Patentiflorin A analogs as antiviral agents

Abstract

The present disclosure relates to patentiflorin A analogs useful as antiviral agents, such as anti-HIV, anti-coronavirus, anti-Ebola virus, and anti-influenza virus agents, and methods of their use.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 62 / 891,441, filed on August 26, 2019, and U.S. Non-Provisional Patent Application Serial No. 16 / 947,935, filed on August 25, 2020, which are hereby incorporated by reference in their entirety for all purposes. Technical Field

[0003] The present disclosure generally relates to aryl naphthoxyside derivatives, methods for preparing the same and their use as antiviral agents. More particularly, the present disclosure relates to patentiflorin A analogs useful as antiviral agents such as anti-HIV, anti-coronavirus, anti-Ebola, anti-Marburg and anti-influenza agents. The present disclosure also provides methods for treating viral infections such as HIV, coronavirus, Ebola, Marburg and influenza infections. Background Art

[0004] Viruses are important pathogens that cause infectious diseases in humans and other mammals. They vary greatly in size, shape, chemical composition, host range, and effects on the host. After decades of research, only a limited number of antiviral agents can be used to treat and / or prevent diseases caused by viruses such as HIV, coronaviruses, Ebola virus, Marburg virus, influenza A and B viruses, and hepatitis C virus. Due to their toxic effects on the host, many antiviral agents are limited in their application. Resistance to antiviral agents usually develops very rapidly, and many viral diseases such as HIV do not have available vaccines to treat or prevent them. Therefore, a safe and effective antiviral agent with no or low toxicity to the host is needed to combat a wide spectrum of viruses.

[0005] AIDS (Acquired Immune Deficiency Syndrome) remains one of the most serious threats to public health. According to the UNAIDS (Uniting the world against AIDS) report, approximately 77 million people are infected with human immunodeficiency virus (HIV), and 37.9 million people have died from AIDS-related diseases since the HIV epidemic began in 1981. Since the development and approval of the first anti-HIV drug zidovudine (AZT) in 1987, more than 40 anti-HIV drugs have been officially approved by the US Food and Drug Administration (FDA) for the treatment of HIV infection. These drugs are classified as nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), entry and fusion inhibitors, and HIV integrase strand transfer inhibitors. Although these drugs have significantly extended the life expectancy of HIV-positive people, it is worrying that the prevalence of HIV resistance has increased from 11% to 29% since the global promotion of antiretroviral therapy (ART) in 2001. In addition, the high cost and limited availability of current ART prevent patients in developing countries from benefiting from combination therapy. Therefore, there is an urgent need to continue to develop new, more effective, easily accessible and inexpensive anti-HIV therapeutics.

[0006] Influenza, a severe viral infection of the respiratory system, remains a major threat to human health. Worldwide outbreaks of the highly pathogenic H5N1 subtype of avian influenza virus (AIV) and the emergence of novel human influenza A / H1N1 have increased public awareness of a potential global influenza pandemic. In addition to poultry, AIV can infect wild birds, pigs, cats, humans, and other animals. Three drugs, baloxavir, zanamivir, and oseltamivir phosphate, have been approved for the treatment of influenza. However, the low oral bioavailability and rapid renal elimination of zanamivir, as well as the rapid emergence of oseltamivir resistance, make it urgent to further develop more effective and longer-lasting therapeutic drugs to combat potential pandemics caused by human influenza viruses.

[0007] Viruses belonging to the Filoviridae contain negative-strand RNA as their genome. There are two genera under the Filoviridae, namely the Marburgvirus genus and the Ebolavirus genus. Marburg virus is the only member in the genus Marburgvirus. There are five members in the genus Ebolavirus, namely the Zaireebolavirus, the Sudan ebolavirus, the Cote d'Ivoireebolavirus, the Reston ebolavirus and the Bundibugyo ebolavirus. Due to their pathogenic potential, high case fatality rate and lack of effective therapeutic agents for infected people, members of the Filoviridae have been classified as "biosafety level 4" viruses. Filovirus infections may cause hemorrhagic fever. In fact, both genera contain species that can cause severe hemorrhagic fever epidemics in humans and non-human primates. Outbreaks of Ebola virus (EBOV) disease have occurred multiple times in the Democratic Republic of the Congo. Since 1976, there have been multiple outbreaks of Ebola. The first outbreak occurred in Yambuku in 1976, with 318 cases reported and a mortality rate of 88%. Later, there were two large outbreaks in 1995 and 2007, with more than 250 Ebola cases reported in each outbreak. In 2014-2015, West Africa experienced the largest Ebola outbreak. This outbreak had more than 28,000 cases and a mortality rate of 40%. Most recently, there has been another Ebola outbreak since April 4, 2018. As of May 30, 2019, a total of 1945 cases have been reported with a mortality rate of 67%. There are no FDA-approved therapeutic agents specifically for the treatment of subjects infected with filoviruses. During the Ebola outbreak, patients suffering from filovirus infections mainly rely on whole blood or plasma from recovered patients for treatment. However, this type of empirical treatment has many limitations, including difficulties in large-scale production and compatibility of blood types between donors and recipients. The use of some potential candidate drugs, including favipiravir, ZMapp, and GS-5734, is still under investigation. More clinical data are needed to demonstrate the safety and efficacy of these candidate drugs in the treatment of filovirus infections.

[0008] The emergence of the novel coronavirus (SARS-CoV-2) has attracted international attention, and scientists have sought to discover effective inhibitors against the novel coronavirus. Coronaviruses (CoV) are enveloped, single-stranded, positive-sense RNA viruses that belong to the families Coronaviridae, Arteriviridae, and Roniviridae. SARS-CoV-2, which causes the current COVID-19 pandemic, is a beta-coronavirus. Six CoVs have been identified as susceptible viruses in humans. Two of them, SARS-CoV and MERS-CoV, can cause severe or even fatal respiratory infections. As of August 21, 2020, the COVID-19 epidemic has caused 797,428 deaths in more than 15.5 million cases of infection. Several EBOV inhibitors such as remdesivir, toremifene, and favipiravir have been repurposed as antiviral agents active against SARS-CoV-2. However, none of them is highly effective in controlling the COVID-19 epidemic. Therefore, highly effective viral inhibitors are urgently needed to combat coronaviruses.

[0009] In modern drug discovery, natural products have become a rich source for the discovery of lead compounds. By screening more than 3,500 plant extracts, we identified Justicia cf. patentiflora as having potent anti-HIV activity. Bioactivity-guided fractionation of methanol extracts of the stem and bark of this plant yielded three ANL (arylnaphthalene) glycoside compounds. The compounds exhibited potent inhibitory activity against a wide range of HIV clinical strains, with antiviral EC 50 The values ​​were in the range of 14-37 nM [Zidovudine (AZT): 77-95 nM]. They also showed a significant inhibitory effect on drug-resistant HIV strains.

[0010] Some arylnaphthyl lignans have been reported in the literature to have antiviral activity. Although some of these compounds showed significant antiviral activity against various viral strains, they were not considered as potential antiviral drug candidates due to their low selectivity index (SI).

[0011] Therefore, there is a need to develop improved antiviral agents that address at least some of the aforementioned needs. Summary of the invention

[0012] The present disclosure relates to a new class of patentiflorin A analogs, the preparation of these compounds and novel intermediates, and their use in the treatment of viral infections such as HIV, CoV, EBOV and AIV.

[0013] In a first aspect, provided herein is the use of a compound in the preparation of a medicament for treating a viral infection, wherein the compound has formula (I):

[0014]

[0015] or a pharmaceutically acceptable salt or prodrug thereof, wherein

[0016] X is oxygen or sulfur;

[0017] R 1 For R 15 、-OR 15 、-C(O)R 15 , or -C(O)OR 15 ;

[0018] R 2 , R 5 , R 6 , R 10 , R 13 and R 14 Each is hydrogen;

[0019] R 3 and R 4 Each independently selected from -OR 15 and -OC(O)R 15 ; or R 3 and R 4 Together with the carbon atom to which they are attached, they form a 16 A 5-6 membered heterocyclic group substituted with a group;

[0020] R 7 , R 8 and R 9 Each independently selected from -OR 15 and -OC(O)R 15 ; or R 7 and R 8 Together with the carbon atom to which they are attached, they form a 16 A 5-6 membered heterocyclic group substituted with a group; or R 8 and R 9 Together with the carbon atom to which they are attached, they form a 16 A 5-6 membered heterocyclic group substituted with a group;

[0021] R 11 and R 12 together to form an oxo group; or in R 11 and R 12 When one of them is hydrogen or halogen, R11 and R 12 The other one is selected from R 15 、-OR 15 、-C(O)R 15 and -C(O)OR 15 ;

[0022] R 15 is independently selected at each occurrence from hydrogen, halogen, trichloromethyl, trifluoromethyl, cyano, nitro, heteroaryl, -OR 17 、-C(O)R 18 、-C(O)N(R 17 )R 18 、-C(O)OR 17 、-OC(O)R 17 、-S(O)2R 17 、-S(O)2N(R 17 )R 18 、-N=C(R 17 )R 18 、-N(R 17 )R 18 、-N(R 17 )N(R 17 )R 18 、-N(R 17 )C(O)R 18 、-N(R 17 )S(O)2R 18 , 1,3,2-dioxaborolane optionally substituted by 1, 2, 3, or 4 groups independently selected from alkyl, a glycoside group, an alkynyl group optionally substituted by a trialkylsilane, a 1,2,3,4, or 5 group independently selected from R 16 A hydrocarbon group substituted with a group, optionally substituted with 1, 2, 3, 4 or 5 independently selected from R 16 and optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from R 16 -(CH2) substituted by k -heterocyclyl, wherein k is an integer of 1 to 6;

[0023] R 16 is independently selected at each occurrence from alkynyl, halogen, trichloromethyl, trifluoromethyl, cyano, nitro, oxo, =NR 17 、-OR 17 、-C(O)R 18 、-C(O)N(R 17 )R 18 、-C(O)OR 17 、-OC(O)R 17 、-S(O)2R 17、-S(O)2N(R 17 )R 18 、-N(R 17 )R 18 、-N(R 17 )N(R 17 )R 18 、-N(R 17 )C(O)R 18 and -N(R 17 )S(O)2R 18 ;and

[0024] R 17 and R 18 is independently hydrogen, alkyl, alkynyl, cycloalkyl, aryl, or heteroaryl at each occurrence, or is selected from alkyl and heterocyclyl, any of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halogen, cyano, amino, hydroxy, C 1-6 Alkyl and C 1-6 Alkoxy group substitution;

[0025] Provided that the compound of formula (I) is not selected from the group consisting of 5, 15a, 15b, 16, 17b, 19d, 25a-25g and 26a-26g:

[0026]

[0027]

[0028] In certain embodiments of the use, R 3 and R 4 Each of R is -O-alkyl; 8 and R 9 Together with the carbon atoms to which they are attached, they form a methylenedioxy ring;

[0029] R 1 is heteroaryl, -OR 15 、-C(O)R 15 、-N(R 17 )R 18 、-N(R 17 )C(O)R 18 、-N=C(R 17 )R 18 , pinacol boronyl, -OS(O)2CF3, glycosidic group, optionally 1 or 2 independently selected from R 16 A heterocyclic group substituted with a group, or an alkynyl group optionally substituted with a trialkylsilane; or

[0030] R 1 -O(CH2) m -Cyano, -O(CH2)m -Alkynyl, -O(CH2) m -C(O)N(R 17 )R 18 , or -O(CH2) m -C(O)OR 17 , wherein m is an integer selected from 1-4; and R 11 and R 12 Together they form an oxo group.

[0031] In certain embodiments of the use, the compound is selected from 12a, 12b, 13, 14a, 14b, 17a, 17c, 17d, 17e, 17f, 17g, 17h, 18, 19a, 19b, 19c, 19e, 19f, 19g, 19h, 19i, 19j, 19k, 19l, 19m, 19n, 19o, 19p, 20, 21, 22, 23, and 24:

[0032]

[0033]

[0034]

[0035] In certain embodiments of the use, the viral infection is selected from HIV, coronavirus, influenza virus, Ebola virus, and Marburg virus.

[0036] In certain embodiments of the use, R 1 Alkynyl, pinacol boron, -OCH2-cyano, -OCH2-C(O)N(R 17 )R 18 , or -OCH2-C(O)OR 17 ; R 3 and R 4 Each of them is -OCH3; R 8 and R 9 Together with the carbon atoms to which they are attached, they form a methylenedioxy ring; R 11 and R 12 Together they form an oxo group; and the viral infection is HIV.

[0037] In certain embodiments of the use, R 1 is a glycoside group represented by formula (V):

[0038]

[0039] Where R 19 and R 20 together to form an oxo group; or in R 19 and R 20When one of them is hydrogen or halogen, R 19 and R 20 The other one is selected from R 27 、-OR 27 、-OC(O)R 27 、-OC(O)N(R 27 )R 27 and-OC(O)OR 27 ;

[0040] R 21 and R 22 together to form an oxo group; or in R 21 and R 22 When one of them is hydrogen or halogen, R 21 and R 22 The other one is selected from R 27 、-OR 27 、-OC(O)R 27 、-OC(O)N(R 27 )R 27 and-OC(O)OR 27 ; or R 20 and R 22 Together with the carbon atom to which they are attached, they form a 16 A 5-6 membered heterocyclic group substituted with a group;

[0041] R 23 and R 24 together to form an oxo group; or in R 23 and R 24 When one of them is hydrogen or halogen, R 23 and R 24 The other one is selected from R 27 、-OR 27 、-OC(O)R 27 、-OC(O)N(R 27 )R 27 and-OC(O)OR 27 ; or R 22 and R 24 Together with the carbon atom to which they are attached, they form a 16 A 5-6 membered heterocyclic group substituted with a group;

[0042] R 25 and R 26 together to form an oxo group; or in R 25 and R 26 When one of them is hydrogen or halogen, R 25 and R 26 The other one is selected from R27 、-OR 27 、-OC(O)R 27 、-OC(O)N(R 27 )R 27 、-OC(O)OR 27 、-CH2R 27 and -C(O)R 27 ; or R 24 and R 26 Together with the carbon atom to which they are attached, they form a 16 A 5-6 membered heterocyclic group substituted with a group;

[0043] R 27 is independently selected at each occurrence from hydrogen, halogen, trichloromethyl, trifluoromethyl, cyano, nitro, -OR 29 、-C(O)R 30 、-C(O)N(R 29 )R 30 、-C(O)OR 29 、-OC(O)R 29 、-S(O)2R 29 、-S(O)2N(R 29 )R 30 、-N(R 29 )R 30 、-N(R 29 )N(R 29 )R 30 、-N(R 29 )C(O)R 30 、-N(R 29 )S(O)2R 30 , optionally 1, 2, 3, 4 or 5 independently selected from R 28 A hydrocarbon group substituted with a group, optionally substituted with 1, 2, 3, 4 or 5 independently selected from R 28 and optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from R 28 -(CH2) substituted by k -heterocyclyl, wherein k is an integer of 1 to 6;

[0044] R 28 is independently selected at each occurrence from halogen, trichloromethyl, trifluoromethyl, cyano, nitro, oxo, =NR 29 、-OR 29 、-C(O)R 30 、-C(O)N(R 29 )R 30 、-C(O)OR 29 、-OC(O)R29 、-S(O)2R 29 、-S(O)2N(R 29 )R 30 、-N(R 29 )R 30 、-N(R 29 )N(R 29 )R 30 、-N(R 29 )C(O)R 30 and -N(R 29 )S(O)2R 30 ;and

[0045] R 29 and R 30 is independently hydrogen at each occurrence, or is selected from hydrocarbon and heterocyclyl, any of which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogen, cyano, amino, hydroxy, C 1-6 Alkyl and C 1-6 Alkoxy groups are substituted.

[0046] In certain embodiments of the use, R 19 , R 21 , R 23 and R 25 Each is hydrogen; R 20 , R 22 and R 24 Each independently selected from -OR 27 、-OC(O)N(R 27 )R 27 、-OC(O)R 27 and-OC(O)OR 27 ; and R 26 is hydrogen, methyl, -OR 27 、-OC(O)R 27 or -CH2-OC(O)R 27 ; or R 20 and R 22 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected C 1-6 Alkyl and C 1-6 Alkoxy group substitution; or R 22 and R 24 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected C 1-6 Alkyl and C 1-6 Alkoxy group substitution; or R 24 and R 26Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected C 1-6 Alkyl and C 1-6 Alkoxy groups are substituted; and glycosides are monosaccharides.

[0047] In certain embodiments of the use, the glycoside is a monosaccharide selected from the group consisting of the α-L isomer and the β-L isomer.

[0048] In certain embodiments of use, the compound is selected from 27aa, 27ab, 27ac, 27ad, 27ae, 27af, 27ba, 27bb, 27bc, 27bd, 27be, 27bf, 28ab1, 28ab2, 28ab3, 28bb1, 28bb2, 28bb3, 29a, 29b, 30a, 30b, 30c, 30d, 30e, 30f, 30g, 30h, 30i, 30j, 30k, 30l, 31a, 31b, 31c, 31d, 31e, 31f, 31g, 31h, 31i, 31j, 31k, 31l, 32a, 32b, 32c, and 32d:

[0049]

[0050]

[0051]

[0052]

[0053] In certain embodiments of the use, the viral infection is selected from HIV, coronavirus, influenza virus, Ebola virus, and Marburg virus.

[0054] In certain embodiments of the use, R 3 and R 4 Each of them is -OCH3; R 8 and R 9 Together with the carbon atoms to which they are attached, they form a methylenedioxy ring; R 11 and R 12 Together they form an oxo group; R 19 , R 21 , R 23 R 25 Each is hydrogen; R 20 , R 22 and R 24 Each independently selected from -OR 27 、-OC(O)N(R 27 )R 27 、-OC(O)R 27and-OC(O)OR 27 ; R 26 is hydrogen, methyl, -OR 27 、-OC(O)R 27 or -CH2-OC(O)R 27 ; or R 20 and R 22 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group, the 5-6 membered heterocyclic group is optionally substituted by 1 or 2 independently selected 1-6 Alkyl radical substitution; or R 22 and R 24 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group, the 5-6 membered heterocyclic group is optionally substituted by 1 or 2 independently selected 1-6 Alkyl radical substitution; or R 24 and R 26 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group, the 5-6 membered heterocyclic group is optionally substituted by 1 or 2 independently selected 1-6 The alkyl group is substituted; and the glycoside is a monosaccharide; and the viral infection is HIV, coronavirus, influenza virus, Ebola virus, or Marburg virus.

[0055] In a second aspect, there is provided a compound of formula (I):

[0056]

[0057] or a pharmaceutically acceptable salt or prodrug thereof, wherein

[0058] X is oxygen or sulfur;

[0059] R 1 For R 15 、-OR 15 、-C(O)R 15 , or -C(O)OR 15 ;

[0060] R 2 , R 5 , R 6 , R 10 , R 13 and R 14 Each is hydrogen;

[0061] R 3 and R 4 Each independently selected from -OR 15 and -OC(O)R 15 ; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a1-6 Alkyl and C 1-6 a 5-6 membered heterocyclic group substituted with an alkoxy group;

[0062] R 7 , R 8 and R 9 Each independently selected from -OR 15 and -OC(O)R 15 ; or R 7 and R 8 Together with the carbon atoms to which they are attached, they form a 1-6 Alkyl and C 1-6 5-6 membered heterocyclic group substituted with an alkoxy group; or R 8 and R 9 Together with the carbon atoms to which they are attached, they form a 1-6 Alkyl and C 1-6 a 5-6 membered heterocyclic group substituted with an alkoxy group;

[0063] R 11 and R 12 together to form an oxo group; or in R 11 and R 12 When one of them is hydrogen or halogen, R 11 and R 12 The other one is selected from R 15 、-OR 15 、-C(O)R 15 and -C(O)OR 15 ;

[0064] R 15 is independently selected at each occurrence from hydrogen, halogen, trichloromethyl, trifluoromethyl, cyano, nitro, heteroaryl, -OR 17 、-C(O)R 18 、-C(O)N(R 17 )R 18 、-C(O)OR 17 、-OC(O)R 17 、-S(O)2R 17 、-S(O)2N(R 17 )R 18 、-N=C(R 17 )R 18 、-N(R 17 )R 18 、-N(R 17 )N(R 17 )R 18 、-N(R 17 )C(O)R18 、-N(R 17 )S(O)2R 18 , 1,3,2-dioxaborolane optionally substituted by 1, 2, 3, or 4 groups independently selected from alkyl, a glycoside group, an alkynyl group optionally substituted by a trialkylsilane, a 1,2,3,4, or 5 group independently selected from R 16 A hydrocarbon group substituted with a group, optionally substituted with 1, 2, 3, 4 or 5 independently selected from R 16 and optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from R 16 -(CH2) substituted by k -heterocyclyl, wherein k is an integer of 1 to 6;

[0065] R 16 is independently selected at each occurrence from alkynyl, halogen, trichloromethyl, trifluoromethyl, cyano, nitro, oxo, =NR 17 、-OR 17 、-C(O)R 18 、-C(O)N(R 17 )R 18 、-C(O)OR 17 、-OC(O)R 17 、-S(O)2R 17 、-S(O)2N(R 17 )R 18 、-N(R 17 )R 18 、-N(R 17 )N(R 17 )R 18 、-N(R 17 )C(O)R 18 and -N(R 17 )S(O)2R 18 ;and

[0066] R 17 and R 18 is independently hydrogen, alkyl, alkynyl, cycloalkyl, aryl, or heteroaryl at each occurrence, or is selected from alkyl and heterocyclyl, any of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halogen, cyano, amino, hydroxy, C 1-6 Alkyl and C 1-6 Alkoxy group substitution,

[0067] Provided that the compound of formula (I) is not selected from the group consisting of 5, 15a, 15b, 16, 17b, 19d, 25a-25g and 26a-26g:

[0068]

[0069]

[0070] In certain embodiments of the compound, R 3 and R 4 Each of R is -O-alkyl; 8 and R 9 Together with the carbon atoms to which they are attached, they form a methylenedioxy ring; and R 11 and R 12 Together they form an oxo group.

[0071] In certain embodiments of the compound, R 1 is heteroaryl, -OR 15 、-C(O)R 15 、-N(R 17 )R 18 、-N(R 17 )C(O)R 18 、-N=C(R 17 )R 18 , pinacol boronyl, -OS(O)2CF3, alkynyl optionally substituted with trialkylsilane, or optionally substituted with 1 or 2 independently selected R 16 A heterocyclic group substituted with a group; or R 1 -O(CH2) m -Cyano, -O(CH2) m -Alkynyl, -O(CH2) m -C(O)N(R 17 )R 18 , or -O(CH2) m -C(O)OR 17 , wherein m is an integer selected from 1-4.

[0072] In certain embodiments of the compound, R 1 is heteroaryl, -OR 15 、-C(O)R 15 、-N(R 17 )R 18 、-N(R 17 )C(O)R 18 、-N=C(R 17 )R 18 , pinacol boronyl, -OS(O)2CF3, optionally 1 or 2 independently selected from R 16 A heterocyclic group substituted with a group, or an alkynyl group optionally substituted with a trialkylsilane; or R 1 -O(CH2) m -Cyano, -O(CH2) m -Alkynyl, -O(CH2)m -C(O)N(R 17 )R 18 , or -O(CH2) m -C(O)OR 17 , wherein m is an integer selected from 1-4; R 3 and R 4 Each of them is -OMe; R 8 and R 9 Together with the carbon atoms to which they are attached, they form a methylenedioxy ring; and R 11 and R 12 Together they form an oxo group.

[0073] In certain embodiments of the compound, R 1 is an alkynyl group or a pinacol boron group; -N(R 17 )R 18 , -OCH2-cyano, -OCH2-alkynyl, -OCH2-C(O)N(R 17 )R 18 , or -OCH2-C(O)OR 17 .

[0074] In certain embodiments of the compound, the compound is selected from 12a, 12b, 13, 14a, 14b, 17a, 17c, 17d, 17e, 17f, 17g, 17h, 18, 19a, 19b, 19c, 19e, 19f, 19g, 19h, 19i, 19j, 19k, 19l, 19m, 19n, 19o, 19p, 20, 21, 22, 23, and 24:

[0075]

[0076]

[0077]

[0078] In certain embodiments of the compound, R 1 It is a glycosidic group selected from monosaccharides, disaccharides, trisaccharides, tetrasaccharides and polysaccharide groups containing less than 30 monosaccharides, wherein the glycosidic group comprises one or more monosaccharide isomers selected from α-D, α-L, β-D and β-L.

