pharmaceutically acceptable" means compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, or otherwise approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary animals.

[0127] "Pharmaceutically acceptable salt" means both acid and base addition salts.

[0128] A "therapeutically effective amount" or "effective amount" refers to the amount of a compound that, when administered to a subject, is sufficient to treat a disease or disorder described herein. The amount of a compound that results in a therapeutically effective amount varies depending on the compound, the disorder and its severity, and the age of the subject being treated, but can be routinely determined by one of ordinary skill in the art. An effective amount is an amount that reduces or improves symptoms, usually by at least 10%, more usually by at least 20%, most usually by at least 30%, typically by at least 40%, more typically by at least 50%, most typically by at least 60%, often by at least 70%, more often by at least 80%, and most often by at least 90%, conveniently by at least 95%, more conveniently by at least 99%, and most conveniently by at least 99.9%.

[0129] As used herein, "Treating" or "treatment" includes treatment of a disease or disorder as described herein in a subject, preferably a human, and further includes: i. inhibiting a disease or disorder, i.e., preventing its occurrence; ii. Relieving the disease or disorder, i.e., causing regression of the disorder; iii. slowing the progression of the disorder; and / or iv. Arresting, alleviating, ameliorating, or slowing the progression of one or more symptoms of a disease or disorder.

[0130] As used herein, "limiting" a disease or disorder or "limiting development" of a disease or disorder means reducing the occurrence of the disease or disorder in a subject who does not have the disease or disorder. For example, "limiting" or "limiting the development" of a viral infection includes: i. Suppression of infectious disease outbreaks; ii. Reduced severity of infection; and / or iii. Suppression of the onset of symptoms after infection.

[0131] "Subject" means a warm-blooded animal such as a mammal, preferably a human or human child, that is afflicted with or susceptible to being afflicted with a disease as described herein.

[0132] Preparation method Gallocatechin Another aspect of the present disclosure is a method for preparing gallocatechin. The present inventors have prepared gallocatechin: [ka] has been noted to be an important precursor to certain desirable (2S,3R)-compounds described herein, such as compounds 40, 41, 50, 51, 59, and 68 in Table 1 above. Surprisingly, the inventors have discovered that gallocatechin: [ka] concluded that epigallocatechin can be prepared in desirably high yield and preferably in high purity by treatment with aqueous buffer at elevated temperatures. Furthermore, the inventors note that the crude reaction product obtained by precipitation and filtration can be preferably purified by simple recrystallization.

[0133] Thus, in certain embodiments described elsewhere herein, the method includes contacting epigallocatechin with an aqueous buffer system at a first time and a first temperature to obtain a crude reaction mixture containing gallocatechin. In certain embodiments described elsewhere herein, the buffer system has a pH of 7-8. For example, in certain such embodiments, the buffer system has a pH of 7-7.5, e.g., a pH of 7.2. In certain embodiments described elsewhere herein, the buffer system is a phosphate buffer. In certain embodiments described elsewhere herein, the buffer system is a HEPES buffer.

[0134] In certain embodiments described elsewhere herein, the first temperature is greater than 50°C, e.g., greater than 60°C, or greater than 70°C, or greater than 80°C. In certain embodiments described elsewhere herein, the first temperature is reflux. In certain embodiments described elsewhere herein, the first period of time is at least 1 hour. For example, in certain such embodiments, the first period of time is 1 to 8 hours, e.g., 1 to 5 hours, or 1 to 3 hours.

[0135] In certain embodiments described elsewhere herein, the method includes cooling the crude reaction mixture after the first time period to a second temperature lower than the first temperature to obtain a precipitated crude material comprising the gallocatechins, and then separating the precipitated crude material (e.g., by filtration). In certain embodiments described elsewhere herein, the second temperature is less than 40° C., e.g., less than 30° C. In certain embodiments described elsewhere herein, the second temperature is room temperature.

[0136] In certain embodiments described elsewhere herein, the method includes recrystallizing the filtered crude product in an aqueous solvent system to obtain a purified material containing gallocatechins. In certain embodiments described elsewhere herein, the aqueous solvent system is deionized water. In certain embodiments described elsewhere herein, the purified material contains at least 90% by weight, e.g., at least 95% by weight, or at least 97.5% by weight, of gallocatechins.

[0137] general law Many general references are available that provide generally known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds (see, for example, Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001; or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York: Longman, 1978).

[0138] The compounds described herein can be purified by any method known in the art, including chromatographic methods such as HPLC, preparative thin-layer chromatography, flash column chromatography, and ion-exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phase and ionic resins. Most typically, the disclosed compounds are purified by silica gel and / or alumina chromatography. See, for example, "Introduction to Modern Liquid Chromatography," 2nd Edition, ed. L.S. Snyder and J.J. Kirkland, John Wiley and Sons, 1979; and "Thin Layer Chromatography," ed. E. Stahl, Springer-Verlag, New York, 1969.

[0139] During any of the processes for preparation of the compounds of the present invention, it may be necessary and / or desirable to protect any sensitive or reactive groups on any of the molecules concerned. Authoritative explanations describing many alternatives for the skilled practitioner are found in J.F.W.M. Comie, "Protective Groups in Organic Chemistry," Plenum Press, London and New York 1973; in T.W. Greene and P.G.W. Muts, "Protective Groups in Organic Synthesis," Third Edition, Wiley, New York 1999; in "The Peptides;" Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981; in "Methoden der organischen Chemie," Houben-Weyl, 4th edition, Vol. 15 / 1, Georg Thieme Verlag, Stuttgart 1974; in H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Protein," Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982; and / or in Jochen This can be achieved by conventional protecting groups as described in standard works such as Lehmann, "Chemie der Kohlenhydrate: Monosaccharide and Derivate," Georg Thieme Verlag, Stuttgart 1974. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0140] The compounds disclosed herein can be made as described herein using methods familiar to those skilled in the art. For example, compounds of Formula I can be prepared by Schemes 1-19, the general procedures (below), and / or analogous synthetic methods. One skilled in the art can adapt the reaction sequences of Schemes 1-19, the general procedures, and Example 1 to a target molecule of interest. Of course, in certain situations, one skilled in the art will use different reagents to perform one or more individual steps or to use protected forms of particular substituents. Furthermore, one skilled in the art will understand that the compounds of the present disclosure can be synthesized using entirely different routes.

[0141] Basic steps Representative synthetic procedures for the preparation of compounds of the present invention are outlined in Schemes 1-19. Scheme 1 [ka] Scheme 2 [ka] Scheme 3 [ka] Scheme 4 [ka] Scheme 5 [ka] Scheme 6 [ka] Scheme 7 [ka] Scheme 8 [ka] Scheme 9 [ka] Scheme 10 [ka] Scheme 11 [ka] Scheme 12 [ka] Scheme 13 [ka] Scheme 14 [ka] Scheme 15 [ka] Scheme 16 [ka] Scheme 17 [ka] Scheme 18 [ka] Scheme 19 [ka]

[0142] Example The compositions and methods of the present disclosure are further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the disclosure to the particular procedures and compounds described therein.

[0143] Example 1. Preparation of the compounds in Table 1 compound 9 [ka] Step 1: Synthesis of (2). To a solution of (-)-EGC1 (45.0 g, 0.147 mol) and K2CO3 (203.1 g, 1.469 mol, 10 equiv.) in DMF (400 mL) was added benzyl bromide (130.7 g, 0.764 mol, 5.2 equiv.) at -20 °C. The mixture was stirred at room temperature for 48 h and then poured into water (1500 mL). The resulting mixture was extracted with ethyl acetate, and the extract was dried over Na2SO4. After evaporation of the solvent, the residue was recrystallized several times from Et2O to 95+% NMR purity, affording compound 2 as a white solid (33.2 g, 30% yield).

[0144] Step 2: Synthesis of (3). Triethylamine (3.0 g, 29.7 mmol, 1.5 equiv.) was added to a solution of compound 2 (15.0 g, 19.8 mmol) and methanesulfonyl chloride (2.95 g, 25.7 mmol, 1.3 equiv.) in EtOAc (800 mL) under nitrogen at 0° C. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was washed with saturated aqueous NaHCO, brine, dried over NaSO, filtered, and concentrated under reduced pressure at 40° C. to give the title compound 3 as a yellow oil (15.9 g, 96% yield). Mesylate 3 should be used in the next step immediately after preparation.

[0145] Step 3: Synthesis of (4). To a solution of compound 3 (15.9 g, 19.0 mmol) in 250 mL of anhydrous DMSO, sodium azide (2.47 g, 38.1 mmol, 2 equivalents) was added, and the reaction mixture was stirred at 100° C. for 12 hours. The mixture was poured into cold water (1000 mL). The resulting mixture was extracted with ethyl acetate, and the extract was washed with water, brine, and dried over NaSO. The residue was purified by silica gel chromatography using CHCl. ​​Yield: 14.0 g, 94%.

[0146] Step 4: Synthesis of (5). Compound 5 (14.0 g, 17.9 mmol) and PPh3 (9.39 g, 35.8 mmol, 2.0 equiv.) in a mixture of THF and water (800 mL and 20 mL) were heated under reflux in an inert atmosphere for 12 hours. The solvent was evaporated, and the residue was purified by silica gel chromatography using CHCl3:MeOH = 80:1. Yield 10.9 g, 81%.

[0147] Step 5: Synthesis of (6). A mixture of compound 5 (700 mg, 0.926 mmol), acid 8 (1000 mg, 0.926 mmol, 1 equiv.), EDC (195 mg, 1.019 mmol, 1.1 equiv.), HOBT (125 mg, 0.926 mmol, 1 equiv.), and DIPEA (239 mg, 1.852 mmol, 2 equiv.) in 100 ml of CHCl was stirred overnight. After completion of the reaction (TLC control), the mixture was washed with water, 5% citric acid, and dried over NaSO. The residue was purified by silica gel chromatography using CHCl:MeOH = 180:1. Yield 610 mg, 55%.

[0148] Step 6: Synthesis of compound 9. To a solution of compound 6 (600 mg, 0.51 mmol) in 1:1 THF:MeOH (total 160 mL) was added 300 mg of 20% palladium hydroxide on carbon, and the mixture was stirred under H atmosphere for 12-24 h (LCMS monitoring). After filtration, evaporation, and purification by HPLC on a YMC-Pack ODS-AQ column under neutral conditions using a gradient of H2O-acetonitrile, (2R,3S)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5-trihydroxybenzoate was obtained. Yield 46 mg, 20%.

[0149] compound 28 [ka] Step 1: Synthesis of benzyl 3,4-bis(benzyloxy)benzoate (SM2). To a solution of compound SM1 (1 g, 3.45 mmol) and K2CO3 (3.57 g, 25.87 mmol) in DMF (20 mL) was added BnBr (2.48 g, 14.49 mmol) at 0 °C. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O (50 mL) and extracted with EA (50 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA = 3 / 1) to give compound SM2 (1.68 g, 75% yield) as a yellow solid. MS calculated: 650.3; MS found: 651.0 [M+H] + .

[0150] Step 2: Synthesis of benzyl 3,4-bis(benzyloxy)benzoate (A1-2). To a solution of compound A1-1 (1 g, 36.5 mmol) and K2CO3 (3.13 g, 22.7 mmol) in DMF (20 mL) was added BnBr (4.13 g, 22.7 mmol) at 0 °C. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O (50 mL) and extracted with EA (50 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA = 2 / 1) to give compound A1-2 (2.04 g, 74% yield) as a yellow solid. MS calculated: 424; MS found: 425 [M+H] + .

[0151] Step 3: Synthesis of 3,4-bis(benzyloxy)benzoic acid (A1-3). To a mixture of compound A1-2 (8.5 g, 0.02 mol) in MeOH (60 mL) was added LiOH·H2O (0.962 g, 0.04 mol) in HO (20 mL). The solution was stirred at 50 °C overnight. The reaction mixture was concentrated to remove MeOH. The mixture was then diluted with HO (30 mL) and extracted with EA (80 mL x 2). The aqueous phase was adjusted to pH < 3 with 1 N HCl. Next, the mixture was filtered, and the filter cake was dried to give compound A1-3 (5.3 g, 79% yield) as a white solid. MS calculated: 334.1; MS found: 333.0 [MH]. - .

[0152] Step 4: Synthesis of (2R,3S)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)benzoate (A1-4). To a mixture of compound SM2 (1 g, 1.54 mmol) and A1-3 (617 mg, 1.85 mmol) in DCM (20 mL), EDCI (589 mg, 308 mmol), DMAP (56.4 mg, 0.462 mmol), and TEA (311 mg, 3.08 mmol) were added under ice-water bath. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with HO (50 mL), and the phases were separated. The organic layer was washed with brine (30 mL x 2), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA=5 / 1) to give compound A1-4 (780 mg, 52% yield) as a yellow oil. MS calculated: 966.1; MS observed: 967.0 [M+H] + .

[0153] Step 5: Synthesis of Compound 28. To a mixture of Compound A1-4 (500 mg, 0.517 mmol) in THF (10 mL) and MeOH (10 mL), Pd(OH) (10 wt%, 50 mg) was added. The mixture was stirred overnight at room temperature under a H atmosphere (15 psi). The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give (2R,3S)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)benzoate (60 mg, 27.2% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ:9.76(s,1H),9.32(s,2H),9.09(s,1H),8.89(s,2 H),7.24(d,J=2.0Hz,1H),7.29-7.18(m,1H),6.76(d,J=8.4Hz,2H),6.68-6 .61(m,2H),5.94(d,J=2.0Hz,1H),5.81(d,J=2.0Hz,1H),5.27-5.22(m,1H ),5.05(d,J=6.4Hz,1H),2.73-2.58(m,2H).MS calculation: 426.1;MS actual measurement: 427.0[M+H] + .

[0154] compound 29 [ka] Step 1: Synthesis of methyl 5-hydroxy-6-nitronicotinate (A2-2). To a solution of compound A2-1 (5 g, 32.67 mmol) in H2SO4 (50 mL) was added HNO3 (4.12 g, 65.34 mmol) at 0 °C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into 100 mL of ice water and stirred for 20 minutes. The mixture was filtered to give compound A2-2 (3.5 g, 54% yield) as a yellow solid. MS calculated: 198.03; MS found: 199 [M+H] + .

[0155] Step 2: Synthesis of methyl 5-(benzyloxy)-6-nitronicotinate (A2-3). To a solution of compound A2-2 (2.64 g, 13.33 mmol) and K2CO3 (3.69 g, 26.67 mmol) in DMF (25 mL) was added BnBr (4.56 g, 26.67 mmol) at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O (50 mL) and extracted with EA (50 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA = 3 / 1) to give compound A2-3 (2.1 g, 54.7% yield) as a yellow solid. MS calculated: 288.1; MS found: 289 [M+H] + .

[0156] Step 3: Synthesis of 5-(benzyloxy)-6-nitronicotinic acid (A2-4). To a mixture of compound A1-2 (2.1 g, 7.29 mmol) in THF (60 mL) was added LiOH·H2O (0.35 g, 14.58 mmol) in HO (8 mL). The solution was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to remove THF. The mixture was diluted with HO (30 mL) and extracted with EtOAc (50 mL x 2). The aqueous phase was adjusted to pH < 3 with 1N HCl and extracted with DCM (50 mL x 2) to give compound A2-4 (1.7 g, 85% yield) as a white solid. MS calculated: 274.1; MS found: 273.0 [MH] - .

[0157] Step 4: Synthesis of (2R,3S)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-yl 5-(benzyloxy)-6-nitronicotinate (A2-5). To a mixture of compound SM2 (700 mg, 1.077 mmol) and compound A2-4 (354 mg, 1.29 mmol) in DCM (20 mL), EDCI (412 mg, 2.15 mmol), DMAP (39.4 mg, 0.32 mmol), and TEA (218 mg, 2.15 mmol) were added under ice-water bath. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with HO (50 mL), and the phases were separated. The organic layer was washed with brine (50 mL x 2), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA=5 / 1) to give compound A2-5 (550 mg, 56% yield) as a yellow oil. MS calculated: 906.3; MS observed: 907.0 [M+H] + .

[0158] Step 5: Synthesis of Compound 29. To a mixture of Compound A2-5 (500 mg, 0.517 mmol) in THF (10 mL) and MeOH (10 mL), Pd(OH) (10 wt%, 50 mg) was added. The reaction mixture was stirred overnight at room temperature under a H atmosphere (15 psi). The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give (2R,3S)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 6-amino-5-hydroxynicotinate (90 mg, 29.8% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ:9.90(s,1H),9.34(s,1H),9.09(s,1H),8.91(d,J=4.4H z,2H),7.97(d,J=2.0Hz,1H),7.14(d,J=2.0Hz,1H),6.76(d,J=2.0Hz,1H),6.69- 6.62(m,2H),6.41(s,2H),5.95(d,J=2.4Hz,1H),5.81(d,J=2.0Hz,1H),5.28-5. 21(m,1H),5.05(d,J=1Hz,1H),2.77-2.57(m,2H).MS calculation: 426.1;MS actual measurement: 427.1[M+H] + .

[0159] compound 30 [ka] Step 1: Synthesis of benzyl 3-(benzyloxy)-4-nitrobenzoate (A3-2). To a solution of compound A3-1 (1 g, 5.46 mmol) and K2CO3 (1.51 g, 10.92 mmol) in DMF (20 mL) was added BnBr (2.8 g, 16.38 mmol) at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O (40 mL) and extracted with EA (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA = 3 / 1) to give compound A3-2 (1.8 g, 90.9% yield) as a white solid. MS calculated: 363.1; MS found: 364.0 [M+H] + .

[0160] Step 2: Synthesis of benzyl 3,4-bis(benzyloxy)benzoate (A3-3). To a mixture of compound A3-2 (1 g, 2.75 mmol) in THF (10 mL) was added LiOH·HO (132 mg, 5.51 mmol) in HO (4 mL). The solution was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to remove THF. The mixture was diluted with HO (10 mL) and extracted with EA (30 mL x 2). The aqueous phase was adjusted to pH < 3 with 1N HCl and extracted with DCM (30 mL x 2) to give compound A3-3 (700 mg, 93.1% yield) as a white solid. MS calculated: 273.1; MS found: 272.0 [MH] - .

[0161] Step 3: Synthesis of (2R,3S)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-yl 3-(benzyloxy)-4-nitrobenzoate (A3-4). To a mixture of compound SM2 (1 g, 1.54 mmol) and A3-3 (420 mg, 1.85 mmol) in DCM (20 mL), EDCI (589 mg, 308 mmol), DMAP (56.4 mg, 0.462 mmol), and TEA (311 mg, 3.08 mmol) were added under ice-water bath. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with HO (50 mL), and the phases were separated. The organic layer was washed with brine (30 mL x 2), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA=5 / 1) to give compound A1-4 (780 mg, 52% yield) as a yellow oil. MS calculated: 905.3; MS observed: 906.6 [M+H] + .

[0162] Step 4: Synthesis of (2R,3S)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-yl 4-amino-3-(benzyloxy)benzoate (A3-5). A mixture of NHCl (45.6 mg, 0.85 mmol) and Fe (241.2 mg, 4.2 mmol) in 50 mL of EtOH and 10 mL of HO was stirred at 90 °C for 1 h. Next, compound A3-4 (780 mg, 0.86 mmol) in ACN (5 mL) was slowly added, and the mixture was stirred at 90 °C for 3 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to give the crude product, which was diluted with HO (30 mL) and extracted with DCM (30 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA=1 / 1) to give compound A3-5 (550 mg, 66.2% yield) as a yellow oil. MS calculated: 875.3; MS observed: 876.0 [M+H] + .

[0163] Step 5: Synthesis of (2R,3S)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-yl 3-(benzyloxy)-4-(methylsulfonamido)benzoate (A3-6). To a solution of compound A3-5 (500 mg, 0.801 mmol) and TEA (485.4 mg, 4.806 mmol) in DCM (20 mL) was added MsCl (182.6 mg, 1.602 mmol) at 0 °C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with HO (30 mL), and the phases were separated. The organic layer was washed with brine (30 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA = 3 / 1) to give compound A3-6 (180 mg, 33% yield) as a white solid. MS calculation: 953.3;MS actual measurement: 954.0[M+H] + .

[0164] Step 6: Synthesis of Compound 30. To a mixture of Compound A3-6 (180 mg, 0.14 mmol) in THF (10 mL) and MeOH (10 mL), Pd(OH) (10 wt%, 18 mg) was added. The mixture was stirred overnight at room temperature under a H atmosphere (15 PSI). The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC to give (2S,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3-hydroxy-4-(methylsulfonamido)benzoate (96 mg, 8.7% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ:9.35(s,1H),9.04(s,1H),8.88(s,2H),7.36-7.27(m,3H),6.77(d,J=1.6Hz,1H),6.69-6.62(m,2H),5.94(d,J=2 .0Hz,1H),5.81(d,J=2.4Hz,1H),5.31-5.27(m,1H),5.08(d,J=6.0Hz,1H),2.75(s,3H),2.77-2.50(m,3H).MS calculation: 503.9;MS actual measurement: 502.0[MH] - .

[0165] compound 31 [ka] Step 1: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-ol (1-2). To a solution of compound 1-1 (1 g, 3.45 mmol) in DMF (20 mL), NaH (579 mg, 14.47 mmol, 60 wt % in mineral oil) was added at 0 °C. The mixture was stirred at 0 °C for 20 min. BnCl (1.83 g, 14.47 mmol) was added at 0 °C, and the solution was stirred at room temperature overnight. The reaction mixture was diluted with HO (50 mL) and extracted with EA (50 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA = 3 / 1) to give compound 1-2 (1.72 g, 77% yield) as a yellow oil. MS calculation: 650.3; MS measurement: 651.0 [M+H] + .

[0166] Step 2: Synthesis of (2R,3S)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)benzoate (1-3). To a solution of compound 1-2 (600 mg, 0.92 mmol) in THF (15 mL), PPh3 (362 mg, 1.38 mmol), compound A1-3 (370 mg, 1.11 mmol), and DEAD (240 mg, 1.38 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (30 mL) and extracted with EA (30 mL × 3). The combined organic layer was dried over Na2SO4 and concentrated. The filtrate was concentrated to give the crude product, which was purified by reverse-phase silica gel flash chromatography (ACN / HO = 5% to 95%, 214 nm, 30 min) to give compound 1-3 (100 mg, 11% yield) as a yellow solid. MS calculated: 966.4; MS observed: 967 [M+H]. + .

[0167] Step 3: Synthesis of Compound 31. To a mixture of compound 1-3 (100 mg, 0.1 mmol) in EA (10 mL) was added Pd(OH) (10 wt%, 10 mg). The mixture was stirred at room temperature under a H balloon for 5 hours. The reaction mixture was filtered and concentrated. The residue was purified by reverse-phase silica gel flash chromatography (ACN / H2O = 5% to 95%, 214 nm, 30 min) to afford (2R,3S)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4-dihydroxybenzoate (21.6 mg, 49% yield) as a white solid. 1 H NMR(400MHz,CD3OD)δ:7.34-7.30(m,2H),6.86-6.69(m,4H),5.96-5.93(m,2H),5.40-5.33(m ,1H),5.07-5.03(m,1H),2.88-2.83(m,1H),2.74-2.68(m,1H).MS calculation: 426.1;MS measurement: 427.1[M+H] + .

[0168] compound 33 [ka] Step 1: Synthesis of 5,8-dihydronaphthalen-1-ol (2). To a solution of naphthalen-1-ol (1 g, 6.944 mmol, 1 equiv.) in ethanol (40 mL) was added ammonia in THF (0.7 mL, 34.72 mmol, 5 equiv.). The reaction mixture was then cooled to -70 °C, followed by the slow addition of sodium metal (0.798 g, 34.72 mmol, 5 equiv.) in small portions over 10 min, resulting in the formation of a deep green naphthalene / sodium complex. After quenching the entire complex with t-BuOH, the solution was stirred at room temperature for 4 h. The solid portion was filtered off and washed with ethanol. The combined solution was concentrated, and the resulting crude product was dissolved in diethyl ether (50 mL), washed with water and brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude compound was purified by flash column chromatography eluting with 10% EtOAc in hexanes as eluent to give the desired 5,8-dihydronaphthalen-1-ol as a pale yellow solid (0.8 g, 80% yield).1 H NMR(400MHz,DMSO-d6):δ7.05-6.96(m,1H),6.70(q,J=6.8Hz,1H),6.60(t,J=4.8Hz,1H),5.90(t,J=12.8Hz,1H) ,4.65(d,J=14.0Hz,1H),3.39(d,J=6.0Hz,1H),3.26(d,J=6.0Hz,1H),2.63(t,J=6.0Hz,2H),1.86-1.73(m,1H).

[0169] Step 2: 5-(benzyloxy)-1,4-dihydronaphthalene (3). To a solution of 5,8-dihydronaphthalen-1-ol (0.8 g, 5.479 mmol, 1 equiv.) in 10 mL of DMF, K2CO3 (1.1 g, 8.219 mmol, 1.5 equiv.) and benzyl bromide (0.8 mL, 8.219 mmol, 1.5 equiv.) were added at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. The reaction mixture was quenched with cold water, extracted with EtOAc (150 mL x 3), washed with brine, and dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure to give the crude compound. The crude compound was purified by flash column chromatography eluting with 20% EtOAc in hexanes as the eluent to give the desired 5-(benzyloxy)-1,4-dihydronaphthalene as a yellow solid (0.7 g, 58% yield). 1 H NMR(400MHz,DMSO-d6):δ 7.54-7.24(m,5H),7.10(t,J=8.0Hz,1H),6.75-6.69(m,2H),5.89(q,J=10.4Hz,1H) ,5.07(s,2H),3.38(d,J=16.8Hz,1H),2.75(d,J=2.4Hz,1H),1.78(d,J=1.6Hz,1H).

[0170] Step 3: Synthesis of 5-(benzyloxy)-1,4-dihydronaphthalene (4). To a solution of 5-(benzyloxy)-1,4-dihydronaphthalene (0.7 g, 2.966 mmol, 1 equiv.) in 15 mL of DCM, m-CPBA (0.76 g, 4.449 mmol, 1.5 equiv.) was added at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. The reaction mixture was quenched with hypo solution, extracted with EtOAc (150 mL x 3), washed with brine, and dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure to give the crude compound. The crude compound was purified by flash column chromatography eluting with 15% EtOAc in hexane as the eluent to give the desired compound 3-(benzyloxy)-1a,2,7,7a-tetrahydronaphtho[2,3-b]oxirane as a yellow solid (0.1 g, 14% yield). 1 H NMR(400MHz,DMSO-d6)δ7.42-7.32(m,4H),7.09(t,J=7.6Hz,1H),6.74(d,J=8.8Hz,1H),6.69(d,J=8.8Hz,1H),5.03(s, 2H),3.62(d,J=18.6Hz,1H),3.48(d,J=8.0Hz,1H),3.33(d,J=18.4Hz,1H),3.18(d,J=18Hz,1H),2.87(d,J=18.6Hz,1H).

[0171] Step 4: Synthesis of (2R,3S)-5-(benzyloxy)-3-(3,4,5-tris(benzyloxy)phenyl)-1,2,3,4-tetrahydronaphthalen-2-ol (6). To a solution of (((5-bromobenzene-1,2,3-triyl)tris(oxy))tris(methylene))tribenzene (0.37 g, 0.796 mmol, 2 equiv.) in 6 mL of THF was added n-BuLi (1.6 M, 0.3 mL, 0.871 mmol, 2.2 equiv.) at −70° C., and the reaction mixture was stirred at −70° C. for 2 hours. After this time, bromobenzene 3-(benzyloxy)-1a,2,7,7a-tetrahydronaphtho[2,3-b]oxirane (0.1 g, 0.396 mmol, 1 equiv.) and BF3-Et2O (0.084 g, 0.594 mmol, 1.5 equiv.) were added to the above reaction mixture at -70 °C. The reaction mixture was stirred at 0 °C for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with aqueous NH4Cl, extracted with EtOAc (150 mL x 2), washed with brine, and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column chromatography eluting with 30% EtOAc in hexane as the eluent to give the desired compound (2R,3S)-5-(benzyloxy)-3-(3,4,5-tris(benzyloxy)phenyl)-1,2,3,4-tetrahydronaphthalen-2-ol as a white solid (0.05 g, 20% yield). 1 H NMR(400MHz,DMSO-d6)δ7.42-7.26(m,20H),7.07(d,J=7.2Hz,1H),6.84(d,J=8.0Hz,1H),6.73(d,J=13.6Hz,3H),5.07 (s,6H),4.88(s,2H),4.62(d,J=3.6Hz,1H),4.07(s,1H),2.99(d,J=16.4Hz,2H),2.72(s,1H),2.65(d,J=15.6Hz,2H).

[0172] Step 5: Synthesis of (2R,3S)-5-(benzyloxy)-3-(3,4,5-tris(benzyloxy)phenyl)-1,2,3,4-tetrahydronaphthalen-2-yl 3,4,5-tris(benzyloxy)benzoate (8). To a solution of 6(2R,3S)-5-(benzyloxy)-3-(3,4,5-tris(benzyloxy)phenyl)-1,2,3,4-tetrahydronaphthalen-2-ol (0.5 g, 0.661 mmol, 1 equiv.) in 10 mL of DCM was added 3,4,5-tris(benzyloxy)benzoic acid (0.43 g, 1.322 mmol, 2 equiv.), EDCI (0.39 g, 3.305 mmol, 3 equiv.), EtN (0.5 mL, 3.305 mmol, 3 equiv.), and DMAP (0.05 g, 0.396 mmol, 0.6 equiv.) at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with hypo solution, extracted with DCM (50 mL x 3), washed with brine, and dried over anhydrous NaSO. The organic layer was concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column chromatography eluting with 20% EtOAc in hexane to give the desired compound (2R,3S)-5-(benzyloxy)-3-(3,4,5-tris(benzyloxy)phenyl)-1,2,3,4-tetrahydronaphthalen-2-yl 3,4,5-tris(benzyloxy)benzoate as a white solid (0.5 g, 71% yield). 1 H NMR(400MHz,DMSO-d6)δ7.45-7.28(m,35H),7.22(t,J=6.8Hz,2H),7.11(d,J=8.8Hz,1H),6.87(s,2H),6.42(s,2H),6.28(s,1H)5.40(d,J=6.4H) z,1H),5.21(s,2H),5.16(d,J=8.8Hz,1H),5.07(s,6H),5.00(s,2H),4.89(s,2H),4.85(s,2H),2.91(dd,J=5.2Hz,2H),2.76(dd,J=6.8Hz,2H).

[0173] Step 6: Synthesis of Compound 33. To a solution of (2S,3S)-5-(benzyloxy)-3-(3,4,5-tris(benzyloxy)phenyl)-1,2,3,4-tetrahydronaphthalen-2-yl 3,4,5-tris(benzyloxy)benzoate (0.2 g, 0.186 mmol, 1 equiv.) in 12 mL of 1:1 THF:MeOH, palladium hydroxide (20 wt%, 0.42 g) was added at room temperature, and the reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give (2S,3S)-5-hydroxy-3-(3,4,5-trihydroxyphenyl)-1,2,3,4-tetrahydronaphthalen-2-yl 3,4,5-trihydroxybenzoate as a grey solid (0.025 g, 31% yield). 1 H NMR (400MHz, DMSO-d6): δ6.93(t,J=8.0Hz,1H),6.63(d,J=8.0Hz,1H),6.54(t,J=7.2Hz,1H),6.17(s,2H),5.25(d,J LCMS:(MH - ): m / z: 439.1.

[0174] compound 32 [ka] Step 1: Synthesis of methyl 3,4,5-trihydroxybenzoate (A2). To a solution of compound A1 (20 g, 0.12 mol) in MeOH (200 mL) was added concentrated sulfuric acid (6 mL) at 0 °C. The mixture was stirred at 80 °C overnight. After cooling to room temperature, the reaction mixture was neutralized with saturated Na2CO3 solution at 0 °C and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated to give compound A2 (15 g, 70% yield) as a yellow solid. MS calculated: 184; MS found: 185 [M+H] + .

[0175] Step 2: Synthesis of methyl 3,4,5-tris(benzyloxy)benzoate (A3). To a solution of compound A2 (1.8 g, 9.77 mmol) and K2CO3 (5.4 g, 39.13 mmol) in DMF (20 mL) was added BnCl (5.54 g, 43.97 mmol) at 0 °C. The solution was stirred at 60 °C for 4 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EA (50 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA = 5 / 1) to give compound A3 (4.05 g, 91% yield) as a white solid. MS calculated: 454; MS found: 455 [M+H] + .

[0176] Step 3: Synthesis of (3,4,5-tris(benzyloxy)phenyl)methanol (A4). To a mixture of compound A3 (4.0 g, 8.81 mmol) in THF (50 mL) was added LiAlH (502 mg, 13.2 mol). The solution was stirred at room temperature for 3 hours. At 0 °C, the reaction mixture was diluted with HO (0.5 mL) and 15% NaOH solution (1 mL) and extracted with DCM (30 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried over NaSO, filtered, and concentrated to give compound A4 (3.6 g, 96% yield) as a yellow solid. MS calculated: 426; MS found: 427 [M+H]. + .

[0177] Step 4: Synthesis of 3,4,5-tris(benzyloxy)benzaldehyde (A5). To a mixture of compound A4 (3.6 g, 8.45 mmol) in DCM (30 mL) was added PCC (2.73 g, 12.67 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated, and the residue was purified by silica gel flash chromatography (PE / EA = 5 / 1 to 3 / 1) to give compound A5 (2.98 g, 83% yield) as a white solid. MS calculated: 424; MS found: 425 [M+H]. + .

[0178] Step 5: Synthesis of 1-(2-(benzyloxy)-6-hydroxyphenyl)ethanone (2). To a solution of compound 1 (5.0 g, 32.9 mmol) in DMF (50 mL) was added KCO (5.5 g, 39.47 mmol) and BnCl (5.0 g, 39.47 mmol) at 0 °C, and the reaction mixture was stirred at 60 °C overnight. The reaction mixture was diluted with water (50 mL) and extracted with EA (30 mL × 2). The combined organic layers were dried over NaSO and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel flash chromatography (PE / EA = 10 / 1 to 5 / 1) to give compound 2 (5.6 g, 70% yield) as a yellow solid. MS calculated: 242; MS found: 243 [M+H] + .

[0179] Step 6: Synthesis of (E)-1-(2-(benzyloxy)-6-hydroxyphenyl)-3-(3,4,5-tris(benzyloxy)phenyl)prop-2-en-1-one (3). To a solution of compound 2 (1.4 g, 5.78 mmol) in EtOH (20 mL), compound A5 (2.7 g, 6.36 mmol) and KOH (1.62 g, 28.9 mmol) were added. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was diluted with HO (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over NaSO, filtered, and concentrated. The solid was triturated with EtOH (20 mL), filtered, and washed with EtOH (10 mL) to give compound 3 (3.25 g, 87% yield) as a yellow solid. MS calculation: 648;MS actual measurement: 649[M+H] + .

[0180] Step 7: Synthesis of 5-(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)-2H-chromene (4). To a solution of compound 3 (1.0 g, 1.54 mmol) in THF / EtOH (20 mL / 6 mL) was added CeCl (951 mg, 3.86 mmol) and NaBH (147 mg, 3.86 mmol) at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (30 mL) and extracted with DCM (20 mL x 2). The combined organic layers were dried over NaSO and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel flash chromatography (PE / EA = 10 / 1) to give compound 4 (692 mg, 71% yield) as a yellow solid. MS calculated: 632; MS found: 633 [M+H] + .

[0181] Step 8: Synthesis of (2S,3R)-5-(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (5). To a solution of compound 4 (50 mg, 0.08 mmol) in 15 mL of THF was added BH3·THF (1 M, 0.8 mL) for 2 h under ice-water bath. 3N NaOH solution (0.22 mL, 0.68 mmol) and 30% aqueous HO2 solution (77 mg, 0.68 mmol) were added to the mixture at 0 °C. The reaction was stirred at 65 °C overnight. The reaction mixture was then diluted with HO (10 mL) and extracted with EA (20 mL × 2). The organic phase was concentrated and purified by silica gel flash chromatography (PE / EA = 3 / 1) to give compound 5 (40 mg, 80% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ:7.48-7.38(m,18H),7.35-7.28(m,3H),7.10(t,J=4.2Hz,1H),7.06(s,2H),6.64(d,J=8.0Hz,1H),6.48(d,J=8.0Hz,1 H),5.14-5.09(m,6H),4.93(s,2H),4.69(d,J=7.6Hz,1H),4.11-4.04(m,1H),2.90-2.84(m,1H),2.61-2.55(m,1H).MS calculation: 650;MS measurement: 651[M+H] + .

[0182] Step 9: Synthesis of (2S,3R)-5-(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)benzoate (6). To a mixture of compound 5 (288 mg, 0.44 mmol) in DCM (30 mL), 3,4,5-tris(benzyloxy)benzoic acid (234 mg, 0.53 mmol), EDCI (226 mg, 1.32 mmol), and DMAP (54 mg, 0.44 mmol) were added under ice-water bath. The solution was stirred overnight at room temperature. The reaction mixture was diluted with HO (50 mL) and extracted with DCM (30 mL x 2). The combined organic layer was washed with brine (30 mL x 2), dried over NaSO, filtered, and concentrated. The residue was purified by reverse-phase silica gel flash chromatography (ACN / HO = 5% to 95%, 254 nm, 40 min) to give compound 6 (295 mg, 62% yield) as a yellow oil. MS calculated: 1072; MS found: 1073 [M+H]. + .

[0183] Step 10: Synthesis of compound 32. To a mixture of compound 6 (295 mg, 0.28 mmol) in EA (20 mL) was added Pd(OH) (10% by weight, 30 mg). The mixture was stirred overnight at room temperature under a H balloon. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC to give (2R,3R)-2-(4-((ethylcarbamoyl)oxy)-3,5-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate (35 mg, 29% yield) as a white solid. 1 H NMR(400MHz,CD3OD)δ:6.99-6.95(m,3H),6.46(d,J=8.4Hz,1H),6.41-6.36(m,3H),5.4 5-5.41(m,1H),5.10(d,J=5.6Hz,1H),2.85(t,J=4.6Hz,2H).MS calculation: 442;MS actual measurement: 441[M+H] - .

[0184] Scaffold 1 [ka] Step 1: Synthesis of gallocatechin (GC). (2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol (EGC) (50 g) was treated with phosphate buffer pH = 7.2 (c = 0.1 M, 140 mL). The solution was refluxed for 2 hours, and after cooling, a white precipitate of gallocatechin was obtained. After filtration, the solid was crystallized from water (500 mL), which gave the desired GC in good yield and purity.

[0185] Step 2: Synthesis of Scaffold 1. To a stirred solution of (2S,3R)-2-(3,4,5-trihydroxyphenyl)chroman-3,5,7-triol (GC) (5.0 g, 16.33 mmol, 1 equiv.) in anhydrous DMF (30 mL), K2CO3 (11.30 g, 81.63 mmol, 5.0 equiv.) was added and stirred at room temperature for 0.5 h. To this, BnBr (9.2 mL, 81.63 mmol, 5.0 equiv.) was slowly added dropwise at -20 °C. The suspension was slowly warmed to room temperature and stirred at room temperature for 24 h. After complete consumption of the starting material, the reaction mixture was filtered through a Celite pad to remove K2CO3. The Celite pad was washed with EtOAc (100 mL). The combined organic phase was washed with cold HO (50 mL x 2), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography (EtOAc:hexane, (6:1)) to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (4.5 g, 36% yield) as a white solid. 1 H NMR(400MHz,CDCl3):δ 7.48-7.20(m,25H),6.82(s,2H),6.34(s,1H),6.13(s,1H),5.07(s,8H),5.04(s,1H),4.91(s,2H),4 .64(d,J=7.2Hz,1H),4.03(bs,1H),2.78(dd,J=16.0Hz,4.8Hz,1H),2.46(dd,J=16.4Hz,4.8Hz,1H).

[0186] Scaffold 2 [ka] To a solution of 1-(2,4,6-trihydroxyphenyl)ethan-1-one (10 g, 59.52 mmol, 1.0 equiv.) in HMPA (85 mL) was added K2CO3 (24.65 g, 178.56 mmol, 3.0 equiv.) at room temperature. BnCl (15.0 mL, 130.95 mmol, 2.2 equiv.) was added at 0 °C and stirred at room temperature for 10 min. The resulting mixture was further stirred at 90 °C for 3 h. The reaction mixture was filtered, and the filtrate was poured into ice-cold water (100 mL). It was then acidified with 3 N HCl (pH = 4). The formed precipitate was filtered, and the resulting solid was dried to give 1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)ethan-1-one (4.0 g, 19.3% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ13.75(s,1H),7.51-7.31(m,10H),6.31(d,J=2.4Hz,1H),6.18(d,J=2.4Hz,1H),5.18(s,2H),5.16(s,2H),2.48(s,3H).

[0187] Scaffold 3 [ka] Step 1: Synthesis of methyl 3,4,5-trihydroxybenzoate (2). To a solution of methyl 3,4,5-trihydroxybenzoate (20 g, 117.564 mmol, 1 equiv.) in 200 mL of MeOH was added HSO (11.5 mL, 117.564 mmol, 2 equiv.) at 0 °C, and the reaction mixture was stirred at 80 °C for 22 h. The reaction progress was monitored by TLC. After this time, the reaction mixture was concentrated under reduced pressure, and the resulting crude material was diluted with cold water to give the desired product as a solid. The resulting solid was filtered, washed with water, and the wet cake was dried to give methyl 3,4,5-trihydroxybenzoate as a white solid (20 g, 92% yield). 1H NMR (400MHz, DMSO-d6) δ9.29(s,3H), 6.92(s,2H), 3.72(s,3H).

[0188] Step 2: Synthesis of methyl 3,4,5-tris(benzyloxy)benzoate (3). To a suspension of methyl 3,4,5-trihydroxybenzoate (19 g, 103.182 mmol, 1 equiv.) in DMF (200 mL) at 0 °C, KCO (71.304 g, 515.591 mmol, 5 equiv.) was added, followed by benzyl bromide (61 mL, 515.591 mmol, 5 equiv.). The mixture was heated at 80 °C for 16 h. After this time, ice was added to the reaction mixture to afford the desired product as a solid. The resulting solid was filtered and washed with water to afford methyl 3,4,5-tris(benzyloxy)benzoate as a white solid (30 g, 64% yield). 1 H NMR (400MHz, DMSO-d6) δ7.43-7.26 (m, 17H), 5.33 (s, 2H), 5.16 (s, 2H), 5.01 (s, 2H), 3.83 (s, 3H).

[0189] Step 3: Synthesis of methyl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (4). To a solution of methyl 3,4,5-tris(benzyloxy)benzoate (30 g, 66.006 mmol, 1 equiv.) in 200 mL of ACN was added Selectfluor (46.7 g, 132.013 mmol, 2 equiv.) at 0 °C and stirred at room temperature for 96 h. The reaction progress was monitored by TLC. After this time, the reaction mixture was quenched with a saturated solution of NaHCO3, and the product was extracted with EtOAc (100 mL x 3). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound obtained was purified by flash column chromatography eluting with 10% EtOAc in hexane as the eluent to give 3,4,5-tris(benzyloxy)-2-fluorobenzoate as a light brown solid (7 g, 22% yield). 1H NMR(400MHz,DMSO-d6)δ7.42-7.28(m,16H),5.33(s,2H),5.16(s,2H),5.14(s,2H),3.81(s,3H), 19 F NMR (400MHz, DMSO-d6) δ-134.52.

[0190] Step 4: Synthesis of Scaffold 3. To a solution of 3,4,5-tris(benzyloxy)-2-fluorobenzoate (7 g, 14.814 mmol, 1 equiv.) in THF / HO (3:1) (50 mL) was added NaOH (5.9 g, 148.145 mmol, 10 equiv.) and stirred at 80 °C for 6 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with HO (30 mL). The product was extracted with EtOAc (80 mL x 2). The aqueous phase was adjusted to pH < 3 with 1 N HCl. The mixture was then filtered, and the filter cake was dried. The crude compound was purified by flash column chromatography using 10% MeOH in DCM as the eluent to give 3,4,5-tris(benzyloxy)-2-fluorobenzoic acid as a white solid (3.8 g, 60% yield). 1 H NMR (400MHz, DMSO-d6): δ13.22(s,1H),7.42(d,J=1.2Hz,2H),7.44-7.26(m,10H),5.14(s,2H),5.12(s,2H),3.81(s,3H).

[0191] Scaffold 4 [ka] To a suspension of methyl 3,4,5-trihydroxybenzoate (50 g, 294.110 mmol, 1 equiv.) in DMF (250 mL) at 0 °C was added DBU (70 mL, 588.200 mmol, 2 equiv.), followed by benzyl bromide (178 mL, 588.200 mmol, 2 equiv.). The reaction was stirred at room temperature for 48 h. After this time, the reaction mixture was diluted with ice-cold water, and the precipitated solid was filtered and washed with water. The crude compound was purified by column chromatography using EtOAc in hexanes to give methyl 3,4-bis(benzyloxy)-5-hydroxybenzoate as a yellow solid (9.5 g, 9% yield). 1 H NMR (400MHz, DMSO-d6) δ9.77(s,1H),7.45-7.33(m,7H),7.29-7.27(m,3H),17.5(d,J=2.0Hz,2H),5.12(s,2H),5.02(s,2H),3.79(s,3H).

[0192] Scaffold 5 [ka] To a solution of (2S,3R)-2-(3,4-dihydroxyphenyl)chroman-3,5,7-triol (1.26 g, 4.36 mmol, 1 equiv.) in anhydrous DMF (15 mL), K2CO3 (2.41 g, 17.44 mmol, 4.0 equiv.) was added and stirred at room temperature for 0.5 h. To this, BnBr (2.1 mL, 17.44 mmol, 4.0 equiv.) was slowly added dropwise at -20 °C. The suspension was slowly warmed to room temperature and stirred at room temperature for 96 h. After complete consumption of the starting material as monitored by TLC, the reaction mixture was filtered through a Celite pad to remove K2CO3. The Celite pad was washed with EtOAc (100 mL). The combined organic phase was washed with cold H2O (50 mL x 2) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography using EtOAc:hexane (5:1) to give (2R,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (1.28 g, 45% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ7.50-7.26(m,20H),7.16-6.98(m,2H),6.87(d,J=8.4Hz,1H),6.32(d,J=2.0Hz,1H),6.12(d,J=2 .0Hz,1H),5.16-4.98(m,9H),4.63(d,J=7.6Hz,1H),4.02-3.90(m,1H),2.76(dd,J=16.8Hz,5.6Hz,1H),2.56-2.41(m,1H).

[0193] compound 34 [ka] Step 1: Synthesis of benzyl 3,4-bis(benzyloxy)benzoate (2). To a suspension of 3,4-dihydroxybenzoic acid (2 g, 12.976 mmol, 1 equiv.) in DMF (40 mL) was added KCO (5.9 g, 43.602 mmol, 3.3 equiv.) followed by benzyl bromide (5.2 mL, 43.602 mmol, 3.3 equiv.) at 0 °C. The mixture was stirred at room temperature for 20 h until TLC showed the reaction was complete. The reaction mixture was diluted with water and extracted with EtOAc. The solvent was evaporated, and the residue was purified by flash chromatography eluting with 10% EtOAc in hexane to give benzyl 3,4-bis(benzyloxy)benzoate as a white solid (3 g, 54% yield). 1 H NMR (400MHz, DMSO-d6): δ7.67(s,2H)7.47-7.30(m,15),6.93(d,J=8.8Hz,1H),5.32(s,2H),5.23(s,2H),5.19(s,2H).

[0194] Step 3: Synthesis of 3,4-bis(benzyloxy)benzoic acid (3). To a mixture of 3,4-bis(benzyloxy)benzoate (0.5 g, 1.179 mmol, 1 equiv.) in THF / HO (1:1) (10 mL) was added LiOH·HO (0.098 g, 2.358 mmol, 2 equiv.). The solution was stirred at 50 °C for 4 h. The reaction mixture was concentrated to remove THF. Next, the mixture was diluted with HO (30 mL) and extracted with EA (20 mL x 1). The aqueous phase was adjusted to pH < 3 with 1 N HCl. The mixture was then filtered, and the filter cake was dried to give 3,4-bis(benzyloxy)benzoic acid as a white solid (0.35 g, 89% yield). 1 H NMR (400MHz, DMSO-d6): δ12.67(s,1H),7.53(d,J=7.2Hz,2H),7.46-7.29(m,10),7.14(d,J=8.8Hz,1H),5.21(s,2H),5.16(s,2H).

[0195] Step 4: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)benzoate (4). To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (0.5 g, 0.661 mmol, 1 equiv.) in 10 mL of DCM, 3,4-bis(benzyloxy)benzoic acid (0.43 g, 1.322 mmol, 2 equiv.), EDCI (0.606 g, 3.305 mmol, 5 equiv.), EtN (0.5 mL, 3.305 mmol, 5 equiv.), and DMAP (0.05 g, 0.396 mmol, 0.6 equiv.) were added at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After this time, the reaction mixture was quenched with hypo solution, extracted with DCM (50 mL x 3), washed with brine, and dried over anhydrous NaSO. The organic layer was concentrated under reduced pressure to give the crude compound, which was purified by flash column chromatography eluting with 20% EtOAc in hexane to give the desired (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)benzoate as a white solid (0.5 g, 71% yield). 1 H NMR(400MHz,DMSO-d6):7.45-7.28(s,32H),7.22(t,J=6.8Hz,3H),7.11(d,J=8.8Hz,1H),6.87(s,2H),6.42(s,1H),6.28(s,1H),5.40(d,J=6.8 Hz,1H),5.21(s,2H),5.16(d,J=8.8Hz,1H),5.07(s,6H),4.97(s,2H),4.92(s,2H),4.85(s,2H),2.91(dd,J=5.2Hz,1H),2.74(dd,J=6.8Hz,1H).

[0196] Step 5: Synthesis of Compound 34. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)benzoate (0.45 g, 0.419 mmol, 1 equiv.) in 4 mL of THF:MeOH (1:1), palladium hydroxide (20 wt%, 0.94 g) was added at room temperature, and the reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The crude compound obtained was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4-dihydroxybenzoate as a gray solid (0.025 g, 13% yield). 1 HMR(400MHz,DMSO-d6):7.23(s,1H),7.18(d,J=8.4Hz,1H),6.74(d,J=8.8Hz,1H),6.25(s,2H),5.91 (s,1H),5.80(s,1H),5.20(q,J=4.8Hz,1H),4.99(d,J=5.2Hz,1H),2.60(dd,J=4.0Hz,2H).LCMS:(MH + ):m / Z:441.0.

[0197] compound 35 [ka] Step 1: Synthesis of methyl 3-(benzyloxy)-4-nitrobenzoate (2). To a stirred suspension of methyl 3-hydroxy-4-nitrobenzoate (2.5 g, 12.69 mmol, 1.0 equiv.) and KCO (5.25 g, 38.07 mmol, 3.0 equiv.) in anhydrous CHCN (25 mL) was added BnBr (2.26 mL, 19.03 mmol, 1.5 equiv.) dropwise at 0 °C. The mixture was stirred at 60 °C for 3 h and cooled to room temperature. The reaction mixture was filtered through a Celite pad and washed with EtOAc (100 mL). The combined organic phase was washed with HO (50 mL), brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (PE / EA=10 / 1) to give methyl 3-(benzyloxy)-4-nitrobenzoate (2.0 g, 54.9% yield) as a pale yellow solid. 1 H NMR (400MHz, CDCl3): δ7.90-7.80(m,2H),7.70(dd,J=8.4Hz,1.6Hz,1H),7.50-7.30(m,5H),5.28(s,2H),3.96(s,3H).

[0198] Step 2: Synthesis of 3-(benzyloxy)-4-nitrobenzoic acid (3). To a solution of methyl 3-(benzyloxy)-4-nitrobenzoate (1.4 g, 4.87 mmol, 1.0 equiv.) in MeOH:THF:HO (1:1:1) (15 mL) was added LiOH·HO (0.41 g, 9.75 mmol, 2.0 equiv.) at room temperature and stirred for 12 h at room temperature. The solvent was evaporated from the reaction mixture and diluted with HO (30 mL). The aqueous layer was acidified with 1 N HCl to pH < 3, and the resulting solid was filtered and washed with HO to give 3-(benzyloxy)-4-nitrobenzoic acid (1.10 g, 82.7% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6); δ13.65(s,1H),7.98(d,J=8.4Hz,1H),7.86(s,1H),7.65(d,J=8.4Hz,1H),7.46-7.30(m,5H),5.38(s,2H).

[0199] Step 3: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3-(benzyloxy)-4-nitrobenzoate (4). To a mixture of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (0.05 g, 0.06 mmol, 1.0 equiv.) and 3-(benzyloxy)-4-nitrobenzoic acid (0.036 g, 0.13 mmol, 2.0 equiv.) in CHCl (10 mL), EDCI (0.038 g, 0.19 mmol, 3.0 equiv.), DMAP (0.005 g, 0.04 mmol, 0.6 equiv.), and TEA (0.05 mL, 0.33 mmol, 5.0 equiv.) were added under ice-water bath. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with HO (10 mL) and CHCl (30 mL). The organic layer was separated, washed with brine (10 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (PE / EA=5 / 1) to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3-(benzyloxy)-4-nitrobenzoate (0.025 g, 37.3% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ7.76(d,J=8.4Hz,1H),7.62(d,J=1.2Hz,1H),7.51(dd,J=8.4Hz,1.2Hz,1H),7.44-7.19(m,30H),6.70(s,2H) ,6.31(d,J=6.4Hz,1H),6.51(q,J=5.6,1H),5.15(s,2H),5.12(d,J=6.0Hz,1H),5.08-4.93(m,10H),2.91(dq,J=19.2,5.2Hz,2H).

[0200] Step 4: Synthesis of Compound 35. To a mixture of the compound (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3-(benzyloxy)-4-nitrobenzoate (0.2 g, 0.19 mmol, 1.0 equiv.) in THF (3 mL) and MeOH (3 mL), Pd(OH) (20 wt%, 0.02 g) was added. The mixture was stirred at room temperature under an H atmosphere for 12 hours. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The crude compound obtained was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 4-amino-3-hydroxybenzoate (0.030 g, 33% yield) as a gray solid. 1 H NMR(400MHz,DMSO-d6)δ9.39(bs,1H),9.29(s,1H),9.06(s,1H),8.87(bs,1H),7.13(s,2H),6.53(d,J=8.4Hz,1H ),6.25(s,2H),5.91(s,1H),5.80(s,1H),5.38(s,2H),5.20(d,J=5.2Hz,1H),5.00(d,J=5.2Hz,1H),2.59(m,2H).

[0201] compound 36 [ka] Step 1: Synthesis of methyl 5-hydroxy-6-nitronicotinate (2). To a solution of methyl 5-hydroxynicotinate (1.0 g, 6.53 mmol, 1.0 equiv) in HSO (10 mL) was added HNO (0.8 g, 13.06 mmol) at 0 °C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into 100 mL of ice water and stirred for 20 minutes. The mixture was filtered to give methyl 5-hydroxy-6-nitronicotinate (0.390 g, 30.2% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ12.21 (bs, 1H), 8.44 (s, 1H), 8.03 (d, J = 1.2Hz, 1H), 3.90 (s, 3H).

[0202] Step 2: Synthesis of methyl 5-(benzyloxy)-6-nitronicotinate (3). To a solution of methyl 5-hydroxy-6-nitronicotinate (0.3 g, 1.51 mmol, 1.0 equiv.) and K2CO3 (0.418 g, 3.03 mmol, 2.0 equiv.) in DMF (5 mL) was added BnBr (0.518 g, 3.03 mmol, 2.0 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (PE / EA = 9 / 1) to give methyl 5-(benzyloxy)-6-nitronicotinate (0.33 g, 76.7% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): 8.60 (s, 1H), 8.39 (s, 1H), 7.44-7.28 (m, 5H), 5.46 (s, 2H), 3.93 (s, 3H).

[0203] Step 3: Synthesis of 5-(benzyloxy)-6-nitronicotinic acid (4). To a mixture of methyl 5-(benzyloxy)-6-nitronicotinate (0.4 g, 1.38 mmol, 1.0 equiv.) in THF (15 mL) and HO (2 mL), LiOH·HO (0.140 g, 3.34 mmol, 2.4 equiv.) was added. The solution was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to remove THF. The mixture was diluted with HO (30 mL) and extracted with EtOAc (30 mL x 2). The aqueous phase was adjusted to pH < 3 with 1 N HCl. The resulting solid was filtered and washed with cold water to give 5-(benzyloxy)-6-nitronicotinic acid (0.32 g, 84% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6): 14.14 (bs, 1H), 8.57 (s, 1H), 8.35 (s, 1H), 7.44-7.28 (m, 5H), 5.46 (s, 2H).

[0204] Step 4: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 5-(benzyloxy)-6-nitronicotinate (5). To a mixture of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (0.5 g, 0.66 mmol, 1.0 equiv) and 5-(benzyloxy)-6-nitronicotinic acid (0.215 g, 0.79 mmol, 2 equiv) in CHCl (10 mL) was added EDCI·HCl (0.378 g, 1.98 mmol, 3.0 equiv), DMAP (0.048 g, 0.39 mmol, 0.6 equiv), and TEA (0.5 mL, 3.30 mmol, 5.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with HO (20 mL), and the phases were separated. The organic phase was washed with brine (20 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA=4 / 1) to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 5-(benzyloxy)-6-nitronicotinate (0.2 g, 29.8% yield) as a pale yellow solid. 1 HNMR(400MHz,DMSO-d6)δ:8.46(s,1H),8.18(s,1H),7.45-7.17(m,31H),6.94(s,2H),6.44(s,1H),6.28(s,1H),5.5 2(q,J=6.0Hz,1H),5.34(q,J=12.0Hz,2H),5.19(q,J=7.6Hz,1H),5.13-4.93(m,8H),4.87(s,2H),3.08-2.78(m,2H).

[0205] Step 5: Synthesis of Compound 36. To a mixture of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 5-(benzyloxy)-6-nitronicotinate (0.280 g, 0.27 mmol, 1.0 equiv.) in THF (5 mL) and MeOH (5 mL), Pd(OH) (20 wt%, 0.100 g) was added. The mixture was stirred overnight at room temperature under an H atmosphere. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 6-amino-5-hydroxynicotinate (0.040 g, 31.2% yield) as a gray solid. 1 H NMR(400MHz,DMSO-d6)δ:9.99(bs,1H),9.31(s,1H),9.07(s,1H),8.85(d,J=4.4Hz,2H),8.09(s,1H),7.95(d,J=1.6Hz,1H),7.13(s,1H), 6.51(bs,2H),6.25(s,2H),5.91(d,J=2.4Hz,1H),5.79(d,J=2.4Hz,1H),5.21(q,J=5.2Hz,1H),5.00(d,J=5.2Hz,1H),2.65-2.57(m,2H).

[0206] compound 37 [ka] Step 1: Synthesis of methyl 3-(benzyloxy)-4-nitrobenzoate (2). To a stirred suspension of methyl 3-hydroxy-4-nitrobenzoate (2.5 g, 12.69 mmol, 1.0 equiv.) and KCO (5.25 g, 38.07 mmol, 3.0 equiv.) in anhydrous CHCN (25 mL) was added BnBr (2.26 mL, 19.03 mmol, 1.5 equiv.) dropwise at 0 °C. The mixture was stirred at 60 °C for 3 h and cooled to room temperature. The reaction mixture was filtered through a pad of Celite (100 mL) and washed with HCl (100 mL). The combined organic phase was washed with HO (50 mL), brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (PE / EA=10 / 1) to give methyl 3-(benzyloxy)-4-nitrobenzoate (2.0 g, 54.9% yield) as a pale yellow solid. 1 H NMR (400MHz, CDCl3): δ7.90-7.80(m,2H),7.70(dd,J=8.4Hz,1.6Hz,1H),7.50-7.30(m,5H),5.28(s,2H),3.96(s,3H).

[0207] Step 2: Synthesis of methyl 4-amino-3-(benzyloxy)benzoate (3). A mixture of NHCl (0.093 g, 1.74 mmol, 1.0 equiv) and Fe (0.486 g, 8.71 mmol, 5.0 equiv) in 20 mL of EtOH:HO (5:1) was stirred at 90 °C for 1 h. Next, methyl 3-(benzyloxy)-4-nitrobenzoate (0.5 g, 1.74 mmol, 1.0 equiv) in CHCN (10 mL) was slowly added at room temperature, and the resulting mixture was stirred at 90 °C for 3 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to give the crude product, which was diluted with HO (30 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give methyl 4-amino-3-(benzyloxy)benzoate (0.400 g, 84.2% yield) as a white solid. 1H NMR(400MHz,DMSO-d6);δ7.50(d,J=7.2Hz,2H),7.41-7.36(m,4H),7.32(q, J=8.8Hz,1H),6.66(d,J=8.8Hz,1H),5.65(s,2H),5.13(s,2H),3.72(s,3H).