[0079] In certain embodiments of the compound, R 1 is a glycoside group represented by formula (V):

[0080]

[0081] Where R 19 and R 20 together to form an oxo group; or in R19 and R 20 When one of them is hydrogen or halogen, R 19 and R 20 The other one is selected from R 27 、-OR 27 、-OC(O)R 27 、-OC(O)N(R 27 )R 27 and-OC(O)OR 27 ;

[0082] R 21 and R 22 together to form an oxo group; or in R 21 and R 22 When one of them is hydrogen or halogen, R 21 and R 22 The other one is selected from R 27 、-OR 27 、-OC(O)R 27 、-OC(O)N(R 27 )R 27 and-OC(O)OR 27 ; or R 20 and R 22 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected C 1-6 Alkyl and C 1-6 Alkoxy group substitution;

[0083] R 23 and R 24 together to form an oxo group; or in R 23 and R 24 When one of them is hydrogen or halogen, R 23 and R 24 The other one is selected from R 27 、-OR 27 、-OC(O)R 27 、-OC(O)N(R 27 )R 27 and-OC(O)OR 27 ; or R 22 and R 24 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected C 1-6 Alkyl and C 1-6 Alkoxy group substitution;

[0084] R 25 and R 26together to form an oxo group; or in R 24 and R 25 When one of them is hydrogen or halogen, R 25 and R 26 The other one is selected from R 27 、-OR 27 、-OC(O)R 27 、-OC(O)N(R 27 )R 27 、-OC(O)OR 27 、-CH2R 27 and -C(O)R 27 ; or R 24 and R 26 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected C 1-6 Alkyl and C 1-6 Alkoxy group substitution;

[0085] R 27 is independently selected at each occurrence from hydrogen, halogen, trichloromethyl, trifluoromethyl, cyano, nitro, -OR 29 、-C(O)R 30 、-C(O)N(R 29 )R 30 、-C(O)OR 29 、-OC(O)R 29 、-S(O)2R 29 、-S(O)2N(R 29 )R 30 、-N(R 29 )R 30 、-N(R 29 )N(R 29 )R 30 、-N(R 29 )C(O)R 30 、-N(R 29 )S(O)2R 30 , optionally 1, 2, 3, 4 or 5 independently selected from R 28 A hydrocarbon group substituted with a group, optionally substituted with 1, 2, 3, 4 or 5 independently selected from R 28 and optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from R 28 -(CH2) substituted by k -heterocyclyl, wherein k is an integer of 1 to 6;

[0086] R 28is independently selected at each occurrence from halogen, trichloromethyl, trifluoromethyl, cyano, nitro, oxo, =NR 29 、-OR 29 、-C(O)R 30 、-C(O)N(R 29 )R 30 、-C(O)OR 29 、-OC(O)R 29 、-S(O)2R 29 、-S(O)2N(R 29 )R 30 、-N(R 29 )R 30 、-N(R 29 )N(R 29 )R 30 、-N(R 29 )C(O)R 30 and -N(R 29 )S(O)2R 30 ;and

[0087] R 29 and R 30 is independently hydrogen at each occurrence, or is selected from hydrocarbon and heterocyclyl, any of which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogen, cyano, amino, hydroxy, C 1-6 Alkyl and C 1-6 Alkoxy groups are substituted.

[0088] In certain embodiments of the compound, R 19 , R 21 , R 23 and R 25 Each is hydrogen; R 20 , R 22 and R 24 Each independently selected from -OR 27 、-OC(O)N(R 27 )R 27 、-OC(O)R 27 and-OC(O)OR 27 ; and R 26 is hydrogen, methyl, -OR 27 、-OC(O)R 27 , or -CH2-OC(O)R 27 ; or R 20 and R 22 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected C 1-6 Alkyl and C 1-6Alkoxy group substitution; or R 22 and R 24 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected C 1-6 Alkyl and C 1-6 Alkoxy group substitution; or R 24 and R 26 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected C 1-6 Alkyl and C 1-6 Alkoxy groups are substituted; and glycosides are monosaccharides.

[0089] In certain embodiments of the compound, the glycoside is a monosaccharide selected from the group consisting of the α-L isomer and the β-L isomer.

[0090] In certain embodiments of the compound, the compound is selected from 27aa, 27ab, 27ac, 27ad, 27ae, 27af, 27ba, 27bb, 27bc, 27bd, 27be, 27bf, 28ab1, 28ab2, 28ab3, 28bb1, 28bb2, 28bb3, 29a, 29b, 30a, 30b, 30c, 30d, 30e, 30f, 30g, 30h, 30i, 30j, 30k, 30l, 31a, 31b, 31c, 31d, 31e, 31f, 31g, 31h, 31i, 31j, 31k, 31l, 32a, 32b, 32c, and 32d:

[0091]

[0092]

[0093]

[0094]

[0095] In a third aspect, provided herein is a pharmaceutical composition comprising a compound as described herein and at least one pharmaceutically acceptable excipient.

[0096] Also provided herein is an aryl naphthyl lignan compound having the general formula (I) or (II) or a pharmaceutically acceptable salt or prodrug thereof for use in treating, preventing or delaying the progression of viral infection in a patient.

[0097]

[0098] or a stereoisomer thereof; or an enantiomer thereof; or a pharmaceutically acceptable salt or prodrug thereof, wherein

[0099] X is oxygen or sulfur;

[0100] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, halogen, or a moiety comprising 1 to 30 polyvalent atoms selected from carbon, boron, nitrogen, oxygen, silicon, and sulfur; or R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , R 6 and R 7 , R 7 and R 8 , R 8 and R 9 , or R 9 and R 10 may form, together with the carbon atom to which they are attached, a cyclic group optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from halogen and moieties comprising 1 to 30 polyvalent atoms selected from carbon, boron, nitrogen, oxygen, silicon and sulfur;

[0101] R 11 and R 12 together to form an oxo group; or in R 11 and R 12 When one of them is hydrogen or halogen, R 11 and R 12 The other one is selected from R 15 、-OR 15 、-C(O)R 15 and -C(O)OR 15 ;

[0102] R 13 and R 14 together to form an oxo group; or in R 13 and R 14 When one of them is hydrogen or halogen, R 13 and R 14 The other one is selected from R 15 、-OR 15 、-C(O)R 15 and -C(O)OR 15;

[0103] R 15 are independently selected from hydrogen, halogen, trichloromethyl, trifluoromethyl, cyano, nitro, -OR 17 、-C(O)R 18 、-C(O)N(R 17 )R 18 、-C(O)OR 17 、-OC(O)R 17 、-S(O)2R 17 、-S(O)2N(R 17 )R 18 、-N(R 17 )R 18 、-N(R 17 )N(R 17 )R 18 、-N(R 17 )C(O)R 18 、-N(R 17 )S(O)2R 18 , optionally 1, 2, 3, 4 or 5 independently selected from R 16 A hydrocarbon group substituted with a group, optionally substituted with 1, 2, 3, 4 or 5 independently selected from R 16 and optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from R 16 -(CH2) substituted by k - heterocyclyl, wherein k is an integer from 1 to 6 (eg, 1, 2 or 3);

[0104] R 16 independently selected from halogen, trichloromethyl, trifluoromethyl, cyano, nitro, oxo, =NR 17 、-OR 17 、-C(O)R 18 、-C(O)N(R 17 )R 18 、-C(O)OR 17 、-OC(O)R 17 、-S(O)2R 17 、-S(O)2N(R 17 )R 18 、-N(R 17 )R 18 、-N(R 17 )N(R 17 )R 18 、-N(R 17 )C(O)R 18 and -N(R 17 )S(O)2R 18 ;

[0105] R 17 and R 18 are each independently hydrogen, or selected from hydrocarbon groups and heterocyclic groups, any of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy group substituted; and

[0106] R is hydrogen, or is selected from hydrocarbon and heterocyclic groups, any of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy groups are substituted.

[0107] The present disclosure also provides an aryl naphthyl lignan compound having the general formula (III) or (IV) or a pharmaceutically acceptable salt or prodrug thereof for use in treating, preventing or delaying the progression of viral infection in a patient.

[0108]

[0109] or a stereoisomer thereof; or an enantiomer thereof; or a pharmaceutically acceptable salt or prodrug thereof, wherein

[0110] X is oxygen or sulfur;

[0111] The glycosidic group is usually a carbohydrate group, in particular a monosaccharide, disaccharide, trisaccharide, tetrasaccharide or polysaccharide group, and can exist in various isomeric forms, such as α-D, α-L, β-D or β-L form; the carbohydrate group may optionally be substituted by other types of substituents or even additional glycosidic groups; the total number of monosaccharides and substituted monosaccharides contained in the chemical structure of the compounds of formula (III) and formula (IV) may not exceed 30;

[0112] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently hydrogen, halogen, or a moiety comprising 1 to 30 polyvalent atoms selected from carbon, nitrogen, oxygen, and sulfur; or R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 5 and R 6 , R 6 and R 7, R 7 and R 8 , R 8 and R 9 may form, together with the carbon atom to which they are attached, a cyclic group optionally substituted with halogen or a moiety comprising 1 to 30 polyvalent atoms selected from carbon, nitrogen, oxygen and sulfur;

[0113] R 10 and R 11 can form an oxo group together; or in R 10 and R 11 When one of them is hydrogen or halogen, R 10 and R 11 The other one is selected from R 27 、-OR 27 、-C(O)R 27 and -C(O)OR 27 ;

[0114] R 12 and R 13 can form an oxo group together; or in R 12 and R 13 When one of them is hydrogen or halogen, R 12 and R 13 The other one is selected from R 27 、-OR 27 、-C(O)R 27 and -C(O)OR 27 ;

[0115] R 19 and R 20 together to form an oxo group; or in R 19 and R 20 When one of them is hydrogen or halogen, R 19 and R 20 The other one is selected from R 27 、-OR 27 、-C(O)R 27 、-C(O)OR 27 , monosaccharides, substituted monosaccharides, disaccharides, substituted disaccharides, trisaccharides, substituted trisaccharides, tetrasaccharides, and substituted tetrasaccharides;

[0116] R 21 and R 22 together to form an oxo group; or in R 21 and R 22 When one of them is hydrogen or halogen, R 21 and R 22 The other one is selected from R 27 、-OR 27 、-C(O)R 27、-C(O)OR 27 , monosaccharides, substituted monosaccharides, disaccharides, substituted disaccharides, trisaccharides, substituted trisaccharides, tetrasaccharides, and substituted tetrasaccharides;

[0117] R 23 and R 24 together to form an oxo group; or in R 23 and R 24 When one of them is hydrogen or halogen, R 23 and R 24 The other one is selected from R 27 、-OR 27 、-C(O)R 27 、-C(O)OR 27 , monosaccharides, substituted monosaccharides, disaccharides, substituted disaccharides, trisaccharides, substituted trisaccharides, tetrasaccharides, and substituted tetrasaccharides;

[0118] R 25 and R 26 together to form an oxo group; or in R 25 and R 26 When one of them is hydrogen or halogen, R 25 and R 26 The other one is selected from R 27 、-OR 27 、-C(O)R 27 、-C(O)OR 27 、-CH2R 31 and -C(O)R 31 ;

[0119] R 27 are independently selected from hydrogen, halogen, trichloromethyl, trifluoromethyl, cyano, nitro, -OR 29 、-C(O)R 30 、-C(O)N(R 29 )R 30 、-C(O)OR 29 、-OC(O)R 29 、-S(O)2R 29 、-S(O)2N(R 29 )R 30 、-N(R 29 )R 30 、-N(R 29 )N(R 29 )R 30 、-N(R 29 )C(O)R 30 , and -N(R 29 )S(O)2R 30 , optionally 1, 2, 3, 4 or 5 independently selected from R 28A hydrocarbon group substituted with a group, optionally substituted with 1, 2, 3, 4 or 5 independently selected from R 28 and optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from R 28 -(CH2) substituted by k - heterocyclyl, wherein k is an integer from 1 to 6 (eg, 1, 2 or 3);

[0120] R 28 independently selected from halogen, trichloromethyl, trifluoromethyl, cyano, nitro, oxo, =NR 29 、-OR 29 、-C(O)R 30 、-C(O)N(R 29 )R 30 、-C(O)OR 29 、-OC(O)R 29 、-S(O)2R 29 、-S(O)2N(R 29 )R 30 、-N(R 29 )R 30 、-N(R 29 )N(R 29 )R 30 、-N(R 29 )C(O)R 30 and -N(R 29 )S(O)2R 30 ;

[0121] R 29 and R 30 are each independently hydrogen, or selected from hydrocarbon groups and heterocyclic groups, any of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy group substitution;

[0122] R 31 are independently selected from hydrogen, halogen, trichloromethyl, trifluoromethyl, cyano, nitro, -OR 29 、-C(O)R 30 、-C(O)N(R 29 )R 30 、-C(O)OR 29 、-OC(O)R 29 、-S(O)2R 29 、-S(O)2N(R 29 )R 30 、-N(R 29 )R 30 、-N(R 29 )N(R29 )R 30 、-N(R 29 )C(O)R 30 、-N(R 29 )S(O)2R 30 , monosaccharides, substituted monosaccharides, disaccharides, substituted disaccharides, trisaccharides, substituted trisaccharides, tetrasaccharides, substituted tetrasaccharides, optionally substituted by 1, 2, 3, 4 or 5 independently selected from R 28 and optionally substituted by 1, 2, 3, 4 or 5 independently selected from R 28 A heterocyclic group substituted with a group; and

[0123] R is hydrogen, or is selected from hydrocarbon and heterocyclic groups, any of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy groups are substituted.

[0124] The fourth aspect of the present invention is a pharmaceutical preparation comprising an aryl naphthyl lignan compound or a pharmaceutically acceptable salt or prodrug thereof for use in treating, preventing or delaying the progression of a viral infection in a patient.

[0125] The fifth aspect of the present invention is a pharmaceutical preparation comprising a glycoside aryl naphthyl lignan compound or a pharmaceutically acceptable salt or prodrug thereof for use in treating, preventing or delaying the progression of a viral infection in a patient.

[0126] The sixth aspect of the present invention is a pharmaceutical preparation comprising a schizofiarin analog or a pharmaceutically acceptable salt or prodrug thereof for use in treating, preventing or delaying the progression of a viral infection in a patient.

[0127] The seventh aspect of the present invention is a pharmaceutical formulation comprising a patentiflorin A analog or a pharmaceutically acceptable salt or prodrug thereof for use in treating, preventing or delaying the progression of a viral infection in a patient.

[0128] Another aspect of the present invention relates to providing a method for synthesizing novel aryl naphthyl lignan compounds and intermediate compounds during the synthesis. In addition, the present invention relates to an intermediate compound that can be used to prepare other compounds of the present invention.

[0129] The compounds of the present invention can exist in different forms, such as free acids, free bases, esters and other prodrugs, salts and tautomers, and the present disclosure includes all variant forms of these compounds.

[0130] The degree of protection includes counterfeit or false products that contain or purport to contain compounds of the invention, regardless of whether they actually contain such compounds and regardless of whether any such compounds are contained in a therapeutically effective amount.

[0131] Included within the scope of protection are packages that include descriptions or instructions indicating that the package contains species or pharmaceutical preparations of the present invention and products that are or contain, or purport to be or contain, such preparations or species. Such packages may, but are not necessarily, counterfeit or false.

[0132] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. BRIEF DESCRIPTION OF THE DRAWINGS

[0133] Figure 1 Shown are the structure and carbon numbering of patentiflorin A and the schematic preparation of feroxanthin (5).

[0134] Figure 2 Schematic preparation of schizofiarin analogs 12-17 is shown (for the preparation of compound 14a, reaction reagents and conditions are a: NH4Cl, HATU, Et3N, CH2Cl2; for the preparation of compound 14b, reaction reagents and conditions are b: MeNH2, EDCI, HOBt and THF; for the preparation of compound 15a, reaction reagents and conditions are c: PdCl2, K2CO3, TBAB, H2O, 60°C; for the preparation of compound 15b, reaction reagents and conditions are d: Cs2CO3, DMF, 120°C; for the preparation of compounds 17a-17c, reaction reagents and conditions are e: Cs2CO3, acetone, room temperature; for the preparation of compound 17d, reaction reagents and conditions are f: K2CO3, DMF, 100°C; for the preparation of compounds 17e-17h, reaction reagents and conditions are g: Et3N, DMAP, CH2Cl2, 25°C).

[0135] Figure 3Schematic preparation of schizoflavone analogs 18-24 is shown (for the preparation of compound 19a, the reaction reagents and conditions are a: [Pd(dppf)Cl2]CH2Cl2, KOAc, B2(Pin)2, dioxane, 100°C; for the preparation of compound 19b, the reaction reagents and conditions are b: [Pd(dppf)Cl2]CH2Cl2, AlMe3, toluene, 100°C; for the preparation of compound 19c, the reaction reagents and conditions are c: [Pd(dppf)Cl2]CH2Cl2, Na2CO3, pyridine-4-boric acid, H2O, dioxane, 100°C; for the preparation of compound 19d, the reaction reagents and conditions are d: Pd(OAc)2, P Ph3, Et3N, HCO2H, DMF, 100°C; for the preparation of compounds 19e and 19f, the reaction reagents and conditions were e: Pd(OAc)2, BINAP, Cs2CO3, RH, toluene, 100°C; for the preparation of compound 19g, the reaction reagents and conditions were f: Pd(PPh3)4, Et2Zn, THF, 100°C; for the preparation of compounds 19h-19j, the reaction reagents and conditions were g: Pd(PPh3)4, K2CO3, RB(OH)2, DMF, 100°C; for the preparation of compound 19k, the reaction reagents and conditions were h: Pd(PPh3)4, Na2CO3, furan-2-boric acid, H2O, dioxane, 100 ℃; for the preparation of compound 19l, the reaction reagents and conditions are i: Pd(PPh3)4, Na2CO3, 1-Boc-3,6-dihydro-2H-pyridine-4-boronic acid pinacol ester, H2O, dioxane, 100℃; for the preparation of compound 19m, the reaction reagents and conditions are j: Pd2(dba)3, XantPhos, Cs2CO3, morpholine DMF, 100℃; for the preparation of compound 19n, the reaction reagents and conditions are k: Pd(PPh3)2Cl2, tributyl(1-ethoxyvinyl)tin, PhMe, 100℃, followed by 50% HCl; for the preparation of compound 19o, the reaction reagents and conditions are l: Pd(PPh3)2Cl2, C uI, Et3N, DMF, trimethylsilyl acetylene, 80°C; for the preparation of compound 19p, the reaction reagents and conditions are m: Pd(OAc)2, Cs2CO3, Xantphos, Et3N, benzophenone imine, dioxane, 100°C; for the preparation of compound 20, the reaction reagents and conditions are n: NaBH4, MeOH, room temperature; for the preparation of compound 21, the reaction reagents and conditions are o: K2CO3, MeOH, room temperature; for the preparation of compound 22, the reaction reagents and conditions are p: HCl, THF, room temperature, followed by KOH, room temperature; for the preparation of compound 23, the reaction reagents and conditions are q: Cs2CO3, propargyl bromide, MeCN, room temperature;For the preparation of compound 24, the reaction reagents and conditions are: Ac2O, pyridine, room temperature).

[0136] Figure 4 Schematic preparation of patentiflorin A analogs 25a-25g and 26a-26g is shown. Compounds 26a, 26b, 26c, 26d, 26e, 26f and 26g were generated from 25a, 25b, 25c, 25d, 25e, 25f and 25g, respectively.

[0137] Figure 5 Schematic preparation of patentiflorin A analogs 27aa-27af, 27ba-27bf, 28ab1-28ab3, 28bb1-28bb3, 29a, 29b, 30a-301 and 31a-311 are shown (for the preparation of compounds 27aa-27af and 27ba-27bf, the reaction reagents and conditions are a: Ac2O, TBAOAc, MeCN, 40°C; for the preparation of compounds 28ab1 to 28ab3 and 28bb1 to 28bb3, the reaction reagents and conditions are b: AllocOCl, Et3N, CH2Cl2, 0°C to Room temperature; for the preparation of compounds 29a and 29b, the reaction reagents and conditions were c: AcCl, CH2Cl2, MeOH, 0°C to room temperature; for the preparation of compounds 30a-k, the reaction reagents and conditions were d: Et3N, DMAP, anhydrous CH2Cl2, 0°C to room temperature; for the preparation of compound 30l, the reaction reagents and conditions were e: KOH, 18-crown ether-6, THF, room temperature; for the preparation of compounds 31a-l, the reaction reagents and conditions were f: (PPh3)4Pd, PPh3, Et3N, HCOOH, THF, N2, 55°C). Compounds 27aa, 27ab, 27ac, 27ad, 27ae and 27af were generated from 26a. Compounds 27ba, 27bb, 27bc, 27bd, 27be and 27bf were generated from 26b. Compounds 28ab1, 28ab2 and 28ab3 were generated from 27ab. Compounds 28bb1, 28bb2 and 28bb3 were generated from 27bb. Compounds 29a and 29b were generated from 28ab3 and 28bb3, respectively. Compounds 30a and 301 were generated from 29a. Compounds 30b, 30c, 30d, 30e, 30f, 30g, 30h, 30i, 30j and 30k were generated from 29b. Compounds 31a, 31b, 31c, 31d, 31e, 31f, 31g, 31h, 31i, 31j, 31k and 311 were generated from 30a, 30b, 30c, 30d, 30e, 30f, 30g, 30h, 30i, 30j, 30k and 301, respectively.

[0138] Figure 6 Schematic preparation of patentiflorin A analogs 32a-32d is shown. Compound 32a was generated from 26f. Compounds 32b-32d were generated from 26g. DETAILED DESCRIPTION

[0139] The present disclosure is not to be limited in scope by any specific embodiments described herein.The following embodiments are provided for illustration only.

[0140] Throughout the description and claims of this specification, the word "comprise" and other forms of the word such as "comprising" and "comprises" mean including but not limited to, and are not intended to exclude, for example, other additives, components, integers or steps.

[0141] As used in the description and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes mixtures of two or more such compositions, reference to "the compound" includes mixtures of two or more such compounds, reference to "an agent" includes mixtures of two or more such agents, etc.

[0142] "Optional" or "optionally" means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0143] As used herein, "subject" means an individual. Thus, "subject" may include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mice, rabbits, rats, guinea pigs, etc.), and birds. "Subject" may also include mammals, such as primates or humans.

[0144] By "reduce" or other forms of the word, such as "reducing" or "reduction" is meant a reduction in an event or characteristic (e.g., tumor growth). It will be understood that this is usually related to some standard or expected value, in other words, it is relative, but it is not always necessary to refer to the standard or relative value. For example, "reduce tumor growth" means a reduction in tumor growth rate relative to a standard or control.

[0145] So-called "prevention" or other forms of the term, such as "preventing" or "prevention" means stopping a particular event or feature, stabilizing or slowing the development or progression of a particular event or feature, or minimizing the chance of a particular event or feature occurring. Prevention does not need to be compared with a control because it is usually more absolute than, for example, reduction. As used herein, something can be reduced but not prevented, but something that is reduced can also be prevented. Similarly, something can be prevented but not reduced, but something that is prevented can also be reduced. It should be understood that in the case of using reduction or prevention, unless otherwise specifically noted, the use of other words is also explicitly disclosed.

[0146] By "treat" or other forms of the word, such as "treated" or "treatment" is meant administering a composition or performing a method to reduce, prevent, inhibit, or eliminate a particular characteristic or event (e.g., tumor growth or survival). The term "control" is used synonymously with the term "treatment".

[0147] The term "antiviral" refers to the ability to inhibit the replication of a specific virus, inhibit viral transmission, or prevent a virus from establishing itself in its host, as well as to ameliorate or alleviate the symptoms of disease caused by viral infection. If the viral load is reduced, mortality and / or morbidity is reduced, the treatment is considered therapeutic.

[0148] The term "therapeutically effective" means that the amount of the composition used is sufficient to improve one or more causes or symptoms of the disease or disorder. Such improvement only requires reduction or modification, not elimination.

[0149] As used herein, the term "pharmaceutically acceptable salt" refers to any salt of a compound of the invention which retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical use. Such salts can be derived from and include a variety of organic and inorganic counterions known in the art. Such salts include: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxyphenyl)-1-ol benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, or (2) when an acidic proton present in the parent compound is (a) replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion or an aluminum ion), or an alkali metal or alkaline earth metal hydroxide (e.g., sodium, potassium, calcium, magnesium, aluminum, lithium, zinc and barium hydroxide), ammonia, or (b) coordinated with an organic base, such as an aliphatic, alicyclic, or aromatic organic amine, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.In addition, examples of salts include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like, and when the compound contains a basic functional group, include salts of non-toxic organic or inorganic acids such as hydrohalides (e.g., hydrochlorides and hydrobromides), sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates; fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoate, picrates, cinnamates, mandelates, phthalates , laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethylsulfonate, benzenesulfonate (benzenesulfonate (besylate)), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylaminosulfonate, quinate, muconate, and the like.

[0150] As used herein, the terms "glycoside" or "glycosidic" compound are interchangeable and include any of the classes of compounds mentioned that upon hydrolysis produce a sugar and aglycone.

[0151] As used herein, the terms "ANL" or "aryl naphthalene lignan" or "arylnaphthalene lignan" compounds are interchangeable.

[0152] As used herein, the term "aryl naphthalene lignan" or "arylnaphthalene lignan" or "ANL" includes reference to compounds containing the base structure of 2,3-dimethyl-1-phenyl-naphthalene as shown below:

[0153]

[0154] As used herein, carbon numbering of arylnaphthyl lignan molecules includes reference to compounds comprising the numbering system shown below:

[0155]

[0156] In the core structure of a class of arylnaphthalene compounds, two methyl groups form a γ-lactone ring to become arylnaphthofuran-2-one lignans or arylnaphthofuran-3-one lignans as shown below:

[0157]

[0158] As used herein, carbon numbering of arylnaphthyl lignan glycoside molecules includes reference to compounds comprising the numbering system shown below:

[0159]

[0160] As used herein, the term "hydrocarbyl" includes reference to moieties consisting only of hydrogen and carbon atoms; such moieties may contain aliphatic and / or aromatic moieties. The moieties may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. Examples of hydrocarbyl groups include C 1-6 alkyl (e.g., C1, C2, C3 or C4 alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl); C1, C2, C3 or C4 alkyl substituted by aryl (e.g., benzyl) or by cycloalkyl (e.g., cyclopropylmethyl); 1-6 Alkyl; cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl); aryl (e.g., phenyl, naphthyl or fluorenyl); C 1-6 alkenyl (e.g., ethenyl, 2-propenyl or 3-butenyl); C 1-6 Alkynyl (e.g., ethynyl, 2-propynyl or 3-butynyl) and the like.

[0161] As used herein, the terms "alkyl" and "C 1-6 "Alkyl" includes references to straight or branched chain alkyl moieties having 1, 2, 3, 4, 5 or 6 carbon atoms. The term includes references to groups such as methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl or tert-butyl), pentyl, hexyl, etc. In particular, the alkyl moiety may have 1, 2, 3 or 4 carbon atoms.

[0162] As used herein, the term "alkenyl" includes references to straight or branched chain alkyl moieties having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms and additionally having at least one double bond, and where applicable, E or Z stereochemistry. The term includes references to groups such as ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl and 3-hexenyl.

[0163] As used herein, the term "alkynyl" includes references to straight or branched chain alkyl moieties having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms and additionally having at least one triple bond. The term includes references to groups such as ethynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl and 3-hexynyl.

[0164] As used herein, the terms "alkoxy" and "C 1-6 "Alkoxy" includes references to -O-alkyl, wherein the alkyl is straight or branched and contains 1, 2, 3, 4, 5 or 6 carbon atoms. In one class of embodiments, the alkoxy has 1, 2, 3 or 4 carbon atoms. The term includes references to groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0165] As used herein, the term "cycloalkyl" includes references to alicyclic moieties having 3, 4, 5, 6, 7 or 8 carbon atoms. The group may be a bridged or polycyclic ring system. The more common cycloalkyl groups are monocyclic. The term includes references to groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl, and the like.

[0166] As used herein, the term "aryl" includes references to aromatic ring systems containing 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring carbon atoms. Aryl is typically phenyl, but may be a polycyclic ring system having two or more rings, at least one of which is aromatic. The term includes references to groups such as phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthracenyl, and the like.

[0167] "Cyclic group" means a ring or ring system which may be unsaturated or partially unsaturated, but is typically saturated, and typically contains 5 to 13 ring atoms, such as a 5- or 6-membered ring. It includes carbocyclyl and heterocyclyl moieties.

[0168] As used herein, the term "carbocyclyl" includes reference to saturated (e.g., cycloalkyl) or unsaturated (e.g., aryl) ring moieties having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 carbon ring atoms. In particular, carbocyclyl includes 3- to 10-membered rings or ring systems, particularly 5- or -6-membered rings, which may be saturated or unsaturated. The carbocyclyl moiety is, for example, selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl, phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthracenyl, etc.

[0169] As used herein, the term "heterocyclyl" includes reference to saturated (e.g., heterocycloalkyl) or unsaturated (e.g., heteroaryl) heterocyclic moieties having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, at least one of which is selected from boron, nitrogen, oxygen, phosphorus, silicon, and sulfur. In particular, heterocyclyl includes 3- to 10-membered rings or ring systems, more particularly 5- or -6-membered rings, which may be saturated or unsaturated.

[0170] The heterocyclic moiety is selected, for example, from oxiranyl, aziridine, 1,2-oxathiolanyl, imidazolyl, thienyl, furanyl, tetrahydrofuranyl, pyranyl, thiopyranyl, thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolizidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, piperazinyl, pyridazinyl, morpholinyl, thiomorpholinyl, especially thiomorpholinyl, indolizinyl, isoindolyl, 3H-indolyl yl, indolyl, benzimidazolyl, coumarinyl (cumaryl), indazolyl, triazolyl, tetrazolyl, purinyl, 4N-quinolizinyl, isoquinolyl, quinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, B-carbolinyl, phenanthridinyl, acridinyl, furidinyl, phenanthrolinyl, furazolyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl, chromanyl, 1,3,2-dioxaborolane, etc.

[0171] As used herein, the term "heterocycloalkyl" includes reference to saturated heterocyclic moieties having 3, 4, 5, 6 or 7 ring carbon atoms and 1, 2, 3, 4 or 5 ring heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur. The group can be a polycyclic ring system, but is more typically a monocyclic ring. The term includes groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl, imidazolyl, indolizidinyl, piperazinyl, tetrahydrothiazolyl, morpholinyl, thiomorpholinyl, quinolizinyl and the like.

[0172] As used herein, the term "heteroaryl" includes reference to aromatic heterocyclic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen and sulfur. The group may be a polycyclic ring system having two or more rings, at least one of which is aromatic, but more typically a monocyclic ring. The term includes reference to groups such as pyrimidinyl, furanyl, benzothienyl, thienyl, pyrrolyl, imidazolyl, pyrrolidinyl, pyridyl, benzofuranyl, pyrazinyl, purinyl, indolyl, benzimidazolyl, quinolyl, phenothiazinyl, triazinyl, phthalazinyl, 2H-chromenyl, oxazolyl, isoxazolyl, thiazolyl, isoindolyl, indazolyl, purinyl, isoquinolyl, quinazolinyl, pteridinyl, etc.

[0173] As used herein, the term "halogen" includes reference to F, Cl, Br or I.

[0174] As used herein, the expression "halogen-containing moiety" includes reference to a moiety containing 1 to 30 polyvalent atoms selected from carbon, nitrogen, oxygen and sulfur, which moiety includes at least one halogen. The moiety may be a hydrocarbon group, such as C 1-6 Alkyl or C 1-6 an alkoxy group, or a carbocyclic group such as an aryl group.

[0175] As used herein, the term "substituted" referring to a moiety means that one or more, especially up to 5, more especially 1, 2 or 3 hydrogen atoms in the moiety are replaced independently of each other by the corresponding number of described substituents. As used herein, the term "optionally substituted" means substituted or unsubstituted. Of course, it should be understood that the substituents are only in chemically possible positions, and a person skilled in the art will be able to determine (experimentally or theoretically) whether a particular substitution is possible without undue effort.

[0176] When two or more moieties are described as being "each independently" selected from a list of atoms or groups, this means that the moieties may be the same or different. Thus, the identity of each moiety is independent of the identity of one or more other moieties.

[0177] As used herein, the term "enantiomer" means one of two stereoisomers that are mirror images of each other.

[0178] As used herein, the term "stereoisomer" refers to a class of isomeric molecules that have the same molecular formula and sequence of bonded atoms but different three-dimensional orientations of their atoms in space.

[0179] The term "tautomer" refers to isomeric molecules that are easily interconverted by chemical reactions. The reaction usually results in the migration of a hydrogen atom, which results in the conversion of a single bond and an adjacent double bond.

[0180] A prodrug is a drug that is administered as an inactive (or less than fully active) chemical derivative that is subsequently converted in vivo to the active agent, typically by normal metabolic processes.

[0181] CC 50 It is a measure of cytotoxicity at the concentration of the test drug that inhibits cell growth by 50%.

[0182] EC 50 or IC 50 It is a measure of the antiviral activity of the effective concentration of the test drug that inhibits 50% of viral growth.

[0183] The term "selection index" or "SI" means the value of a given CC 50 The value was divided by the EC of the tested drug 50 or IC 50 Value (CC 50 / EC 50 or CC 50 / IC 50 ) to measure the ratio of the window between cytotoxic and antiviral activity. A higher SI ratio means that the test drug will be more effective and safer against a given viral infection in in vitro experiments.

[0184] Symbols in chemical structures or or Indicates the position where a specified chemical structure is bonded to another chemical structure.

[0185] The symbol "β" in a chemical structure indicates that the bond is attached above (or in front of) the plane of the paper or screen. The symbol "α" in a chemical structure indicates that the bond is attached below (or behind) the plane of the paper or screen.

[0186] A solid wedge in a chemical structure indicates that the bond is above (or in front of) the plane of the paper or screen toward the viewer. A dashed (or broken) wedge in a chemical structure indicates that the bond is below (or behind) the plane of the paper or screen away from the viewer.

[0187] Provided herein is a compound and the use of the compound in the manufacture of a medicament for treating a viral infection, and a method of using the compound to treat a viral infection in a subject, the method comprising the step of administering to the subject a therapeutically effective amount of the compound, wherein the compound has formula (I):

[0188]

[0189] or a pharmaceutically acceptable salt or prodrug thereof, wherein

[0190] X is oxygen or sulfur;

[0191] R 1 For R15 、-OR 15 、-C(O)R 15 , or -C(O)OR 15 ;

[0192] R 2 , R 5 , R 6 , R 10 , R 13 and R 14 are each independently hydrogen or halogen;

[0193] R 3 and R 4 Each independently selected from -OR 15 and -OC(O)R 15 ; or R 3 and R 4 Together with the carbon atom to which they are attached, they form a 16 A 5-6 membered heterocyclic group substituted with a group;

[0194] R 7 , R 8 and R 9 Each independently selected from -OR 15 and -OC(O)R 15 ; or R 7 and R 8 Together with the carbon atom to which they are attached, they form a 16 A 5-6 membered heterocyclic group substituted with a group; or R 8 and R 9 Together with the carbon atom to which they are attached, they form a 16 A 5-6 membered heterocyclic group substituted with a group;

[0195] R 11 and R 12 together to form an oxo group; or in R 11 and R 12 When one of them is hydrogen or halogen, R 11 and R 12 The other one is selected from R 15 、-OR 15 、-C(O)R 15 and -C(O)OR 15 ;

[0196] R 15 is independently selected at each occurrence from hydrogen, halogen, trichloromethyl, trifluoromethyl, cyano, nitro, heteroaryl, -OR 17、-C(O)R 18 、-C(O)N(R 17 )R 18 、-C(O)OR 17 、-OC(O)R 17 、-S(O)2R 17 、-S(O)2N(R 17 )R 18 、-N=C(R 17 )R 18 、-N(R 17 )R 18 、-N(R 17 )N(R 17 )R 18 、-N(R 17 )C(O)R 18 、-N(R 17 )S(O)2R 18 , 1,3,2-dioxaborolane optionally substituted by 1, 2, 3, or 4 groups independently selected from alkyl, a glycoside group, an alkynyl group optionally substituted by a trialkylsilane, a 1,2,3,4, or 5 group independently selected from R 16 A hydrocarbon group substituted with a group, optionally substituted with 1, 2, 3, 4 or 5 independently selected from R 16 and optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from R 16 -(CH2) substituted by k -heterocyclyl, wherein k is an integer of 1 to 6;

[0197] R 16 is independently selected at each occurrence from alkynyl, halogen, trichloromethyl, trifluoromethyl, cyano, nitro, oxo, =NR 17 、-OR 17 、-C(O)R 18 、-C(O)N(R 17 )R 18 、-C(O)OR 17 、-OC(O)R 17 、-S(O)2R 17 、-S(O)2N(R 17 )R 18 、-N(R 17 )R 18 、-N(R 17 )N(R 17 )R 18 、-N(R 17 )C(O)R 18 and -N(R 17 )S(O)2R 18;and

[0198] R 17 and R 18 is independently hydrogen, alkyl, alkynyl, cycloalkyl, aryl, or heteroaryl at each occurrence, or is selected from alkyl and heterocyclyl, any of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halogen, trichloromethyl, trifluoromethyl, cyano, amino, hydroxy, C 1-6 Alkyl and C 1-6 Alkoxy groups are substituted.

[0199] In certain embodiments, the compound of formula (I) is not selected from the group consisting of 5, 15a, 15b, 16, 17b, 19d, 25a-25g, and 26a-26g:

[0200]

[0201]

[0202] In certain embodiments, R 1 is hydrogen, alkyl, aryl, heteroaryl (such as furan, thiophene, pyridine, etc.), -N(R 17 )R 18 、-N=C(R 17 )(R 18 ), an alkynyl group optionally substituted by a trialkylsilane, a glycoside group, 1,3,2-dioxaborolane optionally substituted by 1, 2, 3, or 4 groups independently selected from alkyl, or -O-(CR2) m -R 16 , wherein m is an integer selected from 1-4, 1-3, or 1-2; R is independently hydrogen, alkyl, cycloalkyl, or aryl at each occurrence; and R 16 Alkynyl, cyano, -OR 17 、-N(R 17 )R 18 、-C(O)N(R 17 )R 18 , or -C(O)OR 17 .

[0203] In certain embodiments, R 1 -O-CH2-R 16 , where R 16 Alkynyl, cyano, -OR 17 、-N(R 17 )R 18 、-C(O)N(R 17 )R 18 , or -C(O)OR 17 .

[0204] In certain embodiments, R 3 and R 4 Each of which is independently selected from -OR 15 and -OC(O)R 15 , where R 15 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or R 3 and R 4 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group. 3 and R 4 For-OR 15 , where R 15 It is a C1-C6 alkyl group, a C1-C4 alkyl group, or a C1-C2 alkyl group.

[0205] In certain embodiments, R 8 and R 9 Each of which is independently selected from -OR 15 and -OC(O)R 15 , where R 15 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; or R 8 and R 9 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group. 8 and R 9 Together with the carbon atoms to which they are attached they form a methylenedioxy ring.

[0206] In certain embodiments, R 11 and R 12 Together they form an oxo group.

[0207] In certain embodiments, R 3 and R 4 Each of R is -O-alkyl; 8 and R 9 Together with the carbon atoms to which they are attached, they form a methylenedioxy ring; R 1 is heteroaryl, -OR 15 、-C(O)R 15 、-N(R 17 )R 18 、-N(R 17 )C(O)R 18 、-N=C(R 17 )R 18 , pinacol boronyl, -OS(O)2CF3, glycosidic group, optionally 1 or 2 independently selected from R 16 A heterocyclic group substituted with a group, or an alkynyl group optionally substituted with a trialkylsilane; or R 1-OCH2-cyano, -OCH2-C≡CH, -OCH2-C(O)N(R 17 )R 18 , or -C(O)OR 17 ; and R 11 and R 12 Together they form an oxo group.

[0208] In certain embodiments, the compound is selected from compounds 12a, 12b, 13, 14a, 14b, 17a, 17c, 17d, 17e, 17f, 17g, 17h, 18, 19a, 19b, 19c, 19e, 19f, 19g, 19h, 19i, 19j, 19k, 19l, 19m, 19n, 19o, 19p, 20, 21, 22, 23, and 24:

[0209]

[0210]

[0211] In certain embodiments, R 1 is a glycoside group represented by formula (V):

[0212]

[0213] Where R 19 and R 20 together to form an oxo group; or in R 19 and R 20 When one of them is hydrogen or halogen, R 19 and R 20 The other one is selected from R 27 、-OR 27 、-OC(O)R 27 、-OC(O)N(R 27 )R 27 and-OC(O)OR 27 ;

[0214] R 21 and R 22 together to form an oxo group; or in R 21 and R 22 When one of them is hydrogen or halogen, R 21 and R 22 The other one is selected from R 27 、-OR 27 、-OC(O)R 27 、-OC(O)N(R 27 )R 27 and-OC(O)OR 27 ; or R 20and R 22 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy group substitution;

[0215] R 23 and R 24 together to form an oxo group; or in R 23 and R 24 When one of them is hydrogen or halogen, R 23 and R 24 The other one is selected from R 27 、-OR 27 、-OC(O)R 27 、-OC(O)N(R 27 )R 27 and-OC(O)OR 27 ; or R 22 and R 24 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy group substitution;

[0216] R 25 and R 26 together to form an oxo group; or in R 25 and R 26 When one of them is hydrogen or halogen, R 25 and R 26 The other one is selected from R 27 、-OR 27 、-OC(O)R 27 、-OC(O)N(R 27 )R 27 、-OC(O)OR 27 、-CH2R 27 and -C(O)R 27 ; or R 24 and R 26 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy group substitution;

[0217] R 27is independently selected at each occurrence from hydrogen, halogen, trichloromethyl, trifluoromethyl, cyano, nitro, -OR 29 、-C(O)R 30 、-C(O)N(R 29 )R 30 、-C(O)OR 29 、-OC(O)R 29 、-S(O)2R 29 、-S(O)2N(R 29 )R 30 、-N(R 29 )R 30 、-N(R 29 )N(R 29 )R 30 、-N(R 29 )C(O)R 30 、-N(R 29 )S(O)2R 30 , optionally 1, 2, 3, 4 or 5 independently selected from R 28 A hydrocarbon group substituted with a group, optionally substituted with 1, 2, 3, 4 or 5 independently selected from R 28 and optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from R 28 -(CH2) substituted by k -heterocyclyl, wherein k is an integer of 1 to 6;

[0218] R 28 is independently selected at each occurrence from halogen, trichloromethyl, trifluoromethyl, cyano, nitro, oxo, =NR 29 、-OR 29 、-C(O)R 30 、-C(O)N(R 29 )R 30 、-C(O)OR 29 、-OC(O)R 29 、-S(O)2R 29 、-S(O)2N(R 29 )R 30 、-N(R 29 )R 30 、-N(R 29 )N(R 29 )R 30 、-N(R 29 )C(O)R 30 and -N(R 29 )S(O)2R 30 ;and

[0219] R 29 and R30 is independently hydrogen at each occurrence, or is selected from hydrocarbon and heterocyclyl, any of which is optionally substituted by 1, 2, 3, 4 or 5 independently selected from halogen, cyano, amino, hydroxy, C 1-6 Alkyl and C 1-6 Alkoxy groups are substituted.

[0220] In certain embodiments, the glycoside group is a monosaccharide, disaccharide, trisaccharide, tetrasaccharide or polysaccharide group, and can exist in any isomeric form (e.g., α-D, α-L, β-D or β-L form). In certain embodiments, the glycoside is a monosaccharide selected from the α-L isomer and the β-L isomer.

[0221] In certain embodiments, R 19 , R 21 , R 23 and R 25 Each is hydrogen; R 20 , R 22 and R 24 Each independently selected from -OR 27 、-OC(O)N(R 27 )R 27 、-OC(O)R 27 and-OC(O)OR 27 ; and R 26 is hydrogen, methyl, -OR 27 、-OC(O)R 27 or -CH2-OC(O)R 27 ; or R 20 and R 22 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected C 1-6 Alkyl and C 1-6 Alkoxy group substitution; or R 22 and R 24 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected C 1-6 Alkyl and C 1-6 Alkoxy group substitution; or R 24 and R 26 Together with the carbon atoms to which they are attached, they form a 5-6 membered heterocyclic group, which is optionally substituted by 1, 2, 3, 4 or 5 independently selected C 1-6 Alkyl and C 1-6 Alkoxy groups are substituted; and glycosides are monosaccharides.

[0222] In certain embodiments, R 20 , R 22 and R24 Each independently selected from -OR 27 、-OC(O)N(R 27 )R 27 、-OC(O)R 27 and-OC(O)OR 27 , where R 27 is independently selected at each occurrence from hydrogen, alkyl, cycloalkyl, alkenyl, aryl, aralkyl, heteroaryl, perhaloalkyl, and -C(O)CH2CN.

[0223] In R 1 In the case of a glycoside group, the compound can be selected from: 27aa, 27ab, 27ac, 27ad, 27ae, 27af, 27ba, 27bb, 27bc, 27bd, 27be, 27bf, 28ab1, 28ab2, 28ab3, 28bb1, 28bb2, 28bb3, 29a, 29b, 30a, 30b, 30c, 30d, 30e, 30f, 30g, 30h, 30i, 30j, 30k, 30l, 31a, 31b, 31c, 31d, 31e, 31f, 31g, 31h, 31i, 31j, 31k, 31l, 32a, 32b, 32c and 32d:

[0224]

[0225]

[0226]

[0227]

[0228] The present disclosure also provides aryl naphthoxyside compounds that can be used to treat viral infections, including derivatives of sarmentin, patentiflorin A, justiprocumin A or justiprocumin B.

[0229] In certain embodiments, the compound has formula (I) or (II):

[0230]

[0231] or a stereoisomer thereof; or an enantiomer thereof; or a pharmaceutically acceptable salt or prodrug thereof, wherein

[0232] X is oxygen or sulfur;

[0233] R 1 , R 2 , R 3 , R 4 , R 5 , R6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, halogen, or a moiety comprising 1 to 30 polyvalent atoms selected from carbon, nitrogen, oxygen, and sulfur; or R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , R 6 and R 7 , R 7 and R 8 , R 8 and R 9 , or R 9 and R 10 may form, together with the carbon atom to which they are attached, a cyclic group optionally substituted with halogen and a moiety comprising 1 to 30 polyvalent atoms selected from carbon, nitrogen, oxygen and sulfur;

[0234] R 11 and R 12 together to form an oxo group; or in R 11 and R 12 When one of them is hydrogen or halogen, R 11 and R 12 The other one is selected from R 15 、-OR 15 、-C(O)R 15 and -C(O)OR 15 ;

[0235] R 13 and R 14 together to form an oxo group; or in R 13 and R 14 When one of them is hydrogen or halogen, R 13 and R 14 The other one is selected from R 15 、-OR 15 、-C(O)R 15 and -C(O)OR 15 ;

[0236] R 15 independently selected from hydrogen, halogen, trichloromethyl, trifluoromethyl, cyano, nitro, optionally substituted by 1, 2, 3, 4 or 5 R 16 substituted hydrocarbon group, optionally substituted by 1, 2, 3, 4 or 5 R 16 substituted heterocyclic group, optionally substituted by 1, 2, 3, 4 or 5 R 16 Substituted -(CH2) k-Heterocyclic group, -OR 17 、-C(O)R 18 、-C(O)N(R 17 )R 18 、-C(O)OR 17 、-OC(O)R 17 、-S(O)2R 17 、-S(O)2N(R 17 )R 18 、-N(R 17 )R 18 、-N(R 17 )N(R 17 )R 18 、-N(R 17 )C(O)R 18 and -N(R 17 )S(O)2R 18 , wherein k is an integer from 1 to 6 (e.g., 1, 2 or 3);

[0237] R 16 independently selected from halogen, trichloromethyl, trifluoromethyl, cyano, nitro, oxo, =NR 17 、-OR 17 、-C(O)R 18 、-C(O)N(R 17 )R 18 、-C(O)OR 17 、-OC(O)R 17 、-S(O)2R 17 、-S(O)2N(R 17 )R 18 、-N(R 17 )R 18 、-N(R 17 )N(R 17 )R 18 、-N(R 17 )C(O)R 18 and -N(R 17 )S(O)2R 18 ;and

[0238] R 17 and R 18 are each independently hydrogen, or selected from hydrocarbon groups and heterocyclic groups, any of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl and C 1-6 The substituents of the alkoxy group are substituted.