[0208] Step 3: Synthesis of methyl 3-(benzyloxy)-4-(N-(methylsulfonyl)methylsulfonamido)benzoate (4). To a solution of methyl 4-amino-3-(benzyloxy)benzoate (0.4 g, 1.55 mmol, 1.0 equiv) in CHCl (4 mL) was added EtN (1.3 mL, 9.32 mmol, 6.0 equiv) and mesyl chloride (0.534 g, 4.66 mmol, 3.0 equiv) at 0 °C. The mixture was stirred at room temperature for 12 h. The reaction mixture was neutralized with saturated aqueous NaHCO (10 mL) and extracted with CHCl (50 mL × 2). The combined organic layers were washed with HO (20 mL), brine (20 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (PE / EA=9 / 1) to give 3-(benzyloxy)-4-(N-(methylsulfonyl)methylsulfonamido)benzoate (0.6 g, 93% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ7.71(d,J=1.6Hz,1H),7.68(d,J=8.0Hz,1H),7.60(dd,J=8.0Hz,J= 1.6Hz, 1H), 7.51 (d, J=7.2Hz, 2H), 7.41-7.30 (m, 3H), 5.31 (s, 2H), 3.87 (s, 3H), 3.42 (s, 6H).

[0209] Step 4: Synthesis of 3-(benzyloxy)-4-(methylsulfonamido)benzoic acid (5). To a solution of methyl 3-(benzyloxy)-4-(N-(methylsulfonyl)methylsulfonamido)benzoate (0.6 g, 1.45 mmol, 1.0 equiv) in MeOH:HO (1:1) (20 mL) was added 2 N NaOH (20 mL) at room temperature, followed by stirring under reflux for 2 hours. After completion of the reaction, the solvent was evaporated from the reaction mixture. The reaction mixture was diluted with HO (30 mL) and extracted with ethyl acetate (50 mL). The aqueous layer was acidified with 2 N HCl and extracted with EtOAc (50 mL × 2). The combined organic phase was dried over NaSO, filtered, and concentrated to give 3-(benzyloxy)-4-(methylsulfonamido)benzoic acid (0.42 g, 90% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6): δ12.88 (s, 1H), 9.22 (s, 1H), 7.59-7.52 (m, 4H), 7.42-7.29 (m, 4H), 5.23 (s, 2H), 3.01 (s, 3H).

[0210] Step 5: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3-(benzyloxy)-4-(methylsulfonamido)benzoate (6). To a mixture of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (0.6 g, 0.79 mmol, 1.0 equiv) and 3-(benzyloxy)-4-(methylsulfonamido)benzoic acid (0.306 g, 0.95 mmol, 1.2 equiv) in DCM (8 mL) was added EDCI (0.454 g, 2.37 mmol, 3.0 equiv), DMAP (0.058 g, 0.47 mmol, 0.6 equiv), and TEA (0.6 mL, 3.96 mmol, 5.0 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 24 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with HO (20 mL) and CHCl (50 mL). The phases were separated. The organic layer was washed with brine (20 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (PE / EA=5 / 1) to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3-(benzyloxy)-4-(methylsulfonamido)benzoate (0.22 g, 26% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ7.60-7.50(m,3H),7.44-7.27(m,26H),7.26-7.19(m,4H),7.02(s,1H),6.72(s,2H),6.30(dd,J=7.6,2.4 Hz,2H),5.50(d,J=5.6,1H),5.10(d,J=6.8,1H),5.08-5.02(m,6H),4.99-4.93(m,6H),3.08-2.81(m,2H),2.88(d,J=3.6,1H).

[0211] Step 6: Synthesis of Compound 37. To a mixture of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3-(benzyloxy)-4-(methylsulfonamido)benzoate (0.2 g, 0.18 mmol, 1.0 equiv.) in THF (4 mL) and MeOH (4 mL) was added Pd(OH) (20 wt%, 0.038 g). The mixture was stirred overnight at room temperature under an H atmosphere. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3-hydroxy-4-(methylsulfonamido)benzoate (0.058 g, 59.5% yield) as a gray solid. 1 H NMR(400MHz,DMSO-d6)δ9.08(bs,7H),7.34(s,1H),7.30-7.26(m,2H),6.27(s,2H),5.92(d,J=2.4Hz ,1H),5.80(d,J=2.0Hz,1H),5.27(q,J=5.2Hz,1H),5.04(d,J=5.2Hz,1H),2.99(s,3H),2.63(m,2H).

[0212] compound 38 [ka] Step 1: Synthesis of benzyl 2,3,4-tris(benzyloxy)benzoate (2). To a solution of 2,3,4-trihydroxybenzoic acid (10 g, 58.780 mmol, 1 equiv.) and K2CO3 (3.24 g, 558.235 mmol, 10 equiv.) in DMF (100 mL) was added BnBr (69.4 mL, 558.235 mmol, 10 equiv.) at 0 °C. The mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with cold HO (500 mL) to obtain the free solid, which was filtered and dried under reduced pressure to give the desired compound, benzyl 2,3,4-tris(benzyloxy)benzoate, as a brown solid (27.1 g, 87% yield). 1H NMR (400MHz, DMSO-d6): δ7.57(d,J=8.8Hz,1H),7.48(d,J=7.2Hz,2H),7.41-7. 28(m,18),7.26(d,J=5.6Hz,1H),5.26(s,2H),5.22(s,2H),4.96(s,2H).LC-MS m / z(M+H):355.10.

[0213] Step 2: Preparation of 2,3,4-tris(benzyloxy)benzoic acid (3). To a mixture of compound 2,3,4-tris(benzyloxy)benzoate (1 g, 1.88 mmol, 1 equiv.) in THF / HO (1:1) (20 mL) was added LiOH·HO (0.237 g, 5.65 mmol, 3.0 equiv.). The solution was stirred at 70 °C for 2 h. The reaction mixture was concentrated to remove THF. Next, the mixture was diluted with HO (30 mL) and extracted with EA (80 mL x 2). The aqueous phase was adjusted to pH < 3 with 1 N HCl. The mixture was then filtered, and the filter cake was dried to give 2,3,4-tris(benzyloxy)benzoic acid (0.8 g, 96% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6);δ12.62(s,1H),7.53(d,J=8.8Hz,1H),7.51(d,J=8.0Hz,2H),7.47-7.32 (m,10H),7.31-7.28(m,3H),7.04(d,J=8.8Hz,1H),5.21(s,2H),4.99(s,2H),4.96(s,2H).LC-MS m / z(M+H):441.20.

[0214] Step 3: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 2,3,4-tris(benzyloxy)benzoate (4). To a mixture of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (0.1 g, 0.13 mmol, 1.0 equiv.) and 2,3,4-tris(benzyloxy)benzoic acid (0.116 g, 0.264 mmol, 2 equiv.) in DCM (3 mL), EDCI (0.075 g, 0.393 mmol, 3.0 equiv.), DMAP (0.08 g, 0.066 mmol, 0.5 equiv.), and TEA (0.09 mL, 0.665 mmol, 5 equiv.) were added under ice-water bath. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with HO (20 mL), and the phases were separated. The organic layer was washed with brine (20 mL x 2), dried over NaSO, filtered, and concentrated. The crude compound was purified by flash column chromatography eluting with 15% EtOAc in hexane as the eluent to give the desired compound (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 2,3,4-tris(benzyloxy)benzoate (0.050 g, 32% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ7.44-7.19(m,42H),6.70(s,2H),6.65-6.64(m,1H),6.25(dd,J=8.0,2.0Hz,2H),5. 52(d,J=5.6Hz,1H),5.08-4.93(m,16H),2.99(dd,J=17.2,5.6Hz,1H),2.82(dd,J=16.8,6.8Hz,1H).LC-MS m / z(M+H):1179.53.

[0215] Step 4: Synthesis of Compound 38. To a mixture of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 2,3,4-tris(benzyloxy)benzoate (0.25 g, 0.217 mmol) in THF (15 mL) and MeOH (15 mL) was added Pd(OH) (20 wt%, 0.25 g). The mixture was stirred overnight at room temperature under an H atmosphere. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,3,4-trihydroxybenzoate (0.027 g, 27% yield) as a gray solid. 1 H NMR(400MHz,DMSO-d6)δ9.08(bs,8H),6.98(d,J=8.8Hz,1H),6.33(d,J=8.8Hz,1H),6.27(s,2H),5.92( d,J=2.0Hz,1H),5.80(d,J=2.0Hz,1H),5.28(q,J=5.6Hz,1H),5.06(d,J=5.6Hz,1H),2.65(m,2H).LC-MS m / z(M+H):459.1.

[0216] compound 39 [ka] Step 1: Synthesis of (3,4,5-tris(benzyloxy)phenyl)methanol (2). To a solution of methyl 3,4,5-tris(benzyloxy)benzoate (4.0 g, 8.81 mmol, 1.0 equiv.) in THF (40 mL) was added LiAlH (0.5 g, 13.2 mmol, 1.5 equiv.) at 0 °C. The mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with HO (0.5 mL) and 15% NaOH (1 mL) at 0 °C. The resulting mixture was filtered through a Celite pad, the filtrate was concentrated, and the residue was purified by silica gel flash column chromatography (PE / EA = 4 / 1) to give 3,4,5-tris(benzyloxy)phenyl)methanol (3.6 g, 94% yield) as a white solid. 1H NMR (400MHz, DMSO-d6): δ7.48-7.20(m,15H),6.75(s,2H),5.17(t,J=17.2Hz,1H),5.09(s,4H),4.91(s,2H),4.41(d,J=5.6Hz,2H).

[0217] Step 2: Synthesis of 3,4,5-tris(benzyloxy)benzaldehyde (3). To a mixture of 3,4,5-tris(benzyloxy)phenyl)methanol (3.6 g, 8.29 mmol, 1.0 equiv.) in CHCl (20 mL) was added PCC (2.68 g, 12.44 mmol, 1.5 equiv.) at 0 °C. The mixture was stirred at room temperature for 4 h, and the solvent was evaporated from the reaction mixture under reduced pressure. The resulting residue was purified by flash column chromatography to afford 3,4,5-tris(benzyloxy)benzaldehyde (2.8 g, 78% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ9.85 (s, 1H), 7.48-7.20 (m, 17H), 5.21 (s, 4H), 5.06 (s, 2H).

[0218] Step 3: Synthesis of (E)-1-(2-hydroxyphenyl)-3-(3,4,5-tris(benzyloxy)phenyl)prop-2-en-1-one (5). To a mixture of 3,4,5-tris(benzyloxy)benzaldehyde (1.8 g, 4.16 mmol, 1.0 equiv.) and 1-(2-hydroxyphenyl)ethan-1-one (0.51 g, 3.75 mmol, 0.9 equiv.) in EtOH (40 mL), KOH (1.16 g, 20.83 mmol, 5.0 equiv.) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated. The residue was diluted with HO (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated. The resulting residue was purified by flash column chromatography to give (E)-1-(2-hydroxyphenyl)-3-(3,4,5-tris(benzyloxy)phenyl)prop-2-en-1-one (1.2 g, 53% yield) as a yellow solid. 1H NMR (400MHz, CDCl3): δ12.81(s,1H),7.86(d,J=7.6,1H),7.77(d,J=15.2,1H), 7.50-7.20(m,17H),7.10-6.90(m,2H),6.93(s,2H),5.16(s,4H),5.13(s,2H).

[0219] Step 4: Synthesis of 2-(3,4,5-tris(benzyloxy)phenyl)-2H-chromene (6). To a solution of (E)-1-(2-hydroxyphenyl)-3-(3,4,5-tris(benzyloxy)phenyl)prop-2-en-1-one (1.2 g, 2.21 mmol, 1.0 equiv.) in THF (20 mL) and EtOH (6 mL) was added anhydrous CeCl (1.36 g, 5.53 mmol, 2.5 equiv.) and NaBH (0.21 g, 5.53 mmol, 2.5 equiv.) at 0 °C. The mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with HO (50 mL) and extracted with CHCl (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (PE / EA=10 / 1) to give 2-(3,4,5-tris(benzyloxy)phenyl)-2H-chromene (0.81 g, 69% yield) as a colorless liquid. 1 H NMR(400MHz,CDCl3):7.48-7.24(m,14H),7.12(m,1H),7.02(m,1H),6.89(m,1H),6.78(m, 1H),6.76(s,2H),6.51(d,J=9.2,1H),5.79(s,1H),5.72(m,1H),5.07(s,4H),5.13(s,2H).

[0220] Step 5: Synthesis of 2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (7). To a solution of 2-(3,4,5-tris(benzyloxy)phenyl)-2H-chromene (0.8 g, 1.52 mmol, 1.0 equiv.) in anhydrous THF (10 mL), BH₃·DMS (2 M, 1.9 mL, 3.80 mmol, 2.5 equiv.) was added over 10 min at 0 °C. The mixture was stirred at room temperature until the starting material disappeared. Then, 3 N aqueous NaOH (1.26 mL, 3.80 mmol, 2.5 equiv.) and 30% aqueous HO (0.05 mL, 3.80 mmol, 2.5 equiv.) were added dropwise at 0 °C. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (PE / EA=10 / 1) to give 2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (0.22 g, 26.6% yield) as a white solid. 1 H NMR (400MHz, CDCl3):7.48-7.24(m,14H),7.20-7.09(m,3H),6.93-6.89(m,2H),6. 76(s,2H),5.20-5.01(m,7H),4.65(d,J=8.0,1H),3.99(m,1H),3.10-2.81(m,2H).

[0221] Step 6: Synthesis of 2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)benzoate (8). To a mixture of 2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (0.26 g, 0.47 mmol, 1.0 equiv.) and 3,4,5-tris(benzyloxy)benzoic acid (0.52 g, 1.19 mmol, 2.5 equiv.) in CHCl (10 mL), EDCI (0.36 g, 1.91 mmol, 4.0 equiv.), DMAP (0.03 g, 0.29 mmol, 0.6 equiv.), and TEA (0.4 mL, 2.86 mmol, 6.0 equiv.) were added under ice-water bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with HO (30 mL) and extracted with CHCl (50 mL × 2). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA = 5 / 1) to give 2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)benzoate (0.185 g, 40% yield) as a white solid. 1 H NMR (400MHz, CDCl3): δ7.44-7.19(m,33H),7.13-6.93(m,3H),6.68(s,2H),5.45( d,J=4.8,1H),5.21(d,J=6.0,1H),5.10-4.91(m,12H),2.97(dq,J=16.4,4.0,2H).

[0222] Step 7: Synthesis of Compound 39. To a mixture of 2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)benzoate (0.180 g, 0.18 mmol, 1.0 equiv.) in THF (2.5 mL) and MeOH (2.5 mL), Pd(OH) / C (20 wt%, 26 mg) was added. The mixture was stirred at room temperature under an H atmosphere for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give 2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5-trihydroxybenzoate (0.035 mg, 44.3% yield) as a gray solid.1 H NMR(400MHz,DMSO-d6)δ8.83(bs,6H),7.22-7.04(m,2H),6.96-6.83(m,2H),6.8 2(s,2H),6.26(s,2H),5.31(d,J=4.8Hz,1H),5.18(d,J=4.4Hz,1H),2.88(m,2H).

[0223] compound 40 [ka] Step 1: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (1). To a stirred solution of 3,4,5-tris(benzyloxy)-2-fluorobenzoic acid (2.2 g, 4.761 mmol, 1.2 equiv.) in DCM (10 mL) under a N atmosphere, oxalyl chloride (2.1 mL, 19.840 mmol, 5 equiv.) and 2 drops of DMF were added at 0 °C. The reaction mixture was stirred at room temperature for 3 h. After this time, the reaction mixture was concentrated under reduced pressure to provide the acid chloride. The resulting acid chloride was added to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (3.0 g, 3.968 mmol, 1 equiv.), DMAP (1.93 g, 15.870 mmol, 4 equiv.), and EtN (2.2 mL, 15.870 mmol, 4 equiv.) in CHCl (10 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. Finally, the reaction was quenched with saturated aqueous sodium bicarbonate solution (5 mL). The organic layer was separated, and the aqueous layer was extracted with CHCl (30 mL). The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by flash column chromatography (EtOAc in hexanes) to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate as a white solid (1.2 g, 70% yield). 1H NMR(400MHz,DMSO-d6)δ7.44-7.22(m,40H),7.04(d,J=5.6Hz,1H),6.90(s,2H),6.34(s,1H),6.28(s,1H),5.48(d,J=5.2Hz,1H),5.1 8(d,J=7.2Hz,1H),5.12(s,2H),5.06(s,2H),5.01(s,4H),4.94(s,6H),4.87(s,2H),2.98(dd,J=5.2Hz,1H),2.81(dd,J=7.6Hz,1H), 19 F NMR(400MHz,DMSO-d6)δ-133.68.LCMS:(M+H + ):m / Z:1197.5.

[0224] Step 2: Synthesis of Compound 40. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (2.0 g, 1.670 mmol, 1 equiv.) in 20 mL of THF:MeOH (1:1), palladium hydroxide / carbon powder, Pd(OH) (20 wt%, 2.0 g) was added at room temperature, and the reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate as an off-white solid (0.46 g, 60% yield). 1 H NMR(400MHz,DMSO-d6):6.67(d,J=6.4Hz,1H),6.24(s,2H),5.90(d,J=2.4Hz,1H) ,5.79(d,J=2.4Hz,1H),5.29(q,J=5.2Hz,1H),5.03(d,J=4.8Hz,1H),2.58(m,2H), 19 F NMR(400MHz,DMSO-d6)δ-140.76.LCMS:(MH + ):m / Z:475.20.

[0225] compound 41 [ka] Step 1: Synthesis of benzyl 4,5-bis(benzyloxy)-2-fluorobenzoate (2). To a suspension of 2-fluoro-4,5-dihydroxybenzoic acid (0.5 g, 2.906 mmol, 1 equiv.) in DMF (10 mL), K2CO3 (1.6 g, 11.626 mmol, 4 equiv.) was added and stirred at room temperature for 30 minutes, followed by benzyl bromide (1.4 mL, 11.626 mmol, 4 equiv.) at 0 °C. The mixture was stirred for 16 hours until TLC showed the reaction was complete. The reaction mixture was diluted with water and extracted with EtOAc. The solvent was evaporated, and the residue was purified by flash chromatography using 15% EtOAc in hexane as eluent to obtain the desired compound, benzyl 4,5-bis(benzyloxy)-2-fluorobenzoate, as a white solid (0.8 g, 62% yield). 1 H NMR (400MHz, DMSO-d6): δ6.51(d,J=7.2Hz,1H),7.42-7.25(m,15),6.67(d,J=12Hz,1H),5.23(s,2H),5.17(s,2H),5.12(s,2H).

[0226] Step 2: Synthesis of 4,5-bis(benzyloxy)-2-fluorobenzoic acid (3). To a mixture of benzyl 4,5-bis(benzyloxy)-2-fluorobenzoate (0.94 g, 2.126 mmol, 1 equiv.) in THF / HO (3:1) (20 mL) was added LiOH·HO (0.446 g, 10.629 mmol, 5.0 equiv.). The solution was stirred at 60 °C for 24 h. The reaction mixture was concentrated to remove THF. Next, the mixture was diluted with HO (20 mL) and extracted with EA (10 mL x 1). The aqueous phase was adjusted to pH < 3 with 1 N HCl. The mixture was then filtered, and the filter cake was dried to give 4,5-bis(benzyloxy)-2-fluorobenzoic acid as a white solid (0.7 g, 97% yield). 1H NMR (400MHz, DMSO-d6): δ12.92(s,1H),7.46-7.28(m,11),7.09(d,J=12.4Hz,1H),5.22(s,2H),5.12(s,2H).

[0227] Step 3: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 4,5-bis(benzyloxy)-2-fluorobenzoate (5). To a stirred solution of 4,5-bis(benzyloxy)-2-fluorobenzoic acid (0.4 g, 1.136 mmol, 1 equiv.) in DCM (6 mL) under a N atmosphere was added oxalyl chloride (0.4 mL, 5.681 mmol, 5 equiv.) and 2 drops of DMF at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was concentrated under reduced pressure to provide the acid chloride. The resulting acid chloride was added to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (0.68 g, 0.900 mmol, 0.8 equiv.), DMAP (0.03 g, 1.36 mmol, 1 equiv.) in DCM (6 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. Finally, the reaction was quenched with saturated aqueous sodium bicarbonate solution (5 mL). The organic layer was separated, and the aqueous layer was extracted with CHCl (30 mL). The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by flash column chromatography (EtOAc in hexanes) to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 4,5-bis(benzyloxy)-2-fluorobenzoate as a white solid (0.25 g, 20% yield). 1H NMR(400MHz,DMSO-d6):7.41-7.03(m,34H),7.09(d,J=12.0Hz,1H),6.86(s,2H),6.42(s,1H),6.27(s,1H),5.74(s,2H),5.42(d,J=6 .0Hz,1H),5.15(d,J=10Hz,1H),5.10(s,2H),5.06(s,4H),4.97(s,6H),4.84(s,2H),2.91(dd,J=4.4Hz,1H),2.77(dd,J=8.0Hz,1H), 19 F NMR (375MHz, DMSO-d6) δ -139.80, -138.95.

[0228] Step 4: Synthesis of Compound 41. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 4,5-bis(benzyloxy)-2-fluorobenzoate (0.35 g, 0.321 mmol, 1 equiv.) in 10 mL of THF:MeOH (1:1), palladium hydroxide (20 wt%, 0.35 g) was added at room temperature, and the reaction mixture was stirred under a hydrogen atmosphere for 16 hours. After this time, the mixture was filtered to remove the catalyst. The filtrate was evaporated under reduced pressure. The crude compound was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-4,5-dihydroxybenzoate as an off-white solid (0.078 g, 52% yield). 1 H NMR(400MHz,DMSO-d6):9.12(bs,7H),7.18(d,J=7.2Hz,1H),7.18(d,J=12.0Hz,1H),6.25(s,2H),5.90(d,J=2. 0Hz,1H),5.79(d,J=2.0Hz,1H),5.27(d,J=5.2Hz,1H),5.01(d,J=5.2Hz,1H),2.60(dd,J=5.6Hz,2H).LCMS:(M+H + ):m / Z:461.1.

[0229] compound 42 [ka] Step 1: Synthesis of benzyl 2,4,5-tris(benzyloxy)benzoate (2). To a suspension of 2,4,5-trihydroxybenzoic acid (0.5 g, 2.939 mmol, 1 equiv.) in DMF (10 mL) was added KCO (2 g, 14.695 mmol, 5 equiv.) followed by benzyl bromide (1.7 mL, 14.695 mmol, 5 equiv.) at 0 °C. The mixture was heated to 60 °C for 12 h until TLC showed the reaction was complete. The reaction mixture was diluted with water and extracted with EtOAc. The solvent was evaporated, and the residue was purified by flash chromatography eluting with 15% EtOAc in hexane to give benzyl 2,4,5-tris(benzyloxy)benzoate as a white solid (1.3 g, 84% yield). 1 H NMR (400MHz, DMSO-d6): δ7.54(s,1H),7.41(d,J=6.8Hz,2H),7.37-7.30(m,18),6.56(s,1H),5.30(s,2H),5.12(s,2H),5.09(s,2H),5.00(s,2H).

[0230] Step 2: Synthesis of 2,4,5-tris(benzyloxy)benzoic acid (3). To a mixture of 2,4,5-tris(benzyloxy)benzoate (1 g, 1.886 mmol, 1 equiv.) in THF / HO (1:1) (20 mL) was added LiOH·HO (0.237 g, 5.660 mmol, 3 equiv.). The solution was stirred at room temperature for 4 h. The reaction mixture was concentrated to remove THF. Next, the mixture was diluted with HO (40 mL) and extracted with EA (15 mL). The aqueous phase was adjusted to pH < 3 with 1 N HCl. The mixture was then filtered, and the filter cake was dried to give 2,4,5-tris(benzyloxy)benzoic acid as a white solid (0.68 g, 82% yield). 1 H NMR (400MHz, DMSO-d6): δ7.48-7.45(m,4H), 7.41-7.29(m,12), 6.95(s,1H), 5.20(s,2H), 5.13(s,2H), 5.05(s,2H).

[0231] Step 3: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 2,4,5-tris(benzyloxy)benzoate (4). To a stirred solution of 2,4,5-tris(benzyloxy)benzoic acid (0.510 g, 1.157 mmol, 1 equiv.) in DCM (8 mL) under a N atmosphere was added oxalyl chloride (0.49 mL, 5.795 mmol, 5 equiv.) and 2 drops of DMF at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was concentrated under reduced pressure to provide the acid chloride. The resulting acid chloride was added to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (0.7 g, 0.925 mmol, 0.8 equiv.), DMAP (0.564 g, 4.628 mmol, 0.5 equiv.) in CHCl (12 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. Finally, the reaction was quenched with saturated aqueous NaHCO (5 mL). The organic layer was separated, and the aqueous layer was extracted with CHCl (30 mL). The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by flash column chromatography (EtOAc in hexanes) to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 2,4,5-tris(benzyloxy)benzoate as a light brown solid (0.3 g, 22% yield). 1 H NMR(400MHz,DMSO-d6):7.40-7.11(s,41H),7.11(s,1H),6.91(d,J=3.2Hz,1H),6.84(d,J=6.0Hz,1H),6.41(s,1H),6.26(s,1 H),5.44(d,J=6.8Hz,1H),5.16(d,J=8.8Hz,1H),5.15(s,8H),4.91(s,2H),4.88(s,2H),4.83(s,4H),2.64(dd,J=6.8Hz,2H).

[0232] Step 4: Synthesis of Compound 42. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 2,4,5-tris(benzyloxy)benzoate (0.3 g, 0.254 mmol, 1 equiv.) in 10 mL of THF:MeOH (1:1), palladium hydroxide (20 wt%, 0.3 g) was added at room temperature, and the reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was then filtered through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,4,5-trihydroxybenzoate as a light brown solid (0.03 g, 26% yield). 1 H NMR(400MHz,DMSO-d6):9.02(s,8H),6.93(bs,1H),6.25(d,J=5.6Hz,3H),5.91(d,J=2.0Hz,1H),5. 81(d,J=2.4Hz,1H),5.34(q,J=4.8Hz,1H),5.11(d,J=4.8Hz,1H),2.59(dd,J=4.0Hz,2H).LCMS:(MH + ):m / Z:457.1.

[0233] Compounds 43 and 44 [ka] Step 1: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl(1r,4R)-4-hydroxycyclohexane-1-carboxylate (3A & 3B). To a mixture of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (0.1 g, 0.13 mmol, 1.0 equiv.) and 4-hydroxycyclohexane-1-carboxylic acid (0.02 g, 0.10 mmol, 0.8 equiv.) in CHCl (5 mL) was added EDCI (0.07 g, 0.39 mmol, 3.0 equiv.), DMAP (0.01 g, 0.08 mmol, 0.6 equiv.), and TEA (0.1 mL, 0.66 mmol, 5.0 equiv.) at 0 °C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with HO (20 mL) and extracted with CHCl (50 mL × 2). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA=5 / 1) to give the major isomer (30 mg) and the minor isomer (15 mg) as a white solid in an overall yield of 38.7%. Major isomer analysis data: 1 H NMR (400 MHz, CDCl): δ 7.48-7.20 (m, 25H), 6.67 (s, 2H), 6.27 (d, J = 2.4 Hz, 1H), 6.24 (d, J = 2.0 Hz, 1H), 5.31 (q, J = 6.8 Hz, 1H), 5.10-4.90 (m, 11H), 3.51 (m, 1H), 2.80 (dq, J = 16.8, 5.2 Hz, 2H), 2.11 (m, 1H), 2.00-1.80 (m, 3H), 1.80-1.70 (m, 1H), 1.50-1.11 (m, 4H). Analytical data for the minor isomer: 1H NMR (400MHz, CDCl3): δ7.48-7.30(m,25H),6.69(s,2H),6.27(d,J=2.4Hz,1H),6.24(d,J=2.0Hz,1H),5.31(q,J=6.8Hz,1H),5.15 -4.90(m,12H),3.76(m,1H),2.70(dq,J=16.8,5.6Hz,2H),2.27(m,1H),2.10-1.95(m,3H),1.90-1.70(m,2H),1.60-1.16(m,3H).

[0234] Step 2: Synthesis of Compound 43. To a mixture of compound (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 4-hydroxycyclohexane-1-carboxylate (120 mg, 0.13 mmol, 1.0 equiv.) in THF (3 mL) and MeOH (3 mL) was added Pd(OH) (20 wt%, 0.024 g). The mixture was stirred overnight at room temperature under an H atmosphere. The reaction mixture was passed through a Celite bed, and the filtrate was concentrated. The residue was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 4-hydroxycyclohexane-1-carboxylate (0.022 g, 37.9% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ9.36(bs,1H),9.10(bs,1H),8.88(bs,2H),8.15(bs,1H),6.21(s,2H),5.89(d,J=2.0Hz,1H),5.75(d,J=2.4Hz,1H),5 .03(q,J=6.0Hz,1H),4.80(d,J=6.0Hz,1H),4.36(s,1H),3.59(bs,1H) ,2.70-2.40(m,2H),2.22(m,1H),1.80-1.55(m,2H),1.55-1.30(m,6H).

[0235] Step 3: Synthesis of Compound 44. To a mixture of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 4-hydroxycyclohexane-1-carboxylate (0.190 g, 0.21 mmol, 1.0 equiv.) in THF (5 mL) and MeOH (5 mL), Pd(OH) (20 wt%, 0.030 g) was added at room temperature, and the reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 4-hydroxycyclohexane-1-carboxylate (0.050 g, 53.7% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ9.32(s,1H),9.05(s,1H),8.85(bs,2H),8.09(bs,1H),6.21(s,2H),5.90(d,J=2.4Hz,1H),5.74(d,J=2.0Hz,1H),5.01(q,J =6.0Hz,1H),4.78(d,J=6.4Hz,1H),4.52(d,J=4.0Hz,1H),3.27(m,1H),2. 70-2.40(m,2H),2.11-2.01(m,1H),1.80-1.60(m,4H),1.40-1.01(m,4H).

[0236] compound 45 [ka] Step 1: Synthesis of (4,5-bis(benzyloxy)-2-fluorophenyl)methanol (2). To a mixture of methyl 4,5-bis(benzyloxy)-2-fluorobenzoate (0.3 g, 0.678 mmol, 1 equiv.) in THF (10 mL) was added LiAlH (2 M, 0.5 mL, 1.017 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. After this time, at 0 °C, the reaction mixture was diluted with HO (0.5 mL) and 15% NaOH solution (1 mL) and extracted with DCM (30 mL × 3). The combined organic phase was washed with brine (30 mL × 2), dried over NaSO, filtered, and concentrated to give (4,5-bis(benzyloxy)-2-fluorophenyl)methanol as a white solid (0.19 g, 83% yield). 1 H NMR (400MHz, DMSO-d6): δ7.43-7.31(m,10H),7.11(d,J=7.6Hz,1H),6.94(d,J=11.6Hz,1H),5.12(s,2H),5.05(s,2H),4.41(d,J=5.6Hz,2H).

[0237] Step 2: Synthesis of 4,5-bis(benzyloxy)-2-fluorobenzaldehyde (3). To a mixture of the compound (4,5-bis(benzyloxy)-2-fluorophenyl)methanol (0.1 g, 0.295 mmol) in DCM (3 mL) was added PCC (0.096 g, 0.443 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by flash chromatography eluting with 50% EtOAc in hexanes to give 4,5-bis(benzyloxy)-2-fluorobenzaldehyde as a white solid (0.088 g, 89% yield). 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),7.47-7.25(m,11H),6.69(d,J=11.6Hz,1H),5.21(s,2H),5.14(s,2H),5.09(s,2H).