[0239] In certain embodiments, the compound has formula (III) or (IV):

[0240]

[0241] or a stereoisomer thereof; or an enantiomer thereof; or a pharmaceutically acceptable salt or prodrug thereof, wherein

[0242] X is sulfur or oxygen;

[0243] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently hydrogen, halogen, or a moiety comprising 1 to 30 polyvalent atoms selected from carbon, nitrogen, oxygen, and sulfur; or R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , R 5 and R 6 , R 6 and R 7 , R 7 and R 8 , and / or R 8 and R 9 together with the carbon atom to which they are attached, form a cyclic group which is optionally substituted by 1, 2, 3, 4 or 5 groups selected from halogen and moieties comprising 1 to 30 polyvalent atoms selected from carbon, nitrogen, oxygen and sulfur;

[0244] R 10 and R 11 together to form an oxo group; or in R 10 and R 11 When one of them is hydrogen or halogen, R 10 and R 11 The other one is selected from R 27 、-OR 27 、-C(O)R 27 and -C(O)OR 27 ;

[0245] R 12 and R 13 together to form an oxo group; or in R 12 and R 13 When one of them is hydrogen or halogen, R 12 and R 13 The other one is selected from R 27 、-OR 27 、-C(O)R27 and -C(O)OR 27 ;

[0246] R 19 and R 20 together to form an oxo group; or in R 19 and R 20 When one of them is hydrogen or halogen, R 19 and R 20 The other one is selected from R 27 、-OR 27 、-C(O)R 27 、-C(O)OR 27 , monosaccharides, substituted monosaccharides, disaccharides, substituted disaccharides, trisaccharides, substituted trisaccharides, tetrasaccharides, and substituted tetrasaccharides;

[0247] R 21 and R 22 together to form an oxo group; or in R 21 and R 22 When one of them is hydrogen or halogen, R 21 and R 22 The other one is selected from R 27 、-OR 27 、-C(O)R 27 、-C(O)OR 27 , monosaccharides, substituted monosaccharides, disaccharides, substituted disaccharides, trisaccharides, substituted trisaccharides, tetrasaccharides, and substituted tetrasaccharides;

[0248] R 23 and R 24 together to form an oxo group; or in R 23 and R 24 When one of them is hydrogen or halogen, R 23 and R 24 The other one is selected from R 27 、-OR 27 、-C(O)R 27 、-C(O)OR 27 , monosaccharides, substituted monosaccharides, disaccharides, substituted disaccharides, trisaccharides, substituted trisaccharides, tetrasaccharides, and substituted tetrasaccharides;

[0249] R 25 and R 26 together to form an oxo group; or in R 25 and R 26 When one of them is hydrogen or halogen, R 25 and R 26 The other one is selected from R 27 、-OR 27 、-C(O)R 27 、-C(O)OR 27、-CH2R 31 and -C(O)R 31 ;

[0250] R 27 are independently selected from hydrogen, halogen, trichloromethyl, trifluoromethyl, cyano, nitro, -OR 29 、-C(O)R 30 、-C(O)N(R 29 )R 30 、-C(O)OR 29 、-OC(O)R 29 、-S(O)2R 29 、-S(O)2N(R 29 )R 30 、-N(R 29 )R 30 、-N(R 29 )N(R 29 )R 30 、-N(R 29 )C(O)R 30 、-N(R 29 )S(O)2R 30 , optionally 1, 2, 3, 4 or 5 selected from R 23 A hydrocarbon group substituted with a group, optionally substituted with 1, 2, 3, 4 or 5 groups selected from R 28 and optionally 1, 2, 3, 4 or 5 independently selected R 28 -(CH2) substituted by a group k - heterocyclyl, wherein k is an integer from 1 to 6 (eg, 1, 2 or 3);

[0251] R 28 independently selected from halogen, trichloromethyl, trifluoromethyl, cyano, nitro, oxo, =NR 29 、-OR 29 、-C(O)R 30 、-C(O)N(R 29 )R 30 、-C(O)OR 29 、-OC(O)R 29 、-S(O)2R 29 、-S(O)2N(R 29 )R 30 、-N(R 29 )R 30 、-N(R 29 )N(R 29 )R 30 、-N(R 29 )C(O)R 30 and -N(R29 )S(O)2R 30 ;

[0252] R 29 and R 30 are each independently hydrogen, or selected from hydrocarbon groups and heterocyclic groups, any of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy group substitution;

[0253] R 31 are independently selected from hydrogen, halogen, trichloromethyl, trifluoromethyl, cyano, nitro, -OR 29 、-C(O)R 30 、-C(O)N(R 29 )R 30 、-C(O)OR 29 、-OC(O)R 29 、-S(O)2R 29 、-S(O)2N(R 29 )R 30 、-N(R 29 )R 30 、-N(R 29 )N(R 29 )R 30 、-N(R 29 )C(O)R 30 、-N(R 29 )S(O)2R 30 , monosaccharides, substituted monosaccharides, disaccharides, substituted disaccharides, trisaccharides, substituted trisaccharides, tetrasaccharides, substituted tetrasaccharides, optionally substituted by 1, 2, 3, 4 or 5 selected from R 28 A hydrocarbon group substituted with a group, and optionally substituted with 1, 2, 3, 4 or 5 groups selected from R 28 A heterocyclic group substituted with a group; and

[0254] R is hydrogen, or is selected from hydrocarbon and heterocyclic groups, any of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy groups are substituted.

[0255] In certain embodiments, the glycosidic group may be a carbohydrate group, such as a monosaccharide, disaccharide, trisaccharide, tetrasaccharide or polysaccharide group, and may exist in any isomeric form (e.g., α-D, α-L, β-D or β-L form). The carbohydrate group may optionally be substituted with other types of substituents or even additional glycosidic groups. However, the total number of monosaccharides and substituted monosaccharides contained in the chemical structure of the compound is typically 30 or less.

[0256] In certain embodiments, the glycosidic group may comprise one or more monosaccharide units of formula (V) or (VI):

[0257]

[0258] Where R 19 and R 20 together to form an oxo group; or in R 19 and R 20 When one of them is hydrogen or halogen, R 19 and R 20 The other one is selected from R 27 、-OR 27 、-C(O)R 27 、-C(O)OR 27 , monosaccharides, substituted monosaccharides, disaccharides, substituted disaccharides, trisaccharides, substituted trisaccharides, tetrasaccharides, and substituted tetrasaccharides;

[0259] R 21 and R 22 together to form an oxo group; or in R 21 and R 22 When one of them is hydrogen or halogen, R 21 and R 22 The other one is selected from R 27 、-OR 27 、-C(O)R 27 、-C(O)OR 27 , monosaccharides, substituted monosaccharides, disaccharides, substituted disaccharides, trisaccharides, substituted trisaccharides, tetrasaccharides and substituted tetrasaccharides; or R in formula (V) 20 and R 22 Together with the carbon atom to which they are attached, they form a 28 A 5-6 membered heterocyclic group substituted with a group;

[0260] R 23 and R 24 together to form an oxo group; or in R 23 and R 24 When one of them is hydrogen or halogen, R 23 and R 24 The other one is selected from R 27 、-OR 27 、-C(O)R 27 、-C(O)OR 27 , monosaccharides, substituted monosaccharides, disaccharides, substituted disaccharides, trisaccharides, substituted trisaccharides, tetrasaccharides and substituted tetrasaccharides; or R in formula (V) 22 and R 24Together with the carbon atom to which they are attached, they form a 28 A 5-6 membered heterocyclic group substituted with a group;

[0261] R 25 and R 26 together to form an oxo group; or in R 25 and R 26 When one of them is hydrogen or halogen, R 25 and R 26 The other one is selected from R 27 、-OR 27 、-C(O)R 27 、-C(O)OR 27 、-CH2R 31 and -C(O)R 31 ; or R in formula (V) 24 and R 26 Together with the carbon atom to which they are attached, they form a 28 A 5-6 membered heterocyclic group substituted with a group;

[0262] R 27 are independently selected from hydrogen, halogen, trichloromethyl, trifluoromethyl, cyano, nitro, -OR 29 、-C(O)R 30 、-C(O)N(R 29 )R 30 、-C(O)OR 29 、-OC(O)R 29 、-S(O)2R 29 、-S(O)2N(R 29 )R 30 、-N(R 29 )R 30 、-N(R 29 )N(R 29 )R 30 、-N(R 29 )C(O)R 30 、-N(R 29 )S(O)2R 30 , optionally 1, 2, 3, 4 or 5 independently selected from R 28 A hydrocarbon group substituted with a group, optionally substituted with 1, 2, 3, 4 or 5 independently selected from R 28 and optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from R 28 -(CH2) substituted by k - heterocyclyl, wherein k is an integer from 1 to 6 (eg, 1, 2 or 3);

[0263] R 28 independently selected from halogen, trichloromethyl, trifluoromethyl, cyano, nitro, oxo, =NR 29 、-OR 29 、-C(O)R 30 、-C(O)N(R 29 )R 30 、-C(O)OR 29 、-OC(O)R 29 、-S(O)2R 29 、-S(O)2N(R 29 )R 30 、-N(R 29 )R 30 、-N(R 29 )N(R 29 )R 30 、-N(R 29 )C(O)R 30 and -N(R 29 )S(O)2R 30 ;

[0264] R 29 and R 30 are each independently hydrogen, or selected from hydrocarbon groups and heterocyclic groups, any of which is optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from halogen, cyano, amino, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy group substituted; and

[0265] R 31 are independently selected from hydrogen, halogen, trichloromethyl, trifluoromethyl, cyano, nitro, -OR 29 、-C(O)R 30 、-C(O)N(R 29 )R 30 、-C(O)OR 29 、-OC(O)R 29 、-S(O)2R 29 、-S(O)2N(R 29 )R 30 、-N(R 29 )R 30 、-N(R 29 )N(R 29 )R 30 、-N(R 29 )C(O)R 30 、-N(R 29 )S(O)2R 30, monosaccharides, substituted monosaccharides, disaccharides, substituted disaccharides, trisaccharides, substituted trisaccharides, tetrasaccharides, substituted tetrasaccharides, optionally substituted by 1, 2, 3, 4 or 5 independently selected from R 28 A hydrocarbon group substituted with a group, optionally substituted with 1, 2, 3, 4 or 5 independently selected from R 28 and optionally substituted by 1, 2, 3, 4 or 5 groups independently selected from R 28 -(CH2) substituted by k -heterocyclyl, wherein k is an integer from 1 to 6 (eg, 1, 2 or 3).

[0266] In certain embodiments, the glycosidic group comprises 1, 2, 3, or 4 monosaccharide units, wherein each monosaccharide unit in the glycosidic group is independently a monosaccharide unit of formula (V) or formula (VI) at each occurrence.

[0267] In certain embodiments, R 1 , R 4 , R 5 , R 8 and R 9 are each independently hydrogen, hydroxy or methoxy; R 2 and R 3 Each is independently hydrogen, hydroxyl, methoxy, or together with the carbon atom to which they are attached, forms a [1,3]dioxole cyclic group; R 6 and R 7 are independently hydrogen, hydroxyl, methoxy; or R 6 and R 7 Together with the carbon atoms to which they are attached, they form a [1,3]dioxole ring group; R 10 and R 11 Together they form an oxo group; R 12 and R 13 are each independently hydrogen; and X is oxygen.

[0268] Exemplary glycoside groups include glucopyranoside, galactopyranoside, mannopyranoside, fucopyranoside, arabinopyranoside, glucopyranoside, galactopyranoside, glucuronide, lactopyranoside, xylopyranoside, aminoglucoside, aminogalactoside, alloside, lyxoside, taloside, threoside, riboside, fructoside, rhamnoside, and guloside groups. More particularly, the glycoside group may be selected from α-D-glucopyranoside, α-D-galactopyranoside, α-D-mannopyranoside, α-L-fucopyranoside, α-L-arabinopyranoside, β-D-glucopyranoside, β-D-galactopyranoside, β-D-glucuronide, β-D-lactopyranoside, β-D-xylopyranoside, β-D-glucosaminide, β-D-galactosaminide, β-D-alloside, β-D-lyxoside, β-D-taloside, β-D-threoside, β-D-riboside, β-D-fructoside, β-D-rhamnoside and β-L-glucoside groups.

[0269] Examples of compounds of the present disclosure include those shown below. Of course, it should be understood that each compound may be in the form of a free compound, an acid or base addition salt, or a prodrug, where appropriate.

[0270] The present disclosure also provides a pharmaceutical composition comprising at least one compound described herein and at least one pharmaceutically acceptable excipient.

[0271] According to standard pharmaceutical practice, the compounds described herein and their pharmaceutically acceptable salts can be administered to a subject alone or in combination with a pharmaceutically acceptable excipient, carrier and / or diluent as a pharmaceutical composition. The compound can be administered orally or parenterally. Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous and topical, with preferred methods being intravenous and topical administration.

[0272] Thus, the present disclosure provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more compounds described herein, formulated with one or more pharmaceutically acceptable excipients, carriers (additives) and / or diluents. The pharmaceutical compositions of the present disclosure can be particularly formulated for administration in solid or liquid form, including those suitable for: (1) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous or epidural injection, such as, for example, sterile solutions or suspensions, or sustained release formulations; and (2) oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., for buccal, sublingual and systemic absorption), boluses, powders, granules, pastes for application to the tongue.

[0273] As stated herein, some embodiments of the compounds described herein may contain basic functional groups, such as amino groups, and therefore can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. In this regard, the term "pharmaceutically acceptable salts" refers to relatively nontoxic inorganic and organic acid addition salts of compounds disclosed herein. These salts can be prepared in situ in the administration vehicle or dosage form manufacturing process, or by reacting the purified compounds of the present invention in the form of its free alkali with suitable organic or inorganic acids individually, and separating the salts thus formed during subsequent purification to prepare. Representative salts include hydrobromate, hydrochloride, sulfate, bisulfate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate and lauryl sulfonate etc.

[0274] Pharmaceutically acceptable salts of compounds of the present disclosure include conventional non-toxic salts or quaternary ammonium salts of the compounds, such as from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothiocarboxylic acid, etc.

[0275] In other cases, the compounds described herein may contain one or more acidic functional groups, and thus can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salts" refers to relatively nontoxic inorganic and organic base addition salts of the compounds disclosed herein. These salts can also be prepared in situ during the preparation of administration vehicles or dosage forms, or by reacting purified compounds in their free acid form with suitable bases (such as pharmaceutically acceptable metal cation hydroxides, carbonates or bicarbonates), with ammonia, or with pharmaceutically acceptable organic primary amines, secondary amines or tertiary amines separately to prepare. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts, etc. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc.

[0276] Wetting agents, emulsifiers and lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives, solubilizers, buffers and antioxidants can also be present in the compositions.

[0277] The method for preparing these preparations or compounds includes the step of combining the compounds described herein with carriers or excipients and optionally one or more auxiliary components. Typically, the compounds disclosed herein are combined uniformly and closely with liquid carriers (liquid preparations), liquid carriers followed by freeze drying (for powder preparations reconstituted with sterile water, etc.), or fine-grained solid carriers, or both, and then the product is shaped or packaged as needed to prepare the preparation.

[0278] Pharmaceutical compositions of the present disclosure suitable for parenteral administration comprise one or more compounds described herein in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, chelating agents, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0279] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Appropriate fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0280] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. Various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc., may be included to ensure that microorganisms are prevented from acting on the compounds of the present disclosure. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc., in the compositions. In addition, extended absorption of injectable pharmaceutical forms may be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0281] The present disclosure provides analogs of sargentin and patentiflorin A having anti-HIV and anti-influenza virus activities and their synthesis. The compounds of the present disclosure were synthesized and their anti-HIV and anti-influenza virus activities were evaluated.

[0282] Examples of synthetic or semi-synthetic analogs of schizofiarin include 12a, 12b, 13, 14a, 14b, 15a, 15b, 16, 17a, 17b, 17c, 17d, 17e, 17f, 17g, 17h, 18, 19a, 19b, 19c, 19d, 19e, 19f, 19g, 19h, 19i, 19j, 19k, 19l, 19m, 19n, 19o, 19p, 20, 21, 22, 23 and 24.

[0283] Examples of synthetic or semisynthetic analogs of Patentiflorin A include 25a, 25b, 25c, 25d, 25e, 25f, 25g, 26a, 26b, 26c, 26d, 26e, 26f, 26g, 27aa, 27ab, 27ac, 27ad, 27ae, 27af, 27ba, 27bb, 27bc, 27bd, 27be, 27bf, 28ab1, 28ab2, 28ab3, 28bb1, 28bb2, 28bb3, 29a, 29b, 30a, 30b, 30c, 30d, 30e, 30f, 30g, 30h, 30i, 30j, 30k, 30l, 31a, 31b, 31c, 31d, 31e, 31f, 31g, 31h, 31i, 31j, 31k, 31l, 32a, 32b, 32c and 32d.

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291] Example

[0292] The following examples are set forth below to illustrate methods and results according to the disclosed subject matter. These examples are not intended to include all aspects of the subject matter disclosed herein, but rather to illustrate representative methods, compositions and results. These examples are not intended to exclude equivalents and variations of the present invention, which are apparent to those skilled in the art.

[0293] Unless otherwise indicated, parts are by weight, temperature is ° C. or is ambient temperature, and pressure is at or near atmospheric pressure. There are many variations and combinations of reaction conditions, such as component concentrations, temperature, pressure, and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained by the described process. Only reasonable and routine experimentation is required to optimize such process conditions.

[0294] Examples of compounds of the present disclosure include those shown below. Of course, it should be understood that each compound may be in the form of a free compound, an acid or base addition salt, or a prodrug, where appropriate.

[0295] By using sargassum (5) as the structural skeleton, the general synthetic route of its CO derivatization at C-7 is shown in Figure 2 Esters 12a and 12b were prepared from 5 by substitution reactions. Acidic hydrolysis of ester 12a provided acid 13, which was converted to amides 14a and 14b by coupling with ammonium chloride (NH4Cl) or amines in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) or 1-hydroxybenzotriazole hydrate (HOBt). O-Alkoxy alcohols 15a and 15b were obtained by reaction of 5 with the corresponding epoxides, namely ethylene oxide and methyl oxirane, respectively. Derivatives 17a-17h were prepared from 5 in one step, respectively. Alkylation of 5 with cesium carbonate (Cs2CO3) followed by bromoacetonitrile, methyl iodide or propargyl bromide gave derivatives 17a-17c, respectively. Potassium carbonate (K2CO3) and 2-chloropyrimidine were added to dimethylformamide (DMF) containing 5 at 100°C to provide compound 17d. Similarly, trimethylamine (Me3N), 4-dimethylaminopyridine (DMAP) and the corresponding acid chloride were added to 5 to give 17e-17h, respectively. Synthesis of C-7 alkyl derivatives ( Figure 3 ) It is envisaged that 5 would be converted to the corresponding triflate 18, which would undergo a palladium-catalyzed coupling reaction to afford derivatives 19a-19p and 20-24.

[0296] preparation Figure 4 The ANL analogs and compounds 25a-25g and 26a-26g containing different sugar units are summarized and further modified to provide Figure 5 Additional ANL analogs 27aa-27bf, 28ab1-28bb3, 29a, 29b, 30a-301, and 31a-301 are outlined.

[0297] A series of schizoflavone glycosides (26a-26g) were synthesized by glycosylation of schizoflavone (5) with different sugar units (ag) at C-7. Figure 4 ). The synthesis involves the production of brominated sugars by bromination of peracetylated glycosides followed by phase transfer catalysis (PTC) glycosylation with 0.1 mol / L aqueous sodium hydroxide (NaOH) in the presence of tetrabutylammonium bromide (TBAB) at 40°C. The resulting peracetylated glycosides 25a-25g are then deacetylated with K2CO3 in methanol (MeOH) to afford deprotected glycosides 26a-26g, respectively.

[0298] In order to significantly increase the number of ANL library compounds, further structural modifications of the hydroxyl groups in the sugar units of ANL are recommended ( Figure 5 ). First, 3″-O-acetyl oxadiazole glycosides 27aa-27af and 27ba-27bf were prepared by the reaction of acetic anhydride (Ac2O) and tetrabutylammonium acetate (TBOAc) with the corresponding 26a and 26b. The reaction mixture of 26a was separated by silica gel column chromatography to obtain six single compounds 27aa-27af (27aa, 27ab, 27ac, 27ad, 27ae and 27af). The reaction mixture of 26b was separated by silica gel column chromatography. The reaction mixture of 27ab was separated by silica gel column chromatography to obtain three single compounds 28ab1-28ab3 (28ab1, 28ab2 and 28ab3). The reaction mixture of 27bb was separated by silica gel column chromatography to obtain three single compounds 28bb1-28ab3 (28bb1, 28bb2 and 28bb3). The acetyl group in compound 28ab3 or 28bb3 was removed by further treatment with acetyl chloride (AcCl) to give bischloroformate protected ANL glycosides 29a and 29b, respectively. The reaction mixture of 27ab was separated by silica gel column chromatography to obtain three single compounds 28ab1-28ab3 (28ab1, 28ab2 and 28bb3). The acetyl group in compound 28ab3 or 28bb3 was removed by further treatment with acetyl chloride (AcCl) to give bischloroformate protected ANL glycosides 29a and 29b, respectively. The reaction mixture of 27ab was separated by silica gel column chromatography to obtain three single compounds 28ab1-28ab3 (28ab1, 28bb2 and 28bb3). Different acyl chlorides replace 29a or 29b to give derivatives 30a-k, respectively. Potassium hydroxide (KOH), 18-crown-6 and benzyl bromide are added to tetrahydrofuran (THF) containing 29a at room temperature to provide compound 301. The two allyl groups of 30a-1 are deprotected by treatment with tetrakis(triphenylphosphine)palladium(0)[Pd(PPh3)4], triphenylphosphine (PPh3), Et3N and HCOOH in THF to produce derivatives 31a-1, respectively.

[0299] The compounds described herein can exhibit a wide range of antiviral properties. According to the method disclosed herein, the compound of formula (I) is administered to a patient to inhibit the replication of a virus (such as HIV, coronavirus, Ebola virus, Marburg virus or influenza virus) or to reduce the cytopathic effect of the virus. Other viruses that can be inhibited by the compound of formula (I) include, but are not limited to, cytomegalovirus (CMV), HSV-1 (herpes simplex virus type 1), HSV-2 (herpes simplex virus type 2), HBV (hepatitis B virus), HCV (hepatitis C virus), HPV (human papillomavirus), influenza A, influenza B, RSV (respiratory syncytial virus), RV (rhinovirus), AV (adenovirus), PIV (human parainfluenza virus), Epstein-Barr virus (EBV), varicella zoster virus (VZV), dengue virus and Zika virus.

[0300] The compounds, pharmaceutical compositions and methods of treatment described herein can be used to prevent or treat or ameliorate HIV infection.

[0301] The compounds, pharmaceutical compositions and treatment methods described herein can be used to prevent, treat, or ameliorate infection caused by influenza viruses, including but not limited to: any subtype of influenza A, influenza B, or influenza C.

[0302] In certain embodiments, the compounds, pharmaceutical compositions, and methods of treatment disclosed herein can be used to prevent, treat, or ameliorate infection caused by influenza A viruses, including but not limited to strains H1N1, H1N2, H1N3, H1N4, H1N5, HIN6, H1N7, HIN8, H1N9, H2N1, H2N2, H2N3, H2N4, H2N5, H2N6, H2N7, H2N8, H2N9, H3N1, H3N2, H3N3, H3N4, H3N5, H3N6, H3N7, H3N8, H3N9, H4N1, H5N2, H5N3, H5N4, H5N5, H5N6, H5N7, H5N8, H5N9, H6N1, H6N2, H6N3, H6N4, H6N5, H6N6, H6N7, H6N8 , H6N9, H7N1, H7N2, H7N3, H7N4, H7N5, H7N6, H7N7, H7N8, H7N9, H8N1, H8N2, H8N3, H8N4, H8N5, H8N6, H8N7, H8N8, H8N 9. H9N1, H9N2, H9N3, H9N4, H9N5, H9N6, H9N7, H9N8, H9N9, H10N1, H10N2, H10N3, H10N4, H10N5, H10N6, H10N7, H10N 8. H10N9, H11N1, H11N2, H11N3, H11N4, H11N5, H11N6, H11N7, HI1N8, H11N9, H12N1, H12N2, H12N3, H12N4, H12N5, H1 Any of H12N6, H12N7, H12N8, H12N9, H13N1, H13N2, H13N3, H13N4, H13N5, H13N6, H13N7, H13N8, H13N9, H14N1, H14N2, H14N3, H14N4, H14N5, H14N6, H14N7, H14N8, H14N9, H15N1, H15N2, H15N3, H15N4, H15N5, H15N6, H1N7, H15N8 and H15N9.

[0303] In certain embodiments, the compounds, pharmaceutical compositions, and methods of treatment disclosed herein can be used to prevent, treat, or ameliorate infection caused by an influenza A virus strain having a type 5 hemagglutinin protein. In certain embodiments, the influenza A virus strain has a type 5 hemagglutinin protein and a neuraminidase protein selected from types 1 to 11. In certain embodiments, the influenza A virus is selected from H5N1 and H5N2.

[0304] In certain embodiments, the compounds, pharmaceutical compositions, and methods of treatment disclosed herein can be used to prevent, treat, or ameliorate infection caused by H5N1.

[0305] As used herein, the term "HIV" refers to human immunodeficiency virus, and includes HIV-1, HIV-2 and SIV. In certain embodiments, HIV refers to HIV-1 and / or HIV-2. "HIV-1" means human immunodeficiency virus type 1. HIV-1 may include, but is not limited to, extracellular viral particles and HIV-1 forms associated with cells infected by HIV-1. HIV-1 viruses may include any known major subtypes (A, B, C, D, E, F, G and H classes) or remote subtypes (O group), including laboratory strains and primary isolates. "HIV-2" means human immunodeficiency virus type 2. HIV-2 may include, but is not limited to, extracellular viral particles and HIV-2 forms associated with cells infected by HIV-2. The term "SIV" refers to simian immunodeficiency virus, which is an HIV-like virus that infects monkeys, chimpanzees and other non-human primates. SIV may include, but is not limited to, extracellular viral particles and SIV forms associated with cells infected by SIV.