[0238] Step 3: Synthesis of (E)-3-(4,5-bis(benzyloxy)-2-fluorophenyl)-1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)prop-2-en-1-one (4). To a solution of 1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)ethan-1-one (0.072 g, 0.208 mmol, 1 equiv.) in EtOH (2 mL), KOH (0.316 g, 0.624 mmol, 3 equiv.) was added at room temperature. The mixture was stirred at room temperature for 30 minutes. Then, to the above reaction mixture, compound 4,5-bis(benzyloxy)-2-fluorobenzaldehyde (0.07 g, 0.208 mmol, 1 equiv.) was added. The reaction mixture was stirred at room temperature for 24 hours. After this time, the reaction mixture was concentrated, and the resulting crude was diluted with HO (15 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over NaSO, filtered, and concentrated. The solid was triturated with EtOH (20 mL), filtered, washed with EtOH (10 mL), and then dried to give (E)-3-(4,5-bis(benzyloxy)-2-fluorophenyl)-1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)prop-2-en-1-one as a yellow solid (0.029 g, 21% yield). 1 H NMR(400MHz,DMSO-d6)δ12.97(s,1H),7.62(d,J=14.4Hz,1H),7.46-7.29(s,17H),(s,1H),7.24(d,J=6.4Hz,1H),7.19(t,J=4.0H z,3H),6.07(d,J=22.0Hz,1H),6.37(d,J=2.0Hz,1H),6.23(d,J=2.0Hz,1H),5.21(s,2H),5.19(s,2H),5.16(s,2H),4.92(s,2H).

[0239] Step 4: Synthesis of 5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)-2-fluorophenyl)-2H-chromene (5). To a solution of (E)-3-(4,5-bis(benzyloxy)-2-fluorophenyl)-1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)prop-2-en-1-one (0.5 g, 0.750 mmol, 1 equiv.) in THF / EtOH (4 mL / 2 mL), CeCl (0.46 g, 1.876 mmol, 2 equiv.) and NaBH (0.71 g, 1.876 mmol, 2 equiv.) were added at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with DCM (20 mL × 2). The combined organic layers were dried over NaSO and filtered. The filtrate was concentrated to give the crude product, and the residue was purified by flash chromatography eluting with 30% EtOAc in hexanes as eluent to give 5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)-2-fluorophenyl)-2H-chromene as a pale yellow solid (0.25 g, 5% yield). 1 H NMR(400MHz,DMSO-d6)δ7.46-7.24(m,24H),7.04-6.99(m,3H),6.94-6.85(m,2H)6.82(dd,J=13.6Hz,1 H),6.52(s,1H)5.62(dd,J=4.0Hz,1H),5.14(s,4H),5.08(s,2H),4.87(s,2H),3.73(q,J=14.0Hz,1H).

[0240] Step 5: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-fluorophenyl)chroman-3-ol (6). To a solution of 5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-fluorophenyl)-2H-chromene (1.2 g, 1.846 mmol, 1 equiv.) in 12 mL of THF was added BH DMS (2 M, 2.8 mL, 5.538 mmol, 3 equiv.) over 2 h under ice-water bath conditions. 3N NaOH solution (0.228 g, 5.538 mmol, 3 equiv.) was added to the mixture, followed by 30% aqueous HO (0.62 mL, 5.538 mmol, 3 equiv.) at 0 °C. The reaction was stirred at room temperature for 16 h. After this time, the reaction mixture was diluted with HO (20 mL) and extracted with EA (30 mL x 2). The organic phase was concentrated and the crude residue was purified by flash chromatography eluting with 30% EtOAc in hexanes to give (2S,3R)-5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-fluorophenyl)chroman-3-ol as a white solid (1.0 g, 83% yield). 1 H NMR(400MHz,DMSO-d6)δ7.45-7.27(m,18H),7.07(d,J=6.8Hz,1H),6.99(d,J=6.4Hz,1H),6.34(d,J=2.0Hz,1H),6.10(d,J =2.0Hz,1H),5.14(d,J=5.2Hz,1H),5.10(s,2H),5.07(s,2H),4.99(s,4H),3.79(d,J=8.4Hz,1H),2.86(dd,J=4.8Hz,2H).

[0241] Step 6: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-fluorophenyl)chroman-3-yl 3,4,5-tris(benzyloxy)benzoate (8). To a stirred solution of 3,4,5-tris(benzyloxy)benzoic acid (0.8 g, 1.807 mmol, 3 equiv.) in DCM (8 mL) under a N atmosphere was added oxalyl chloride (0.4 mL, 3.612 mmol, 6 equiv.) and 2 drops of DMF at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was concentrated under reduced pressure to provide the acid chloride. The resulting acid chloride was added to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-fluorophenyl)chroman-3-ol (0.4 g, 0.602 mmol, 1 eq.), DMAP (0.1 g, 3.611 mmol, 3 eq.) in CHCl (10 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. Finally, the reaction was quenched with saturated aqueous NaHCO (5 mL). The organic layer was separated, and the aqueous layer was extracted with CHCl (30 mL). The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by flash column chromatography (EtOAc in hexanes) to give (2S,3R)-5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-fluorophenyl)chroman-3-yl 3,4,5-tris(benzyloxy)benzoate as a pale yellow solid (0.25 g, 35% yield). 1 H NMR(400MHz,DMSO-d6):δ7.49-7.16(m,43H),7.06-6.99(m,2H),6.41(dd,J=2.0Hz,1H),6.19(dd,J=2.0Hz,1H),5.36(q,J=6.0Hz) ,1H),5.24(d,J=7.2Hz,1H),5.14(s,2H),5.08(s,2H),5.05(s,2H),4.98(s,2H),2.89(dd,J=7.6Hz,1H),2.66(dd,J=7.6Hz,1H).

[0242] Step 7: Synthesis of Compound 45. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-fluorophenyl)chroman-3-yl 3,4,5-tris(benzyloxy)benzoate (0.2 g, 0.183 mmol, 1 equiv.) in 8 mL of THF:MeOH (1:1), palladium hydroxide (20 wt%, 0.2 g) was added at room temperature, and the reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The crude compound obtained was purified by preparative HPLC to give (2S,3R)-2-(2-fluoro-4,5-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate as a gray solid (0.020 g, 23% yield). 1 H NMR (400MHz, DMSO-d6): δ9.24(s,7H),6.81(s,2H),6.67(d,J=7.2Hz,1H),6.52(d,J=11.6Hz,1H),5.95(d,J=2.0Hz,1H),6. 41(d,J=2.0Hz,1H),5.25(q,J=6.8Hz,1H),5.21(d,J=6.0Hz,1H),2.77(dd,J=7.6Hz,1H),2.57(dd,J=7.6Hz,1H).LCMS:(M+H + ):m / Z:461.0.

[0243] compound 46 [ka] Step 1: Synthesis of (3,4,5-tris(benzyloxy)-2-fluorophenyl)methanol (2). To a mixture of methyl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (5 g, 10.550 mmol, 1 equiv.) in THF (30 mL) was added LiAlH (2 M, 7.9 mL, 15.820 mmol, 1.5 equiv.) at 0 °C. The solution was stirred at room temperature for 6 h. After this time, at 0 °C, the reaction mixture was diluted with HO (8 mL) and 15% NaOH solution (2 mL) and extracted with DCM (30 mL × 3). The combined organic phase was washed with brine (30 mL × 2), dried over NaSO, filtered, and concentrated to give the compound (3,4,5-tris(benzyloxy)-2-fluorophenyl)methanol as a white solid (3.0 g, 65% yield). 1 H NMR(400MHz,DMSO-d6)δ7.46(d,J=7.2Hz,2H),7.40-7.21(m,13H),6.97(d,J=1.2H z,1H),5.10(s,2H),5.03(s,2H),4.91(s,2H),4.35(s,1H),3.37(d,J=4.8Hz,2H).

[0244] Step 2: Synthesis of 3,4,5-tris(benzyloxy)benzaldehyde (3). To a mixture of 3,4,5-tris(benzyloxy)-2-fluorophenyl)methanol (3 g, 6.756 mmol, 1 equiv.) in DCM (30 mL) was added PCC (2.17 g, 10.135 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated, and the residue was purified by flash chromatography eluting with 30% EtOAc in hexanes to give 3,4,5-tris(benzyloxy)benzaldehyde as a white solid (2 g, 68% yield). 1 H NMR (400MHz, DMSO-d6) δ10.11 (s, 1H), 7.47-7.25 (m, 16H), 5.19 (s, 2H), 5.15 (s, 2H), 5.09 (s, 2H).

[0245] Step 3: Synthesis of (E)-1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)-3-(3,4,5-tris(benzyloxy)-2-fluorophenyl)prop-2-en-1-one (4). To a solution of 1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)ethan-1-one (2 g, 5.429 mmol, 1.2 equiv) in EtOH (10 mL) was added KOH (1.2 g, 21.25 mmol, 5 equiv). The mixture was stirred at room temperature for 30 min. Then, 3,4,5-tris(benzyloxy)-2-fluorobenzaldehyde (2 g, 4.524 mmol, 1 equiv) was added. The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated. The residue was diluted with HO (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (30 mL × 2), dried over NaSO, filtered, and concentrated. The solid was triturated with EtOH (20 mL), filtered, washed with EtOH (10 mL), and then dried to give (£)-1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)-3-(3,4,5-tris(benzyloxy)-2-fluorophenyl)prop-2-en-1-one as a yellow solid (3.2 g, 96% yield). 1 H NMR(400MHz,DMSO-d6)δ12.83(s,1H),7.73(d,J=9.2Hz,1H),7.46-7.31(14)7.19-7.14(m,10H),6.61(s,1H),6. 38(s,1H),6.25(s,1H),5.28(d,J=8.0Hz,1H),5.19(s,2H),5.11(s,2H),5.10(s,2H),5.03(s,2H),4.93(s,2H).

[0246] Step 4: Synthesis of 5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)-2-fluorophenyl)-2H-chromene (5). To a solution of (E)-1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)-3-(3,4,5-tris(benzyloxy)-2-fluorophenyl)prop-2-en-1-one (3 g, 4.464 mmol, 1 equiv.) in THF / EtOH (15 mL / 3 mL) was added CeCl (3.3 g, 13.390 mmol, 3 equiv.) and NaBH (0.5 g, 13.390 mmol, 3 equiv.) at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (30 mL) and extracted with DCM (20 mL × 2). The combined organic layers were dried over NaSO and filtered. The filtrate was concentrated to give a crude residue which was purified by flash chromatography eluting with 30% EtOAc in hexanes as eluent to give 5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)-2-fluorophenyl)-2H-chromene as a white solid (2.0 g, 68% yield). 1 H NMR(400MHz,DMSO-d6)δ7.47-7.26(m,24H),7.06-6.98(m,3H),6.88(d,J=6.8Hz,1H),6.78(d,J=11.2Hz,1H),6.38(d,J=2.0Hz, 1H),6.13(d,J=2.0Hz,1H),5.62(dd,J=13.6Hz,1H),5.13(s,2H),4.50(s,2H),4.99(s,4H),4.98(s,2H),3.73(d,J=14.8Hz,1H).

[0247] Step 5: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)-2-fluorophenyl)chroman-3-ol (6). To a solution of 5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)-2-fluorophenyl)-2H-chromene (2 g, 4.385 mmol, 1 equiv.) in 20 mL of THF was added BH DMS (1 M, 13.157 mL, 13.157 mmol, 3 equiv.) over 1 h at 0 °C. After this time, 3 N NaOH solution (0.52 g, 13.157 mmol, 3 equiv.) and 30% aqueous HO (1.8 mL, 13.157 mmol, 3 equiv.) were added at 0 °C. The reaction was stirred at room temperature for 16 h. The reaction mixture was then diluted with HO (20 mL) and extracted with EA (20 mL × 2). The organic phase was concentrated, and the crude residue was purified by flash chromatography eluting with 30% EtOAc in hexanes to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)-2-fluorophenyl)chroman-3-ol as a white solid (1.1 g, 33% yield). 1 H NMR(400MHz,DMSO-d6)δ7.46-7.28(m,24H),7.13(d,J=6.8Hz,2H),6.96(d,J=6.4Hz,1H),6.37(d,J=2.0Hz,1H),6.13(d,J=2.0Hz) ,1H),5.22(dd,J=5.2Hz,1H),5.11(s,2H),5.05(s,4H),5.00(s,2H),4.97(s,2H),3.79(q,J=7.2Hz,1H),2.90(dd,J=4.8Hz,2H).

[0248] Step 6: Synthesis of (2S,3R)-5-(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)benzoate (7). To a stirred solution of 3,4,5-tris(benzyloxy)benzoic acid (0.17 g, 0.387 mmol, 3 equiv.) in DCM (4 mL) under a N atmosphere, oxalyl chloride (0.08 mL, 0.645 mmol, 5 equiv.) and 2 drops of DMF were added and stirred at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was concentrated under reduced pressure to provide the acid chloride. The resulting acid chloride was added to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)-2-fluorophenyl)chroman-3-ol (0.1 g, 0.129 mmol, 1 equiv.), DMAP (0.015 g, 0.129 mmol, 1 equiv.) in CHCl (10 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. Finally, the reaction was quenched with saturated aqueous NaHCO (5 mL). The organic layer was separated, and the aqueous layer was extracted with CHCl (30 mL). The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by flash column chromatography (EtOAc in hexanes) to give (2S,3R)-5-(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)benzoate as a pale yellow solid (0.12 g, 26% yield). 1 H NMR(400MHz,DMSO-d6):δ7.46-7.23(m,39H),7.15(d,J=6.8Hz,2H),6.88(d,J= 6.8Hz,1H),6.63(d,J=6.4Hz,1H),6.42(d,J=2.0Hz,1H),6.21(d,J=2.0Hz,1H), 5.51(q,J=6.0Hz,1H),5.29(d,J=7.2Hz,1H),5.18(s,2H),5.15(s,2H),5.11(s ,4H),4.00(s,4H),4.96(s,4H),2.84(dd,J=7.6Hz,1H),2.72(dd,J=7.6Hz,1H).

[0249] Step 7: Synthesis of Compound 46. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)-2-fluorophenyl)chroman-3-yl 3,4,5-tris(benzyloxy)benzoate (0.4 g, 0.334 mmol, 1 equiv.) in 8 mL of THF:MeOH (1:1), palladium hydroxide (20 wt%, 0.040 g) was added at room temperature, and the reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The crude compound obtained was purified by preparative HPLC to give (2S,3R)-2-(2-fluoro-3,4,5-trihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate as a gray solid (0.05 g, 3% yield). LCMS: (M+H + ):m / Z:477.0.

[0250] compound 47 [ka] Step 1: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)-2-fluorophenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (2). To a stirred solution of 3,4,5-tris(benzyloxy)-2-fluorobenzoic acid (0.88 g, 1.937 mmol, 3 equiv.) in DCM (5 mL) under a N atmosphere was added oxalyl chloride (2.5 mL, 3.874 mmol, 6 equiv.) and 2 drops of DMF at 0° C. The reaction mixture was stirred at room temperature for 1 hour. After this time, the reaction mixture was concentrated under reduced pressure to provide the acid chloride. The resulting acid chloride was added to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)-2-fluorophenyl)chroman-3-ol (0.5 g, 0.645 mmol, 1 equiv.), DMAP (0.314 g, 2.580 mmol, 4 equiv.), and EtN (0.36 mL, 2.580 mmol, 4 equiv.) in CHCl (5 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. Finally, the reaction was quenched with saturated aqueous NaHCO (5 mL). The organic layer was separated, and the aqueous layer was extracted with CHCl (30 mL). The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by flash column chromatography (EtOAc in hexanes) to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)-2-fluorophenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate as a white solid (0.22 g, 28% yield). 1 H NMR(400MHz,DMSO-d6)δ7.55-7.16(m,40H),7.06(d,J=6.4Hz,1H),6.45(d,J=2Hz,1H),6.26(d,J=2Hz,1H),5.48( d,J=6Hz,1H),5.37(d,J=8.4Hz,1H),5.16(s,2H),5.10(s,4H),4.98(s,6H),4.94(s,2H),2.49(dd,J=1.6Hz,2H). 19F NMR(400MHz,DMSO-d6)δ-123.50,-81.87.LCMS:(M+H + ):m / Z:1215.

[0251] Step 2: Synthesis of Compound 47. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)-2-fluorophenyl)chroman-3-yl 3,4,5-bis(benzyloxy)-2-fluorobenzoate (0.210 g, 0.175 mmol, 1 equiv.) in 12 mL of THF:MeOH (1:1), palladium hydroxide (20 wt%, 0.21 g) was added at room temperature and stirred under a hydrogen atmosphere for 16 hours. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give (2S,3R)-2-(2-fluoro-3,4,5-trihydroxyphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate as an off-white solid (0.010 g, 11% yield). 1 H NMR(400MHz,DMSO-d6):6.62(d,J=6.8Hz,1H),6.17(d,J=6.4Hz,1H),5.93(d,J=2.0Hz,1H),5.78(d,J=2 .4Hz,1H),5.32(q,J=6.0Hz,1H),5.23(d,J=6.4Hz,1H),2.70(dd,J=5.5Hz,1H),2.61(dd,J=6.4Hz,1H), 19 F NMR(400MHz,DMSO-d6)δ-141.04,-149.92.LCMS:(MH - ):m / Z:494.

[0252] compound 48 [ka] Step 1: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-fluorophenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (2). Under a N atmosphere, to a stirred solution of 3,4,5-tris(benzyloxy)-2-fluorobenzoic acid (1 g, 2.245 mmol, 3 equiv.) in DCM (12 mL) was added oxalyl chloride (4.3 mL, 4.488 mmol, 5 equiv.) and 2 drops of DMF at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Excess oxalyl chloride was removed by distillation, and the residue was dried under organic gas to give the acid chloride. This solution was added dropwise to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-fluorophenyl)chroman-3-ol (0.5 g, 0.748 mmol, 1 equiv.), DMAP (0.36 g, 2.992 mmol, 4 equiv.), and EtN (0.4 mL, 2.992 mmol, 4 equiv.) in CHCl (15 mL) at 0 °C. The mixture was stirred at room temperature for 16 h, after which saturated aqueous NaHCO was added. The organic layer was separated, and the aqueous layer was extracted with CHCl. ​​The organic phases were combined, dried (MgSO), and evaporated. The crude compound was purified by flash column chromatography eluting with 20% EtOAc in hexane as eluent to give (2S,3R)-5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-fluorophenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate as a white solid (0.22 g, 24% yield). 1 H NMR(400MHz,DMSO-d6):δ7.47-7.15(m,36H),7.01(s,2H),6.61(d,J=2.4Hz,1H),6.22(d,J=1.6Hz,1H),5.32(d ,J=8Hz,1H),5.19(d,J=4.8Hz,1H),5.12(s,2H),5.08(s,4H),4.98(s,6H),4.94(s,2H),2.49(dd,J=1.6Hz,2H). 19 F NMR(400MHz,DMSO-d6)δ-123.50,-81.87.LCMS:(M+H +):m / Z:1197.46.

[0253] Step 2: Synthesis of Compound 48. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-fluorophenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (0.22 g, 0.183 mmol, 1 equiv.) in 8 mL of THF:MeOH (1:1), palladium hydroxide (20 wt%, 0.22 g) was added at room temperature and stirred under a hydrogen atmosphere for 16 hours. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give (2S,3R)-2-(2-fluoro-4,5-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate as an off-white solid (0.05 g, 5% yield). LCMS: (MH + ):m / Z:479.0.

[0254] compound 49 [ka] Step 1: Synthesis of 3,4-bis(benzyloxy)-5-methoxybenzaldehyde (2). To a suspension of 3,4-dihydroxy-5-methoxybenzaldehyde (1 g, 5.952 mmol, 1 equiv.) in DMF (10 mL) was added KCO (3.3 g, 23.808 mmol, 4 equiv.) followed by benzyl bromide (2.6 mL, 23.808 mmol, 4 equiv.) at 0 °C. The reaction mixture was stirred at 60 °C for 16 h until TLC showed the reaction was complete. The reaction product was diluted with water (15 mL) and extracted with EtOAc (45 mL). The organic layer was separated, washed with brine solution (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with 15% EtOAc in hexanes as the eluent to give the desired compound 3,4-bis(benzyloxy)-5-methoxybenzaldehyde as a white solid (1.2 g, 57% yield). 1H NMR (400MHz, DMSO-d6) δ9.86 (s, 1H), 7.46-7.27 (m, 12H), 5.19 (s, 2H), 5.04 (s, 2H), 3.86 (s, 3H).

[0255] Step 2: Synthesis of (E)-3-(3,4-bis(benzyloxy)-5-methoxyphenyl)-1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)prop-2-en-1-one (3). To a solution of 1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)ethan-1-one (1.2 g, 7.183 mmol, 1 equiv.) in MeOH (20 mL) was added KOH (1.2 g, 35.915 mmol, 5 equiv.). The mixture was stirred at room temperature for 30 minutes. Then, the compound 3,4-bis(benzyloxy)-5-methoxybenzaldehyde (2.5 g, 7.183 mmol, 1 equiv.) was added. The reaction mixture was stirred at 60 °C for 16 hours. After this time, the reaction mixture was concentrated. The resulting residue was diluted with HO (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (30 mL × 2), dried over NaSO, filtered, and concentrated. The solid was triturated with EtOH (20 mL), filtered, washed with EtOH (10 mL), and then dried to give (E)-3-(3,4-bis(benzyloxy)-5-methoxyphenyl)-1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)prop-2-en-1-one as a yellow solid (2.1 g, 38% yield). 1 H NMR(400MHz,DMSO-d6):δ7.65(d,J=15.6Hz,1H),7.53(d,J=13.6Hz,1H),7.46-7.28(m,14H),7.22-7.16(m,4H),7.02(d,J=4.0Hz,3H) ,6.92(d,J=2.0Hz,1H),6.39(d,J=2.0Hz,1H),6.24(d,J=2.0Hz,1H),5.20(s,2H),5.16(s,2H),4.98(s,2H),4.96(s,2H),3.69(s,3H).

[0256] Step 3: Synthesis of 5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)-5-methoxyphenyl)-2H-chromene (4). To a solution of (E)-3-(3,4-bis(benzyloxy)-5-methoxyphenyl)-1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)prop-2-en-1-one (0.25 g, 0.368 mmol, 1 equiv.) in THF / EtOH (15 mL / 5 mL) was added CeCl (0.27 g, 1.106 mmol, 3 equiv.) and NaBH (0.43 g, 1.106 mmol, 3 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After this time, the reaction mixture was diluted with water (30 mL) and extracted with DCM (30 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated to give the crude product. The resulting crude product was purified by flash chromatography eluting with 30% EtOAc in hexanes as the eluent to give 5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)-5-methoxyphenyl)-2H-chromene as a yellow solid (0.18 g, 74% yield). 1 H NMR(400MHz,DMSO-d6):δ7.45-7.28(m,17H),7.72(d,J=14.0Hz,1H),6.83(d ,J=2.0Hz,1H),6.73(dd,J=2.0Hz,2H),6.35(d,J=2.0Hz,1H),6.82(d,J=2.0 Hz,1H),5.79(d,J=1.6Hz,1H),5.72(dd,J=3.6Hz,1H),5.13(d,J=13.6Hz,1H ),5.09(s,2H)5.05(s,4H),4.88(s,2H),4.47(d,J=5.6Hz,1H),3.74(s,3H).

[0257] Step 4: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)-5-methoxyphenyl)chroman-3-ol (5). To a solution of 5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)-5-methoxyphenyl)-2H-chromene (1 g, 1.515 mmol, 1 equiv.) in 10 mL of THF, BH DMS (2 M, 2.2 mL, 4.540 mmol, 3 equiv.) was added at 0 °C and stirred for 2 h. To the above reaction mixture, 3 N NaOH solution (0.18 g, 4.545 mmol, 3 equiv.) and 30% aqueous HO solution (0.49 mL, 4.545 mmol, 3 equiv.) were added at 0 °C. The reaction was stirred at room temperature for 16 h. After this time, the reaction mixture was diluted with HO (20 mL) and extracted with EA (30 mL x 2). The organic phase was concentrated and the crude product was purified by flash chromatography eluting with 20% EtOAc in hexanes to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)-5-methoxyphenyl)chroman-3-ol as a pale yellow solid (0.36 g, 36% yield). 1 H NMR(400MHz,DMSO-d6):δ7.45-7.28(m,21H),6.81(s,1H),6.71(s,1H),6.34(d,J=2.0Hz,1H),6.14(d,J=2Hz,1H),5. 06(d,J=3.6Hz,1H),5.05(s,2H)5.03(s,4H),4.89(s,2H),4.02(t,J=6.8Hz,1H),3.75(s,3H),2.78(dd,J=5.6Hz,2H).

[0258] Step 5: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)-5-methoxyphenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (5). Under a N atmosphere, to a stirred solution of 3,4,5-tris(benzyloxy)-2-fluorobenzoic acid (0.29 g, 0.635 mmol, 1.2 equiv.) in DCM (8 mL) was added oxalyl chloride (0.23 mL, 2.640 mmol, 5 equiv.) and 2 drops of DMF at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Excess oxalyl chloride was removed by distillation, and the residue was dried to give the acid chloride. This solution was added dropwise to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)-5-methoxyphenyl)chroman-3-ol (0.36 g, 0.529 mmol, 1 equiv.), DMAP (0.26 g, 2.116 mmol, 4 equiv.), and EtN (0.3 mL, 2.116 mmol, 4 equiv.) in CHCl (10 mL) at 0 °C. The mixture was stirred at room temperature overnight, after which saturated aqueous NaHCO was added. The organic layer was separated, and the aqueous layer was extracted with CHCl. ​​The combined organic phases were dried over MgSO and concentrated under reduced pressure. The crude compound was purified by flash column chromatography eluting with 12% EtOAc in hexane as eluent to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)-5-methoxyphenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate as a white solid (0.38 g, 53% yield). 1 H NMR(400MHz,DMSO-d6):δ7.43-7.23(m,37H),7.04(d,J=6.4Hz,1H),6.87(s,1H),6.7(s,1H),6.42(d,J=2.0Hz,1H),6.28(d,J=2.0Hz,1H),5.48(q,J =6.0Hz,1H),5.17(d,J=7.2Hz,1H),5.03(s,4H)4.98(s,4H),4.92(s,2H), 4.85(s,2H),3.67(s,3H),2.99(dd,J=7.6Hz,1H),2.28(dd,J=7.6Hz,1H).

[0259] Step 6: Synthesis of Compound 49. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)-5-methoxyphenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (1 g, 0.836 mmol, 1 equiv.) in 10 mL of THF:MeOH (1:1), palladium hydroxide (20 wt%, 1.0 g) was added at room temperature. The reaction mixture was stirred under a hydrogen atmosphere for 16 hours. After this time, the reaction mixture was passed through a pad of Celite to remove the catalyst. The filtrate was concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give (2S,3R)-2-(3,4-dihydroxy-5-methoxyphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate as an off-white solid (0.48 g, 16% yield). 1 H NMR (400MHz, DMSO-d6): δ9.17(bs,7H)6.68(d,J=6.4Hz,1H),6.44(d,J=1.6Hz,1H),6.41(s,1H),5.92(d,J=2.0Hz,1H),5.80(d,J =2.0Hz,1H),5.30(q,J=6.0Hz,1H),5.02(d,J=6.0Hz,1H),3.66(s,3H),2.67(dd,J=6.0Hz,1H),2.58(dd,J=6.0Hz,1H).LCMS:(M+H + ):m / Z:491.0.

[0260] compound 50 [ka] Step 1: Synthesis of benzyl 3,4-bis(benzyloxy)-5-methoxybenzoate (2). To a solution of 3,4-dihydroxy-5-methoxybenzoic acid (5 g, 27.159 mmol) in DMF (50 mL) was added KCO (22.4 g, 162.950 mmol, 6 equiv.) followed by benzyl bromide (16 mL, 1135.790 mmol, 5 equiv.) at 0 °C. The mixture was stirred at 80 °C for 16 h until TLC showed the reaction was complete. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography. The desired product was eluted with 15% EtOAc in hexane to give benzyl 3,4-bis(benzyloxy)-5-methoxybenzoate as a yellow liquid (10.1 g, 82% yield). 1 H NMR (400MHz, DMSO-d6) δ7.43-7.26 (m, 17H), 5.33 (s, 2H), 5.14 (s, 2H), 5.01 (s, 2H), 3.83 (s, 3H).

[0261] Step 2: Synthesis of benzyl 4,5-bis(benzyloxy)-2-fluoro-3-methoxybenzoate (3). To a solution of benzyl 3,4-bis(benzyloxy)-5-methoxybenzoate (11 g, 24.240 mmol, 1 equiv.) in ACN (100 mL) was added Selectfluor (17.1 g, 4.400 mmol, 2 equiv.) at 0 °C, and the reaction mixture was stirred at room temperature for 48 h. The reaction progress was monitored by TLC. After this time, the reaction mixture was quenched with cold water and extracted with EtOAc (100 mL x 3). The organic layer was washed with brine solution, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column chromatography. The desired product was eluted with 10% EtOAc in hexane. The fractions were concentrated to give benzyl 4,5-bis(benzyloxy)-2-fluoro-3-methoxybenzoate as a yellow solid (1.1 g, 9% yield). 1H NMR(400MHz,DMSO-d6):δ7.42-7.28(m,16H),5.33(s,2H),5.16(s,2H),5.14(s,2H),3.81(s,3H), 19 F NMR (400MHz, DMSO-d6) δ-134.52.

[0262] Step 3: Synthesis of 4,5-bis(benzyloxy-2-fluoro-3-methoxybenzoic acid) (4). To a solution of 4,5-bis(benzyloxy)-2-fluoro-3-methoxybenzoate (1 g, 2.118 mmol, 1.0 equiv.) in THF / HO (3:1) (20 mL) was added LiOH·HO (0.88 g, 21.186 mmol, 10.0 equiv.). The solution was stirred at room temperature for 16 h. The reaction mixture was concentrated, and the resulting crude product was diluted with HO (30 mL) and extracted with EtOAc (80 mL x 2). The aqueous phase was adjusted to pH < 3 with 1 N HCl. The resulting solid was filtered, and the filter cake was dried. The crude compound was purified by flash column chromatography eluting with 10% EtOAc in hexanes to give 4,5-bis(benzyloxy)-2-fluoro-3-methoxybenzoic acid as a white solid (0.502 g, 62% yield). 1 H NMR (400MHz, DMSO-d6): δ13.22(s,1H),7.42(d,J=1.2Hz,2H),7.44-7.26(m,10H),5.14(s,2H),5.12(s,2H),3.81(s,3H).

[0263] Step 4: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 4,5-bis(benzyloxy)-2-fluoro-3-methoxybenzoate (5). Under a N atmosphere, to a stirred solution of 4,5-bis(benzyloxy)-2-fluoro-3-methoxybenzoic acid (0.265 g, 0.693 mmol, 1 equiv.) in DCM (5 mL) was added oxalyl chloride (0.22 mL, 2.665 mmol, 5 equiv.) and two drops of DMF at 0 °C. The reaction mixture was stirred at room temperature for 3 h. Excess oxalyl chloride was removed by distillation, and the residue was dried to give the acid chloride. The resulting acid chloride was added dropwise to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (0.203 g, 0.533 mmol, 1 equiv.), DMAP (0.325 g, 2.665 mmol, 5 equiv.), and EtN (0.36 mL, 2.665 mmol, 5 equiv.) in CHCl (6 mL) at 0 °C. The mixture was stirred overnight at room temperature. After this time, saturated aqueous NaHCO was added to the reaction mixture. The organic layer was then separated, and the aqueous layer was extracted with CHCl. ​​The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by flash column chromatography eluting with 15% EtOAc in hexane as eluent to give the desired compound (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 4,5-bis(benzyloxy)-2-fluoro-3-methoxybenzoate as a pale yellow solid (0.506 g, 64% yield). 1 H NMR(400MHz,DMSO-d6)δ7.43-7.21(m,35H),7.01(d,J=9.6Hz,1H),6.89(s,2H),6.42(s,1H),6.27(s,1H),5.51(d,J=5.2Hz,1H),5.1 8(d,J=7.2Hz,1H),5.11(s,2H),5.06(s,2H),5.04(s,4H),4.97(s,4H),4.87(s,2H),3.75(s,3H),2.62(dd,J=7.6Hz,2H).LCMS:(M+H +):m / Z:1121.1.

[0264] Step 5: Synthesis of Compound 50. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 4,5-bis(benzyloxy)-2-fluoro-3-methoxybenzoate (0.5 g, 0.351 mmol, 1 equiv.) in 8 mL of THF:MeOH (1:1), palladium hydroxide (20 wt%, 0.5 g) was added at room temperature and stirred under a hydrogen atmosphere for 16 hours. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give the desired compound (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-4,5-dihydroxy-3-methoxybenzoate as an off-white solid (0.058 g, 27% yield). 1 H NMR(400MHz,DMSO-d6):9.02(s,5H),5.88(d,J=6.8Hz,1H),6.25(s,2H),5.91(d,J=2.0Hz,1H),5.79(d, LCMS:(MH + ):m / Z:490.1.

[0265] compound 51 [ka] Step 1: Synthesis of methyl 3,4,5-tris(benzyloxy)-2,6-difluorobenzoate (2). To a solution of methyl 3,4,5-tris(benzyloxy)benzoate (50 g, 110.132 mmol, 1 equiv.) in ACN (60 mL) was added Selectfluor (77 g, 220.264 mmol, 2 equiv.) at 0 °C, and the reaction mixture was stirred at room temperature for 48 h. The reaction progress was monitored by TLC. After this time, the reaction mixture was quenched with cold water, extracted with EtOAc (100 mL x 3), washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound obtained was purified by flash column chromatography eluting with 5% EtOAc in hexane as the eluent to give methyl 3,4,5-tris(benzyloxy)-2,6-difluorobenzoate as a yellow solid (0.6 g, 1% yield). 1 H NMR(400MHz,DMSO-d6)δ7.38-7.34(m,15H),5.27(s,2H),5.02(s,4H),3.85(s,3H), 19 F NMR(400MHz,DMSO-d6)δ-133.38.

[0266] Step 2: Synthesis of 3,4,5-tris(benzyloxy)-2,6-difluorobenzoic acid (3). To a solution of 3,4,5-tris(benzyloxy)-2,6-difluorobenzoate (0.6 g, 1.224 mmol, 1 equiv.) in THF / HO (3:1) (12 mL), LiOH·HO (0.513 g, 12.240 mmol, 10 equiv.) was added and stirred at room temperature for 16 h. The reaction mixture was concentrated, and the resulting crude product was diluted with HO (30 mL) and extracted with EA (10 mL x 1). The aqueous phase was adjusted to pH < 3 with 1 N HCl. The resulting solid was filtered and dried to give 3,4,5-tris(benzyloxy)-2,6-difluorobenzoic acid as a yellow solid (0.352 g, 60% yield). 1 H NMR(400MHz,DMSO-d6)δ13.85(s,1H),7.35-7.33(m,15H),5.15(s,2H),5.02(s,4H), 19 F NMR(400MHz,DMSO-d6)δ-134.14.

[0267] Step 3: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2,6-difluorobenzoate (4). Under a N atmosphere, to a stirred solution of 3,4,5-tris(benzyloxy)-2,6-difluorobenzoic acid (0.35 g, 0.735 mmol, 1 equiv.) in DCM (8 mL) was added oxalyl chloride (0.31 mL, 7.350 mmol, 10 equiv.) in anhydrous CHCl (8 mL) and two drops of DMF at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The excess oxalyl chloride was then concentrated, and the residue was dried to give the acid chloride. This solution was added dropwise to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (0.44 g, 0.588 mmol, 0.8 equiv.), DMAP (0.448 g, 3.675 mmol, 5 equiv.), and EtN (0.53 mL, 3.675 mmol, 5 equiv.) in CHCl (12 mL) at 0 °C. The mixture was stirred at room temperature overnight. After this time, saturated aqueous NaHCO was added. The organic layer was separated and the aqueous layer was extracted with CHCl. ​​The combined organic phases were dried over MgSO, filtered, and evaporated. The resulting crude compound was purified by flash column chromatography eluting with 12% EtOAc in hexane as the eluent to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2,6-difluorobenzoate as a red solid (0.109 g, 12% yield). 1 H NMR(400MHz,DMSO-d6)δ7.41-7.21(m,40H),6.86(s,2H),6.40(d,J=2Hz,1H),6.26(d,J=1.6Hz,1H),5.63(d,J=5.2Hz) ,1H),5.17(s,4H),5.11(s,2H),5.06(s,4H),5.02(d,J=5.2Hz,1H),4.95(s,4H),4.98(s,2H),2.80(dd,J=4.0Hz,2H), 19F NMR(400MHz,DMSO-d6)δ-133.17.LCMS:(M+H+):m / Z:1215.47.

[0268] Step 4: Synthesis of Compound 51. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2,6-difluorobenzoate (0.1 g, 0.082 mmol, 1 equiv.) in 10 mL of THF:MeOH (1:1), palladium hydroxide (20 wt%, 0.1 g) was added at room temperature, and the reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,6-difluoro-3,4,5-trihydroxybenzoate as an off-white solid (0.026 g, 65% yield). 1 H NMR(400MHz,DMSO-d6):δ6.23(s,2H),5.89(d,J=2.0Hz,1H),5.77(d,J=2.0Hz,1H),5.33(q,J=4.8Hz,1H),5.01(d,J=4.8Hz,1H),2.58(dd,J=4.0Hz,2H), 19 F NMR(400MHz,DMSO-d6)δ-145.35.LCMS:(MH + ):m / Z:494.95.

[0269] compound 52 [ka] Step 1: Synthesis of benzyl 4,5-bis(benzyloxy)-2-methylbenzoate (2). To a solution of 4,5-dihydroxy-2-methylbenzoic acid (0.2 g, 1.17 mmol, 1 equiv.) in anhydrous DMF (5 mL), K2CO3 (0.81 g, 5.88 mmol, 5.0 equiv.) and BnBr (0.7 mL, 5.88 mmol, 5.0 equiv.) were added dropwise at 0 °C. The mixture was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (50 mL x 2). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (PE / EA = 9 / 1) to give benzyl 4,5-bis(benzyloxy)-2-methylbenzoate. was obtained as a white solid (0.47 g, 90% yield). 1 H NMR (400MHz, CDCl3): δ7.61(s,1H),7.46-7.25(m,15H),6.76(s,1H),5.28(s,2H),5.19(s,2H),5.14(s,2H),2.52(s,3H).

[0270] Step 2: Synthesis of (4,5-bis(benzyloxy)-2-methylphenyl)methanol (3). To a solution of benzyl 4,5-bis(benzyloxy)-2-methylbenzoate (6.0 g, 13.69 mmol, 1.0 equiv.) in THF (60 mL) was added LiAlH (0.78 g, 20.53 mmol, 1.5 equiv.) at 0 °C. The mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated aqueous NaSO (5 mL) and filtered through a Celite pad. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel flash column chromatography (PE / EA = 5 / 1) to afford (4,5-bis(benzyloxy)-2-methylphenyl)methanol (3.3 g, 72% yield) as a white solid. 1H NMR (400MHz, CDCl3): δ7.46-7.40(m,4H),7.39-7.27(m,6H),6.98(s,1H),6.78 (s,1H),5.13(s,4H),4.57(d,J=5.6Hz,2H),2.25(s,3H),1.43(t,J=5.6Hz,1H).

[0271] Step 3: Synthesis of 4,5-bis(benzyloxy)-2-methylbenzaldehyde (4). To a mixture of 4,5-bis(benzyloxy)-2-methylphenyl)methanol (0.2 g, 0.59 mmol, 1.0 equiv.) in CHCl (4 mL), PCC (0.19 g, 0.89 mmol, 1.5 equiv.) was added. The solution was stirred at room temperature for 3 h. The reaction mixture was concentrated, and the residue was purified by flash column chromatography to give 4,5-bis(benzyloxy)-2-methylbenzaldehyde (0.165 g, 83% yield) as a white solid. 1 H NMR (400MHz, CDCl3): δ10.14(s,1H), 7.48-7.28(m,11H), 6.75(s,1H), 5.23(s,2H), 5.17(s,2H), 2.57(s,3H).

[0272] Step 4: Synthesis of (E)-3-(4,5-bis(benzyloxy)-2-methylphenyl)-1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)prop-2-en-1-one (6). To a mixture of 4,5-bis(benzyloxy)-2-methylbenzaldehyde (0.05 g, 0.15 mmol, 1.0 equiv.) and 1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)ethan-1-one (0.05 g, 0.15 mmol, 1.0 equiv.) in EtOH (2 mL) was added 50% aqueous NaOH (0.5 mL, 0.63 mmol, 4.0 equiv.). The mixture was stirred at 50 °C for 5 h and then at room temperature for 48 h. The reaction mixture was diluted with HO (20 mL) and acidified with 1 N HCl (5 mL). The formed precipitate was filtered. The yellow precipitate was dissolved in EtOAc (30 mL), washed with HO (10 mL) and brine (10 mL), dried over NaSO, filtered, and concentrated. The resulting solid was purified by column chromatography to give (£)-3-(4,5-bis(benzyloxy)-2-methylphenyl)-1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)prop-2-en-1-one (0.086 g, 80% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3):14.28(s,1H),8.01(d,J=15.2Hz,1H),7.69(d,J=15.2Hz,1H),7.48-7.24(m,17H),7.23-7.16(m,3H),6.91(s ,1H),6.75(s,1H),6.22(d,J=2.4Hz,1H),6.15(d,J=2.4Hz,1H),5.16(s,2H),5.10(s,2H),5.08(s,2H),4.67(s,2H),2.36(s,3H).

[0273] Step 5: Synthesis of 5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-methylphenyl)-2H-chromene (7). To a solution of (E)-3-(4,5-bis(benzyloxy)-2-methylphenyl)-1-(2,4-bis(benzyloxy)-6-hydroxyphenyl)prop-2-en-1-one (0.2 g, 0.30 mmol, 1.0 equiv) in THF:EtOH (4:1) (5 mL) was added anhydrous CeCl (0.22 g, 0.90 mmol, 3.0 equiv) and NaBH (0.035 g, 0.90 mmol, 3.0 equiv) sequentially at 0 °C. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (50 mL x 2). The combined organic phase was washed with brine (30 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (PE / EA=10 / 1) to give 5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-methylphenyl)-2H-chromene (0.11 g, 56% yield) as a white solid. 1 H NMR(400MHz,CDCl3):7.48-7.14(m,19H),7.12(s,1H),6.87(dd,J=10.0,2.0Hz,1H),6.78(s,1H),6.19(d,J=2.4Hz,1H),6.10(d,J=2.5H) z,1H),5.95(t,J=2.4Hz,1H),5.46(dd,J=10.0,3.2Hz,1H),5.13(s,2H),5.07(q,J=12.8Hz,2H),5.04(s,2H),4.97(s,2H),2.33(s,3H).

[0274] Step 6: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-methylphenyl)chroman-3-ol (8). To a solution of 5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-methylphenyl)-2H-chromene (1.0 g, 1.54 mmol, 1.0 equiv.) in anhydrous THF (10 mL) was added BH DMS (2 mL, 3.86 mmol, 2.5 equiv.) over 10 min at 0 °C. The mixture was stirred at room temperature until the starting material disappeared. Next, 3N aqueous NaOH (1.3 mL, 3.86 mmol, 2.5 equiv.) and 30% aqueous HO (0.4 mL, 3.86 mmol, 2.5 equiv.) were added dropwise at 0 °C. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (PE / EA = 10 / 1) to give (2S,3R)-5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-methylphenyl)chroman-3-ol (0.31 g, 30% yield) as a white solid. 1 H NMR(400MHz,CDCl3):7.48-7.24(m,20H),7.01(s,1H),6.79(s,1H),6.28(d,J=2.4Hz,1H),6.18(d,J=2.0Hz,1H),5.16(s,2H) ,5.12(q,J=7.2Hz,2H),5.04(s,2H),4.99(s,2H),4.89(d,J=8.4Hz,1H),4.02(m,1H),3.17(dd,J=16.4,5.6Hz,1H),3.17(dd,J =16.4,9.2Hz,1H),2.31(s,3H).

[0275] Step 7: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-methylphenyl)chroman-3-yl 3,4,5-tris(benzyloxy)benzoate (9). To a solution of 3,4,5-tris(benzyloxy)-2-fluorobenzoic acid (0.26 g, 0.56 mmol, 1.5 equiv.) in CHCl (5 mL) was added (COCl) (0.1 mL, 0.75 mmol, 2.0 equiv.) and 2 drops of anhydrous DMF at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was concentrated under reduced pressure to provide the acid chloride. The resulting acid chloride was added to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-methylphenyl)chroman-3-ol (0.25 g, 0.37 mmol, 1.0 equiv), DMAP (0.18 g, 1.50 mmol, 4.0 equiv), and TEA (0.22 mL, 1.50 mmol, 4.0 equiv) in CHCl (10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with HO (30 mL) and extracted with CHCl (50 mL × 2). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA=6 / 1) to give (2S,3R)-5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-methylphenyl)chroman-3-yl 3,4,5-tris(benzyloxy)benzoate (0.33 g, 79.5% yield) as a white solid. 1 H NMR(400MHz,CDCl3):7.48-7.14(m,35H),6.99(s,1H),6.97(d,J=6.4Hz,1H),6.71(s,1H),6.29(d,J=2.0Hz,1H),6.23(d,J=2.0Hz,1H),5.50(q ,J=5.6Hz,1H),5.31(d,J=7.6Hz,1H),5.08-4.94(m,12H),4.89(s,2H),3.15(dd,J=16.8,5.6Hz,1H),3.17(dd,J=16.4,7.2Hz,1H),2.35(s,3H).

[0276] Step 8: Synthesis of Compound 52. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(4,5-bis(benzyloxy)-2-methylphenyl)chroman-3-yl 3,4,5-tris(benzyloxy)benzoate (0.3 g, 0.27 mmol, 1.0 equiv.) in THF (3 mL) and MeOH (3 mL) was added Pd(OH) (20 wt%, 0.039 g). The mixture was stirred overnight at room temperature under an H atmosphere. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give (2S,3R)-2-(4,5-dihydroxy-2-methylphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate (0.040 g, 31% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):9.88-8.80(bs,7H),6.62(s,1H),6.61(s,1H),6.50(s,1H),5.93(d,J=2.4Hz,1H),5.75(d,J=2.0Hz) ,1H),5.22(q,J=5.6Hz,1H),5.17(d,J=6.4Hz,1H),2.80(dd,J=16.0,4.8Hz,1H),2.63(dd,J=16.4,6.8Hz,1H),2.20(s,3H).

[0277] compound 54 [ka] Step 1: Synthesis of 1a,2,7,7a-tetrahydronaphtho[2,3-b]oxirane (2). To a solution of 1,4-dihydronaphthalene (1.8 g, 13.800 mmol, 1 equiv.) in DCM (25 mL) was added m-CPBA (3.57 g, 20.700 mmol, 1.5 equiv.) in portions over 20 min at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. Excess mCPBA was removed by washing with aqueous NaHCO 3 . The combined organic layers were washed with water and brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude compound was purified by flash column chromatography (EtOAc in hexanes) to give 1a,2,7,7a-tetrahydronaphtho[2,3-b]oxirane as a white solid (1.53 g, 75% yield). 1 H NMR (400MHz, DMSO-d6): δ 7.10-7.07(m,2H),7.04-7.00(m,2H),3.41(t,J=1.2Hz,2H),3.15(t,J=18.8Hz,4H).

[0278] Step 2: Synthesis of (2R,3S)-3-(3,4,5-tris(benzyloxy)phenyl)-1,2,3,4-tetrahydronaphthalen-2-ol (4). To a solution of (5-bromobenzene-1,2,3-triyl)tris(oxy))tris(methylene))tribenzene (1.23 g, 2.599 mmol, 1 equiv.) in 10 mL of THF was added n-BuLi (3.2 mL of 2 M in hexanes, 5.198 mmol, 2 equiv.) at -70 °C and stirred at -70 °C for 2 h. Then, 1a,2,7,7a-tetrahydronaphtho[2,3-b]oxirane (380 mg, 2.599 mmol, 1 equiv.) and BF3-Et2O (0.1 mL, 0.779 mmol, 0.3 equiv.) were added to the above reaction mixture at -70 °C and stirred at room temperature for 16 h. The reaction mixture was quenched with aqueous NH4Cl, and the product was extracted with EtOAc (50 mL x 2). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by flash column chromatography (EtOAc in hexane) to give the desired compound (2R,3S)-3-(3,4,5-tris(benzyloxy)phenyl)-1,2,3,4-tetrahydronaphthalen-2-ol as a red solid (0.310 g, 22% yield). 1 H NMR(400MHz,DMSO-d6)δ7.40-7.30(m,11H),7.25(d,J=1.2Hz,2H),7.24(d,J=2.0Hz,2H),7.06(t,J=8.0Hz,4H),6.69(s,2H),5.03(s,4H),4.84( s,2H),4.02(q,J=5.6Hz,1H),2.99-2.87(m,2H),2.81(t,J=8.8Hz,1H),2.71(t,J=7.6Hz,1H),2.49(d,J=1.6Hz,1H).LCMS:(M+H+):m / Z:625.05.

[0279] Step 3: Synthesis of (2R,3S)-3-(3,4,5-tris(benzyloxy)phenyl)-1,2,3,4-tetrahydronaphthalen-2-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (5). To a stirred solution of 3,4,5-tris(benzyloxy)-2-fluorobenzoic acid (0.428 g, 0.935 mmol, 1.3 equiv) in DCM (8 mL) was added oxalyl chloride (0.3 mL, 3.597 mmol, 5 equiv) and 2 drops of DMF at 0° C. The reaction mixture was stirred at room temperature for 1 hour. After this time, the reaction mixture was concentrated under reduced pressure to provide the acid chloride. The resulting acid chloride was added to a solution of (2R,3S)-3-(3,4,5-tris(benzyloxy)phenyl)-1,2,3,4-tetrahydronaphthalen-2-ol (0.390 g, 0.719 mmol, 1 equiv.), DMAP (0.439 g, 3.597 mmol, 5 equiv.), and EtN (0.49 mL, 3.597 mmol, 5 equiv.) in CHCl (12 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. Finally, the reaction was quenched by adding saturated aqueous sodium bicarbonate solution. The organic layer was separated, and the aqueous layer was extracted with CHCl. ​​The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by flash column chromatography (EtOAc in hexanes) to give (2R,3S)-3-(3,4,5-tris(benzyloxy)phenyl)-1,2,3,4-tetrahydronaphthalen-2-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate as a brownish solid (0.302 g, 43% yield). 1 H NMR(400MHz,DMSO-d6)δ7.43-7.15(m,30H),6.91(s,2H),6.79(d,J=6.0Hz,2H),5.32(q,J=8Hz,1H),5.06 (d,J=4.8Hz,1H),5.03(s,4H),4.98(s,4H),4.81(s,4H),3.26(dd,J=1.6Hz,2H),3.10(dd,J=1.6Hz,2H). 19 F NMR (400MHz, DMSO-d6)δ-134.71.

[0280] Step 4: Synthesis of Compound 54. To a solution of (2R,3S)-3-(3,4,5-tris(benzyloxy)phenyl)-1,2,3,4-tetrahydronaphthalen-2-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (0.3 g, 0.305 mmol, 1 equiv.) in 8 mL of THF:MeOH (1:1), palladium hydroxide (20 wt%, 0.3 g) was added at room temperature and stirred under a hydrogen atmosphere for 16 hours. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give (2R,3S)-3-(3,4,5-trihydroxyphenyl)-1,2,3,4-tetrahydronaphthalen-2-yl 2-fluoro-3,4,5-trihydroxybenzoate as an off-white solid (0.072 g, 53% yield). 1 H NMR(400MHz,DMSO-d6):8.84(s,6H),7.15-7.09(m,4H),6.81(s,2H),6.17(s,2H),5.32(q,J=5.6Hz,1H ),3.10(d,J=4.4Hz,1H),3.05(d,J=4.8Hz,2H),2.93(t,J=8.4Hz,1H),2.85(dd,J=6.8Hz,1H).LCMS:(MH + ):m / Z:441.1.

[0281] compound 53 [ka] Step 1: Synthesis of (2R,3S)-3-(3,4,5-tris(benzyloxy)phenyl)-1,2,3,4-tetrahydronaphthalen-2-yl 3,4,5-tris(benzyloxy)benzoate (3). To a solution of 3,4,5-tris(benzyloxy)benzoic acid (0.411 g, 0.719 mmol, 1 equiv.) in DCM (8 mL) was added oxalyl chloride (0.3 mL, 3.597 mmol, 5 equiv.) and 2 drops of DMF at 0° C. The reaction mixture was stirred at room temperature for 1 hour. After this time, the reaction mixture was concentrated under reduced pressure to provide the acid chloride. The resulting acid chloride was added to a solution of (2R,3S)-3-(3,4,5-tris(benzyloxy)phenyl)-1,2,3,4-tetrahydronaphthalen-2-ol (0.411 g, 0.935 mmol, 1 equiv.), DMAP (0.439 g, 3.597 mmol, 5 equiv.), and EtN (0.49 mL, 3.597 mmol, 5 equiv.) in CHCl (12 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. Finally, saturated aqueous sodium bicarbonate solution (5 mL) was added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted with CHCl (30 mL). The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by flash column chromatography (EtOAc in hexanes) to give (2R,3S)-3-(3,4,5-tris(benzyloxy)phenyl)-1,2,3,4-tetrahydronaphthalen-2-yl 3,4,5-tris(benzyloxy)benzoate as an off-white solid (0.310 g, 45% yield). 1 H NMR(400MHz,DMSO-d6)δ7.46-7.18(m,34H),7.09(s,2H),6.94(s,2H),5.48(q,J=8Hz,1H),5.09(s,4H),5. 03(s,4H),4.91(s,2H),4.78(s,2H),3.44(d,J=1.6Hz,1H),3.24(d,J=1.6Hz,2H),3.06(dd,J=1.6Hz,2H).

[0282] Step 2: Synthesis of Compound 53. To a solution of (2R,3S)-3-(3,4,5-tris(benzyloxy)phenyl)-1,2,3,4-tetrahydronaphthalen-2-yl 3,4,5-tris(benzyloxy)benzoate (0.3 g, 0.3110 mmol, 1 equiv.) in 8 mL of THF:MeOH (1:1), palladium hydroxide (20 wt%, 0.3 g) was added at room temperature, and the reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give (2R,3S)-3-(3,4,5-trihydroxyphenyl)-1,2,3,4-tetrahydronaphthalen-2-yl 3,4,5-trihydroxybenzoate as an off-white solid (0.101 g, 77% yield). 1 H NMR(400MHz,DMSO-d6):8.84(s,6H),7.15-7.09(s,4H),6.81(s,1H),6.17(s,2H),5.32(q,J=5.6Hz,1H ),3.10(d,J=4.4Hz,1H),3.05(d,J=4.8Hz,2H),2.93(t,J=8.4Hz,1H),2.85(dd,J=6.8Hz,1H).LCMS:(MH + ):m / Z:423.1.

[0283] compound 55 [ka] Step 1: Synthesis of (-)-catechin. A mixture of (2R,3R)-2-(3,4-dihydroxyphenyl)chroman-3,5,7-triol (4.7 g, 16.19 mmol, 1.0 equiv.) and 0.1 M phosphate buffer (40 mL) was heated at 110 °C for 2.5 h in the dark. The reaction mixture was then allowed to warm to room temperature and stirred for an additional 1 h. The reaction mixture was then allowed to stand at room temperature for 10 h and then filtered. The resulting solid was purified by preparative HPLC to give (2R,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (1.28 g, 27% yield) as a white solid. 1H NMR (400MHz, DMSO-d6): δ9.16(s,1H),8.92(s,1H),8.84(s,1H),8.80(s,1H),6.75-6.52(m,3H),5.87(d,J=2.0Hz,1H),5.66(d,J=2.4H) z,1H),4.84(d,J=5.2Hz,1H),4.45(d,J=7.6Hz,1H),3.79(quintet,J=5.2Hz,1H),2.63(dd,J=16.0Hz,5.2Hz,1H),2.33(q,J=16.4,1H).

[0284] Step 2: Synthesis of (2R,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (1). To a solution of (2R,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (1.26 g, 4.36 mmol, 1.0 equiv) in anhydrous DMF (15 mL) was added K2CO3 (2.41 g, 17.44 mmol, 4.0 equiv) and stirred at room temperature for 0.5 h. To this was added BnBr (2.1 mL, 17.44 mmol, 4.0 equiv) slowly dropwise at -20 °C. The suspension was allowed to warm slowly to room temperature and stirred at room temperature for 96 h. After complete consumption of the starting material as monitored by TLC, the reaction mixture was filtered through a Celite pad to remove the K2CO3. The Celite pad was washed with EtOAc (100 mL). The combined organic phase was washed with cold HO (50 mL x 2) and brine (50 mL), dried over NaSO, filtered, and concentrated. The resulting residue was purified by flash column chromatography using EtOAc:hexane (5:1) to give (2R,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (1.28 g, 45% yield) as an off-white solid. 1H NMR(400MHz,DMSO-d6):δ7.50-7.26(m,20H),7.16-6.98(m,2H),6.87(d,J=8.4Hz,1H),6.32(d,J=2.0Hz,1H),6.12(d,J=2 .0Hz,1H),5.16-4.98(m,9H),4.63(d,J=7.6Hz,1H),4.02-3.90(m,1H),2.76(dd,J=16.8Hz,5.6Hz,1H),2.56-2.41(m,1H).

[0285] Step 3: Synthesis of (2R,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (2). To a solution of 3,4,5-tris(benzyloxy)-2-fluorobenzoic acid (2.32 g, 5.07 mmol, 1.5 equiv) in CHCl (30 mL) was added (COCl) (1.8 mL, 20.29 mmol, 6.0 equiv) and 2 drops of anhydrous DMF at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was concentrated under reduced pressure to provide the acid chloride. The resulting acid chloride was added to a solution of (2R,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (2.2 g, 3.38 mmol, 1.0 equiv.), DMAP (1.65 g, 13.52 mmol, 4.0 equiv.), and TEA (1.9 mL, 13.52 mmol, 4.0 equiv.) in CHCl (40 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with HO (50 mL) and extracted with CHCl (100 mL × 2). The combined organic phase was washed with brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (PE / EA=6 / 1) to give (2R,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (3.04 g, 82% yield) as a white solid. 1H NMR (400MHz, CDCl3): δ7.43-7.21(m,35H),7.06-7.01(m,2H),6.94(d,J=1.6Hz,1H),6.88(d,J=8.4Hz,1H),6 .28(dd,J=6.0,2.0Hz,2H),5.48(q,J=7.2Hz,1H),5.12-4.90(m,15H),3.14-2.80(dq,J=16.4Hz,5.2Hz,2H).

[0286] Step 4: Synthesis of Compound 55. To a mixture of (2R,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (3.0 g, 2.75 mmol, 1.0 equiv.) in THF (15 mL) and MeOH (15 mL) was added Pd(OH) / C (20 wt%, 0.39 g). The mixture was stirred overnight at room temperature under an H atmosphere. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated. The residue was purified by preparative HPLC to give (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate (0.65 g, 51.3% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ9.12(bs,7H),6.72(d,J=1.6Hz,1H),6.66(d,J=2.8Hz,1H), 6.65(s,1H),.59(dd,J=8.4,2.0Hz,1H),5.91(d,J=2.0Hz,1H),5.78(d,J=2.0Hz,1H ),5.28(q,J=5.6Hz,1H),5.04(d,J=6.0Hz,1H),2.70-2.54(dq,J=9.2,5.6Hz,2H).

[0287] Compounds 55 and 56 [ka] Step 1: Synthesis of (3R)-2-(3,4-dihydroxyphenyl)chroman-3,5,7-triol (1). A stirred mixture of (2R,3R)-2-(3,4-dihydroxyphenyl)chroman-3,5,7-triol (5.0 g, 17.22 mmol, 1.0 equiv.) and 0.1 M phosphate buffer (50 mL) was heated at 110 °C for 2 h. The reaction progress was monitored by LCMS. The reaction mixture was then cooled to room temperature and lyophilized to give (3R)-2-(3,4-dihydroxyphenyl)chroman-3,5,7-triol (5.0 g) as a brown solid.

[0288] Step 2: Synthesis of (3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-ol (2). To a solution of (3R)-2-(3,4-dihydroxyphenyl)chroman-3,5,7-triol (3.0 g, 10.33 mmol, 1.0 equiv.) in anhydrous DMF (100 mL), K2CO3 (5.71 g, 41.34 mmol, 4.0 equiv.) was added and stirred at room temperature for 0.5 h. To this was added BnBr (4.9 mL, 41.34 mmol, 4.0 equiv.) slowly dropwise at -20 °C. The suspension was allowed to warm to room temperature and stirred for 96 h. Consumption of the starting material was monitored by TLC. After complete consumption of the starting material, the reaction mixture was filtered through a Celite pad to remove K2CO3. The Celite pad was washed with EtOAc (100 mL). The combined organic phase was washed with cold HO (50 mL × 2) and brine (50 mL), dried over NaSO, filtered, and concentrated. The resulting residue was purified by flash column chromatography (EtOAc:hexane, (6:1)) to give (3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-ol (0.8 g, 11% yield) as a pale yellow solid.