[0306] In certain embodiments, the compounds, pharmaceutical compositions and methods of treatment disclosed herein can be used to prevent, treat, or ameliorate infections caused by HIV-1 and / or HIV-2. In certain embodiments, the compounds, pharmaceutical compositions and methods of treatment disclosed herein can be used to prevent, treat, or ameliorate infections caused by HIV-1 subtype B.

[0307] In certain embodiments, the compounds, pharmaceutical compositions, and therapeutic methods disclosed herein can be used to prevent, treat, or ameliorate infection caused by SIV.

[0308] The compounds, pharmaceutical compositions and methods of treatment described herein can be used to prevent, treat, or ameliorate infections caused by filoviruses including, but not limited to, Marburg virus, Zaire ebolavirus, Sudan ebolavirus, Ivory Coast ebolavirus, Reston ebolavirus, and Bundibugyo ebolavirus.

[0309] The compounds, pharmaceutical compositions, and treatment methods described herein can be used to prevent, treat, or ameliorate infections caused by coronaviruses (including but not limited to SARS-CoV-2, SARS-CoV, and MERS-CoV).

[0310] Antiviral evaluation using a "kill two birds with one stone" pseudotype assay.

[0311] Generation of HIV pseudovirions. This protocol was designed to identify potential inhibitors of HIV, coronavirus, Ebola, Marburg, and influenza virus replication (post entry step). HIV / VSVG or HIV / SARSP or HIV / HA or HIV / EBOV or HIV / MARV virions were produced by co-transfection of 0.5 μg VSVG (vesicular stomatitis virus glycoprotein) envelope expression plasmid, 0.5 μg SARSP (SARS-CoV-2 spike protein) expression plasmid or 0.5 μg hemagglutinin (HA) envelope expression plasmid with 0.5 μg neuraminidase (NA) expression plasmid or 0.5 μg EBVG (Ebola virus glycoprotein) envelope expression plasmid or 0.5 μg MAVG (Marburg virus glycoprotein) envelope expression plasmid and 2 μg replication-defective HIV vector (pNL4-3.Luc.RE) via PEI (polyethyleneimine) (Invitrogen, Carlsbad, CA, USA) into human embryonic kidney 293T cells (90% confluence) in six-well plates, respectively, as described previously for the modified procedure. HIV vector pNL4-3.Luc.RE was obtained by AID research and reference reagent project (AIDS Research and Reference Reagent Program) (Division of AIDS, NIAID, NIH). Sixteen hours after transfection, all culture media were replaced with fresh DMEM complete medium. Eight hours after transfection, all culture media were replaced with fresh DMEM complete medium. Forty-eight hours after transfection, supernatant was collected and filtered through a 0.45-μm pore size filter (Millipore, Billerica, MA, USA), and pseudovirus was directly used for infection.

[0312] Anti-HIV and anti-H5N1 influenza virus evaluation assay. This protocol was used to identify potential inhibitors of HIV and influenza virus replication (entry step). In this system, HIV vector pNL4-3.Luc.RE was co-transfected with VSVG to generate HIV / VSVG virions (HIV virions with VSV glycoproteins on the virus surface), and the same HIV vector was co-transfected with H5N1 HA and NA constructs to generate HIV virions with avian influenza HA on the virus surface [HIV / HA (HIV virions with HA and NA glycoproteins on the virus surface)]. The pNL4-3 was derived from an infectious molecular clone of a T-tropic virus of SI (syncytium-inducing type), which is replication-defective because HIV is Env - and Vpr - In addition, the luciferase gene (luc) carried by the recombinant HIV vector serves as a reporter gene for HIV replication (reverse transcription, integration, and HIV gene expression). The infection level is measured as relative light units (RLU) in infected cells. The luciferase activity of 293T cells infected with the HIV vector pNL4-3.Luc.RE reached 10 5 -10 6 The range of RLU is approximately 100 times higher than the background level when measured using HIV virions without VSVG. The principle of evaluation is that the level of luciferase activity in the cells should be proportional to the level of viral entry and replication. If the sample may interfere with HIV replication and / or HA-mediated viral entry, the level of luciferase activity in the infected cells will decrease. Therefore, using this protocol, samples that can inhibit HIV or influenza virus replication can be identified. Test fractions or compounds are evaluated as follows. Target A549 human lung cells are plated at 0.5×10 5 10 cells (24-well plate) were seeded in DMEM complete medium. The lung cell line was used because it is sensitive to HA-mediated viral entry. First, stock HIV / VSVG or HIV / HA virions (approximately 2 × 10 6Relative light units or RLU) are mixed with each sample, and the mixture is incubated with A549 target cells for 24 hours. A series of concentrations of 10 microliters (e.g., 20, 10, 5, 2.5, 1.25, 0.625 and 0.3125 μg / mL) and 190 μL pseudovirus are incubated with target cells. Twenty-four (24) hours after infection, all culture media containing samples and viruses are removed from target cells and replaced with fresh and DMEM complete culture media. Forty-eight (48) hours after infection, target cells are lysed and luciferase activity is measured. Two different test results may occur: 1) Some samples can "inhibit replication" (Luc is lower for HA and VSVG) for both HIV / VSVG and HIV / HA virions, because some of these samples can be blocked during virus entry into target cells or after virus just enters target cells, or some of them only have cytotoxic activity to target cells. These samples are classified as anti-HIV. 2) Samples that specifically inhibit HIV / HA viral entry (Luc is lower for HIV / HA but not for HIV / VSVG) will be classified as anti-HA inhibitors (influenza virus inhibitors). 50 The value is the drug concentration that inhibits viral infectivity by 50%.

[0313] Anti-HIV, anti-Ebola and anti-Marburg virus evaluation assays. This protocol was modified from the aforementioned anti-H5N1 influenza virus evaluation assay and is designed to identify potential inhibitors of HIV, Ebola and Marburg virus replication (invasion step). In this system, the HIV vector pNL4-3.Luc.RE is co-transfected with VSVG to generate HIV / VSVG virions, and the same HIV vector is co-transfected with Ebola or Marburg glycoprotein (GP) constructs to generate HIV virions with Ebola or Marburg GP on the virus surface (HIV / EBVG or HIV / MAVG). The infection level is measured in relative light units (RLU) in infected cells. The luciferase activity of 293T cells infected with the HIV vector pNL4-3.Luc.RE reaches 10 5 -10 6 The range of RLU is approximately 100 times higher than the background level when measured using HIV virions without VSVG. The principle of evaluation is that the level of luciferase activity in the cells should be proportional to the level of viral entry and replication. If the compound may interfere with HIV replication and / or EBVG or MAVG-mediated viral entry, the level of luciferase activity in the infected cells will decrease. Therefore, using this protocol, compounds that can inhibit HIV, EBOV and MARV replication can be identified. Test compounds were evaluated as follows. Target A549 human lung cells were plated at 0.5×10 510 cells (24-well plate) were seeded into complete DMEM medium. The lung cell line was used because it is sensitive to EBVG- or MAVG-mediated viral entry. First, stock HIV / VSVG or HIV / EBVG or HIV / MAVG virions (approximately 2 × 10 on target cells) were plated. 6 Relative light units (RLU) were mixed with each sample, and the mixture was incubated with A549 target cells for 24 hours. Every sample of 10 microliters of different concentrations and 190 μL pseudovirus were incubated with target cells. Twenty-four (24) hours after infection, all culture media containing samples and viruses were removed from target cells, and replaced with fresh DMEM complete medium. Forty-eight (48) hours after infection, target cells were lysed and luciferase activity was measured.

[0314] Anti-SARS-CoV-2 evaluation assay. This protocol was modified from the previous anti-H5N1 influenza virus evaluation assay and was designed to identify potential inhibitors of SARS-CoV-2. In this assay, HIV vector pNL4-3.Luc.RE was co-transfected with a SARS-CoV-2 spike protein (SARSP) expression plasmid to generate SARS-CoV-2 pseudovirions (HIV / SARSP). Target Hep G2 hepatoma cells were plated at 4×10 3 Cells (96-well plates) were seeded into complete EMEM. A hepatocyte cell line was used because it is sensitive to SARS-CoV-2-mediated viral entry. Ten microliters of each sample at different concentrations and 190 μL HIV / SARSP were incubated with the target cells. Forty-eight (48) hours after infection, the target cells were lysed and luciferase activity was determined. Arbidol was used as a positive control in the experiment. IC values ​​of Arbidol against SARS-CoV-2 pseudovirions 50 The value was measured to be 5.23 μM, which is consistent with the value reported in the literature (4.11 μM).

[0315] Anti-HIV evaluation using HIV-1 clinical strains.

[0316] HIV-1 clinical strains such as BAL and SF162 (macrophage-tropic: M-tropic), BAL (T-cell lineage tropic: T-tropic) and 89.6 (dual tropic strain), HIV-1 LAV (wild type), NRTI (nucleoside reverse transcriptase inhibitor)-resistant isolates (HIV-1 1617-1 ) (AZT-resistant strains from the AIDS bank) and NNRTI (non-nucleoside reverse transcriptase inhibitor)-resistant isolates (HIV-1 N119) (nevirapine-resistant strains obtained from the AIDS bank) were used in this study. Standardized human peripheral blood mononuclear cell culture (PBMC) assays were used to determine the compound sensitivity of these HIV-1 strains. AZT (i.e., clinically used anti-HIV drugs) was used as a positive control. All data were generated from three independent experiments, each performed in triplicate. Fresh human PBMCs were used in each experiment before HIV-1 infection. Briefly, donor PBMCs were suspended in R-3 medium [RPMI 1640 medium, supplemented with 15-20% FBS (fetal bovine serum), 5% IL-2 (human interleukin-2), 250U penicillin / mL, 250μg streptomycin / mL and 2mM L-glutamine] and stimulated with PHA (phytohemagglutinin, 2-3μg / mL) for seven days. The preparation (sample) was added to the cultured cells, and the cultured cells in 96-well plates [1×10 per well] were attacked with different HIV-1 strains. 5 cells, with 1000 TCID 50 (50% tissue culture infectious dose of virus) of HIV strain]. After seven days of incubation, supernatants were collected and HIV p24 levels in infected cells were determined using p24 antigen ELISA. To measure IC 50 Values ​​were calculated using a range of concentrations (e.g., 5, 1, 0.2, 0.04, 0.008, 0.016, and 0 μg / mL) for each drug. IC values ​​were calculated by comparing the p24 antigen values ​​of the sample-containing wells with those of the control wells without drug. 50 For the p24 assay, the maximum cutoff should be approximately 120-150 pg / mL.

[0317] Antiviral evaluation using infectious influenza virus.

[0318] A panel of influenza viruses such as influenza H1N1 (A / HK / 415742 / 09), H3N2 (A / Hong Kong / 1 / 1968), H5N1 (A / Vietnam / 1203 / 2004H), H7N1 (A / Rhea / North Carolina / 39482 / 93), H7N7 (A / Netherlands / 219 / 2003), H7N9 (A / Anhui / 1 / 2013) and H9N2 (A / Chicken / Y280 / 97) were used in this study. The antiviral activity of the samples against influenza viruses in A549 cells was evaluated. Briefly, the preparations (samples) were added to the cultured cells and the cultured cells in 24-well plates (1×10 cells per well) were challenged with different influenza strains. 5After removing the unbound virus, the cells were incubated for 48 hours. The viral supernatant was collected and the viral titer was determined by standard plaque assay in MDCK (Madin-Darby dog ​​kidney) cells.

[0319] Cytotoxicity was evaluated using the SRB assay.

[0320] The cytotoxicity of samples to A549 cells was measured using the sulforhodamine B (SRB) assay (Vichai V, Kirtikara K. Nature protocols 2006; 1: 1112–1116). Briefly, 190 μL of A549 cells (2×10 4 Cells / mL) were inoculated into each well of a 96-well cell culture plate. After 24 hours, 10 μL of DMSO alone, 10 μL of 10% DMSO containing zidovudine (AZT, as a positive control), and 10 μL of 10% (v / v) DMSO containing each sample were added to the wells of a 96-well tissue culture plate. 10 μL of 10% (v / v) DMSO was added to each blank well of a 96-well tissue culture plate as a background calculation plate. After incubation at 37°C for 2 days, 50 μL of cold 50% (w / v) trichloroacetic acid (TCA) was added to each well of the plate and further incubated at 4°C for 1 hour. The plate was then washed four times with low-flow tap water and allowed to dry at room temperature (rt). 50 μL of 0.4% (w / v) SRB solution was added to each well. The plate was left to stand at room temperature for 5 to 10 minutes and quickly rinsed with 1% (v / v) acetic acid to remove unbound dye. The plates were allowed to dry at room temperature. 100 mL of 10 mM Tris base solution (pH 10.5) was added to each well, and the plates were shaken on a rotary shaker for at least 30 minutes to dissolve the protein-bound dye. OD values ​​were measured at 515 nm in a microplate reader. CC was calculated using GraphPad Prism version 5.0 (GraphPad Software, San Diego, CA). 50 (agent concentration causing 50% cytotoxicity) value.

[0321] Toxicity evaluation in mice.

[0322] Repeated dose toxicity study in mice was carried out on selected samples. Animal research has been approved and performed according to the Animal Care and Use Guidelines of the Animal Ethics Committee of Hong Kong Baptist University (Hong Kong Baptist University), and performed according to the Animal Care and Use Guidelines set by NIH (National Institute of Health, USA). BALB / c nude mice (SPF grade, male or female, 6-8 weeks old) were purchased from Charles River Laboratories. Before the experiment, mice were kept under SPF grade laboratory conditions to adapt to one week. Then, mice were divided into three groups: ANL compounds of two dosages (25 and 50mg / kg: 10 mice / each dosage group) groups and the vehicle of one dosage (negative control: 10 mice). Within 28 days, it was scheduled to be injected at the ip site every day. The body weight of mice was measured twice a week until the end of the experiment. In addition, the skin condition, food intake, water consumption and posture of mice were checked. All mice were sacrificed at the end of the experiment to examine essential organs such as liver, heart, kidney, lung, and spleen.

[0323] Table 1: Anti-HIV activity of ANL. a

[0324]

[0325]

[0326] a The results are expressed as CC 50 (the concentration that causes 50% inhibition of cell growth in host A549 cells) and EC 50 (Effective concentration of compound that inhibits viral growth by 50%) values ​​(in nM), and data were obtained from triplicate experiments. SI = CC 50 / EC 50 .

[0327] b NE: CC tested in host A549 cells 50 No effect.

[0328] c Positive control compound.

[0329] Table 2: Anti-H5N1 virus activity of ANL. a

[0330]

[0331]

[0332] a Results are from three triplicate experiments.

[0333] b Positive control compound.

[0334] Table 3: Inhibitory effects of selected ANLs against H5N1 virus, EBOV, VSV and A549 cells. a

[0335]

[0336]

[0337] a Results are from three triplicate experiments.

[0338] b Positive control compound.

[0339] Compound 26b (patentiflorin A) was identified as an anti-HIV lead compound from the methanol extracts of J. cf. patentiflora (roots and stems) and J. procumbens (aerial parts), and compound 5 (homophyllin) was isolated as a pure compound from the methanol extract of J. procumbens (aerial parts). Compound 5 was also obtained as an intermediate through the total synthesis of 26b in our previous study. In our current "killing two birds with one stone" evaluation system, compounds 26b and 5 showed anti-HIV activity, and the EC values ​​were determined to be respectively 50 The values ​​were 21.1 and 37.1 nM, and the SI were 16.4 and 97.3, respectively. In order to improve their antiviral activity and reduce their cytotoxicity, we synthesized many analogs of these two compounds. We designed a synthetic route to replace the hydroxyl group of 5 with different functional groups to prepare compounds 12-24 ( Figure 2 We further designed synthetic routes to replace the 6-deoxymethylglucose unit of 26b with different sugar units, or selectively replace one, two, three or four hydroxyl groups on the sugar moiety of 26a-g to prepare compounds 25-32 ( Figure 4-6). The antiviral activity of these compounds was evaluated using a "killing two birds with one stone" system. As shown in the results of Table 1, in terms of SI values, compounds 17a, 17b, 17c, 19a, 19d, 22, 25a, 26d, 27bb, 31c and 31i exhibited much improved anti-HIV activity than patentiflorin A (26b) and schizophrenia repens (5). It was observed that in some cases, the stereochemistry of the sugar unit was observed to be essential for the biological activity in these synthetic schizophrenia repens glycosides. Compared with 26e, 26d had much higher anti-HIV activity (26d, EC 50 =42.3nM, and SI>426.1; 26e, no virus inhibitory activity at a concentration of 9496.9nM). The higher anti-HIV activity and selectivity of 26d are due to the replacement of D-(+)-fucose in 26e by L-(-)-fucose in 26d. Compounds 12b, 17a, 19a and 21 were selected for further evaluation against a broad spectrum of HIV-1 clinical and resistant strains. Compound 12b showed inhibitory effects against SF162, 89.6, Bal, Lav.04, 1617-1 and N119, IC 50 The values ​​were 340, 376, 458, 312, 537 and 638 nM (CC for PBMC) 50 Compound 17a showed inhibitory effects against SF162, 89.6, Bal, Lav.04, 1617-1 and N119, IC 50 The values ​​were 122, 134, 168, 151, 174 and 203 nM (CC for PBMC) 50 Compound 19a showed inhibitory effects against SF162, 89.6, Bal, Lav.04, 1617-1 and N119, IC 50 The values ​​were 154, 143, 188, 138, 152 and 185 nM (CC for PBMC) 50 Compound 21 showed inhibitory effects against SF162, 89.6, Bal, Lav.04, 1617-1 and N119, IC 50 The values ​​were 23.9, 28.7, 26.5, 30.1, 39.3 and 42.1 nM (CC for PBMC) 50The value is 25.6 μM). Compounds 19p, 26f, 28ab1, 31a, 31e, 31g, 31j, 311, 32b, 32c and 32d were selected to test their inhibitory effects against H5N1 virus, EBOV (Ebola virus) and VSV (vesicular stomatitis virus) at several concentrations, and compared with their inhibitory effects against A549 host cells (Table 3). Compounds 28ab1, 31e, 31g, 311, 31j and 32b showed an inhibitory effect of more than 77% against three viruses (H5N1 virus, EBOV and VSV) at a concentration below 12.5 ng / mL. Therefore, the antiviral activity of compound series 26-32 against H5N1 virus, EBOV and VSV was further tested. Compounds 26b, 26f, 26g, 28ab1, 28ab2, 28ab3, 29a, 30a, 31e, 31j, 31l, 32a, 32b, 32c, 32d and AZT (positive control) showed inhibitory effects against H5N1 virus, EC 50 The values ​​were 4.48, 371.3, 63.6, 5.05, 0.23, 1.16, 5.57, 3.88, 0.74, 0.84, 0.013, 0.63, 0.77, 5.20, 199.8 and 3.48 nM, respectively. Compounds 26b, 26f, 26g, 28ab1, 28ab2, 28ab3, 29a, 30a, 31e, 31j, 31l, 32a, 32b, 32c, 32d, AZT (positive control) and toremifene (positive control) showed inhibitory effects against EBOV, EC 50 The values ​​were 54.8, 515.6, 123.0, 18.9, 16.3, 0.98, 10.6, 1.84, 1.13, 0.84, 0.19, 1.20, 0.85, 20.3, 395.7, 3.80 and 212.1 nM, respectively. Compounds 26b, 26f, 26g, 28ab1, 28ab2, 28ab3, 29a, 30a, 31e, 31j, 311, 32a, 32b, 32c, 32d and AZT (positive control) showed inhibitory effects against VSV, with EC 50 The values ​​were 42.5, 1035, 210.1, 3.78, 4.98, 0.85, 10.6, 8.60, 2.41, 0.91, 0.37, 18.1, 3.15, 123.9, 286.1 and 7.06 nM, respectively. Compounds 5, 26b, 26e, 28ab1, 31j, 32a, 32b, 32c, 32d and Abidol (positive control) showed inhibitory effects against SARS-CoV-2, EC 50The values ​​were 150.1, 67.2, 30.4, 26.3, 10.3, 2.95, 3.01, 50.8, 80.4 and 4.110 nM, respectively. Compounds 26b, 26f, 26g, 28ab1, 28ab2, 28ab3, 29a, 30a, 31e, 31j, 311, 32a, 32b, 32c and 32d and paclitaxel (positive control) showed inhibitory effects against the host cell line A549, CC 50 The values ​​were 386.1, 8649, 4129, 190.0, 108.2, 6.14, 121.6, 35.2, 17.7, 6.68, 4.85, 61.6, 30.7, 1038, 1349 and 2.99 nM, respectively. Compared with the vehicle control group, the toxicity of compounds 17a and 25a in mice was further evaluated, and the compounds were each measured at two doses of 25 and 50 mg / kg. At the end of the animal study, no toxic symptoms (weight loss, skin damage, food and water intake disorders and abnormal posture) and mortality were observed in the mice of all groups. The excised organs of all mice all looked normal at the end of the experiment.

[0340] Materials and methods

[0341] General Experimental Procedure

[0342] 1D and 2D NMR spectra were recorded on a Bruker DRX-400 MHz spectrometer (Rheinstetten, Germany). Chemical shifts (δ) are expressed in ppm, and coupling constants (J) are reported in Hz. All NMR experiments were obtained using standard pulse sequences supplied by the supplier. Chemical shifts (δ) are expressed in ppm relative to the solvent signal (CD3OD: 1 H: 3.31ppm, 13 C: 49.00ppm; CDCl3: 1 H: 7.27ppm, 13 C: 77.23ppm; DMSO-d6: 1 H: 2.50ppm, 13 C: 39.51ppm; Acetone-d6: 1 H: 2.05ppm, 13C: 29.92, 206.68 ppm), and coupling constants (J) are reported in Hz. Column chromatography was performed on silica gel (230-400 mesh, Natland International Corporation, Research Triangle Park, NC, USA). Thin layer chromatography (TLC) was performed on EMD glass backing coated with a 0.25 mm layer of silica gel 60 F254 (Kassel, Germany). HRTOFMS spectra were recorded on Micromass QTOF-2 (Milford, MA, USA), Agilent 6540Q-TOF (Santa Clara, CA, USA), Agilent 6460Triple Quadrupole, or Bruker Q-TOF mass spectrometers (Bremen, Germany). All reagents were purchased from commercial sources and used without further purification.

[0343] Compound 5

[0344] Ethylene glycol (14mL, 250mmol) and p-toluenesulfonic acid (TsOH) (5.2g, 25mmol) are added to a suspension of crude 2-bromo-4,5-dimethoxybenzaldehyde (30g, 125mmol) in toluene (1L). The Dean-Stark device filled with toluene (PhMe) is assembled on a round-bottomed flask, and the reaction is refluxed overnight. After cooling to room temperature (rt), toluene is removed under reduced pressure. Then, the crude mixture is dissolved in ethyl acetate (EtOAc), and with sodium bicarbonate (NaHCO3) aqueous solution, water, then washed with brine, dried with anhydrous sodium sulfate (Na2SO4), and concentrated under reduced pressure. The mixture is separated on silica gel flash chromatography (deactivated silica gel, n-hexane containing 16%-25% EtOAc), 2-(2-bromo-4,5-dimethoxyphenyl)-1,3-dioxolane (2) (33.5g, 95%) is obtained as an off-white solid. After cooling to -78°C, to a stirred solution of acetal (2) (30 g, 104 mmol) in 1 L of tetrahydrofuran (THF), n-butyl lithium (n-BuLi) (1.8 M, 69.3 mL, 124.8 mmol) was added dropwise over an additional 30 minutes, the reaction mixture was stirred at -50°C for an additional 30 minutes, and then piperonal (114.4 mmol) was added. The mixture was stirred at -78°C for 0.5 hours, and then the reaction was allowed to warm to room temperature for an additional 2 hours. The reaction was then quenched with water, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, then with brine, dried over Na2SO4 and concentrated under reduced pressure to give a light yellow syrup (3), which was immediately subjected to a Diels-Alder reaction. Acetic acid (AcOH) (35 mL) and dimethyl acetylene dicarboxylate (DMADC) (16.7 mL, 104 mmol) were added to a solution of the crude intermediate in dichloromethane (CH2Cl2) (100 mL). The reaction was stirred at 140 ° C for 12 hours. After cooling to room temperature, the reaction was diluted with water and the aqueous layer was extracted with CH2Cl2. The combined organic layer was washed, dried and filtered through a silica plug to remove most of the impurities. The resulting red viscous oil was purified by recrystallization in ethanol (EtOH). The crude diester (4a, 5mmol) was dissolved in THF (70mL) and sodium borohydride (NaBH4) (0.945g, 25mmol) was added dropwise, and the reaction was stirred at 80 ° C for 12 hours. The reaction was then cooled back to room temperature. The resulting slurry was acidified to a pH of approximately 2 with dilute HCl (2M). After acidification, the aqueous layer was extracted with EtOAc, and the combined organic layer was washed with water, then with brine, dried with Na2SO4 and concentrated. The resulting red viscous oil was purified by silica gel column chromatography to obtain the target compound 5: HR-EIMS m / z[M+H] +381.0974 (calculated value 381.0912); 1 H NMR (400MHz, acetone-d6) δ7.69(1H,s,H-2),7.09(1H,s,H-5),6.96(1H,d,J=7.9Hz,H -5'),6.85(1H,d,J=1.6Hz,H-2'),6.91(1H,dd,J=7.9,1.7Hz,H-6'),6.09(1H,br s,OCH2O),6.07(1H,br s,OCH2O),5.37(2H,s,H-9),3.99(3H,s,3-OCH3),3.73(3H,s,4-OCH3).