[0289] Step 3: ((3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-yl Synthesis of 3,4,5-tris(benzyloxy)-2-fluorobenzoate (3). To a solution of (3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-ol (0.64 g, 1.39 mmol, 1.3 equiv.) in CHCl (10 mL) was added (COCl) (0.5 mL, 5.28 mmol, 5.0 equiv.) and 2 drops of anhydrous DMF at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After this time, the reaction mixture was concentrated under reduced pressure to give the acid chloride. The resulting acid chloride was then condensed under reduced pressure with (3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-ol (0.7 g, 1. To a solution of (3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (0.88 g, 75% yield) was added (3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (0.88 g, 75% yield) as an off-white solid.

[0290] Step 4: Synthesis of Compounds 55 and 56. To a solution of (3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (0.88 g, 0.80 mmol, 1.0 equiv.) in THF (15 mL) and MeOH (15 mL) was added Pd(OH) / C (20 wt%, 0.88 g) and HCOOH (0.8 mL). The mixture was stirred under an H atmosphere at room temperature for 16 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated. The residue was purified by preparative HPLC and separated by chiral HPLC to give 2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate (0.045 g, 12% yield as a black solid) and (2S,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate (0.120 g, 32% yield as a gray solid). Compound 55: 1 H NMR(400MHz,DMSO-d6)δ9.12(bs,7H),6.72(d,J=1.6Hz,1H),6.66(d,J=2.8Hz,1H),6.65(s,1H),6.59(dd,J=8.4,2.0Hz,1H), 5.91(d,J=2.0Hz,1H),5.78(d,J=2.0Hz,1H),5.28(q,J=5.6Hz,1H),5.04(d,J=6.0Hz,1H),2.70-2.54(dq,J=9.2,5.6Hz,2H). Compound 56: 1 H NMR(400MHz,DMSO-d6)δ9.48(bs,1H),9.29(bs,3H),9.03(bs,1H),8.86(bs,1H),8.76(bs,1H),6.87(s,1H),6.73(d,J=8.0Hz,1H),6.69- 6.62(m,2H),5.91(d,J=2.0Hz,1H),5.79(d,J=2.0Hz,1H),5.38(s,1H),5.01(s,1H),2.92(dd,J=17.6,4.4Hz,1H),2.92(d,J=16.0Hz,1H).

[0291] compound 57 [ka] Step 1: Synthesis of 5,6-bis(benzyloxy)picolinaldehyde (2). To a stirred solution of 5,6-dihydroxypicolinaldehyde (0.64 g, 4.672 mmol) and potassium carbonate (1.7 g, 10.279 mmol, 2.2 equiv.) in anhydrous DMF (15 mL), benzyl bromide (1.2 mL, 10.279 mmol, 2.2 equiv.) was added, and the mixture was stirred at room temperature overnight. The solution was diluted with EtOAc, washed with brine, and dried over Na2SO4. After removal of the solvent under reduced pressure, the crude compound was purified by flash column chromatography eluting with 15% EtOAc in hexanes to afford 5,6-bis(benzyloxy)picolinaldehyde as a light brown solid (1 g, 80% yield). 1 H NMR(400MHz,DMSO-d6):δ9.41(s,1H),7.47-7.34(m,5H),7.27(t,J=4.0Hz, 2H), 7.20(t,J=4.0Hz,3H),7.07(d,J=7.8Hz,2H),5.67(s,2H),5.18(s,2H).

[0292] Step 2: Synthesis of 5,6-bis(benzyloxy)picolinic acid (3). To a stirred solution of 5,6-bis(benzyloxy)picolinaldehyde (7 g, 3.134 mmol, 1 equiv.) in t-BuOH:THF (1:1, 20 mL) was added 2-methyl-2-butene (0.65 g, 9.404 mmol, 3 equiv.), aqueous NaHPO (1.1 g, 9.404 mmol, 3 equiv.), and aqueous NaClO (0.84 g, 9.404 mmol, 3 equiv.) sequentially at 20 °C. The reaction mixture was stirred at that temperature for 10 h and then quenched with aqueous NaHSO (3 mL, 1.0 M). The resulting mixture was extracted with DCM (100 mL x 3), and the combined organic phase was dried over NaSO and filtered. After removing the solvent under reduced pressure, the residue was purified by flash column chromatography eluting with 5% MeOH in DCM as eluent to give 5,6-bis(benzyloxy)picolinic acid as a white solid (0.61 g, 55% yield). 1 H NMR (400MHz, DMSO-d6) δ7.45-7.34(m,3H),7.27(t,J=6.8Hz,2H),7.20(t,J=7.6Hz,1H),7.04(d,J=7.2Hz,2H),6.97(s,2H),5.63(s,2H),5.09(s,2H).

[0293] Step 3: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 5,6-bis(benzyloxy)picolinate (4). Under a N atmosphere, to a stirred solution of 5,6-bis(benzyloxy)picolinic acid (0.6 g, 1.791 mmol, 1 equiv.) in DCM (10 mL) was added oxalyl chloride (0.76 mL, 8.955 mmol, 5 equiv.) and 2 drops of DMF at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Excess oxalyl chloride was removed by distillation, and the residue was dried under organochloride to give the acid chloride. This solution was added dropwise to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (1.3 g, 1.791 mmol, 1 equiv.), DMAP (0.87 g, 7.164 mmol, 4 equiv.), and EtN (1 mL, 7.164 mmol, 4 equiv.) in CHCl (12 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. Finally, the reaction was quenched with saturated aqueous NaHCO (5 mL). The organic layer was separated, and the aqueous layer was extracted with CHCl (30 mL). The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by flash column chromatography (EtOAc in hexanes) to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 5,6-bis(benzyloxy)picolinate as a white solid (0.28 g, 15% yield). 1 H NMR(400MHz,DMSO-d6):δ8.14(s,1H),7.43-7.24(m,36H),6.80(s,2H)6.39(s,1H),6.23(s,1H),5.42(d,J= 5.6Hz,1H),5.13(d,J=6.4Hz,1H),5.12(s,6H),5.04(s,6H),4.90(s,2H),2.77(dd,J=7.6Hz,2H).LCMS:(M+H + ):m / Z:1074.3.

[0294] Step 4: Synthesis of Compound 57. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 5,6-bis(benzyloxy)picolinate (0.26 g, 0.242 mmol, 1 equiv.) in 12 mL of THF:MeOH (1:1), palladium hydroxide (20 wt%, 0.26 g) was added at room temperature, and the reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The crude compound obtained was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 5,6-dihydroxypicolinate as an off-white solid (0.040 g, 84% yield). 1 H NMR(400MHz,DMSO-d6):9.35(s.2H),9.07(s,5H),6.77(d,J=7.2Hz,1H),6.67(d,J=7.2Hz,1H),6.26(s,2H),5.92(d ,J=2.0Hz,1H),5.78(d,J=2.0Hz,1H),5.20(q,J=5.6Hz,1H),4.97(d,J=6.0Hz,1H),2.66(dd,J=4.4Hz,2H).LCMS:(MH + ):m / Z:442.1.

[0295] compound 58 [ka] Step 1: Synthesis of (2R,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (1). To a stirred solution of (2R,3R)-2-(3,4,5-trihydroxyphenyl)chroman-3,5,7-triol (1.0 g, 3.26 mmol, 1.0 equiv.) in anhydrous DMF (10 mL), NaH (60 wt % in mineral oil) (0.65 g, 16.33 mmol, 5.0 equiv.) was added at 0 °C and stirred for 0.5 h. To this, BnCl (1.9 mL, 16.33 mmol, 5.0 equiv.) was added dropwise at 0 °C. The suspension was stirred at room temperature for 12 h. After complete consumption of the starting material, the reaction mixture was quenched with saturated aqueous NaSO (2 mL) and filtered through a Celite pad. The Celite pad was washed with EtOAc (100 mL). The combined solvent was washed successively with HO (50 mL) and brine (30 mL). The organic layer was dried over NaSO, filtered, and concentrated. The resulting residue was purified by silica gel flash column chromatography (PE / EA=6 / 1) to give (2R,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (1.02 g, 41% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ7.50-7.19(m,25H),6.94(s,2H),6.34(d,J=2.4Hz,1H),6.17(d,J=2.0Hz,1H) ,5.20-5.01(m,8H),5.00-4.88(m,9H),4.84(d,J=4.4Hz,1H),4.15(d,J=3.6Hz,1H),2.88-2.62(m,2H).

[0296] Step 2: Synthesis of (2R,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (2). To a solution of 3,4,5-tris(benzyloxy)-2-fluorobenzoic acid (0.27 g, 0.59 mmol, 1.5 equiv) in CHCl (5 mL) was added (COCl) (0.3 mL, 1.98 mmol, 5.0 equiv) and 2 drops of anhydrous DMF at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was concentrated under reduced pressure to provide the acid chloride. The resulting acid chloride was added to a solution of (2R,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (0.3 g, 0.39 mmol, 1.0 equiv.), DMAP (0.19 g, 1.58 mmol, 4.0 equiv.), and TEA (0.3 mL, 1.58 mmol, 4.0 equiv.) in CHCl (5 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with HO (20 mL) and extracted with CHCl (50 mL × 2). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA=7 / 1) to give (2R,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (0.37 g, 78% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ7.50-7.17(m,25H),7.07(d,J=6.4Hz,1H),6.97(s,2H),6.43(s,1H),6.33(d,J=2.0Hz,1H),5. 65(s,1H),5.27(s,1H),5.12(s,2H),5.07(s,2H),5.02-4.93(m,4H),4.90(s,4H),4.88-4.78(m,4H),3.22-2.88(m,2H).

[0297] Step 3: Synthesis of Compound 58. To a mixture of (2R,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4,5-(tris(benzyloxy)-2-fluorobenzoate (0.5 g, 0.41 mmol, 1.0 equiv.) in THF (5 mL) and MeOH (5 mL) was added Pd(OH) / C (20 wt%, 0.059 g). The mixture was stirred overnight at room temperature under an H atmosphere. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate (0.068 g, 34% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ9.45(bs,1H),9.25(s,1H),9.19(s,2H),9.00(s,1H),8.68(bs,2H), 8.00(bs,1H),6.64(d,J=6.4Hz,1H),6.39(s,2H),5.92(d,J=2.4Hz,1H),5.80(d,J=2.4Hz,1H) ),5.41(s,1H),4.94(s,1H),2.98-2.57(m,2H).

[0298] compound 59 [ka] Step 1: Synthesis of methyl 3,4-bis(benzyloxy)-5-methoxybenzoate (2). To a suspension of 3,4-bis(benzyloxy)-5-hydroxybenzoate (10.0 g, 27.472 mmol) in DMF (50 mL) was added KCO (8.5 g, 82.413 mmol, 3 equiv.) followed by iodomethane (3.8 mL, 82.413 mmol, 3 equiv.) at 0 °C. The mixture was heated to 50 °C for 16 h until TLC showed the reaction was complete. The reaction mixture was diluted with water and extracted with EtOAc. The solvent was evaporated, and the residue was purified by flash chromatography eluting with 15% EtOAc in hexane to give methyl 3,4-bis(benzyloxy)-5-methoxybenzoate as a white solid (10 g, 96% yield). 1 H NMR (400MHz, DMSO-d6) δ7.46(t,J=1.6Hz,2H),7.42-7.38(m,4H),7.36(d,J=2Hz,2H),7.33-7.25(m,4H),5.17(s,2H),5.02(s,2H),3.84(s,3H).

[0299] Step 2: Synthesis of methyl 3,4-bis(benzyloxy)-2,6-difluoro-5-methoxybenzoate (3). To a solution of methyl 3,4-bis(benzyloxy)-5-methoxybenzoate (14.5 g, 38.317 mmol, 1 equiv.) in ACN (150 mL) was added Selectfluor (54.2 g, 153.200 mmol, 4 equiv.) at 0 °C, and the reaction mixture was stirred at 60 °C for 48 h. The reaction progress was monitored by TLC. The reaction mixture was quenched with cold water, extracted with EtOAc (150 mL x 3), washed with brine, and dried over anhydrous NaSO. The organic layer was evaporated under reduced pressure to give the crude compound. The crude compound was purified by flash column chromatography eluting with 5% EtOAc in hexanes as the eluent to give methyl 3,4-bis(benzyloxy)-2,6-difluoro-5-methoxybenzoate as a yellow solid (1.2 g, 8% yield). 1H NMR(400MHz,DMSO-d6):δ7.43(d,J=6.4Hz,2H),7.39-7.27(m,8H),5.20(s,2H),5.01(s,2H),3.86(s,3H),3.79(s,3H), 19 F NMR (400MHz, DMSO-d6) δ -133.84, -133.85, -134.78, -134.79.

[0300] Step 3: Synthesis of 3,4-bis(benzyloxy)-2,6-difluoro-5-methoxybenzoic acid (4). To a mixture of methyl 3,4-bis(benzyloxy)-2,6-difluoro-5-methoxybenzoate (1 g, 2.50 mmol, 1.0 equiv.) in THF / HO (1:1) (20 mL) was added LiOH·HO (0.31 g, 7.50 mmol, 3.0 equiv.). The solution was stirred at room temperature for 16 h. The reaction mixture was concentrated to remove THF. The mixture was then diluted with HO (30 mL) and extracted with EA (80 mL x 2). The aqueous phase was adjusted to pH < 3 with 1 N HCl. The resulting solid was filtered, and the filter cake was dried to give compound 3,4-bis(benzyloxy)-2,6-difluoro-5-methoxybenzoic acid as a white solid (0.85 g, 85% yield). 1 H NMR(400MHz,DMSO-d6)δ13.82(s,1H),7.42(d,J=1.2Hz,2H),7.37-7.29(m,8H),5.17(s,2H),5.01(s,2H),3.81(s,3H), 19 F NMR (400MHz, DMSO-d6) δ-134.65,-135.57.

[0301] Step 4: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-2,6-difluoro-5-methoxybenzoate (5). To a stirred solution of 3,4-bis(benzyloxy)-2,6-difluoro-5-methoxybenzoic acid (0.6 g, 1.637 mmol, 1 equiv.) in DCM (5 mL) under a N atmosphere, oxalyl chloride (1.0 mL, 8.168 mmol, 5 equiv.) and 2 drops of DMF were added at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was concentrated under reduced pressure to provide the acid chloride. The resulting acid chloride was added to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (1.0 g, 1.637 mmol, 1 equiv.), DMAP (0.79 g, 6.548 mmol, 4 equiv.), and EtN (0.9 mL, 6.548 mmol, 4 equiv.) in CHCl (12 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. Finally, the reaction was quenched with saturated aqueous NaHCO (5 mL). The organic layer was separated, and the aqueous layer was extracted with CHCl (30 mL). The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by flash column chromatography (EtOAc in hexanes) to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-2,6-difluoro-5-methoxybenzoate as a yellow solid (0.7 g, 23% yield). 1 H NMR(400MHz,DMSO-d6)δ7.44-7.25(m,35H),6.87(s,2H),6.42(d,J=2Hz,1H),6.28(d,J=1.6Hz,1H),5.48(d,J=5.2Hz,1H),5.17(d ,J=7.2Hz,1H),5.14(s,2H),5.12(s,2H),5.07(s,2H),5.03(s,4H),4.95(s,2H),4.91(s,2H),3.77(s,3H),2.84(dd,J=7.6Hz,2H), 19F NMR(400MHz,DMSO-d6)δ-134.46,134.45,133.59,133.58.LCMS:(M+H + ):m / Z:1139.

[0302] Step 5: Synthesis of Compound 59. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-2,6-difluoro-5-methoxybenzoate (0.4 g, 0.351 mmol, 1 equiv.) in 8 mL of THF:MeOH (1:1), palladium hydroxide (20 wt%, 0.40 g) was added at room temperature, and the reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,6-difluoro-3,4-dihydroxy-5-isopropoxybenzoate as an off-white solid (0.075 g, 29% yield). 1 H NMR(400MHz,DMSO-d6):9.05(bs,7H),6.26(s,2H),5.92(d,J=2.0Hz,1H),5.80(d,J=2. 0Hz,1H),5.38(q,J=5.2Hz,1H),5.03(d,J=5.2Hz,1H),3.73(s,3H),2.56(t,J=4Hz,2H), 19 F NMR(400MHz,DMSO-d6)δ-141.56,-141.54,-138.98,-138.91.LCMS:(MH + ):m / Z:508.91.

[0303] compound 60 [ka] Step 1: Synthesis of 3,4-bis(benzyloxy)-5-(difluoromethoxy)benzoic acid (2). To a mixture of methyl 3,4-bis(benzyloxy)-5-(difluoromethoxy)benzoate (1 g, 2.415 mmol, 1.0 equiv.) in THF / HO (1:1) (20 mL) was added LiOH·HO (0.25 g, 12.070 mmol, 5.0 equiv.). The solution was stirred at room temperature for 16 h. The reaction mixture was concentrated to remove THF. The mixture was then diluted with HO (25 mL) and extracted with EA (30 mL x 2). The aqueous phase was adjusted to pH < 3 with 1 N HCl. The resulting solid was filtered, and the filter cake was dried to give compound 3,4-bis(benzyloxy)-5-(difluoromethoxy)benzoic acid as a white solid (0.7 g, 72% yield). 1 H NMR(400MHz,DMSO-d6)δ7.64(d,J=1.2Hz,1H),7.46(d,J=6Hz,3H),7.39-7.34(m,5H),7.30(t,J=2.4Hz,3H),7.11(s,1H),5.15(s,2H),5.01(s,2H), 19 F NMR (400MHz, DMSO-d6) δ-80.92,-80.72.

[0304] Step 2: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-5-(difluoromethoxy)benzoate (3). To a stirred solution of 3,4-bis(benzyloxy)-5-(difluoromethoxy)benzoic acid (0.71 g, 1.785 mmol, 1.5 equiv.) in DCM (6 mL) under a N atmosphere, oxalyl chloride (0.5 mL, 5.950 mmol, 5 equiv.) and 2 drops of DMF were added at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was concentrated under reduced pressure to provide the acid chloride. The resulting acid chloride was added to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (1.1 g, 1.190 mmol, 1 equiv.), DMAP (0.58 g, 4.760 mmol, 4 equiv.), and EtN (0.7 mL, 4.760 mmol, 4 equiv.) in CHCl (5 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. Finally, saturated aqueous sodium bicarbonate solution (5 mL) was added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted with CHCl (30 mL). The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by flash column chromatography (EtOAc in hexanes) to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-5-(difluoromethoxy)benzoate as a pale yellow solid (1 g, 75% yield). 1H NMR (400MHz, DMSO-d6): δ7.45-7.21(m,36H),7.14(s,1H),6.94(s,2H),6. 45(d,J=2Hz,1H),6.29(d,J=1.6Hz,1H),5.44(d,J=5.2Hz,1H),5.22(d,J=7 .2Hz,1H),5.20(s,2H),5.18(s,2H),5.14(s,2H),5.12(s,2H),5.08(s,2H) ,4.96(s,2H),4.87(s,2H),3.04(dd,J=7.2Hz,2H),2.82(dd,J=7.2Hz,2H), 19 F NMR(400MHz,DMSO-d6)δ-81.7,-81.38.LCMS:(M+H + ):m / Z:1139.53.

[0305] Step 3: Synthesis of Compound 60. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-5-(difluoromethoxy)benzoate (1 g, 0.878 mmol, 1 equiv.) in 8 mL of THF:MeOH (1:1), palladium hydroxide (20 wt%, 1.0 g) was added at room temperature, and the reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3-(difluoromethoxy)-4,5-dihydroxybenzoate as an off-white solid (0.104 g, 31% yield). 1 H NMR(400MHz,DMSO-d6):9.09(bs,7H),6.26(s,2H),5.92(d,J=2.0Hz,1H),5.80(d,J=2.0Hz,1H),5. 38(q,J=5.2Hz,1H),5.03(d,J=5.2Hz,1H),3.73(s,3H),2.62(dd,J=4Hz,1H),2.55(dd,J=4Hz,1H), 19 F NMR(400MHz,DMSO-d6)δ-81.11.LCMS:(MH +):m / Z:508.88.

[0306] compound 61 [ka] Step 1: Synthesis of methyl 3,4-bis(benzyloxy)-5-isopropoxybenzoate (2). To a suspension of 3,4-bis(benzyloxy)-5-hydroxybenzoate (10.0 g, 27.470 mmol) in DMF (100 mL) was added KCO (5.73 g, 41.20 mmol, 1.2 equiv.) followed by 2-bromopropane (5.08 g, 41.20 mmol, 1.2 equiv.) at 0 °C. The reaction mixture was heated to 60 °C for 12 h. After this time, the reaction product was diluted with water and extracted with EtOAc. The organic layer was evaporated, and the residue was purified by flash chromatography eluting with 25% EtOAc in hexanes to give methyl 3,4-bis(benzyloxy)-5-isopropoxybenzoate as a white solid (8.2 g, 73% yield). 1 H NMR(400MHz,DMSO-d6)δ7.47(d,J=1.2Hz,1H),7.45-7.35(m,4H),7.34-7.30(m,5H),7.23(d,J= 2.0Hz, 2H), 5.16 (s, 2H), 5.02 (s, 2H), 4.66-4.60 (m, 1H), 3.82 (s, 3H), 1.27 (s, 3H), 1.28 (s, 3H).

[0307] Step 2: Synthesis of methyl 3,4-bis(benzyloxy)-2,6-difluoro-5-isopropoxybenzoate (3). To a solution of methyl 3,4-bis(benzyloxy)-5-isopropoxybenzoate (12.2 g, 30.185 mmol, 1 equiv.) in ACN (60 mL) was added Selectfluor (42.7 g, 120.743 mmol, 4 equiv.) at 0 °C, and the reaction mixture was stirred at 60 °C for 32 h. The reaction progress was monitored by TLC. After this time, the reaction mixture was quenched with cold water and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column chromatography to give 3,4-bis(benzyloxy)-2,6-difluoro-5-isopropoxybenzoate as a green solid (1.1 g, 8% yield). 1 H NMR (400MHz, DMSO-d6) δ7.43-7.30(m,10H),5.18(s,2H),5.04(s,2H),4.43-4.28(m,1H),3.56(s,3H),1.24(s,3H),1.16(s,3H).

[0308] Step 3: Synthesis of 3,4-bis(benzyloxy)-2,6-difluoro-5-isopropoxybenzoic acid (4). To a mixture of methyl 3,4-bis(benzyloxy)-2,6-difluoro-5-isopropoxybenzoate (1 g, 2.260 mmol, 1.0 equiv.) in THF / HO (1:1) (20 mL) was added LiOH·HO (0.284 g, 11.300 mmol, 5.0 equiv.). The solution was stirred at room temperature for 2 h. The reaction mixture was concentrated to remove THF. Next, the mixture was diluted with HO (30 mL) and extracted with EA (20 mL x 1). The aqueous phase was adjusted to pH < 3 with 1 N HCl. The resulting solid was filtered and the solid was dried to give 3,4-bis(benzyloxy)-2,6-difluoro-5-isopropoxybenzoic acid as a white solid (0.91 g, 94% yield). 1H NMR(400MHz,DMSO-d6)δ13.82(s,1H),7.43-7.30(m,10H),5.15(s,2H),5.04(s,2H),4.39-4.36(m,1H),1.21(s,3H),1.20(s,3H). 19 F NMR (400MHz, DMSO-d6) δ134.17,134.18,134.48,134.48.

[0309] Step 4: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-2,6-difluoro-5-isopropoxybenzoate (5). To a stirred solution of 3,4-bis(benzyloxy)-2,6-difluoro-5-isopropoxybenzoic acid (0.9 g, 2.102 mmol, 1 equiv.) in DCM (8 mL) under a N atmosphere, oxalyl chloride (0.53 mL, 6.308 mmol, 3 equiv.) and 2 drops of DMF were added at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After this time, the reaction mixture was concentrated under reduced pressure to provide the acid chloride. The resulting acid chloride was added to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (0.079 g, 1.051 mmol, 0.5 equiv.), DMAP (1 g, 8.411 mmol, 4 equiv.), and EtN (1.1 mL, 8.411 mmol, 4 equiv.) in CHCl (15 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. Finally, the reaction was quenched with saturated aqueous NaHCO (5 mL). The organic layer was separated, and the aqueous layer was extracted with CHCl (30 mL). The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The crude compound obtained was purified by flash column chromatography (EtOAc in hexane) to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-2,6-difluoro-5-isopropoxybenzoate as a pale green solid (0.4 g, 32% yield). LCMS: (M+H + ):m / Z:1167.43.

[0310] Step 5: Synthesis of Compound 61. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-2,6-difluoro-5-isopropoxybenzoate (0.39 g, 0.334 mmol, 1 equiv.) in 10 mL of THF:MeOH (1:1), palladium hydroxide (20 wt%, 0.039 g) was added at room temperature, and the reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,6-difluoro-3,4-dihydroxy-5-isopropoxybenzoate as an off-white solid (0.094 g, 52% yield). 1 H NMR(400MHz,DMSO-d6):9.06(bs,7H),6.24(s,2H),5.90(d,J=2.0Hz,1H),5.78(d,J=2.4Hz,1H),5.36(q, J=4.8Hz,1H),5.02(d,J=4.8Hz,1H),4.28-4.22(s,1H),2.60(d,J=4.0Hz,2H),1.19(s,3H),1.17(s,3H), 19 F NMR(400MHz,DMSO-d6)δ-139.80,-138.95.LCMS:(MH + ):m / Z:536.96.

[0311] compound 62 [ka] Step 1: Synthesis of benzyl 4,5-bis(benzyloxy)-2-(trifluoromethyl)benzoate (2). To a solution of 4,5-dihydroxy-2-(trifluoromethyl)benzoic acid (0.5 g, 2.251 mmol, 1 equiv.) and K2CO3 (1.56 g, 11.26 mmol, 4 equiv.) in DMF (20 mL) was added BnBr (1.34 mL, 11.26 mmol, 4 equiv.) at 0 °C, and the reaction mixture was stirred at 60 °C for 10 h. The reaction progress was monitored by TLC. After this time, the reaction mixture was diluted with ice-cold water (50 mL), extracted with ethyl acetate (50 mL x 3), washed with brine, and dried over Na2SO4. The organic layer was evaporated under reduced pressure to give the crude compound. The crude material was purified by flash chromatography eluting with 10% EtOAc in hexanes as eluent to give benzyl 4,5-bis(benzyloxy)-2-(trifluoromethyl)benzoate (0.710 g, 64% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): 7.45-7.32 (m, 15H), 7.27 (s, 1H), 7.26 (s, 1H), 5.32 (s, 2H), 5.21 (s, 2H), 5.20 (s, 1H).

[0312] Step 2: Synthesis of 4,5-bis(benzyloxy)-2-(trifluoromethyl)benzoic acid (3). To a solution of benzyl 4,5-bis(benzyloxy)-2-(trifluoromethyl)benzoate (0.7 g, 1.42 mmol, 1.0 equiv.) in ethanol (24 mL) was added 1.5 M aqueous KOH (0.39 g, 7.106 mmol, 5 equiv.) at 25 °C and stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After this time, the reaction mixture was concentrated under reduced pressure to give the crude compound. The crude compound was diluted with water, and the pH of the aqueous layer was adjusted to 2 with 1 N HCl, causing the formation of a precipitate. The solid compound was collected by filtration and dried under high vacuum to give 4,5-bis(benzyloxy)-2-(trifluoromethyl)benzoic acid (0.69 mg, 98% yield) as an off-white solid. 1H NMR (400MHz, DMSO-d6): 13.33 (Br s, 1H), 7.46-7.32 (m, 10H), 5.29 (s, 2H), 5.27 (s, 2H).

[0313] Step 3: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 4,5-bis(benzyloxy)-2-(trifluoromethyl)benzoate (4). To a solution of 4,5-bis(benzyloxy)-2-(trifluoromethyl)benzoic acid (3 g, 0.560 g, 1.4 mmol, 1 equiv.) in DCM (10 mL) was added oxalyl chloride (0.6 mL, 0.70 mmol, 5 equiv.) and 2 drops of DMF at 0° C. and stirred at room temperature for 1 hour. After this time, the reaction mixture was concentrated under reduced pressure to provide the acid chloride. The resulting acid chloride was added to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (0.6 g, 0.79 mmol, 0.8 equiv.), EtN (0.97 ml, 0.7 mmol, 5 equiv.), and DMAP (0.85 g, 0.7 mmol, 5 equiv.) in DCM (10 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. Finally, the reaction was quenched with saturated aqueous NaHCO (5 mL). The organic layer was separated, and the aqueous layer was extracted with CHCl (30 mL). The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by flash column chromatography (EtOAc in hexane) to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 4,5-bis(benzyloxy)-2-(trifluoromethyl)benzoate (0.315 g, 20% yield) as a pale green solid. LCMS: 74.60%, (M+H=1141.48).

[0314] Step 4: Synthesis of Compound 62. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 4,5-bis(benzyloxy)-2-(trifluoromethyl)benzoate (0.31 g, 0.271 mmol) in THF (15 mL) and MeOH (15 mL) was added Pd(OH) (20 wt%, 0.31 g) at 25° C. The reaction mixture was stirred under an H atmosphere at 25° C. for 16 hours. The progress of the reaction was monitored by LCMS. The reaction mixture was passed through a Celite pad, and the filtrate was evaporated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 4,5-dihydroxy-2-(trifluoromethyl)benzoate (0.074 g, 53% yield) as a pale pink solid. 1 H NMR (400MHz, DMSO-d6): δ9.32(bs,7H),7.01(s,2H),6.25(s,2H),5.91-5.90(d,J=2Hz,1H),5.79-5.78(d,J=2.0H z,1H),5.33-5.30(q,J=4.8Hz,1H),5.04-5.03(d,J=4.8Hz,1H),2.66-2.54(m,2H).LCMS:99.73%,(M+H=510.83).

[0315] compound 63 [ka] Step 1: Synthesis of benzyl 3,4-bis(benzyloxy)-2-methylbenzoate (2). To a solution of 3,4-dihydroxy-2-methylbenzoic acid (0.5 g, 2.97 mmol, 1 equiv.) and K2CO3 (1.64 g, 10.416 mmol, 4 equiv.) in DMF (20 mL), BnBr (1.42 mL, 11.88 mmol, 4 equiv.) was added at 0 °C and stirred at 80 °C for 16 h. The reaction progress was monitored by TLC. The reaction mixture was diluted with ice-cold water (50 mL), and the product was extracted with ethyl acetate (50 mL x 3), washed with brine, and dried over Na2SO4. The organic layer was concentrated under reduced pressure to give the crude compound. The crude material was purified by flash chromatography eluting with 10% EtOAc in hexanes as eluent to give benzyl 3,4-bis(benzyloxy)-2-methylbenzoate (1.1 g, 85% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):7.76-7.74(d,J=8.4Hz,1H),7.45-7.31(m,15H),6.86-6.84(d,J=8.8Hz,1H),5.31(s,2H),5.17(s,2H),4.94(s,2H) ),2.53(s,3H).

[0316] Step 2: Synthesis of 3,4-bis(benzyloxy)-2-methylbenzoic acid (3). To a solution of benzyl 3,4-bis(benzyloxy)-2-methylbenzoate (1.2 g, 2.736 mmol, 1.0 equiv.) in ethanol (20 mL) was added 1.5 M aqueous KOH (0.768 g, 13.682 mmol, 5 equiv.) at 25 °C and stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After this time, the reaction mixture was concentrated under reduced pressure to give the crude compound. The crude compound was diluted with water, and the pH of the aqueous layer was adjusted to 2 with 1 N HCl, causing the formation of a precipitate. The solid compound was collected by filtration and dried under high vacuum to give 3,4-bis(benzyloxy)-2-methylbenzoic acid (0.94 g, 98% yield) as an off-white solid. 1H NMR(400MHz,DMSO-d6):δ12.53(bs,1H),7.66-7.64(d,J=8.4Hz,1H),7.52-7.50(m,3H) ,7.43-7.32(m,8H),7.11-7.09(d,J=8.8Hz,1H),5.24(s,2H),4.90(s,2H),2.40(s,3H).

[0317] Step 3: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-2-methylbenzoate (4). To a stirred solution of 3,4-bis(benzyloxy)-2-methylbenzoic acid (0.86 g, 2.468 mmol, 1 equiv.) in DCM (10 mL) was added oxalyl chloride (1.0 mL, 12.342 mmol, 5 equiv.) and 2 drops of DMF at 0° C. The reaction mixture was stirred at room temperature for 1 hour. After this time, the reaction mixture was concentrated under reduced pressure to provide the acid chloride. The resulting acid chloride was added to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (1.49 g, 1.974 mmol, 0.8 equiv.), EtN (0.32 ml, 12.342 mmol, 5 equiv.), and DMAP (1.5 g, 12.342 mmol, 5 equiv.) in DCM (10 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. Finally, the reaction was quenched with saturated aqueous NaHCO (5 mL). The organic layer was separated, and the aqueous layer was extracted with CHCl (30 mL). The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The crude compound obtained was purified by flash column chromatography (EtOAc in hexane) to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-2-methylbenzoate (0.24 g, 19% yield) as an off-white solid. LCMS: 71.08%, (MH=1087.35).

[0318] Step 4: Synthesis of Compound 63. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-2-methylbenzoate (0.58 g, 0.533 mmol) in THF (15 mL) and MeOH (15 mL) was added Pd(OH) (10 wt%, 0.58 g) at room temperature. The reaction mixture was stirred under an H atmosphere at 25 °C for 16 hours. The progress of the reaction was monitored by LCMS. The reaction mixture was filtered through a Celite pad, and the filtrate was evaporated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4-dihydroxy-2-methylbenzoate (0.062 g, 25% yield) as a pale pink solid. 1 H NMR(400MHz,DMSO-d6):δ9.05(bs,7H),7.04-7.02(d,J=8.8Hz,1H),6.61-6.59(d,J=8.8H z,1H),5.92-5.91(d,J=1.6Hz,1H),5.79-5.78(d,J=2.0Hz,1H),5.24-5.20(q,J=5.2Hz,1H ),5.00-4.99(d,J=5.6Hz,1H),2.68-2.53(m,2H),2.21(s,3H).LCMS:99.72%,(M+H=456.85).

[0319] compound 64 [ka]

[0320] Step 1: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-2,6-difluoro-5-methoxybenzoate (3). To a stirred solution of 3,4-bis(benzyloxy)-2,6-difluoro-5-methoxybenzoic acid (1.2 g, 1.936 mmol, 1 equiv.) in DCM (8 mL) under a N atmosphere, oxalyl chloride (0.49 mL, 5.808 mmol, 3 equiv.) and 2 drops of DMF were added at 0° C. The reaction mixture was stirred at room temperature for 1 hour. After this time, the reaction mixture was concentrated under reduced pressure to provide the acid chloride. The resulting acid chloride was added to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-ol (1 g, 2.710 mmol, 1.4 equiv.), DMAP (0.9 g, 7.744 mmol, 4 equiv.) and EtN (0.94 mL, 7.744 mmol, 4 equiv.) in CHCl (15 mL) at 0° C. The mixture was stirred at room temperature overnight, after which saturated aqueous NaHCO was added. The organic layer was separated and the aqueous layer was extracted with CHCl. ​​The organic phases were combined, dried (MgSO), and evaporated. The crude compound was purified by flash column chromatography eluting with 20% EtOAc in hexane as eluent to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-2,6-difluoro-5-methoxybenzoate as a white solid (0.41 g, 21% yield). 1 H NMR(400MHz,DMSO-d6):7.41-7.26(m,30H),7.12(s,1H),7.03(d,J=8.4Hz,1H),6.90(d,J=8.4Hz,1H),6.37(d,J=2Hz,1H),6.24(d,J=1.6Hz,1H), 5.74(s,1H),5.60(d,J=5.6Hz,1H),5.21(d,J=6Hz,1H),5.15(s,2H),5.0 9(s,4H),5.04(s,4H),4.95(s,2H),3.79(s,3H),2.78(dd,J=7.6Hz,2H), 19F NMR(400MHz,DMSO-d6)δ-133.54,134.49.LCMS:(M+H+):m / Z:1033.36.

[0321] Step 2: Synthesis of Compound 64. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-2,6-difluoro-5-methoxybenzoate (0.39 g, 0.377 mmol, 1 equiv.) in 10 mL of THF:MeOH (1:1), palladium hydroxide (20 wt%, 0.39 g) was added at room temperature, and the reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3-fluoro-4,5-dihydroxybenzoate as a pale pink solid (0.09 g, 49% yield). 1 H NMR(400MHz,DMSO-d6):9.18(bs,6H),6.71(d,J=4Hz,1H),6.67(d,J=8.4Hz,1H),6.58(d,J=8Hz,1H),5.89(d,J=2. 4Hz,1H),5.79(d,J=2.4Hz,1H),5.36(q,J=5.2Hz,1H),5.01(d,J=4.8Hz,1H),3.67(s,3H),2.58(dd,J=5.6Hz,2H), 19 F NMR(400MHz,DMSO-d6)δ-141.56,139.02.LCMS:(M-H+):m / Z:493.02.

[0322] compound 65 [ka] Step 1: Synthesis of methyl 3,4-bis(benzyloxy)-5-(difluoromethoxy)benzoate (2). To a solution of methyl 3,4-bis(benzyloxy)-5-hydroxybenzoate (1.2 g, 3.29 mmol, 1.0 equiv.) in CH3CN:HO (6:4) (10 mL), KOH (0.92 g, 16.48 mmol, 5.0 equiv.) was added at room temperature and stirred for 20 min. Next, the mixture was cooled to -78 °C, and diethyl (bromodifluoromethyl)phosphonate (2.64 g, 9.89 mmol, 3.0 equiv.) was added. The mixture was allowed to warm to room temperature and stirred for 4 h. Finally, the reaction mixture was diluted with HO (50 mL), neutralized with 1N HCl, and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (PE / EA=9 / 1) to give methyl 3,4-bis(benzyloxy)-5-(difluoromethoxy)benzoate (0.48 g, 35% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ7.60(d,J=2.0Hz,1H),7.52-7.47(m,2H),7.45-7.30(m,9H),7.20(t,J=73.6Hz,1H),5.26(s,2H),5.09(s,2H),3.85(s,3H).

[0323] Step 2: Synthesis of methyl 3,4-bis(benzyloxy)-5-(difluoromethoxy)-2-fluorobenzoate (3). To a mixture of methyl 3,4-bis(benzyloxy)-5-(difluoromethoxy)benzoate (1.2 g, 2.89 mmol, 1.0 equiv.) in CH3CN (12 mL) was added Selectfluor (6.15 g, 17.39 mmol, 6.0 equiv.) at 0 °C and stirred at room temperature for 1 h. The reaction mixture was warmed to 50 °C and stirred for an additional 16 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with HO (50 mL), and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (PE / EA=9 / 1) to give methyl 3,4-bis(benzyloxy)-5-(difluoromethoxy)-2-fluorobenzoate (0.051 g, 4% yield) as a pale yellow solid. 1 H NMR (400MHz, CDCl3): δ7.50(d,J=6.4Hz,1H),7.45-7.32(m,9H),6.38(t,J=74.0Hz,1H),5.15(s,2H),5.11(s,2H),3.92(s,3H).

[0324] Step 3: Synthesis of 3,4-bis(benzyloxy)-5-(difluoromethoxy)-2-fluorobenzoic acid (4). To a solution of methyl 3,4-bis(benzyloxy)-5-(difluoromethoxy)-2-fluorobenzoate (0.25 g, 0.57 mmol, 1.0 equiv.) in MeOH:THF:HO (1:1:1) (6 mL) was added LiOH (0.07 g, 2.89 mmol, 5.0 equiv.) at 0 °C, and the mixture was stirred at room temperature for 4 h. After completion of the reaction, the solvent was evaporated under reduced pressure. The resulting solid was diluted with HO (20 mL), acidified with 1 N HCl (pH = 2-3), and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 3,4-bis(benzyloxy)-5-(difluoromethoxy)-2-fluorobenzoic acid (0.215 g, 89% yield) as a white solid. 1H NMR (400MHz, DMSO-d6): 7.45-7.32 (m, 9H), 7.16 (t, J=73.2Hz, 1H), 5.15 (s, 2H), 5.10 (s, 2H).

[0325] Step 4: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-5-(difluoromethoxy)-fluorobenzoate (4). To a solution of 3,4-bis(benzyloxy)-5-(difluoromethoxy)-2-fluorobenzoic acid (0.215 g, 0.51 mmol, 1.0 equiv.) in CHCl (5 mL) was added (COCl) (0.25 mL, 2.57 mmol, 5.0 equiv.) and 2 drops of anhydrous DMF at 0 °C. The mixture was stirred at room temperature for 1 hour. After completion of acid chloride formation, the solvent was evaporated from the reaction mixture and dried under reduced pressure. To this was added a mixture of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (0.39 g, 0.51 mmol, 1.0 equiv), DMAP (0.250 g, 2.05 mmol, 4.0 equiv), and TEA (0.3 mL, 2.05 mmol, 4.0 equiv) in CHCl (5 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with HO (30 mL) and extracted with CHCl (50 mL × 2). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (PE / EA = 6 / 1) to give compound 5 (0.21 g, 64% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ7.51-7.30(m,33H),δ 7.27-7.21(m,3H),6.77(s,2H),6.34(t,J=74.0Hz,1H),6.32(d,J=2.0Hz,1H),6.29(d,J=2.0Hz,1H), 5.51(q,J=7.2Hz,1H),5.12-4.98(m,15H),3.14(dd,J=10.8,5.6Hz,1H),3.14(dd,J=8.8,8.0Hz,1H).

[0326] Step 5: Synthesis of Compound 65. To a mixture of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-5-(difluoromethoxy)-2-fluorobenzoate (0.2 g, 0.17 mmol, 1.0 equiv.) in THF (2.5 mL) and MeOH (2.5 mL) was added Pd(OH) / C (20 wt%, 120 mg). The mixture was stirred under a H atmosphere at room temperature overnight. The reaction mixture was passed through a Celite pad, and the filtrate was concentrated. The residue was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 5-(difluoromethoxy)-2-fluoro-3,4-dihydroxybenzoate (40 mg, 44% yield) as a pale pink solid. 1 H NMR(400MHz,DMSO-d6)δ8.98(bs,7H),6.97(t,J=74.4Hz,1H),6.97(d,J=6.4Hz,1H),6.25(s,2H),5.91(d ,J=2.4Hz,1H),5.78(d,J=2.4Hz,1H)5.29(q,J=5.2Hz,1H),5.02(d,J=5.6Hz,1H),2.62(d,J=5.2Hz,2H).

[0327] compound 66 [ka] Step 1: Synthesis of methyl 3,4-bis(benzyloxy)-5-fluorobenzoate (2). To a solution of methyl 3,4-bis(benzyloxy)benzoate (11.7 g, 33.620 mmol, 1 equiv.) in ACN (50 mL) was added Selectfluor (47.7 g, 134.48 mmol, 4 equiv.) at 0 °C, and the reaction mixture was stirred at room temperature for 72 h. The reaction progress was monitored by TLC. After this time, the reaction mixture was quenched with cold water, extracted with EtOAc (100 mL x 3), washed with brine, and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure to give the crude compound. The crude compound was purified by flash column chromatography eluting with 15% EtOAc in hexanes to give methyl 3,4-bis(benzyloxy)-5-fluorobenzoate as a yellow solid (1.8 g, 15% yield). 1 H NMR(400MHz,DMSO-d6)δ7.58(d,J=2.0Hz,1H),7.56(d,J=1.6Hz,1H),7.46-7.43(m,4 H),7.41-7.29(m,5H),7.18(d,J=9.2Hz,1H),5.22(s,2H),5.17(s,2H),3.79(s,3H), 19 F NMR(375MHz,DMSO-d6)δ-114.10.

[0328] Step 2: Synthesis of 3,4-bis(benzyloxy)-5-fluorobenzoic acid (3). To a mixture of methyl 3,4-bis(benzyloxy)-5-fluorobenzoate (1.8 g, 5.021 mmol, 1 equiv.) in THF / HO (2:1) (30 mL) was added LiOH·HO (2.1 g, 50.210 mmol, 10 equiv.). The solution was stirred at room temperature for 16 h. The reaction mixture was concentrated to remove THF. The resulting crude product was diluted with HO (20 mL) and extracted with EA (20 mL x 1). The aqueous phase was adjusted to pH < 3 with 1 N HCl. The mixture was then filtered, and the filter cake was dried to give 3,4-bis(benzyloxy)-5-fluorobenzoic acid as a white solid (0.8 g, 46% yield). 1H NMR (400MHz, DMSO-d6) δ12.73(s,1H),7.64(s,1H),7.58(d,J=2.0Hz,1H),7.41-7.28(m,9H),7.14(d,J=8.8Hz,1H),5.21(s,2H),5.12(s,2H).

[0329] Step 3: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-5-fluorobenzoate (4). Under a N atmosphere, to a stirred solution of 3,4-bis(benzyloxy)-5-fluorobenzoic acid (0.77 g, 1.085 mmol, 1 equiv.) in DCM (8 mL) was added oxalyl chloride (0.26 mL, 3.055 mmol, 3 equiv.) and 2 drops of DMF at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Excess oxalyl chloride was removed by distillation, and the residue was dried to give the acid chloride. The resulting acid chloride was added dropwise to a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (0.53 g, 1.527 mmol, 1.5 equiv.), DMAP (0.497 g, 4.074 mmol, 4 equiv.), and EtN (0.54 mL, 4.074 mmol, 4 equiv.) in CHCl (10 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. Finally, the reaction was quenched with saturated aqueous NaHCO (5 mL). The organic layer was separated, and the aqueous layer was extracted with CHCl (30 mL). The combined organic phases were dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by flash column chromatography (EtOAc in hexanes) to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-5-fluorobenzoate as a yellow solid (0.36 g, 31% yield). 1H NMR(400MHz,DMSO-d6)δ7.45-7.10(m,36H),7.11(d,J=2.4Hz,1H),6.87(d,J=2.0Hz,2H),6.43(d,J=2.4Hz,1H),6.28(d,J=2.4Hz,1H),5.46(q,J=5 .6Hz,1H),5.16(d,J=8.8Hz,1H),5.12(s,2H),5.04(s,6H),4.98(s,2H), 4.89(s,2H),3.85(s,2H),2.95(dd,J=7.4Hz,1H),2.77(dd,J=8.8Hz,1H), 19 F NMR(400MHz,DMSO-d6)δ-114.00.LCMS:(M+H + ):m / Z:1091.4.

[0330] Step 4: Synthesis of Compound 66. To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-5-fluorobenzoate (0.35 g, 0.321 mmol, 1 equiv.) in 10 mL of THF:MeOH (1:1), palladium hydroxide (20 wt%, 0.35 g) was added at room temperature, and the reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was then passed through a Celite pad to remove the catalyst. The filtrate was concentrated under reduced pressure. The resulting crude compound was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3-fluoro-4,5-dihydroxybenzoate as an off-white solid (0.040 g, 52% yield). 1 H NMR (400MHz, DMSO-d6): δ9.02(bs,7H),7.07(d,J=7.6Hz,1H),6.52(d,J=7.6Hz,1H),6.25(s,2H),5.91(d ,J=2.4Hz,1H),5.79(d,J=2.4Hz,1H),5.26(q,J=5.2Hz,1H),5.01(d,J=5.2Hz,1H),2.60(d,J=4.8Hz,2H), 19 F NMR(400MHz,DMSO-d6)δ-118.04.LCMS:(MH + ):m / Z:459.0.

[0331] compound 67 [ka] Step 1: Synthesis of (2S,3R)-2-(4-(allyloxy)-3,5-dihydroxyphenyl)chroman-3,5,7-triol (1). To a stirred solution of (2S,3R)-2-(3,4,5-trihydroxyphenyl)chroman-3,5,7-triol (12.0 g, 39.44 mmol, 1.0 equiv.) in anhydrous acetone (360 mL) was added KCO (10.88 g, 78.89 mmol, 2.0 equiv.) at 0 °C and stirred at the same temperature for 0.5 h. To this was added allyl bromide (4.09 mL, 47.33 mmol, 1.2 equiv.) at 0 °C. The resulting suspension was stirred at 55 °C for 18 h. The progress of the reaction was monitored by TLC. After complete consumption of the starting material, the solvent was evaporated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (H2O:CH3CN, 1:9) to give (2S,3R)-2-(4-(allyloxy)-3,5-dihydroxyphenyl)chroman-3,5,7-triol (2.34 g, 17.2% yield) as a brownish solid. 1 H NMR(400MHz,MeOH-d4):δ6.46-6.37(m,2H),6.20-6.06(m,1H),5.92(d,J=2.4Hz,1H),5.86(d,J=2.0Hz,1H),5.29(dd,J=17.2,2.0Hz ,1H),5.15(dd,J=9.6,0.8Hz,1H),4.65-4.48(m,3H),3.97(m,1H),3.34(s,2H),2.80(dd,J=16.4,5.2Hz,1H),2.50(q,J=7.6Hz,1H).

[0332] Step 2: Synthesis of (2S,3R)-2-(4-(allyloxy)-3,5-bis(benzyloxy)phenyl)-5,7-bis(benzyloxy)chroman-3-ol (2). To a stirred solution of (2S,3R)-2-(4-(allyloxy)-3,5-dihydroxyphenyl)chroman-3,5,7-triol (7.0 g, 20.23 mmol, 1.0 equiv.) in HMPA (70 mL), KCO (11.16 g, 80.92 mmol, 4.0 equiv.) was added at room temperature and stirred for 15 min. The mixture was then cooled to 0 °C, and BnCl (9.26 mL, 80.92 mmol, 4.0 equiv.) was added dropwise at room temperature. The mixture was stirred at 90 °C for 16 h. After this time, the reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic phase was washed with brine (50 mL), dried over NaSO, filtered and evaporated. The crude compound was purified by silica gel column chromatography (PE / EA=5 / 1) to give (2S,3R)-2-(4-(allyloxy)-3,5-bis(benzyloxy)phenyl)-5,7-bis(benzyloxy)chroman-3-ol (3.68 g, 25.7% yield) as a yellow solid. 1 H NMR(400MHz,MeOH-d4):δ7.46-7.25(m,20H),6.79(s,2H),6.34(d,J=2.0Hz,1H),6.12(d,J=2.0Hz,1H),δ6.04-5.92(m,1H),5.26(d,J=7.2Hz,1H),5 .12(d,J=6.4Hz,1H),5.15-5.00(m,9H),4.62(d,J=7.2Hz,1H),4.43(d,J= 5.6Hz,2H),4.01(m,1H),2.76(dd,J=16.4,5.2Hz,1H),2.55-2.41(m,1H).

[0333] Step 3: Synthesis of (2S,3R)-2-(4-(allyloxy)-3,5-bis(benzyloxy)phenyl)-5,7-bis(benzyloxy)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (3). To a solution of 3,4,5-tris(benzyloxy)-2-fluorobenzoic acid (0.63 g, 1.38 mmol, 1.3 equiv.) in CHCl (5 mL) was added (COCl) (0.27 mL, 3.18 mmol, 3.0 equiv.) and 2 drops of DMF at 0 °C. The mixture was stirred at room temperature for 2 hours. After completion of acid chloride formation, the solvent was evaporated from the reaction mixture and dried under reduced pressure. To this was added a mixture of (2S,3R)-2-(4-(allyloxy)-3,5-bis(benzyloxy)phenyl)-5,7-bis(benzyloxy)chroman-3-ol (0.75 g, 1.06 mmol, 1.0 equiv), DMAP (0.65 g, 5.31 mmol, 5.0 equiv), and TEA (0.73 mL, 5.31 mmol, 5.0 equiv) in CHCl (10 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with H0 (30 mL) and extracted with CHCl (80 mL × 2). The combined organic phase was washed with brine (30 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA=7 / 1) to give (2S,3R)-2-(4-(allyloxy)-3,5-bis(benzyloxy)phenyl)-5,7-bis(benzyloxy)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (0.992 g, 88% yield) as a pale yellow solid. 1 H NMR(400MHz,MeOH-d4):δ7.52-7.20(m,35H),7.03(d,J=6.0Hz,1H),6.87(s,2H),6.42(s,1H),6.26(s,1H),6.00-5 .86(m,1H),5.47(q,J=6.0Hz,1H),5.25-4.87(m,17H),4.39(d,J=5.6Hz,2H),3.00-2.90(m,1H),2.85-2.70(m,1H).

[0334] Step 4: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,5-bis(benzyloxy)-4-hydroxyphenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (4). To a solution of (2S,3R)-2-(4-(allyloxy)-3,5-bis(benzyloxy)phenyl)-5,7-bis(benzyloxy)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (8.2 g, 7.14 mmol, 1.0 equiv.) in THF (160 mL) was added NaBH (0.405 g, 10.72 mmol, 1.5 equiv.) at 0 °C. Then, Pd(PPh) (0.825 g, 0.71 mmol, 0.1 equiv.) was added at room temperature. The resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic phase was washed with brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (PE / EA = 4 / 1) to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,5-bis(benzyloxy)-4-hydroxyphenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (1.6 g, 20% yield) as a pale green solid. 1 H NMR(400MHz,MeOH-d4):δ8.51(s,1H),7.47-7.14(m,35H),6.98(d,J=6.0Hz,1H),6.79(s,2H),6.41(d,J=2.0Hz,1H),6. 24(d,J=2.0Hz,1H),5.42(q,J=5.6Hz,1H),5.20-4.85(m,15H),2.91(d,J=16.8,5.6Hz,1H),2.75(d,J=16.4,7.2Hz,1H).

[0335] Step 5: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,5-bis(benzyloxy)-4-((ethylcarbamoyl)oxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (5). To a solution of (2S,3R)-5,7-bis(benzyloxy)-2-(3,5-bis(benzyloxy)-4-hydroxyphenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (0.1 g, 0.09 mmol, 1.0 equiv.) in CHCl (2 mL) was added EtN (0.07 mL, 0.45 mmol, 5.0 equiv.) and ethyl isocyanate (0.02 g, 0.27 mmol, 3.0 equiv.) at 0 °C. The mixture was stirred at 0° C. for 2 hours, then warmed to room temperature and stirred for 12 hours. After completion of the reaction, the solvent was evaporated from the reaction mixture. The resulting residue was dissolved in THF (5 mL), MeOH (10 mL) was added, and the formed precipitate was filtered and dried to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,5-bis(benzyloxy)-4-((ethylcarbamoyl)oxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (0.085 g, 80% yield) as a white solid. 1 H NMR(400MHz,MeOH-d4):7.47-7.14(m,35H),7.09(d,J=6.0Hz,1H),6.76(s,2H),6.31(d,J=6.8,2.4Hz,1H),5.50(d,J=5.6Hz,1H),5.16(d ,J=6.4Hz,1H),5.10-4.93(m,14H),3.26(quintet,J=6.8Hz,2H),3.04(d,J=5.6Hz,1H),2.88(dd,J=17.2,6.8Hz,1H),1.45-1.25(m,1H).

[0336] Step 6: Synthesis of Compound 67. To a mixture of (2S,3R)-5,7-bis(benzyloxy)-2-(3,5-bis(benzyloxy)-4-((ethylcarbamoyl)oxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)-2-fluorobenzoate (0.8 g, 0.68 mmol, 1.0 equiv.) in THF (10 mL) and MeOH (5 mL) was added Pd(OH) (20 wt%, 0.96 g). The mixture was stirred under an H atmosphere at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give (2S,3R)-2-(4-((ethylcarbamoyl)oxy)-3,5-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate (150 mg, 40.4% yield) as an off-white solid. 1 H NMR(400MHz,MeOH-d4):9.26(bs,7H),7.41(t,J=6.0Hz,1H),6.66(d,J=6.4Hz,1H),6.31(s,2H),5.91(d,J=2.4Hz,1H),5.82(d,J=2.0Hz,1H),5.33(q ,J=4.4Hz,1H),5.14(d,J=4.4Hz,1H),3.02(quintet,J=7.2Hz,2H),2.63(d,J=18.4,1.2Hz,1H),2.50(dd,J=20.0,4.0Hz,1H),1.03(t,J=7.2Hz,3H).

[0337] compound 68 [ka] Step 1: Synthesis of 3,4-bis(benzyloxy)-2-fluoro-5-methoxybenzoic acid (2). To a solution of benzyl 3,4-bis(benzyloxy)-2-fluoro-5-methoxybenzoate (4.70 g, 9.95 mmol, 1.0 equiv.) in THF:MeOH:HO (1:1:1) (50 mL), anhydrous LiOH (1.2 g, 49.77 mmol, 5.0 equiv.) was added at 0 °C and stirred at room temperature for 4 h. After completion of the starting material on TLC, the solvent was evaporated from the reaction mixture. The resulting solid was diluted with HO (50 mL) and washed with diethyl ether (50 mL). The aqueous layer was acidified with 1 N HCl (pH = 3-4), and the product was extracted with EtOAc (100 mL x 2). The combined organic phases were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 3,4-bis(benzyloxy)-2-fluoro-5-methoxybenzoic acid (2.28 g, 60% yield) as a light brown gummy solid. 1 H NMR (400MHz, DMSO-d6): 7.50-7.21 (m, 10H), 7.17 (d, J=6.4Hz, 1H), 5.09 (s, 2H), 5.02 (s, 2H), 3.83 (s, 3H).

[0338] Step 2: Synthesis of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-2-fluoro-5-methoxybenzoate (3). To a solution of 3,4-bis(benzyloxy)-2-fluoro-5-methoxybenzoic acid (1.13 g, 2.97 mmol, 1.5 equiv.) in CHCl (12 mL) was added oxalyl chloride (0.9 mL, 9.92 mmol, 5.0 equiv.) and 2 drops of anhydrous DMF at 0° C. The mixture was stirred at room temperature for 2 hours. After completion of acid chloride formation, the volatile portions were concentrated from the reaction mixture. The resulting acid chloride was added to a mixture of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-ol (1.5 g, 1.98 mmol, 1.0 equiv), DMAP (0.96 g, 7.93 mmol, 4.0 equiv), and TEA (1.2 mL, 7.93 mmol, 4 equiv) in CHCl (20 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with HO (50 mL) and extracted with CHCl (100 mL × 2). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (PE / EA=6 / 1) to give (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-2-fluoro-5-methoxybenzoate (1.51 g, 68% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ7.50-7.20(m,35H),7.00(d,J=6.0Hz,1H),6.79(s,2H),6.32(d,J=2.0Hz,1H),6.30(d,J=2.0Hz,1H),5.5 0(q,J=7.6Hz,1H),5.09(d,J=6.0Hz,1H),5.08-4.98(m,14H),3.76(s,3H),3.17(dd,J=16.8,11.2Hz,1H),2.88(q,J=8.0,1H).

[0339] Step 3: Synthesis of Compound 68. To a mixture of (2S,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,4-bis(benzyloxy)-2-fluoro-5-methoxybenzoate (1.50 g, 1.33 mmol, 1.0 equiv.) in THF (10 mL) and MeOH (10 mL) was added Pd(OH) / C (20% by weight, 190 mg). The mixture was stirred overnight at room temperature under an H atmosphere. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to give (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4-dihydroxy-5-methoxybenzoate (0.335 g, 51% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ9.11(bs,7H),6.60(d,J=6.0Hz,1H),6.31(s,2H),5.92(d,J=2.4Hz,1H),5.78(d,J=2.0Hz,1H) ,5.18(q,J=6.0Hz,1H),4.95(d,J=6.4Hz,1H),3.68(s,3H),2.78(dd,J=16.4,5.2Hz,1H),2.88(dd,J=16.0,6.8Hz,1H).

[0340] compound 72 [ka] Step 1: Synthesis of methyl 3,4,5-trihydroxybenzoate (A2). To a solution of compound A1 (20 g, 0.12 mol) in MeOH (200 mL) was added concentrated sulfuric acid (6 mL) at 0 °C. The reaction mixture was stirred at 80 °C overnight. The reaction mixture was cooled, neutralized with Na2CO3 solution at 0 °C, and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated to give crude compound A2 (15 g, 70% yield) as a yellow solid. MS calculated: 184; MS found: 185 [M+H] + .

[0341] Step 2: Synthesis of methyl 3,4,5-tris(benzyloxy)benzoate (A3). To a solution of compound A2 (1.8 g, 9.77 mmol) and K2CO3 (5.4 g, 39.13 mmol) in DMF (20 mL) was added BnCl (5.54 g, 43.97 mmol) at 0 °C. The solution was stirred at 60 °C for 4 h. The reaction mixture was cooled, diluted with HO (50 mL), and extracted with EA (50 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA = 5 / 1) to give compound A3 (4.05 g, 91% yield) as a white solid. MS calculated: 454; MS found: 455 [M+H] + .

[0342] Step 3: Synthesis of 3,4,5-tris(benzyloxy)benzoic acid (A4). To a solution of compound A3 (4.0 g, 8.88 mmol) in THF (30 mL) and HO (10 mL) was added LiOH·HO (554 mg, 13.2 mol). The solution was stirred at 50 °C overnight. The reaction mixture was concentrated. The residue was adjusted to pH = 3 with 2 N HCl solution and filtered. The filter cake was dried to give crude compound A4 (3.29 g, 85% yield) as a yellow solid. MS calculated: 440; MS found: 441 [M+H] + .