[0345] Compound 12a

[0346] Cs2CO3 (326 mg, 1 mmol) was added to a DMF (5 mL) solution of feroxamine (5, 190 mg, 0.5 mmol) and t-BuOCOCH2Br (193 mg, 1 mmol). The mixture was stirred at room temperature for 2 hours. After quenching with water, the aqueous layer was then extracted with EtOAc, and the combined organic layers were washed with water, then with brine, dried over Na2SO4 and concentrated under reduced pressure. The mixture was purified by preparative TLC to give a light yellow solid (12a, 247 mg, 99%): HR-EIMSm / z[M+H] + 495.1638 (calculated value 495.1655); 1 H NMR (400MHz, CDCl3) δ7.73(1H,s,H-2),7.07(1H,s,H-5),6.96(1H,d,J=7.9Hz,H-5'),6.82(1 H,d,J=1.3Hz,H-2'),6.79(1H,dd,J=7.9,1.7Hz,H-6'),6.09(1H,brs,-OCH2O-),6.05(1H,br s,-OCH2O-),5.48(2H,s,H-9),4.69(2H,s,OCH2C=O),4.09(3H,s,3-OCH3),3.81(3H,s,4-OCH3),1.51(9H,s,t-Bu); 13C NMR(100MHz,CDCl3)δ169.5(C-9'),167.8(OC=O),151.8(C-3),150.4(C-4),147.5(C-4',C -7),146.7(C-3'),135.5(C-7'),130.8(C-6),128.3(C-1'),126.4(C-8'),126.2(C-1),123 .6(C-6'),119.1(C-8),110.7(C-2'),108.2(C-5'),106.2(C-5),101.3(C-2),100.9(-OCH 2O-), 82.9 (t-Bu), 69.8 (OCH2C=O), 66.4 (C-9), 56.2 (3-OCH3), 55.9 (4-OCH3), 28.1 (t-Bu).

[0347] Compound 12b

[0348] Cs2CO3 (65 mg, 0.2 mmol) was added to a 1 mL DMF solution of feroxamine (5, 38 mg, 0.1 mmol) and EtOCOCH2Br (33 mg, 0.2 mmol). The mixture was stirred at room temperature for 2 hours. After quenching with water, the aqueous layer was then extracted with EtOAc, and the combined organic layers were washed with water, then with brine, dried over Na2SO4 and concentrated under reduced pressure. The mixture was purified by preparative TLC to give 12b (46 mg, 99%): HR-EIMS m / z 467.1316 [M+H] + (calculated value 467.1342); 1 HNMR(400MHz,DMSO-d6)δ7.73(1H,s,H-2),7.03(1H,d,J=7.9Hz,H-5'),6.96(1H,s ,H-5),6.87(1H,d,J=1.5Hz,H-2'),6.75(1H,dd,J=7.9,1.7Hz,H-6'),6.12(2H,br s,-OCH2O-),5.59(2H,s,H-9),5.02(2H,s,OCH2C=O),4.23(2H,q,J=7.1Hz ,Et),3.95(3H,s,3-OCH3),3.66(3H,s,4-OCH3),1.24(3H,t,J=7.1Hz,Et); 13C NMR(100MHz,DMSO-d6)δ169.0(C-9'),169.0(OC=O),151.4(C-3),150.1(C-4),147.0(C-3') ,146.9(C-4'),146.0(C-7),133.8(C-7'),129.6(C-6),128.2(C-1'),126.0(C-8'),125.6(C -1),123.6(C-6'),118.8(C-8),110.8(C-2'),108.0(C-5'),105.5(C-5),101.2(C-2),100.9 (-OCH2O-), 68.7 (OCH2C=O), 66.4 (C-9), 61.0 (Et), 55.7 (3-OCH3), 55.3 (4-OCH3), 14.1 (Et).

[0349] Compound 13

[0350] To a solution of 12a (247 mg, 0.5 mmol) in 10 mL of CH2Cl2 was added 1 mL of DMF and 2 mL of TFA. The mixture was stirred at room temperature for 12 hours. TLC showed that the reaction was complete and a new spot with higher polarity appeared. After the reaction mixture was concentrated, EtOH was added to promote precipitation. The solid was collected to give 13 (210 mg, 95%): HR-EIMS m / z[M+H] + 439.100 (calculated value 439.1029); 1 H NMR (400MHz, DMSO-d6) δ7.78(1H,s,H-2),7.04(1H,d,J=8.0Hz,H-5'),6.97(1H,s,H-5),6.89(1H,d,J=1.5Hz,H-2'),6.77(1H,dd,J=7.9, 1.7Hz,H-6'),6.13(2H,s,-OCH2O-),5.76(1H,s,OH),5.60(2H,s,H-9),4.93(2H,s,OCH2C=O),3.96(3H,s,3-OCH3),3.67(3H,s,4-OCH3); 13C NMR(100MHz,DMSO-d6)δ170.9(C-9'),169.4(OC=O),151.7(C-3),150.5(C-4),147.4(C -3'),147.3(C-4'),146.7(C-7),134.1(C-7'),130.0(C-6),128.7(C-1'),126.3(C-6' ),126.1(C-8'),124.0(C-1),119.3(C-8),111.3(C-2'),108.4(C-5'),105.9(C-5),10 1.6(C-2),101.5(-OCH2O-),69.1(OCH2C=O),66.8(C-9),56.1(3-OCH3),55.7(4-OCH3).

[0351] Compound 14a

[0352] To a solution of 13 (44 mg, 0.1 mmol) in CH2Cl2 (10.00 mL) was added Et3N (30 mg, 0.3 mmol), NH4Cl (16 mg, 0.3 mmol) and HATU (114 mg, 0.3 mmol) at 25°C and the reaction was stirred at 25°C for 16 hours. After quenching with water, the aqueous layer was then extracted with EtOAc and the combined organic layers were washed with water, then with brine, dried over Na2SO4 and concentrated under reduced pressure. The mixture was purified by preparative TLC to give 14a (40 mg, 92%): HR-EIMS m / z 438.1167 [M+H] + (calculated value 438.1189); 1 H NMR(400MHz,DMSO-d6)δ7.80(1H,s,NH2),7.70(1H,s,H-2),7.55(1H,s,NH2),7.04(1H,d,J=7.9Hz,H-5'),6.97(1H,s,H-5),6.89(1H,d,J=1.5Hz,H -2'),6.77(1H,dd,J=7.9,1.6Hz,H-6'),6.12(2H,s,-OCH2O-),5.60(2H, s,H-9),4.70(2H,s,OCH2C=O),3.97(3H,s,3-OCH3),3.66(3H,s,4-OCH3); 13C NMR(100MHz,DMSO-d6)δ170.1(C-9'),169.0(OC=O),151.3(C-3),150.0(C-4),147.0 (C-3'),146.9(C-4'),146.1(C-7),133.7(C-7'),129.6(C-6),128.3(C-1'),126.1(C -8'),125.7(C-1),123.6(C-6'),118.9(C-8),110.9(C-2'),108.0(C-5'),105.5(C- 5), 101.2 (C-2,-OCH2O-), 70.6 (OCH2C=O), 66.5 (C-9), 55.8 (3-OCH3), 55.3 (4-OCH3).

[0353] Compound 14b

[0354] To a solution of 13 (44 mg, 0.1 mmol) in CH2Cl2 (10.00 mL) and DMF (1 mL) were added Et3N (30 mg, 0.3 mmol), MeNH2 (0.3 mL, 0.3 mmol) and HATU (114 mg, 0.3 mmol) at 25°C and the resulting mixture was stirred at 25°C for 16 h. After quenching with water, the aqueous layer was then extracted with EtOAc and the combined organic layers were washed with water and then with brine, dried over Na2SO4 and concentrated under reduced pressure. The mixture was purified by preparative TLC to give 14b (30 mg, 66%): HR-EIMS m / z 452.1312 [M+H] + (calculated value 452.1345); 1 H NMR (400MHz, DMSO-d6) δ7.61(1H,s,H-2),6.96(1H,d,J=7.9Hz,H-5'),6.90(1H,s,H-5),6.81(1H,d,J=1.5Hz,H-2'),6.69(1H,dd,J=7.9,1 .7Hz,H-6'),6.04(2H,s,-OCH2O-),5.50(2H,s,H-9),4.65(2H,s,OCH2C=O),3.90(3H,s,3-OCH3),3.58(3H,s,4-OCH3),2.60(3H,s,NH-Me); 13C NMR(100MHz,DMSO-d6)δ169.0(C-9'),168.2(OC=O),151.4(C-3),150.1(C-4),147.0(C-3' ),146.9(C-4'),146.1(C-7),133.9(C-7'),129.6(C-6),128.3(C-1'),126.5(C-8'),125. 8(C-1),123.6(C-6'),118.9(C-8),110.9(C-2'),108.0(C-5'),105.5(C-5),101.2(C-2), 101.1(-OCH2O-), 71.0(OCH2C=O), 66.4(C-9), 55.8(3-OCH3), 55.3(4-OCH3), 25.6(NH-Me).

[0355] Compound 15a

[0356] A mixture of TBAB (16 mg, 0.05 mmol), PdCl2 (1.7 mg, 0.01 mmol) and K2CO3 (6.9 mg, 0.05 mmol) was dissolved in deionized H2O (2.00 mL) and stirred at 60°C for 15 min. Then, feroxamine (5, 38 mg, 0.1 mmol) and 0.3 mL of ethylene oxide were added and stirred at 60°C for 5 h. TLC showed that the reaction was complete and a major spot with less polarity was formed. The mixture was concentrated to give a yellow-green solid, which was washed with EtOH to give the desired product 15a (40 mg, 95%): HR-EIMS 425.1207 m / z [M+H] + (calculated value 425.1236); 1 H NMR(400MHz,DMSO-d6)δ7.76(1H,s,H-2),7.03(1H,d,J=7.9Hz,H-5'),6.97( 1H,s,H-5),6.89(1H,d,J=1.5Hz,H-2'),6.77(1H,dd,J=7.9,1.6Hz,H-6'),6. 12(2H,s,-OCH2O-),5.75(1H,s,OH),5.58(2H,s,H-9),4.28-4.22[2H,m,O(C H2)2OH],3.95(3H,s,3-OCH3),3.81[2H,m,O(CH2)2OH],3.66(3H,s,4-OCH3); 13C NMR(100MHz,DMSO-d6)δ169.2(C-9'),151.2(C-3),150.0(C-4),146.9(C-3'),146.8(C -4'),146.6(C-7),133.3(C-7'),129.6(C-6),128.4(C-1'),126.6(C-8'),126.1(C-1) ,123.7(C-6'),118.9(C-8),110.9(C-2'),108.0(C-5'),105.5(C-5),101.1(C-2,-OCH 2O-),74.4[O(CH2)2OH],66.6(C-9),60.4[O(CH2)2OH],55.7(3-OCH3),55.2(4-OCH3).

[0357] Compound 15b

[0358] Cs2CO3 (100 mg, 0.3 mmol) was added to a mixture of 5 (38 mg, 0.1 mmol) and methyl oxirane (71 mg, 1 mmol) in 2 mL DMF and stirred at 120°C for 12 hours. TLC showed that the reaction was complete and a major spot with less polarity was formed. The mixture was concentrated to give a yellow-green solid, which was washed with EtOH to give the desired product 15b (38 mg, 84%): HR-EIMS m / z [M+H] + 453.1524 (calculated value 453.1549); 1 H NMR (400MHz, DMSO-d6) δ7.71(1H,s,H-2),7.04(1H,d,J=7.9Hz,H-5'),6.97(1H,s,H-5),6.89(1H,d,J=1.6Hz,H-2'),6.77(1H,dd,J=7. 9,1.7Hz,H-6'),6.13(2H,s,-OCH2O-),5.63(2H,s,H-9),4.03(2H,s,CH2),3.95(3H,s,3-OCH3),3.67(3H,s,4-OCH3),1.34(6H,s,Me); 13C NMR(100MHz,DMSO-d6)δ169.1(C-9'),151.1(C-3),149.9(C-4),146.9(C-3'),146.8(C -4'),146.7(C-7),132.8(C-7'),129.5(C-6),128.4(C-1'),125.5(C-8'),125.5(C-1), 123.6(C-6'),118.9(C-8),110.8(C-2'),107.9(C-5'),105.5(C-5),101.1(C-2),101. 0(-OCH2O-),79.9(CH2),69.1(C),66.6(C-9),55.5(3-OCH3),55.2(4-OCH3),26.4(Me).

[0359] Compound 16

[0360] A solution of 5 (19 mg, 0.05 mmol) in anhydrous pyridine (1 mL) was added to Ac2O (7.1 μL, 0.075 mmol). The resulting mixture was stirred at room temperature overnight. After the reaction was completed, it was diluted with CH2Cl2 and washed with 10% HCl solution. The combined organic phase was further extracted with saturated NaHCO3 aqueous solution and dried over Na2SO4. After concentration, the crude product was purified by preparative TLC (1:1 n-hexane: ethyl acetate) to give 16 (20 mg, 94.6%) as a colorless solid: HR-EIMS 423.1077 m / z [M+H] + (calculated value 423.1080); 1 H NMR (400MHz, CDCl3) δ7.17(1H,s,H-2),7.12(1H,s,H-5),6.97(1H,d,J=7.8Hz,H-5'),6.86(1H,d,J=1.4Hz,H-2'),6.83(1H,dd,J=7.9,1.7Hz,H-6 '), 6.10(1H,d,J=1.5Hz,-OCH2O-), 6.05(1H,d,J=1.5Hz,-OCH2O-), 5.26(2H,s,H-9), 4.06(3H,s,3-OCH3), 3.81(3H,s,4-OCH3), 2.53(3H,s,OAc).

[0361] Compound 17a

[0362] To a solution of 5 (38 mg, 0.1 mmol) and bromoacetonitrile (24 mg, 0.2 mmol) in 1 mL of acetone was added Cs2CO3 (65 mg, 0.2 mmol). The mixture was stirred at room temperature for 2 hours. TLC showed a spot with less polarity. The mixture was purified by preparative TLC to give the desired product 17a (40 mg, 95%): HR-EIMS m / z [M+H] + 420.1053 (calculated value 420.1083); 1 H NMR(400MHz,DMSO-d6)δ7.52(1H,s,H-2),7.05(1H,d,J=7.9Hz,H-5'),7.01(1H,s,H-5),6.91(1H,d,J=1.6Hz,H-2'),6.79(1H, dd,J=1.7,7.9Hz,H-6'),6.13(2H,s,-OCH2O-),5.60(2H,s,CH2),5.34(2H,s,H-9),3.99(3H,s,3-OCH3),3.68(3H,s,4-OCH3); 13 CNMR(100MHz,DMSO-d6)δ168.8(C-9'),151.8(C-3),150.2(C-4),147.1(C-3'),147.0 (C-4'),144.7(C-7),135.5(C-7'),129.8(C-6),128.4(C-1'),127.9(C-8'),126.0(C -1),123.6(C-6'),118.8(C-8),117.1(C≡N),110.8(C-2'),108.1(C-5'),105.8(C-5) ,101.2(C-2),100.3(-OCH2O-),66.1(C-9),58.0(CH2),55.9(3-OCH3),55.3(4-OCH3).

[0363] Compound 17b

[0364] Cs2CO3 (32.5 mg, 0.1 mmol) was added to a solution of 5 (19 mg, 0.05 mmmol) in acetone (0.6 mL), and the solution was cooled to 0 ° C. Methyl iodide (10.6 mg, 0.075 mmol) was added dropwise and the mixture was warmed to room temperature. As shown by TLC, the reaction was completed after 12 hours. The mixture was quenched with saturated NH4Cl solution, extracted with EtOAc, and washed with brine. After drying (Na2SO4), the solvent was removed under reduced pressure, and the residue was purified by preparative TLC (n-hexane: ethyl acetate, 3: 1) to give the product 17b (17.7 mg, 90%) as a white solid: HR-EIMS m / z[M+H] + 395.1125 (calculated value 395.1131); 1 HNMR (400MHz, CDCl3) δ7.54(1H,s,H-2),7.05(1H,s,H-5),6.95(1H,d,J=7.8Hz,H-5'),6.78(2H,m,H-2',H-6'),6.09(1H,d,J=1 .5Hz,-OCH2O-), 6.04(1H,d,J=1.5Hz,-OCH2O-), 5.54(2H,s,H-9), 4.13(3H,s,OCH3), 4.07(3H,s,3-OCH3), 3.80(3H,s,4-OCH3).

[0365] Compound 17c

[0366] To a solution of 5 (38 mg, 0.1 mmol) and propargyl bromide (30 mg, 0.2 mmol) in acetone was added Cs2CO3 (65 mg, 0.2 mmol). The mixture was stirred at room temperature for 2 hours. TLC showed a spot with less polarity. The mixture was purified by silica gel column to give the desired product 17c (40 mg, 95%): HR-EIMS m / z [M+H] + 419.1112 (calculated value 419.1131); 1H NMR (400MHz, DMSO-d6) δ7.57(1H,s,H-2),7.04(1H,d,J=7.9Hz,H-5'),6.98(1H,s,H-5),6.91(1H,d,J=1.5Hz,H-2'),6.78(1H,dd,J=7.9,1.6Hz,H -6'),6.12(2H,s,-OCH2O-),5.62(2H,s,H-9),5.04(2H,d,J=2.4Hz,CH2) ,3.96(3H,s,3-OCH3),3.71(1H,t,J=2.4Hz,C≡CH),3.66(3H,s,4-OCH3); 13 C NMR(100MHz,DMSO-d6)δ169.0(C-9'),151.4(C-3),150.1(C-4),147.0(C-3'),147.0( C-4'),145.6(C-7),134.2(C-7'),129.7(C-6),128.2(C-1'),127.2(C-1),126.3(C-8 '),123.7(C-6'),118.8(C-8),110.9(C-2'),108.1(C-5'),105.6(C-5),101.2(C-2), 100.8(-OCH2O-),79.7(CH2),79.5(C≡CH),66.6(C-9),55.7(3-OCH3),55.3(4-OCH3).

[0367] Compound 17d

[0368] To a solution of 5 (38 mg, 0.1 mmol) and 2-chloropyrimidine (23 mg, 0.2 mmol) in 1 mL DMF was added KCO (40 mg, 0.3 mmol). The mixture was stirred at 100 °C for 12 h. TLC showed a spot with less polarity. The mixture was purified by preparative TLC to give the desired product 17d (35 mg, 76%): HR-EIMS m / z [M+H] + 459.1161 (calculated value 459.1192); 1H NMR (400 MHz, DMSO-d6) δ8.71 (2H, d, J = 4.8 Hz, pyrimidine), 7.37 (1H, t, J = 4.8 Hz, pyrimidine), 7.19 (1H, s, H-2), 7.08 (1H, s, H-5), 7.08 (1H, d, J = 7.9 Hz, H-5'), 7.01 (1H, d, J = 1.5 Hz, H-2'), 6.87 (1H, dd, J = 7.9, 1.7 Hz, H-6'), 6.15 (2H, br s, -OCH2O-), 5.24 (2H, s, H-9), 3.81 (3H, s, 3-OCH3), 3.69 (3H, s, 4-OCH3); 13 C NMR (100 MHz, CDCl3) δ 169.8 (pyrimidine), 169.1 (C-9'), 160.1 (pyrimidine), 160.0 (pyrimidine), 151.6 (C-3), 150.2 (C-4), 147.1 (C-4'), 147.1 (C-3'), 146.8 (C-7), 134.9 (C-7'), 129.9 (C-6), 128.8 (C-1'), 1 27.7(C-1),127.0(C-8'),123.8(pyrimidine),123.8(C-6'),119.2(C-8),110.9(C-2'),108.4(C-5'),106.2(C-5),101.0(C-2),100.8(-OCH2O-),66.7(C-9),56.03(3-OCH3),55.4(4-OCH3).

[0369] Compound 17e

[0370] 5 (38 mg, 0.1 mmol), Et3N (30 mg, 0.3 mmol) and DMAP (catalytic amount) were dissolved in 2 mL of anhydrous CH2Cl2. Cyclopropanecarbonyl chloride (31 mg, 0.3 mmol) was added to the mixture at 0°C. The reaction mixture was allowed to warm to 25°C and kept stirring at 25°C for 2 hours. The mixture was purified by silica gel column to give the desired product 17e (43 mg, 98%): HR-EIMS m / z [M+H] + 449.1241 (calculated value 449.1236); 1H NMR (400MHz, CDCl3) δ7.20(1H,s,H-2),7.10(1H,s,H-5),6.96(1H,d,J=7.9Hz,H -5'),6.85(1H,d,J=1.5Hz,H-2'),6.82(1H,dd,J=7.9,1.7Hz,H-6'),6.09(1H,br s,-OCH2O-),6.04(1H,br s, -OCH2O-), 5.24 (2H, s, H-9), 4.05 (3H, s, 3-OCH3), 3.80 (3H, s, 4-OCH3), 2.12-2.04 (1H, m, cyclopropanecarbonyl), 1.34-1.27 (2H, m, cyclopropanecarbonyl), 1.20 (2H, dt, J = 3.3, 8.0 Hz, cyclopropanecarbonyl); 13 C NMR (100 MHz, CDCl3) δ172.2 (cyclopropanecarbonyl), 169.4 (C-9'), 152.3 (C-3), 150.4 (C-4), 147.7 (C-3'), 147.6 (C-4'), 138.2 (C-7), 137.5 (C-7'), 130.7 (C-6), 130.3 (C-1), 128.0 (C-1'), 126. 3(C-8'),123.6(C-6'),119.1(C-8),110.7(C-2'),108.3(C-5'),106.4(C-5),101.3(C-2),99.2(-OCH2O-),66.3(C-9),56.0(3-OCH3),55.9(4-OCH3),12.7(cyclopropanecarbonyl),9.9(cyclopropanecarbonyl).

[0371] Compound 17f

[0372] 5 (38 mg, 0.1 mmol), Et3N (30 mg, 0.3 mmol) and DMAP (catalytic amount) were dissolved in 2 mL of anhydrous CH2Cl2. Cyclopentanecarbonyl chloride (40 mg, 0.3 mmol) was added to the mixture at 0°C. The reaction mixture was allowed to warm to 25°C and kept stirring at 25°C for 2 hours. The mixture was purified by silica gel column to give the desired product 17f (45 mg, 97%): HR-EIMS m / z [M+H] + 477.1547 (calculated value 477.1549); 1H NMR (400MHz, CDCl3) δ7.12(1H,s,H-2),7.04(1H,s,H-5),6.90(1H,d,J=7.9Hz,H -5'),6.79(1H,d,J=1.5Hz,H-2'),6.76(1H,dd,J=7.9,1.7Hz,H-6'),6.09(1H,br s,-OCH2O-),6.04(1H,br s, -OCH2O-), 5.16 (2H, s, H-9), 3.96 (3H, s, 3-OCH3), 3.74 (3H, s, 4-OCH3), 3.16 (1H, p, J = 8.0 Hz, cyclopentanecarbonyl), 2.19-2.08 (2H, m, cyclopentanecarbonyl), 2.07-1.96 (2H, m, cyclopentanecarbonyl), 1.80 (2H, dt, J = 6.1, 17.0 Hz, cyclopentanecarbonyl), 1.70 (2H, tdd, J = 2.2, 4.0, 11.4 Hz, cyclopentanecarbonyl); 13 C NMR (100 MHz, CDCl3) δ 173.8 (cyclopentanecarbonyl), 169.4 (C-9'), 152.2 (C-3), 150.4 (C-4), 147.7 (C-3'), 147.6 (C-4'), 138.2 (C-7), 137.5 (C-7'), 130.7 (C-6), 130.2 (C-1), 128.0 (C-1'), 126.3 (C-8' ),123.7(C-6'),119.1(C-8),110.7(C-2'),108.3(C-5'),106.4(C-5),101.3(C-2),99.2(-OCH2O-),66.3(C-9),56.0(3-OCH3),55.9(4-OCH3),43.8(cyclopentanecarbonyl),30.5(cyclopentanecarbonyl),25.9(cyclopentanecarbonyl).