[0343] Step 4: Synthesis of (2R,3R)-2-(4-(allyloxy)-3,5-dihydroxyphenyl)chroman-3,5,7-triol (SM-1). To a solution of compound SM (10 g, 32.65 mmol) in acetone (100 mL) was added K2CO3 (8.79 g, 63.67 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. Next, 3-bromoprop-1-ene (4.74 g, 39.18 mmol) was added at 0 °C, and the solution was stirred at 55 °C overnight. The reaction mixture was concentrated. The residue was purified by reverse-phase silica gel flash chromatography (ACN / HO = 5% to 95%, 254 nm, 30 min) to give compound SM-1 (3.5 g, 31% yield) as a yellow solid. 1H NMR(400MHz,CD3OD)δ:6.55(s,2H),6.21-6.12(m,1H),5.96-5.94(m,2H),5.34-5.29(m,1H),5.19(d,J=10.4Hz,1H) ,4.79(s,1H),4.56-4.54(m,2H),4.22-4.20(m,1H),2.90-2.85(m,1H),2.77-2.67(m,1H).MS calculation: 346;MS actual measurement: 347[M+H] + .

[0344] Step 5: Synthesis of (2R,3R)-2-(4-(allyloxy)-3,5-bis(benzyloxy)phenyl)-5,7-bis(benzyloxy)chroman-3-ol (SM-2). To a solution of compound SM-1 (6.0 g, 19.35 mmol) in DMF (80 mL) was added NaH (2.91 g, 72.76 mmol, 60 wt% in mineral oil) at 0 °C. The mixture was stirred at 0 °C for 20 min. BnCl (9.21 g, 72.76 mmol) was added at 0 °C, and the solution was stirred at room temperature overnight. The reaction mixture was diluted with HO (50 mL) and extracted with EA (50 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA = 2 / 1) to give a crude product, which was further purified by reverse-phase silica gel flash chromatography (ACN / HO = 5% to 95%, 254 nm, 45 min) to give compound SM-2 (2.55 g, 21% yield) as a yellow oil. MS calculated: 706; MS found: 707 [M+H]. + .

[0345] Step 6: Synthesis of (2R,3R)-2-(4-(allyloxy)-3,5-bis(benzyloxy)phenyl)-5,7-bis(benzyloxy)chroman-3-yl 3,4,5-tris(benzyloxy)benzoate (SM-3). To a solution of compound SM-2 (5.2 g, 7.22 mmol) in DCM (50 mL), compound A4 (4.13 g, 9.38 mmol), EDCI (4.15 g, 21.66 mmol), and DMAP (882 mg, 7.22 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (30 mL) and extracted with DCM (20 mL × 2). The combined organic layer was dried over Na SO and filtered. The filtrate was concentrated to give the crude product, which was purified by reverse-phase silica gel flash chromatography (ACN / HO = 5% to 95%, 254 nm, 40 min) to give compound SM-3 (7.2 g, 88% yield) as a yellow oil. MS calculated: 1128; MS found: 1145 [M+NH] + .

[0346] Step 7: Synthesis of (2R,3R)-5,7-bis(benzyloxy)-2-(3,5-bis(benzyloxy)-4-hydroxyphenyl)chroman-3-yl 3,4,5-tris(benzyloxy)benzoate (SM-4). To a solution of compound SM-3 (7.2 g, 6.38 mmol) in THF (50 mL) was added NaBH (363 mg, 9.56 mmol) under ice-water bath. After stirring for 5 minutes, Pd(PPh) (737 mg, 0.638 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (30 mL) and extracted with DCM (30 mL × 2). The combined organic layer was washed with brine (30 mL × 2), dried over NaSO, filtered, and concentrated to give compound SM-4 (5.31 g, 95% yield) as a yellow oil. MS calculated: 1088; MS observed: 1105 [M+NH4] + .

[0347] Step 8: Synthesis of (2R,3R)-5,7-bis(benzyloxy)-2-(3,5-bis(benzyloxy)-4-((ethylcarbamoyl)oxy)phenyl)chroman-3-yl 3,4,5-tris(benzyloxy)benzoate (SM-5). To a mixture of compound SM-4 (1.4 g, 1.29 mmol) in THF (30 mL), pyridine (408 mg, 5.16 mmol) and bis(trichloromethyl)carbonate (153 mg, 0.52 mmol) were added under ice-water bath. After stirring for 10 minutes, ethanamine (87 mg, 1.93 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with DCM (20 mL × 2). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by reverse-phase silica gel flash chromatography (ACN / HO = 5% to 95%, 254 nm, 40 min) to give compound SM-5 (0.92 g, 62% yield) as a yellow oil. MS calculated: 1159; MS found: 1177 [M+NH] + .

[0348] Step 9: Synthesis of compound 72. To a mixture of compound SM-5 (920 mg, 0.79 mmol) in EA (20 mL) was added Pd(OH) / C (10% by weight, 100 mg). The mixture was stirred at room temperature under a H balloon for 2 days. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC to give (2R,3R)-2-(4-((ethylcarbamoyl)oxy)-3,5-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate (210 mg, 50%) as a white solid. 1 H NMR(400MHz,CD3OD)δ:6.84(s,2H),6.47(s,2H),5.86(s,2H),5.45(s,1H),4.92(s,1H),3.12-3. 07(m,2H),2.92-2.87(m,1H),2.78-2.73(m,1H),1.06(t,J=7.0Hz,3H).MS calculation: 529;MS actual measurement: 530[M+H] + .

[0349] compound 73 [ka] Step 1: Synthesis of methyl 4-(allyloxy)-3,5-dihydroxybenzoate (B1). To a solution of compound A2 (2.92 g, 15.87 mmol) in DMF (30 mL) was added 3-bromoprop-1-ene (1.92 g, 15.87 mmol), NaHCO3 (5.33 g, 63.46 mmol), and KI (2.63 g, 15.87 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with HO (50 mL) and extracted with EA (50 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA = 5 / 1 to 1 / 1) to give compound B1 (2.4 g, 67% yield) as a yellow oil. MS calculated: 224; MS observed: 225 [M+H]. + .

[0350] Step 2: Synthesis of methyl 4-(allyloxy)-3,5-bis(benzyloxy)benzoate (B2). To a solution of compound B1 (1.8 g, 8.03 mmol) in DMF (30 mL), K2CO3 (2.22 g, 16.06 mmol) and BnBr (4.12 g, 24.1 mmol) were added under ice-water bath conditions. The reaction mixture was stirred at 60 °C overnight. The reaction mixture was diluted with H2O (30 mL) and extracted with EA (50 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (PE / EA = 5 / 1 to 3 / 1) to give compound B2 (2.98 g, 92% yield) as a white solid. MS calculated: 404; MS found: 405 [M+H]. + .

[0351] Step 3: Synthesis of 4-(allyloxy)-3,5-bis(benzyloxy)benzoic acid (B3). To a solution of compound B2 (2.98 g, 7.38 mmol) in THF / HO (30 mL / 10 mL) was added LiOH·HO (0.62 g, 14.75 mmol). The reaction mixture was stirred at 50 °C overnight. The reaction mixture was adjusted to pH = 5 with 1 N HCl and extracted with EA (50 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over NaSO, filtered, and concentrated to give compound B3 (2.4 g, 83% yield) as a white solid. MS calculated: 390; MS found: 391 [M+H] + .

[0352] Step 4: Synthesis of (2R,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 4-(allyloxy)-3,5-bis(benzyloxy)benzoate (1). To a mixture of compound SM1 (1.0 g, 1.32 mmol) in DCM (30 mL), compound B3 (774 mg, 1.98 mmol), EDCI (757 mg, 3.96 mmol), and DMAP (32 mg, 0.26 mmol) were added under ice-water bath. The solution was stirred overnight at room temperature. The reaction mixture was diluted with HO (50 mL) and extracted with DCM (30 mL x 2). The combined organic layer was washed with brine (30 mL x 2), dried over NaSO, filtered, and concentrated. The residue was purified by reverse-phase silica gel flash chromatography (ACN / HO = 5% to 95%, 254 nm, 40 min) to give compound 1 (1.2 g, 81% yield) as a yellow oil. MS calculated: 1128; MS found: 1129 [M+H]. + .

[0353] Step 5: Synthesis of (2R,3R)-5,7-bis(benzyloxy)-2-(3,4,5-tris(benzyloxy)phenyl)chroman-3-yl 3,5-bis(benzyloxy)-4-hydroxybenzoate (2). To a mixture of compound 1 (7.0 g, 6.2 ...

Claims

1. Compound of formula I: 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein R １ 、R ２ 、R ３ 、and R ４ are each independently hydrogen, halogen, -NO ２ 、-CN, C １ -C １０ alkyl, C １ -C １０ haloalkyl, -NH ２ 、-NH(C １ -C １０ alkyl), -N(C １ -C １０ alkyl) ２ 、-OH, C １ -C １０ alkoxy, C １ -C １０ haloalkoxy, -SH, hydroxy(C １ -C １０ alkyl), alkoxy(C １ -C １０ alkyl), amino(C １ -C １０ alkyl), -CONH ２ 、-CONH(C １ -C １０ alkyl), -CON(C １ -C １０ alkyl) ２ 、-OC(O)NH ２ 、-OC(O)NH(C １ -C １０ alkyl), -OC(O)N(C １ -C １０ alkyl) ２ 、-CO ２ H, -CO ２ (C １ -C １０ alkyl), -CHO, -CO(C １ -C １０ alkyl), -OC(O)(C １ -C １０ alkyl), -S(O) ０－２ (C １ -C １０ alkyl), or -NH(S(O) ０－２ (C １ -C １０ alkyl)); R ５ and R ９ are each independently hydrogen, halogen, -NO ２ , -CN, C １ -C ６ alkyl, C １ -C ６ haloalkyl, -NH ２ , -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -OH, C １ -C ６ alkoxy, C １ -C ６ haloalkoxy, or -SH; R ７ is hydrogen, halogen, -NO ２ , -CN, C １ -C １０ alkyl, C １ -C １０ haloalkyl, -NH ２ , -NH(C １ -C １０ alkyl), -N(C １ -C １０ alkyl) ２ , -OH, C １ -C １０ alkoxy, C １ -C １０ haloalkoxy, -SH, hydroxy(C １ -C １０ alkyl), alkoxy(C １ -C １０ alkyl), amino(C １ -C １０ alkyl), -CONH ２ , -CONH(C １ -C １０ alkyl), -CON(C １ -C １０ alkyl) ２ , -CO ２ H, -CO ２ (C １ -C １０ alkyl), -CHO, -CO(C １ -C １０ alkyl), -S(O) ０－２ (C １ -C １０ alkyl), or -NH(S(O) ０－２ (C １ -C １０ alkyl)); R ６ and R ８ are each independently hydrogen, halogen, -NO ２ , -CN, C １ -C ６ alkyl, C １ -C ６ haloalkyl, -NH ２ , -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -OH, C １ -C ６ alkoxy, C １ -C ６ haloalkoxy, or -SH; X is O or C; Y is O or NH; and Z is [Chemical Formula 2] , wherein R １０ and R １４ are each independently hydrogen, halogen, -NO ２ , -CN, C １ -C ６ alkyl, C １ -C ６ haloalkyl, -NH ２ , -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -OH, C １ -C ６ alkoxy, C １ -C ６ haloalkoxy, or -SH; R １２ is hydrogen, halogen, -NO ２ , -CN, C １ -C １０ alkyl, C １ -C １０ haloalkyl, -NH ２ , -NH(C １ -C １０ alkyl), -N(C １ -C １０ alkyl) ２ , -OH, C １ -C １０ alkoxy, C １ -C １０ haloalkoxy, -SH, hydroxy(C １ -C １０ alkyl), alkoxy(C １ -C １０ alkyl), amino(C １ -C １０ alkyl), -CONH ２ , -CONH(C １ -C １０ alkyl), -CON(C １ -C １０ alkyl) ２ , -CO ２ H, -CO ２ (C １ -C １０ alkyl), -CHO, -CO(C １ -C １０ alkyl), -S(O) ０－２ (C １ -C １０ alkyl), or -NH(S(O) ０－２ (C １ -C １０ alkyl)) and; R １１ and R １３ each independently represents hydrogen, halogen, -NO ２ , -CN, C １ -C ６ alkyl, C １ -C ６ haloalkyl, -NH ２ , -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -OH, C １ -C ６ alkoxy, C １ -C ６ haloalkoxy, or -SH; or Z is 【Chemical 3】 , wherein n is from 0 to 4, and Each R １５ is, independently, C １ -C ６ alkyl, C １ -C ６ haloalkyl, -NH ２ , -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -OH, C １ -C ６ alkoxy, or C １ -C ６ haloalkoxy; or, Z is 【Chemical Formula 4】 , wherein R １６ is hydrogen, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, -OH, C １ -C ６ -alkoxy, or C １ -C ６ -haloalkoxy; or, Z is 【Chemical Formula 5】 , wherein R １７ is hydrogen, C １ -C ６ -alkyl, or C １ -C ６ -haloalkyl; said compound is (2R,3R)-2-(3,5-dihydroxy-4-methoxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate; (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,5-dihydroxy-4-methoxybenzoate; (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5-trihydroxybenzoate; (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5-trihydroxybenzoate; (2R,3S)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5-trihydroxybenzoate; (2R,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate; (2S,3R)-2-(3,4-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate; (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4-dihydroxy-5-methoxybenzoate; (2R,3S)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4-difluorobenzoate; or (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,3,4-trihydroxybenzoate, a compound of formula I which is not.

2. Said compound is of formula I-A: [Chemical Formula 6] The compound according to claim 1.

3. Said compound is of formula I-B: 【Chemical Formula 7】 The compound according to claim 1.

4. X is O and / or Y is O, the compound according to claim 1.

5. R １ 、R ２ 、R ３ 、and R ４ are each independently hydrogen, -OH, C １ -C １０ alkoxy, -OC(O)(C １ -C １０ alkyl), or -OC(O)NH(C １ -C １０ alkyl), the compound according to claim 1.

6. R ５ and R ９ The compound according to claim 1, wherein each of R and R is independently hydrogen, -F, or -OH.

7. R ７ is -OH, C １ -C １０ alkoxy, -CONH ２ , -CONH(C １ -C １０ alkyl), -CO(C １ -C １０ alkyl), or -NH(S(O) ０－２ (C １ -C １０ alkyl)), the compound according to claim 1

8. R ６ and R ８ each independently represents hydrogen, -OH, C １ -C ６ alkoxy, or C １ -C ６ haloalkoxy, and is the compound according to claim 1.

9. R ５ and R ９ is each independently hydrogen or -F, R ７ is -OH, R ６ and R ８ are each independently hydrogen or —OH; R ５ and R ９ at least one of which is hydrogen, and R ６ and R ８ At least one of which is —OH, the compound according to claim 1.

10. Z is [Chemical Formula 8] , R １０ and R １４ are each independently hydrogen, -F, or -OH; R １２ is -OH, C １ -C １０ alkoxy, -CONH ２ , -CONH(C １ -C １０ alkyl), -CO(C １ -C １０ alkyl), or -NH(S(O) ０－２ (C １ -C １０ alkyl)), and R １１ and R １３ are each independently hydrogen, —OH, C １ —C ６ alkoxy, or C １ —C ６ haloalkoxy, and the compound according to claim 1.

11. R １０ and R １４ at least one of which is -F, and / or R13 and R14 are each hydrogen, and / or R10 and R11 are each -OH, and / or R12 is -OH, and / or at least one of R11 and R13 is -OH, C1-C6 alkoxy, or C1-C6 haloalkoxy, the compound according to claim 10.

12. The compound is of formula II, formula II-A, formula II-B, formula III, formula III-A, or formula III-B: 【Chemical Formula 9】 【Chemical Formula 10】 【Chemical 11】 【Chemical 12】 【Chemical 13】 【Chemical 14】 The compound according to claim 1, which is as such.

13. R ５ 、R ９ 、R １０ 、and R １４ in which at least one of them is not hydrogen, or R5, R9, R10, and R14 are each independently hydrogen, halogen, or -OH, the compound according to claim 12.

14. R ５ 、R ９ 、R １０ 、and R １４ in which at least one of is -F, the compound according to claim 12.

15. R ５ 、 R ９ 、 R １０ 、 and R １４ are each independently hydrogen or -F, and R ５ 、R ９ 、R １０ 、and R １４ one or two of which are -F, Optionally, R7 and R12 are each independently -OH, C1-C10 alkoxy, -CONH2, -CONH(C1-C10 alkyl), -CO(C1-C10 alkyl), or -NH(S(O)0-2(C1-C10 alkyl)), the compound according to claim 12.

16. R ６ 、R ８ 、R １１ 、and R １３ are each independently hydrogen, -OH, C １ -C ６ alkoxy, or C １ -C ６ haloalkoxy, and / or R ６ 、R ８ 、R １１ 、and R １３ at least one of is C １ -C ６ alkoxy, or C １ -C ６ haloalkoxy, and / or R ７ 、R ８ 、R １１ 、and R １２ are each -OH, and R １３ is -OH, C １ -C ６ alkoxy, or C １ -C ６ haloalkoxy, and / or R ５ 、R ９ 、R １０ 、and R １４ at least one of is -OH, C １ -C ６ alkoxy, or C １ -C ６ is -F para to a substituent selected from haloalkoxy, and / or R １３ is -OH, C １ -C ６ alkoxy, or C １ -C ６ haloalkoxy, and R １０ is -F, the compound according to claim 12.

17. (a) R １ 、R ３ 、R ７ 、R ８ 、R １１ 、and R １２ are each —OH, R ２ 、R ４ 、and R ９ are each hydrogen, R ６ and R １３ are each —OH, C １ —C ６ alkoxy, or C １ —C ６ haloalkoxy, and R ５ 、 R １０ 、 and R １４ at least one of which is -F, Optionally, R ５ and R １４ are each hydrogen, and R １０ is -F, or (b) R １ , R ３ , R ７ , and R １２ are each —OH, R ２ 、 R ４ 、 and R ９ are each hydrogen, R ５ 、R １３ ,and R １４ is, independently of one another, hydrogen or -F; R ６ and R ８ are each independently hydrogen or -OH; and R １０ and R １１ are each independently hydrogen, -OH, C １ -C ６ alkoxy, or C １ -C ６ haloalkoxy, Optionally, R １０ and R １１ are each independently —OH, C １ —C ６ alkoxy, or C １ —C ６ haloalkoxy, or (c) R １ , R ３ , R ６ , R ７ , R ８ , R １０ , R １１ , and R １２ are each —OH, and R ２ 、R ４ 、R ５ 、R ９ 、R １３ 、およびR １４ are each independently hydrogen or -F, the compound according to claim 12.

18. (a) Z is 【Chemical Formula 15】 as such, n is from 0 to 2, and Each R １５ is independently, -NH ２ , -OH, or C １ -C ６ is an alkoxy, or (b) Z is 【Chemical 16】 as such, or (c) Z is 【Chemical 17】 as such, and Each R １５ is independently —NH ２ or —OH, or (d) Z is 【Chemical 18】 as such, and Each R １５ is independently —NH ２ or —OH, or (e) Z is 【Chemical 19】 as such, and R １６ is hydrogen or —OH, or (f) Z is 【Chemical 20】 as such, the compound according to claim 1.

19. The compound is N-((2R,3S)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl)-3,4,5-trihydroxybenzamide; N-((2R,3S)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl)-3,4-dihydroxy-5-methoxybenzamide; (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4-dihydroxybenzoate; (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3-((ethylcarbamoyl)oxy)-4,5-dihydroxybenzoate; (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 4-((ethylcarbamoyl)oxy)-3,5-dihydroxybenzoate; (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,5-dihydroxy-4-(isobutyryloxy)benzoate; N-((2R,3S)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl)-3,4-dihydroxybenzamide; N-((2R,3S)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl)-4-hydroxybenzamide; N-((2R,3S)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl)-3,4-difluorobenzamide; (2R,3S)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4-dihydroxy-5-methoxybenzoate; (2R,3S)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4-dihydroxybenzoate; (2R,3S)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 4-hydroxybenzoate; (2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 4-hydroxybenzoate; (2R,3S)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl isonicotinate; (2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl isonicotinate; (2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4-difluorobenzoate; (2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 1-hydroxy-2-oxo-1,2-dihydropyridine-4-carboxylate; (2R,3S)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 5,6-dihydroxyisonicotinate; (2R,3S)-2-(3,4-Dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4-dihydroxybenzoate; (2R,3S)-2-(3,4-Dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 6-amino-5-hydroxyisonicotinate; (2R,3S)-2-(3,4-Dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3-hydroxy-4-(methylsulfonamido)benzoate; (2S,3R)-2-(3,4-Dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4-dihydroxybenzoate; (2S,3R)-5-Hydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5-trihydroxybenzoate; (2R,3S)-5-Hydroxy-3-(3,4,5-trihydroxyphenyl)-1,2,3,4-tetrahydronaphthalen-2-yl 3,4,5-trihydroxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4-dihydroxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 4-amino-3-hydroxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 6-amino-5-hydroxynicotinate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3-hydroxy-4-(methylsulfonamido)benzoate; (2S,3R)-2-(3,4,5-Trihydroxyphenyl)chroman-3-yl 3,4,5-trihydroxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-4,5-dihydroxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,4,5-trihydroxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl (1s,4S)-4-hydroxycyclohexane-1-carboxylate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl (1r,4R)-4-hydroxycyclohexane-1-carboxylate; (2S,3R)-2-(2-Fluoro-4,5-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate; (2S,3R)-2-(2-Fluoro-3,4,5-trihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate; (2S,3R)-2-(2-Fluoro-3,4,5-trihydroxyphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate; (2S,3R)-2-(2-Fluoro-4,5-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate; (2S,3R)-2-(3,4-Dihydroxy-5-methoxyphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-4,5-dihydroxy-3-methoxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,6-difluoro-3,4,5-trihydroxybenzoate; (2S,3R)-2-(4,5-Dihydroxy-2-methylphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate; (2R,3S)-3-(3,4,5-Trihydroxyphenyl)-1,2,3,4-tetrahydronaphthalen-2-yl 3,4,5-trihydroxybenzoate; (2R,3S)-3-(3,4,5-Trihydroxyphenyl)-1,2,3,4-tetrahydronaphthalen-2-yl 2-fluoro-3,4,5-trihydroxybenzoate; (2S,3R)-2-(3,4-Dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate; (2R,3R)-2-(3,4-Dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 5,6-dihydroxypicolinate; (2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,6-difluoro-3,4-dihydroxy-5-methoxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3-(difluoromethoxy)-4,5-dihydroxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,6-difluoro-3,4-dihydroxy-5-isopropoxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 4,5-dihydroxy-2-(trifluoromethyl)benzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4-dihydroxy-2-methylbenzoate; (2S,3R)-2-(3,4-Dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 2,6-difluoro-3,4-dihydroxy-5-methoxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 5-(difluoromethoxy)-2-fluoro-3,4-dihydroxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3-fluoro-4,5-dihydroxybenzoate; (2S,3R)-2-(4-((ethylcarbamoyl)oxy)-3,5-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4-dihydroxy-5-methoxybenzoate; (2R,3R)-5-Hydroxy-7-(propionyloxy)-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5-trihydroxybenzoate; (2R,3R)-7-((ethylcarbamoyl)oxy)-5-hydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5-trihydroxybenzoate; (2R,3R)-7-(hexanoyloxy)-5-hydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4,5-trihydroxybenzoate; (2R,3R)-2-(4-((ethylcarbamoyl)oxy)-3,5-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate; (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,5-dihydroxy-4-((3-methylbutanoyl)oxy)benzoate; (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,5-dihydroxy-4-(propionyloxy)benzoate; (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 4-((ethylcarbamoyl)oxy)-3,5-dihydroxybenzoate; (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 4-((dimethylcarbamoyl)oxy)-3,5-dihydroxybenzoate; (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4-dihydroxy-5-(propionyloxy)benzoate; (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 3,4-dihydroxy-5-(isobutyryloxy)benzoate; (2R,3R)-2-(3,5-dihydroxy-4-(propionyloxy)phenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate; (2R,3R)-2-(4-((ethylcarbamoyl)oxy)-3,5-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 4-((ethylcarbamoyl)oxy)-3,5-dihydroxybenzoate; or (2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate, which is the compound according to claim 1.

20. The compound is (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-4,5-dihydroxybenzoate; (2S,3R)-2-(2-Fluoro-3,4,5-trihydroxyphenyl)-5,7-dihydroxychroman-3-yl 3,4,5-trihydroxybenzoate; (2S,3R)-2-(2-Fluoro-3,4,5-trihydroxyphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate; (2S,3R)-2-(2-Fluoro-4,5-dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-4,5-dihydroxy-3-methoxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,6-difluoro-3,4,5-trihydroxybenzoate; (2S,3R)-2-(3,4-Dihydroxyphenyl)-5,7-dihydroxychroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,6-difluoro-3,4-dihydroxy-5-methoxybenzoate; (2S,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4-dihydroxy-5-methoxybenzoate; or (2R,3R)-5,7-Dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate, which is the compound according to claim 1.

21. The compound is (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4-dihydroxy-5-methoxybenzoate, or The compound is (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4,5-trihydroxybenzoate, the compound according to claim 1.

22. A pharmaceutical composition comprising one or more compounds according to claim 1 and a pharmaceutically acceptable carrier, excipient, adjuvant, and / or diluent.

23. One or more compounds according to claim 1 present in a total amount of 1 to 40% by weight, and A penetration enhancer present in an amount of 0.1 to 20% by weight; A chelating agent / antioxidant present in an amount of 0.1 to 20% by weight; A water retention agent present in an amount of 1 to 30% by weight; and A preservative present in an amount of 0.03 to 2% by weight; Containing one or more of them, and having a pH of 4.0 to 6.5, a nasal pharmaceutical composition.

24. A pharmaceutical composition for treating or suppressing oxidative stress, inflammation, central nervous system disorders, tumors, diabetes, obesity, systemic disorders, neuropathies, viral infections, non-alcoholic fatty liver disease (NAFLD) or meningitis, wherein the pharmaceutical composition comprises a therapeutically effective amount of Formula I 【Chemical 21】 One or more compounds, or pharmaceutically acceptable salts thereof, wherein R １ 、R ２ 、R ３ 、and R ４ are each independently hydrogen, halogen, -NO ２ 、-CN, C １ -C １０ alkyl, C １ -C １０ haloalkyl, -NH ２ 、-NH(C １ -C １０ alkyl), -N(C １ -C １０ alkyl) ２ 、-OH, C １ -C １０ alkoxy, C １ -C １０ haloalkoxy, -SH, hydroxy(C １ -C １０ alkyl), alkoxy(C １ -C １０ alkyl), amino(C １ -C １０ alkyl), -CONH ２ 、-CONH(C １ -C １０ alkyl), -CON(C １ -C １０ alkyl) ２ 、-OC(O)NH ２ 、-OC(O)NH(C １ -C １０ alkyl), -OC(O)N(C １ -C １０ alkyl) ２ 、-CO ２ H, -CO ２ (C １ -C １０ alkyl), -CHO, -CO(C １ -C １０ alkyl), -OC(O)(C １ -C １０ alkyl), -S(O) ０－２ (C １ -C １０ alkyl), or -NH(S(O) ０－２ (C １ -C １０ alkyl)); R ５ and R ９ are each independently hydrogen, halogen, -NO ２ , -CN, C １ -C ６ alkyl, C １ -C ６ haloalkyl, -NH ２ , -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -OH, C １ -C ６ alkoxy, C １ -C ６ haloalkoxy, or -SH; R ７ is hydrogen, halogen, -NO ２ , -CN, C １ -C １０ alkyl, C １ -C １０ haloalkyl, -NH ２ , -NH(C １ -C １０ alkyl), -N(C １ -C １０ alkyl) ２ , -OH, C １ -C １０ alkoxy, C １ -C １０ haloalkoxy, -SH, hydroxy(C １ -C １０ alkyl), alkoxy(C １ -C １０ alkyl), amino(C １ -C １０ alkyl), -CONH ２ , -CONH(C １ -C １０ alkyl), -CON(C １ -C １０ alkyl) ２ , -CO ２ H, -CO ２ (C １ -C １０ alkyl), -CHO, -CO(C １ -C １０ alkyl), -S(O) ０－２ (C １ -C １０ alkyl), or -NH(S(O) ０－２ (C １ -C １０ alkyl)) and; R ６ and R ８ are each independently hydrogen, halogen, -NO ２ , -CN, C １ -C ６ alkyl, C １ -C ６ haloalkyl, -NH ２ , -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -OH, C １ -C ６ alkoxy, C １ -C ６ haloalkoxy, or -SH; X is O or C; Y is O or NH; And Z is 【Chemical 22】 Wherein R １０ and R １４ each independently represents hydrogen, halogen, -NO ２ , -CN, C １ -C ６ alkyl, C １ -C ６ haloalkyl, -NH ２ , -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -OH, C １ -C ６ alkoxy, C １ -C ６ haloalkoxy, or -SH; R １２ is hydrogen, halogen, -NO ２ , -CN, C １ -C １０ alkyl, C １ -C １０ haloalkyl, -NH ２ , -NH(C １ -C １０ alkyl), -N(C １ -C １０ alkyl) ２ , -OH, C １ -C １０ alkoxy, C １ -C １０ haloalkoxy, -SH, hydroxy(C １ -C １０ alkyl), alkoxy(C １ -C １０ alkyl), amino(C １ -C １０ alkyl), -CONH ２ , -CONH(C １ -C １０ alkyl), -CON(C １ -C １０ alkyl) ２ , -CO ２ H, -CO ２ (C １ -C １０ alkyl), -CHO, -CO(C １ -C １０ alkyl), -S(O) ０－２ (C １ -C １０ alkyl), or -NH(S(O) ０－２ (C １ -C １０ alkyl)) and; R １１ and R １３ are each independently hydrogen, halogen, -NO ２ , -CN, C １ -C ６ alkyl, C １ -C ６ haloalkyl, -NH ２ , -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -OH, C １ -C ６ alkoxy, C １ -C ６ haloalkoxy, or -SH; Or Z is 【Chemical 23】 Wherein n is 0 to 4, and Each R １５ is independently C １ -C ６ alkyl, C １ -C ６ haloalkyl, -NH ２ , -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , -OH, C １ -C ６ alkoxy, or C １ -C ６ haloalkoxy; Or Z is 【Chemical 24】 Wherein R １６ is hydrogen, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, -OH, C １ -C ６ -alkoxy, or C １ -C ６ -haloalkoxy; Or Z is 【Chemical 25】 Wherein R １７ is hydrogen, C １ -C ６ -alkyl, or C １ -C ６ -haloalkyl, a pharmaceutical composition.

25. A method for preparing gallocatechin from epigallocatechin, comprising (a) contacting epigallocatechin with an aqueous buffer system at a first temperature above 50°C for a first time to obtain a crude reaction mixture containing gallocatechin; (b) cooling the crude reaction mixture to a second temperature lower than the first temperature to obtain a precipitated crude substance containing gallocatechin; (c) separating the precipitated crude substance from the crude reaction mixture; and then (d) recrystallizing the separated crude substance in an aqueous solvent to obtain a purified substance containing gallocatechin.

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