[0373] Compound 17g

[0374] 5 (38 mg, 0.1 mmol), Et3N (30 mg, 0.3 mmol) and DMAP (catalytic amount) were dissolved in 2 mL of anhydrous CH2Cl2. 4-Fluorobenzoyl chloride (40 mg, 0.3 mmol) was added to the mixture at 0°C. The reaction mixture was allowed to warm to 25°C and kept stirring at 25°C for 2 hours. The mixture was purified by silica gel column to give the desired product 17 g (45 mg, 90%): HR-EIMS m / z [M+H] + 503.1133 (calculated value 503.1142); 1H NMR (400 MHz, CDCl3) δ8.37 (2H, dd, J = 8.9, 5.3 Hz, 4-fluorobenzoyl), 7.29 (2H, t, J = 8.6 Hz, 4-fluorobenzoyl), 7.21 (1H, s, H-2), 7.15 (1H, s, H-5), 6.98 (1H, d, J = 7.9 Hz, H-5'), 6.88 (1H, d, J = 1.3 Hz, H-2'), 6.85 (1H, dd, J = 7.9, 1.7 Hz, H-6'), 6.09 (1H, br s, -OCH2O-), 6.04 (1H, br s,-OCH2O-),5.29(2H,s,H-9),3.95(3H,s,3-OCH3),3.82(3H,s,4-OCH3); 13 C NMR (100 MHz, CDCl3) δ169.7 (C-9'), 168.4 (4-fluorobenzoyl), 165.8 (4-fluorobenzoyl), 163.1 (4-fluorobenzoyl), 152.8 (C-3), 150.9 (C-4), 148.1 (C-3'), 148.0 (C-4'), 138.5 (C-7), 138.3 (C-7'), 133.6 (4-fluorobenzoyl), 133.5 (4-fluorobenzoyl), 131.2 (C-1) ,130.8(C-6),128.3(C-1'),126.7(C-8'),124.1(C-6'),119.6(C-8),116.9(4-fluorobenzoyl),116.7(4-fluorobenzoyl),111.1(C-2'),108.7(C-5'),106.9(C-5),101.7(C-2),99.5(-OCH2O-),66.8(C-9),56.4(3-OCH3),56.3(4-OCH3).

[0375] Compound 17h

[0376] 5 (38 mg, 0.1 mmol), Et3N (30 mg, 0.3 mmol) and DMAP (catalytic amount) were dissolved in 2 mL of anhydrous CH2Cl2. 4-Anisyl chloride (51 mg, 0.3 mmol) was added to the mixture at 0°C. The reaction mixture was allowed to warm to 25°C and kept stirring at 25°C for 2 hours. The mixture was purified by silica gel column to give the desired product 17h (45 mg, 90%): HR-EIMS m / z [M+H] + 515.1338 (calculated value 515.1342); 1H NMR (400 MHz, CDCl3) δ8.33-8.25 (2H, m, 4-methoxybenzoyl), 7.26 (1H, s, H-2), 7.14 (1H, s, H-5), 7.10-7.03 (2H, m, 4-methoxybenzoyl), 6.97 (1H, d, J = 7.9 Hz, H-5'), 6.88 (1H, d, J = 1.4 Hz, H-2'), 6.86 (1H, dd, J = 7.9, 1.7 Hz, H-6'), 6.09 (1H, d, J = 1.4 Hz, -OCH2O-), 6.04 (1H, d, J = 1.4 Hz, -OCH2O-), 5.29 (2H, s, H-9), 3.94 (3H, s, 3-OCH3), 3.93 (3H, s, 4-methoxybenzoyl), 3.81 (3H, s, 4-OCH3); 13 C NMR (100 MHz, CDCl3) δ 169.4 (C-9'), 164.7 (4-methoxybenzoyl), 163.4 (4-methoxybenzoyl), 152.3 (C-3), 150.4 (C-4), 147.7 (C-3'), 147.6 (C-4'), 138.5 (C-7), 137.5 (C-7'), 132.7 (4-methoxybenzoyl), 130.7 (C-6), 130.6 (C-1), 128.0 (C-1' ),126.6(C-8'),123.7(C-6'),120.3(4-methoxybenzoyl),119.2(C-8),114.4(4-methoxybenzoyl),110.7(C-2'),108.3(C-5'),106.4(C-5),101.3(C-2),99.4(-OCH2O-),66.6(C-9),56.0(3-OCH3),55.9(4-OCH3),55.7(4-methoxybenzoyl).

[0377] Compound 18

[0378] Under nitrogen, schizofol (5,760 mg, 2 mmol) and DMAP (488 mg, 4 mmol) were dissolved in 10 mL of anhydrous CH2Cl2. The solution was cooled to 0°C. Then, trifluoromethanesulfonic anhydride (Tf2O) (0.5 mL, 2.4 mmol) was slowly added via a syringe over 5 minutes. The reaction was allowed to warm to room temperature and stirred at room temperature for 4 hours. TLC showed that the reaction was complete and a new spot was formed. The mixture was concentrated in vacuo to give a yellow solid, which was washed with EtOH to give the desired product 18 (0.97 g, 95%): HR-EIMS m / z[M+H] + 513.0455 (calculated value 513.0467); 1H NMR(400MHz,DMSO-d6)δ7.35(1H,s,H-2),7.11(1H,s,H-5),7.08(1H,d,J=7.9Hz,H-5'),7.01(1H,d,J=1.6Hz,H-2'), 6.87(1H,dd,J=7.9,1.7Hz,H-6'),6.15(2H,s,-OCH2O-),5.56(2H,s,H-9),3.99(3H,s,3-OCH3),3.72(3H,s,4-OCH3); 13 C NMR(100MHz,DMSO-d6)δ167.7(C-9'),153.1(C-3),150.6(C-4),147.5(C-3'),147 .1(C-4'),139.7(C-7),135.2(C-7'),131.6(C-6),130.2(C-1),126.8(C-1'),125 .2(C-8'),123.6(C-6'),119.7(OTf),119.4(C-8),110.7(C-2'),108.1(C-5'),10 6.2(C-5),101.3(C-2),98.7(-OCH2O-),65.4(C-9),55.9(3-OCH3),55.5(4-OCH3).

[0379] Compound 19a

[0380] In an oven-dried round-bottom flask, [Pd(dppf)Cl2]CH2Cl2 complex (244 mg, 0.025 mmol), B2Pin2 (191 mg, 0.75 mmol), KOAc (147 mg, 1.5 mmol) and 18 (256 mg, 0.5 mmol) were placed under nitrogen atmosphere. Freshly distilled 1,4-dioxane (2 mL) was added to the flask. The mixture was degassed with N2. The flask was equipped with a reflux condenser and heated at 100°C under nitrogen atmosphere for 3 hours. The mixture was concentrated in vacuo to give a yellow solid, which was washed with EtOH to give the desired product 19a (229.5 mg, 85%): HR-EIMS m / z [M+H] + 491.3626 (calculated value 491.1882); 1H NMR(400MHz,DMSO-d6)δ7.51(1H,s,H-2),7.04(1H,d,J=7.9Hz,H-5'),6.98(1H,s ,H-5),6.92(1H,d,J=1.6Hz,H-2'),6.79(1H,dd,J=7.9,1.7Hz,H-6'),6.13(2H,br s,-OCH2O-),5.43(2H,s,H-9),3.94(3H,s,3-OCH3),3.66(3H,s,4-OCH3),1.06(12H,s,Me); 13 C NMR(100MHz,DMSO-d6)δ169.5(C-9'),151.5(C-3),149.8(C-4),147.0(C-3',C-4'),1 39.9(C-7),138.4(C-7'),133.0(C-6),128.4(C-1'),127.8(C-1),123.5(C-6'),118. 9(C-8),117.9(C-8'),110.7(C-2'),108.0(C-5'),106.7(C-5),105.0(C-2),101.2(- OCH2O-),79.1(CO),73.6(CO),68.1(C-9),55.9(3-OCH3),55.2(4-OCH3),25.0(CH3).

[0381] Compound 19b

[0382] To an oven-dried 10 mL flask was added Pd(dppf)Cl2 (3.7 mg, 0.005 mmol) and 18 (51 mg, 0.1 mmol). The flask was capped and then backfilled with N2. Toluene (2.00 mL) was added via a syringe followed by AlMe3 (0.15 mL, 0.3 mmol). The reaction mixture was heated to 100 °C for 10 hours. After cooling to room temperature, the reaction solution was quenched with water and extracted with CH2Cl2. The obtained solution was concentrated and purified by preparative TLC to give the desired product 19b (25 mg, 66%): HR-EIMS m / z[M+H] + 379.1156 (calculated value 379.1182); 1H NMR(400MHz,DMSO-d6)δ7.40(1H,s,H-2),7.04(1H,d,J=7.9Hz,H-5'),7.01(1H,s,H-5),6.88(1H,d,J=1.6Hz,H-2'),6.77(1H ,dd,J=7.9,1.7Hz,H-6'),6.12(2H,s,-OCH2O-),5.44(s,2H,H-9),3.99(3H,s,3-OCH3),3.65(3H,s,4-OCH3),2.57(3H,s,Me); 13 C NMR(100MHz,DMSO-d6)δ169.9(C-9'),151.3(C-3),149.3(C-4),147.0(C-3',C- 4'),138.2(C-7),136.5(C-7'),131.5(C-6),128.6(C-1'),128.1(C-1),125.6(C -8'),123.6(C-6'),117.4(C-8),110.8(C-2'),108.0(C-5'),105.9(C-5),102. 8(C-2),101.2(-OCH2O-),67.9(C-9),55.8(3-OCH3),55.2(4-OCH3),14.3(CH3).

[0383] Compound 19c

[0384] To an oven-dried 10 mL flask was added Pd(dppf)2Cl2 (7.31 mg, 0.01 mmol), Na2CO3 (65 mg, 0.6 mmol), 18 (102 mg, 0.2 mmol) and pyridine-4-boric acid (52 mg, 0.4 mmol). The flask was capped and then backfilled with N2. Dioxane and H2O (2 / 0.4 mL) were added via a syringe. The reaction mixture was heated to 100°C for 10 hours. After cooling to room temperature, the reaction solution was quenched with water and extracted with CH2Cl2. The obtained solution was concentrated and purified by preparative TLC to give the desired product 19c (22 mg, 50%): HR-EIMS m / z[M+H] + 442.1300 (calculated value 442.1291); 1H NMR (400 MHz, DMSO-d6) δ8.79 (2H, d, J=5.8 Hz, pyridine), 7.62 (2H, s, H-2, pyridine), 7.09 (1H, s, pyridine), 7.08 (1H, d, J=8.1 Hz, H-5'), 7.01 (1H, s, H-5), 6.97 (1H, d, J=1.5 Hz, H-2'), 6.85 (1H, dd, J=7.9, 1.7 Hz, H-6'), 6.14 (2H, s, -OCH2O-), 5.27 (2H, s, H-9), 3.72 (3H, s, 3-OCH3), 3.68 (3H, s, 4-OCH3); 13 C NMR (100 MHz, DMSO-d6) δ 169.2 (C-9'), 151.8 (C-3), 150.4 (pyridine), 149.7 (C-4), 147.1 (C-3'), 147.0 (C-4'), 143.8 (pyridine), 138.9 (C-7), 138.2 (C-7'), 129.9 (C-6), 128.5 (C-1), 12 8.0(C-1'),124.5(pyridine, C-8'),123.5(C-6'),117.9(C-8),110.6(C-2'),108.1(C-5'),105.8(C-5),103.3(C-2),101.2(-OCH2O-),67.5(C-9),55.4(3-OCH3),55.3(4-OCH3).

[0385] Compound 19d

[0386] To an oven-dried 10 mL flask was added Pd(OAc)2 (1.1 mg, 0.01 mmol), PPh3 (2.6 mg, 0.02 mmol) and 18 (0.1 mmol). The flask was capped and then backfilled with argon (this was repeated an additional two times). DMF (1.00 mL) was added via a syringe, followed by Et3N (43 mL, 0.3 mmol) and HCO2H (8 μL, 0.2 mmol) in a similar manner. The reaction mixture was heated to 100 °C for 10 hours. After cooling to room temperature, the reaction solution was quenched with water and extracted with CH2Cl2. The obtained solution was concentrated and purified by preparative TLC to give the desired product 19d (35 mg, 98%): HR-EIMS m / z[M+H] + 365.1010 (calculated value 365.1025); 1H NMR (400MHz, DMSO-d6) δ7.94(1H,s,H-7),7.51(1H,s,H-2),7.05(1H,d,J=7.9Hz,H-5'),6.99(1H,s,H-5),6.92(1H,d,J=1.6Hz ,H-2'),6.80(1H,dd,J=7.9,1.7Hz,H-6'),6.13(2H,s,-OCH2O-),5.43(2H,s,H-9),3.94(3H,s,3-OCH3),3.66(3H,s,4-OCH3); 13 C NMR(100MHz,DMSO-d6)δ169.5(C-9'),151.5(C-3),149.8(C-4),147.0(C-3', C-4'),139.9(C-7),138.3(C-7'),132.9(C-6),128.4(C-1'),127.8(C-1),12 3.5(C-6'),118.8(C-8),117.9(C-8'),110.7(C-2'),108.0(C-5'),106.7(C- 5),105.0(C-2),101.2(-OCH2O-),68.1(C-9),56.0(3-OCH3),55.8(4-OCH3).

[0387] Compound 19e

[0388] To an oven-dried 10 mL flask was added Pd(OAc)2 (1.12 mg, 0.005 mmol), BINAP (5 mg, 0.008 mmol), Cs2CO3 (49 mg, 0.15 mmol) and 18 (51 mg, 0.1 mmol). The flask was capped and then backfilled with N2. A solution of 4-aminotrifluorotoluene (32 mg, 0.2 mmol) in PhMe was added via a syringe. The reaction mixture was heated to 100°C for 10 hours. After cooling to room temperature, the reaction solution was quenched with water and extracted with CH2Cl2. The obtained solution was concentrated and purified by preparative TLC to give the desired product 19e (45 mg, 86%): HR-EIMS m / z[M+H] + (calculated value 524.1321); 1H NMR (400 MHz, CDCl3) δ7.44 (2H, d, J = 8.5 Hz, trifluorotoluene), 7.32 (1H, s, H-2), 7.15 (1H, s, H-5), 6.93 (1H, d, J = 7.9 Hz, H-5'), 6.86 (1H, d, J = 1.5 Hz, H-2'), 6.83 (1H, dd, J = 7.9, 1.7 Hz, H-6'), 6.70 (2H, d, J = 8.4 Hz, trifluorotoluene), 6.06 (1H, br s, -OCH2O-), 5.96 (1H, br s, -OCH2O-), 5.13 (2H, s, H-9), 3.88 (3H, s, 3-OCH3), 3.81 (3H, s, 4-OCH3); 13 C NMR (100 MHz, CDCl3) δ 170.6 (C-9'), 152.6 (C-3), 150.7 (C-4), 148.2 (trifluorotoluene), 148.1 (C-3'), 148.0 (C-4'), 138.3 (C-7), 136.0 (C-7'), 130.9 (trifluorotoluene), 130.8 (C-6), 128.6 (C-8'), 128. 5(C-1),127.3(C-1'),124.0(C-6'),119.4(C-8),114.3(trifluorotoluene),111.0(C-2'),108.6(C-5'),107.1(C-5),101.9(C-2),101.8(-OCH2O-),67.8(C-9),56.5(3-OCH3),56.3(4-OCH3).

[0389] Compound 19f

[0390] Pd(OAc)2 (1.12 mg, 0.005 mmol), BINAP (5 mg, 0.008 mmol), Cs2CO3 (49 mg, 0.15 mmol) and 18 (51 mg, 0.1 mmol) were added to an oven-dried 10 mL flask. The flask was capped and then backfilled with N2. A solution of aminobenzene (19 mg, 0.2 mmol) in PhMe was added via a syringe. The reaction mixture was heated to 100°C for 10 hours. After cooling to room temperature, the reaction solution was quenched with water and extracted with CH2Cl2. The obtained solution was concentrated and purified by preparative TLC to give the desired product 19g (38.7 mg, 85%): HR-EIMS m / z[M+H] + (calculated value 456.1447); 1HNMR (400 MHz, CDCl3) δ7.40 (1H, s, H-2), 7.22 (2H, dd, J = 8.5, 7.4 Hz, aminobenzene), 7.14 (1H, s, H-5), 6.93 (1H, d, J = 7.9 Hz, H-5'), 6.89-6.87 (1H, m, aminobenzene), 6.86 (1H, d, J = 1.5 Hz, H-2'), 6.83 (1H, dd, J = 7.9, 1.7 Hz, H-6'), 6.72 (2H, dd, J = 1.0, 8.5 Hz, aminobenzene), 6.06 (1H, br s, -OCH2O-), 5.98 (1H, br s,-OCH2O-),5.07(2H,s,H-9),3.89(3H,s,3-OCH3),3.80(3H,s,4-OCH3); 13 C NMR (100 MHz, CDCl3) δ 170.4 (C-9'), 151.9 (C-3), 150.1 (C-4), 147.6 (C-3'), 147.6 (C-4'), 144.6 (C-7), 136.4 (C-7'), 133.9 (aminobenzene), 130.4 (C-6), 129.8 (C-1), 129.7 (C-8'), 129.5 (aminobenzene) ,128.6(C-1'),123.7(C-6'),120.2(C-8),119.2(aminobenzene),115.6(aminobenzene),110.8(C-2'),108.2(C-5'),106.7(C-5),101.7(C-2),101.3(-OCH2O-),67.7(C-9),56.1(3-OCH3),55.9(4-OCH3).

[0391] Compound 19g

[0392] To an oven-dried 10 mL flask was added Pd(PPh3)4 (6.22 mg, 0.005 mmol) and 18 (51 mg, 0.1 mmol). The flask was capped and then backfilled with N2. THF (2.00 mL) was added via a syringe followed by Et2Zn. The reaction mixture was heated to 100 °C for 10 hours. After cooling to room temperature, the reaction solution was quenched with water and extracted with CH2Cl2. The obtained solution was concentrated and purified by preparative TLC to give the desired product 19g (25 mg, 64%): HR-EIMS m / z[M+H] + 393.1324 (calculated value 393.1338); 1H NMR (400MHz, DMSO-d6) δ7.43(1H,s,H-2),7.04(1H,d,J=8.1Hz,H-5'),7.02(1H,s,H-5),6.90(1H,d,J=1.3Hz,H-2'),6.77(1H,dd,J=7.7,1.3Hz ,H-6'),6.12(2H,s,-OCH2O-),5.47(2H,s,H-9),3.99(3H,s,3-OCH3),3 .65(3H,s,4-OCH3),3.03(2H,q,J=7.3Hz,Et),1.28(3H,t,J=7.5Hz,Et); 13 C NMR(100MHz,DMSO-d6)δ169.9(C-9'),151.5(C-3),149.3(C-4),147.0(C-3'),146.9 (C-4'),137.7(C-7),136.7(C-7'),131.7(C-6),130.6(C-1),128.7(C-8'),128.5(C -1'),123.6(C-6'),117.6(C-8),110.8(C-2'),108.1(C-5'),106.1(C-5),102.5(C- 2),101.2(-OCH2O-),67.6(C-9),55.8(3-OCH3),55.2(4-OCH3),21.5(Et),13.9(Et).

[0393] Compound 19h

[0394] Pd(PPh3)4 (6.22 mg, 0.005 mmol), K2CO3 (40 mg, 0.3 mmol), 18 (51 mg, 0.1 mmol) and thiophene-2-boronic acid (26 mg, 0.2 mmol) were added to an oven-dried 10 mL flask. The flask was capped and then backfilled with N2. DMF was added via a syringe. The reaction mixture was heated to 100°C for 10 hours. After cooling to room temperature, the reaction solution was quenched with water and extracted with CH2Cl2. The obtained solution was concentrated and purified by preparative TLC to give the desired product 19h (38 mg, 92%): HR-EIMS m / z[M+H] + 447.0889 (calculated value 447.0902); 1H NMR (400 MHz, DMSO-d6) δ 7.87 (1H, dd, J = 5.1, 1.2 Hz, thiophene), 7.42 (1H, dd, J = 3.5, 1.2 Hz, thiophene), 7.41 (1H, s, H-2), 7.33 (1H, dd, J = 5.1, 3.5 Hz, thiophene), 7.07 (1H, d, J = 7.9 Hz, H-5'), 7.06 (1H, s, H-5), 6.95 (1H, d, J = 1.5 Hz, H-2'), 6.83 (1H, dd, J = 7.9, 1.7 Hz, H-6'), 6.13 (2H, br s,-OCH2O-),5.32(2H,s,H-9),3.77(3H,s,3-OCH3),3.67(3H,s,4-OCH3); 13 C NMR (100 MHz, DMSO-d6) δ 169.2 (C-9'), 151.7 (C-3), 149.6 (C-4), 147.0 (C-3', C-4'), 139.6 (C-7), 138.7 (thiophene), 135.4 (C-7'), 131.4 (C-6), 129.0 (C-1), 128.6 (C-1'), 128.1 (thiophene), 12 8.1(thiophene), 128.1(thiophene), 123.6(C-6'), 123.5(C-8'), 118.0(C-8), 110.6(C-2'), 108.1(C-5'), 105.7(C-5), 103.7(C-2), 101.2(-OCH2O-), 67.9(C-9), 55.4(3-OCH3), 55.3(4-OCH3).

[0395] Compound 19i

[0396] Pd(PPh3)4 (6.22 mg, 0.005 mmol), K2CO3 (42 mg, 0.3 mmol), 18 (51 mg, 0.1 mmol) and pyridine-3-boronic acid (25 mg, 0.2 mmol) were added to an oven-dried 10 mL flask. The flask was capped and then backfilled with N2. 2 mL of DMF was added via a syringe. The reaction mixture was heated to 100 °C for 10 hours. After cooling to room temperature, the reaction solution was quenched with water and extracted with CH2Cl2. The obtained solution was concentrated and purified by preparative TLC to give the desired product 19i (30 mg, 75%): HR-EIMS m / z [M+H] + 442.1293 (calculated value 442.1291); 1H NMR (400 MHz, DMSO-d6) δ8.80 (2H, s, pyridine), 8.09 (1H, s, pyridine), 7.71 (1H, s, H-2), 7.09 (1H, s, pyridine), 7.08 (2H, d, J = 8.3 Hz, H-5'), 6.97 (1H, d, J = 4.2 Hz, H-2'), 6.95 (1H, s, H-5), 6.85 (1H, dd, J = 8.6, 4.2 Hz, H-6'), 6.14 (2H, br s, -OCH2O-), 5.36-5.19 (2H, m, H-9), 3.71 (3H, s, 3-OCH3), 3.68 (3H, s, 4-OCH3); 13 C NMR (100 MHz, DMSO-d6) δ 169.3 (C-9'), 151.7 (C-3), 149.6 (C-4, pyridine), 147.1 (C-3', C-4'), 139.0 (C-7, pyridine), 138.7 (pyridine), 138.0 (C-7'), 130.8 (C-6, pyridine), 128.5 (C-1', C-1), 1 28.1(pyridine),127.1(C-8'),123.5(C-6'),117.8(C-8),110.6(C-2'),108.1(C-5'),105.7(C-5),103.4(C-2),101.2(-OCH2O-),67.5(C-9),55.4(3-OCH3),55.3(4-OCH3).

[0397] Compound 19j

[0398] To an oven-dried 10 mL flask was added Pd(PPh3)4 (6.22 mg, 0.005 mmol), K2CO3 (42 mg, 0.3 mmol), 18 (51 mg, 0.1 mmol) and thiophene-3-boronic acid (26 mg, 0.2 mmol). The flask was capped and then backfilled with N2. 2 mL of DMF was added via a syringe. The reaction mixture was heated to 100°C for 10 hours. After cooling to room temperature, the reaction solution was quenched with water and extracted with CH2Cl2. The obtained solution was concentrated and purified by preparative TLC to give the desired product 19j (22 mg, 50%): HR-EIMS m / z[M+H] + 447.0867 (calculated value 447.0902); 1H NMR (400 MHz, DMSO-d6) δ7.91 (1H, d, J = 1.4 Hz, thiophene), 7.84 (1H, d, J = 4.7 Hz, thiophene), 7.44 (1H, d, J = 4.9 Hz, thiophene), 7.27 (1H, s, H-2), 7.06 (1H, d, J = 7.9 Hz, H-5'), 7.05 (1H, s, H-5), 6.95 (1H, d, J = 1.0 Hz, H-2'), 6.83 (1H, dd, J = 7.8, 1.3 Hz, H-6'), 6.13 (2H, s, -OCH2O-), 5.32 (2H, s, H-9), 3.76 (3H, s, 3-OCH3), 3.66 (3H, s, 4-OCH3); 13 C NMR (100 MHz, DMSO) δ 170.0 (C-9'), 151.9 (C-3), 150.0 (C-4), 147.5 (C-3', C-4'), 139.0 (C-7), 138.3 (C-7'), 136.0 (thiophene), 131.3 (C-6), 129.2 (C-1), 129.0 (thiophene), 128.8 (C-1'), 127 .8(C-8'),126.6(thiophene),125.9(thiophene),123.9(C-6'),118.4(C-8),111.1(C-2'),108.5(C-5'),106.1(C-5),104.4(C-2),101.7(-OCH2O-),68.4(C-9),55.8(3-OCH3),55.7(4-OCH3).

[0399] Compound 19k

[0400] To an oven-dried 10 mL flask was added Pd(PPh3)4 (6.22 mg, 0.005 mmol), Na2CO3 (32 mg, 0.3 mmol), 18 (51 mg, 0.1 mmol) and furan-2-boric acid (26 mg, 0.2 mmol). The flask was capped and then backfilled with N2. Dioxane and H2O (2 / 0.4 mL) were added via a syringe. The reaction mixture was heated to 100°C for 10 hours. After cooling to room temperature, the reaction solution was quenched with water and extracted with CH2Cl2. The obtained solution was concentrated and purified by preparative TLC to give the desired product 19k (30 mg, 70%): HR-EIMS m / z[M+H] + 431.1098 (calculated value 431.1131); 1H NMR (400 MHz, DMSO-d6) δ 7.99 (1H, dd, J = 1.8, 0.7 Hz, furan), 7.73 (1H, s, H-2), 7.14 (1H, dd, J = 3.4, 0.6 Hz, furan), 7.07 (1H, d, J = 7.9 Hz, H-5'), 7.06 (1H, s, H-5), 6.95 (d, 1H, J = 1.5 Hz, furan), 6.82 (1H, dd, J = 7.9, 1.8 Hz, H-6'), 6.82 (1H, d, J = 1.9 Hz, H-2'), 6.14 (2H, s, -OCH2O-), 5.51 (2H, s, H-9), 3.92 (3H, s, 3-OCH3), 3.68 (3H, s, 4-OCH3); 13 C NMR (100 MHz, DMSO-d6) δ 169.2 (C-9'), 152.0 (C-3), 149.6 (C-4), 148.9 (furan), 147.1 (C-3'), 147.0 (C-4'), 143.9 (furan), 138.5 (C-7), 138.4 (C-7'), 129.1 (C-6), 128.9 (C-1), 128.2 (C-1' ),123.5(C-6'),119.8(C-8),118.3(C-8'),112.1(furan),111.8(furan),110.7(C-2'),108.1(C-5'),105.9(C-5),104.1(C-2),101.3(-OCH2O-),68.6(C-9),55.5(3-OCH3),55.2(4-OCH3).

[0401] Compound 19l

[0402] To an oven-dried 10 mL flask was added Pd(PPh3)4 (24 mg, 0.02 mmol), Na2CO3 (120 mg, 1.2 mmol), 18 (204 mg, 0.4 mmol), 3,6-dihydro-2H-pyridine-1-N-Boc-4-boronic acid and pinacol ester (186 mg, 0.6 mmol). The flask was capped and then backfilled with N2. Dioxane and water (4 / 0.8 mL) were added via a syringe. The reaction mixture was heated to 80°C for 10 hours. After cooling to room temperature, the reaction solution was quenched with water and extracted with CH2Cl2. The mixture was purified by silica gel column to give the desired product 19l (69 mg, 27%): HR-EIMS m / z[M+H] + 546.2109 (calculated value 546.2128); 1H NMR (400MHz, CDCl3) δ7.12(1H,s,H-2),7.11(1H,s,H-5),6.96(1H,d,J=7.9Hz,H-5'),6.84(1H,br s,H-2'),6.81(1H,d,J=8.1Hz,H-6'),6.09(1H,br s,-OCH2O-),6.04(1H,br s, -OCH2O-), 5.88 (1H, s, 3,6-dihydro-2H-pyridine), 5.29 (2H, s, H-9), 4.42-4.05 (2H, m, 3,6-dihydro-2H-pyridine) 3.99 (3H, s, 3-OCH3), 3.80 (3H, s, 4-OCH3), 3.69 (2H, s, 3,6-dihydro-2H-pyridine), 2.59-2.29 (2H, m, 3,6-dihydro-2H-pyridine), 1.53 (9H, s, Boc); 13 CNMR (100 MHz, CDCl3) δ 170.1 (C-9'), 155.1 (Boc), 151.7 (C-3), 149.8 (C-4), 147.6 (C-3'), 147.6 (C-4'), 138.9 (C-7), 136.9 (C-7'), 131.9 (3,6-dihydro-2H-pyridine), 130.7 (C-6), 129.4 (C-1), 128.4 (C-1'), 124.5 (3,6-dihydro-2H-pyridine), 123.6 (C- 6'), 123.5(C-8'), 118.3(C-8), 108.3(C-2', C-5'), 106.5(C-5), 103.3(C-2), 101.3(-OCH2O-), 80.2(Boc), 67.7(3,6-dihydro-2H-pyridine), 67.1(C-9), 55.9(3-OCH3), 55.9(4-OCH3), 53.5(3,6-dihydro-2H-pyridine), 29.4(3,6-dihydro-2H-pyridine), 28.5(Boc).

[0403] Compound 19m

[0404] Pd2(dba)3 (4.58 mg, 0.005 mmol), XantPhos (2.89 mg, 0.005 mmol), Cs2CO3 (65 mg, 0.2 mmol) and 18 (51 mg, 0.1 mmol) were added to an oven-dried 10 mL flask. The flask was capped and then backfilled with N2. A toluene solution of morpholine (17 mg, 0.2 mmol) was added via a syringe. The reaction mixture was heated to 100 °C for 10 hours. After cooling to room temperature, the reaction solution was quenched with water and extracted with CH2Cl2. The obtained solution was concentrated and purified by preparative TLC to give the desired product 19m (20 mg, 40%): HR-EIMS m / z[M+H] + (calculated value 450.1553); 1 H NMR (400MHz, CDCl3) δ7.79(1H,s,H-2),7.07(1H,s,H-5),6.96(1H,d,J=7.9Hz,H -5'),6.82(1H,d,J=1.4Hz,H-2'),6.79(1H,dd,J=7.9,1.7Hz,H-6'),6.09(1H,br s,-OCH2O-),6.05(1H,br s, -OCH2O-), 5.52 (2H, s, H-9), 4.07 (3H, s, 3-OCH3), 4.05-4.01 (2H, m, morpholine), 3.93 (2H, td, J = 10.9, 2.2 Hz, morpholine), 3.80 (3H, s, 4-OCH3), 3.28 (2H, td, J = 11.3, 2.9 Hz, morpholine), 3.13 (2H, d, J = 11.8 Hz, morpholine); 13 C NMR (100 MHz, CDCl3) δ 169.6 (C-9'), 151.8 (C-3), 150.1 (C-4), 147.5 (C-3', C-4'), 142.2 (C-7), 139.4 (C-7'), 136.8 (C-6), 132.1 (C-1), 130.5 (C-8'), 129.9 (C-1'), 128.6 (C-8), 123.5 (C-6'), 110.6 (C-2'), 108.2 (C-5'), 106.5 (C-5), 102.6 (C-2), 101.2 (-OCH2O-), 67.8 (morpholine), 67.3 (C-9), 55.9 (3-OCH3), 55.9 (4-OCH3), 51.5 (morpholine).

[0405] Compound 19n

[0406] A solution of 18 (256 mg, 0.5 mmol), tributyl(1-ethoxyvinyl)stannane (216 mg, 0.6 mmol) and 5 mL of toluene was degassed under stirring for 30 minutes. PdCl2(PPh3)2 (34 mg, 0.05 mmol) was then added and the solution was heated to 100°C overnight under stirring. 10 mL of 50% HCl (aq) was added to the reaction mixture and the solution was stirred for 6 hours and then filtered through diatomaceous earth, which effectively removed palladium black. The mixture was purified by silica gel column to give the desired product 19n (180 mg, 88%): HR-EIMS m / z [M+H] + 393.1324 (calculated value 393.1338); 1 H NMR(400MHz,DMSO-d6)δ7.64(1H,s,H-2),7.07(1H,d,J=7.9Hz,H-5'),7.06(1H,s,H-5),6.96(1H,d,J=1.6Hz,H-2'),6.82(1H, dd,J=7.9,1.7Hz,H-6'),6.14(2H,s,-OCH2O-),5.55(2H,s,H-9),3.97(3H,s,3-OCH3),3.68(3H,s,4-OCH3),2.76(3H,s,CH3); 13 C NMR(100MHz,DMSO-d6)δ202.0(Me-C=O),168.9(C-9'),152.4(C-3),149.7(C-4),147. 3(C-3'),147.1(C-4'),141.6(C-7),139.6(C-7'),129.4(C-6),129.1(C-1),129.0(C- 8'),127.9(C-1'),123.5(C-6'),118.0(C-8),110.6(C-2'),108.2(C-5'),106.0(C-5) ,104.4(C-2),101.4(-OCH2O-),68.6(C-9),55.9(3-OCH3),55.3(4-OCH3),31.8(CH3).

[0407] Compound 19o

[0408] Pd(PPh3)2Cl2 (17.5 mg, 0.025 mmol), CuI (14.3 mg, 0.075 mmol) and 18 (255 mg, 0.5 mmol) were added to an oven-dried 25-mL flask. The flask was capped and then backfilled with N2. A 5 mL DMF solution of trimethylsilylacetylene (100 mg, 1 mmol) and Et3N (150 mg, 1.5 mmol) was added via a syringe. The reaction mixture was heated to 80°C for 10 hours. After cooling to room temperature, the reaction solution was quenched with water and extracted with CH2Cl2. The obtained solution was concentrated and purified by silica gel column to give the desired product 19o (207 mg, 90%): HR-EIMS m / z[M+H] + 461.1404 (calculated value 461.1420); 1 H NMR (400MHz, CDCl3) δ7.62(1H,s,H-2),7.06(1H,s,H-5),6.90(1H,d,J=7.9Hz,H -5'),6.78(1H,d,J=1.5Hz,H-2'),6.75(1H,dd,J=7.9,1.7Hz,H-6'),6.03(1H,br s,-OCH2O-),5.99(1H,br s,-OCH2O-),5.34(2H,s,H-9),4.02(3H,s,3-OCH3),3.75(3H,s,4-OCH3),0.29(9H,s,TMS); 13 C NMR(100MHz, CDCl3)δ169.9(C-9'),152.6(C-3),150.3(C-4),147.9(C-3'),147.7(C- 4'),143.2(C-7),140.1(C-7'),133.3(C-6),128.9(C-1'),128.1(C-1),123.7(C-8', C-6'),118.5(C-8),110.7(C-2'),108.4(C-5'),106.5(C-5),106.2(C≡C),104.5(C≡C ),101.5(C-2),98.8(-OCH2O-),68.3(C-9),56.1(3-OCH3),56.0(4-OCH3),0.23(TMS).

[0409] Compound 19p

[0410] To a 25mL round-bottom flask (equipped with a thermocouple, overhead stirring and nitrogen inlet) was added cesium carbonate (74.1mg, 0.228mmol), palladium acetate (II) (0.7mg, 0.003mmol) and 4,5-bis-diphenylphosphine-9,9-dimethyl-9H-xanthene (Xantphos, 2.82mg, 0.005mmol). The flask was evacuated and backfilled with nitrogen 3×. Dioxane (2mL) was added, followed by another set of three evacuations and backfilling cycles with nitrogen. The canary yellow slurry was stirred at room temperature for 10 minutes, and triethylamine (0.68μL, 0.005mmol) was added. Stirring was continued at room temperature for 10 minutes, and the color gradually changed from yellow to red. 18 (83 mg, 0.162 mmol) and benzophenone imine (32.7 μL, 0.195 mmol) were added to 1 mL of dioxane (1 mL washings) via a syringe. The reaction mixture was warmed to an internal temperature of 100 ° C for 12 hours. The reaction mixture was cooled to ambient temperature and then the slurry was poured into 10 mL of ethyl acetate. The organic matter was washed with 2 × 50 mL of water, and the ethyl acetate solution was concentrated in vacuo. The mixture was purified by flash chromatography on silica gel, eluting with 1: 1 hexane: ethyl acetate to give 19p (50 mg, 57%) as a yellow solid; 1 H NMR (400 MHz, CDCl3) δ7.88 (2H, dt, J = 7.1, 1.4 Hz, phenyl), 7.64-7.55 (1H, m, H-2), 7.50 (2H, ddd, J = 8.1, 6.5, 1.4 Hz, phenyl), 7.37-7.30 (2H, m, phenyl), 7.25-7.18 (2H, m, phenyl), 7.16-7.10 (2H, m, phenyl), 7.10 (1H, s, H-5), 6.94 (1H, dd, J=7.9,0.5Hz,H-5'),6.82(1H,dd,J=1.7,0.5Hz,H-2'),6.79(1H,dd,J=7.9,1.7Hz,H-6'),6.08(1H,d,J=1. 5Hz,-OCH2O-),6.03(1H,d,J=1.5Hz,-OCH2O-),5.29(2H,s,H-9),3.98(3H,s,3-OCH3),3.82(3H,s,4-OCH3); 13C NMR (100 MHz, CDCl3) δ 170.1 (C-9'), 151.3 (C-3), 149.8 (C-4), 147.2 (C-3'), 147.2 (C-4'), 135.7 (C-7), 134.6 (C-7'), 131.5 (C-6), 130.2 (C-1), 129.9 (C-1'), 129.8 (phenyl), 129.3 (phenyl), 128.4 (phenyl) ,128.3(phenyl),128.2(phenyl),128.1(phenyl),126.0(C-6'),123.6(C-8'),118.3(C-8),110.8(C-2'),107.9(C-5'),106.3(C-5),101.7(C-2),101.0(-OCH2O-),67.0(C-9),56.0(3-OCH3),55.6(4-OCH3).

[0411] Compound 20

[0412] To a solution of 19n (41 mg, 0.1 mmol) in 1 mL of MeOH was added NaBH4 (6 mg, 0.15 mmol). The mixture was stirred at room temperature for 1 hour. TLC showed that the reaction had ended with one spot, and the mixture was purified by preparative TLC to give the desired product 20 (40 mg, 99%): HR-EIMS m / z [M+H] + 409.1272 (calculated value 409.1287); 1 H NMR (400MHz, DMSO-d6) δ7.48(1H,d,J=2.1Hz,H-2),7.03(1H,d,J=7.9Hz,H-5'),6.99(1H,d,J=4.0Hz,H-5),6.89(1H,d d,J=5.8,1.5Hz,H-2'),6.76(1H,ddd,J=7.8,6.0,1.7Hz,H-6'),6.12(2H,s,-OCH2O-),5.70(1H,m,CH-OH),5.59(2H,br s,H-9),3.97(3H,s,3-OCH3),3.64(3H,s,4-OCH3),1.51(3H,dd,J=6.3,1.3Hz,Me); 13C NMR(100MHz,DMSO-d6)δ169.5(C-9'),151.2(C-3),149.2(C-4),147.0(C-3'),146.9( C-4'),137.2(C-7),136.2(C-7'),134.7(C-6),128.8(C-1),128.6(C-1'),123.5(C-8 '),123.4(C-6'),118.2(C-8),110.9(C-2'),108.0(C-5'),105.8(C-5),102.9(C-2), 101.2(-OCH2O-), 68.9(CH-OH), 65.6(C-9), 55.8(3-OCH3), 55.1(4-OCH3), 23.3(CH3).

[0413] Compound 21

[0414] To a solution of 19o (207 mg, 0.45 mmol) was added K2CO3. The mixture was stirred for 2 hours. TLC showed a spot with less polarity. The mixture was purified by silica gel column to give the desired product 21 (122 mg, 70%): HR-EIMS m / z [M+H] + 389.1000 (calculated value 389.1025); 1 H NMR (400MHz, CDCl3) δ7.68(1H,s,H-2),7.14(1H,s,H-5),6.97(1H,d,J=7.9Hz,H -5'),6.85(1H,d,J=1.3Hz,H-2'),6.82(1H,dd,J=7.9,1.7Hz,H-6'),6.03(1H,br s,-OCH2O-),5.99(1H,br s,-OCH2O-),5.43(2H,s,H-9),4.10(3H,s,3-OCH3),3.82(3H,s,4-OCH3),3.78(1H,s,C≡CH); 13C NMR(100MHz, CDCl3)δ169.6(C-9'),152.7(C-3),150.3(C-4),147.8(C-3'),147.6(C -4'),143.8(C-7),140.4(C-7'),133.3(C-6),128.8(C-1'),127.9(C-1),123.5(C-6' ),121.4(C-8'),118.4(C-8),110.5(C-2'),108.3(C-5'),106.4(C-5),104.1(C-2),1 01.4(-OCH2O-),87.7(C≡CH),77.7(C≡CH),68.2(C-9),56.2(3-OCH3),55.9(4-OCH3).

[0415] Compound 22

[0416] Crude ketimine 19p (115.8 mg, 0.21 mmol) was suspended in a 1:1 (v / v) ratio of 1N HCl:THF (4 mL) solution and stirred at room temperature for 3-5 hours. After the ketimine was consumed as determined by TLC, THF was removed and the aqueous residue was basified to a pH of 10-14 using 1N KOH. The aqueous layer was then extracted three times with ethyl acetate (30 mL). The organic layer was dried over anhydrous NaSO4, filtered and concentrated in vacuo to give the crude amine. After purification via column chromatography, pure product 22 (70 mg, 84%) was obtained after removal of the solvent: HR-EIMS m / z[M+H] + 380.0849 (calculated value 380.1134); 1 H NMR(400MHz,DMSO-d6)δ7.62(1H,s,H-2),7.02(1H d,J=7.9Hz,H-5'),6.95(1H,s,H-5),6.86(1H,d,J=1.5Hz,H-2'),6.75(1H,dd,J=7.9,1.6Hz,H-6'), 6.11(2H,s,-OCH2O-),5.75(1H,s,NH2),5.36(2H,s,H-9),3.94(3H,s,3-OCH3),3.65(3H,s,4-OCH3); 13C NMR(100MHz,DMSO-d6)δ169.9(C-9'),150.6(C-3),149.8(C-4),147.0(C-3'), 146.7(C-4'),145.1(C-7),134.8(C-7'),129.6(C-6),129.0(C-1),128.9(C-1' ),123.9(C-6'),123.5(C-8'),121.9(C-8),111.2(C-2'),108.0(C-5'),105.5( C-5),101.2(C-2),101.0(-OCH2O-),67.0(C-9),55.8(3-OCH3),55.3(4-OCH3).

[0417] Compound 23

[0418] CsCO was added to a solution of 22 (38 mg, 0.1 mmol) and propargyl bromide (30 mg, 0.2 mmol) in MeCN (2 mL). The mixture was stirred at 60 °C for 12 h. After TLC showed a spot with less polarity, the reaction solution was quenched with water and extracted with CHCl. ​​The obtained solution was concentrated and purified by preparative TLC to give the desired product 23 (4.6 mg, 11%): HR-EIMS m / z [M+H] + 418.1279 (calculated value 418.1291); 1 H NMR(400MHz, CDCl3)δ7.19(1H,d,J=4.2Hz,H-2),7.14(1H,s,H-5),6.97(1H,d,J= 6.1Hz,H-5'),6.83(1H,d,J=1.6Hz,H-2'),6.80(1H,dd,J=7.9,1.7Hz,H-6'),6.10 (2H,m,-OCH2O-),6.06(2H,m,-OCH2O-),5.75(1H,s,NH),5.30(2H,s,H-9),4.16( 2H,s,CH2C≡CH),4.06(3H,s,3-OCH3),3.83(1H,s,CH2C≡CH),3.81(3H,s,4-OCH3); 13C NMR(100MHz,DMSO-d6)δ169.7(C-9'),150.5(C-3),149.7(C-4),146.8(C-3'),146.6(C-4') ,144.9(C-7),134.8(C-7'),129.5(C-1),129.5(C-1'),128.7(C-6),123.8(C-6'),123.3(C -8'),121.7(C-8),111.0(C-2'),107.9(C-5'),105.4(C-5),101.0(C-2),100.7(-OCH2O-), 79.7(CH2C≡CH), 74.1(CH2C≡CH), 66.6(C-9), 55.6(3-OCH3), 55.1(4-OCH3), 33.2(CH2C≡CH).

[0419] Compound 24

[0420] A solution of 22 (38 mg, 0.1 mmol) in anhydrous pyridine (2 mL) was added to Ac2O (14.2 μL, 0.15 mmol). The resulting mixture was stirred at room temperature overnight. After the reaction was complete, it was diluted with CH2Cl2 and washed with 10% HCl solution. The combined organic phases were further extracted with saturated NaHCO3 aqueous solution and dried over Na2SO4. After concentration, the crude product was purified by preparative TLC (1:1 n-hexane: ethyl acetate) to give 24 (15 mg, 36%) as a white solid: HR-EIMS m / z[M+H] + 433.1149 (calculated value 422.1240); 1 H NMR (400MHz, CDCl3) δ7.18(1H,s,H-2),7.01(1H,s,H-5),6.82(1H,d,J=7.9 Hz,H-5'),6.77(1H,d,J=1.6Hz,H-2'),6.72(1H,dd,J=7.9,1.7Hz,H-6'),6 .01(1H,d,J=1.4Hz,-OCH2O-),5.93(1H,d,J=1.5Hz,-OCH2O-),5.17(2H,s, H-9),3.90(3H,s,3-OCH3),3.75(3H,s,4-OCH3),2.30(3H,d,J=0.9Hz,OAc); 13C NMR (100MHz, CDCl3) δ170.6(OAc),169.7(C-9'),152.2(C-3),150.1(C-4),147.6(C- 3'),147.6(C-4'),138.5(C-7),135.7(C-7'),130.0(C-1),128.9(C-1'),128.2(C-6) ,124.4(C-8'),123.6(C-6'),118.6(C-8),110.7(C-2'),108.2(C-5'),106.5(C-5),1 01.4(C-2),100.9(-OCH2O-),68.3(C-9),56.1(3-OCH3),55.9(4-OCH3),23.40(OAc).

[0421] General Procedure A: Glycosylation modification

[0422] A solution of sugar (0.61mmol) in anhydrous pyridine (2mL) was added to acetic anhydride (Ac2O) (0.4mL, 4.21mmol). The resulting mixture was stirred at room temperature overnight. After the reaction was complete, it was diluted with dichloromethane (CH2Cl2) and washed with 10% hydrogen chloride (HCl) solution. The combined organic phase was further extracted with saturated sodium bicarbonate (NaHCO3) aqueous solution and dried over sodium sulfate (Na2SO4). After concentration, the crude product was directly used in the next step without further purification.

[0423] The crude fully acetylated glycoside was dissolved in CH2Cl2 (5 mL) and cooled to 0°C, then hydrogen bromide (33% in acetic acid, 1.5 mL) was added dropwise. The reaction was warmed to room temperature and stirred for an additional 4 hours. After completion, the reaction was quenched with water and the aqueous layer was extracted with CH2Cl2. The organic layers were combined, washed with water, sodium bicarbonate and brine, dried with Na2SO4 and concentrated under reduced pressure to obtain bromosugar. After concentration, the crude product was directly used in the next step without further purification.

[0424] The schizoferrin (5) (215 mg, 0.61 mmol) was dissolved in chloroform (CHCl3) (15 mL) and aqueous sodium hydroxide solution (NaOH) (0.1 M, 20 mL), and then tetra-n-butylammonium bromide (TBAB) (306 mg, 0.95 mmol) was added. Then, the reaction was heated to 40°C for 10 minutes, and then bromosugar (0.61 mmol) was added, and then the reaction was stirred at 40°C overnight. After cooling to room temperature, the aqueous layer was extracted with CHCl3, and the combined organic layers were washed with brine, dried with Na2SO4 and concentrated under reduced pressure. The reaction mixture was separated by flash chromatography (silica gel, hexane containing 45%-52% ethyl acetate) to obtain the target schizoferrin peracetylated glycosides (25a-25g). The reaction mixtures of compounds 25c-25g were not purified, but they were directly treated with alkaline reagents to produce their corresponding hydrolyzed compounds 26c-26g.

[0425] Potassium carbonate (K2CO3) (168.4mg, 1.2mmol) was added to a MeOH (10mL) solution of feroxetine peracetylated glycosides (25a-25g) and stirred at room temperature for 30 minutes. When no starting material was observed by TLC, the reaction was quenched by adding dilute HCl (2M), filtered through filter paper, and concentrated under reduced pressure. The reaction mixture was separated by flash chromatography (silica gel, CHCl3 containing 2%-10% MeOH) to obtain the target glycosides (26a-26g).

[0426] Fully acetylated 7β-D-xylosyl-shanylin (25a, total yield 80%)

[0427] HR-EIMS m / z[M+H] + 639.5780 (calculated value 639.1714); 1H NMR (400MHz, CDCl3) δ7.51(1H,d,J=1.0Hz,H-2),7.07(1H,s,H-5),6.95(1H,d,J=7.8Hz,H-5'),6.84–6.80(1H,m,H-2 '),6.80–6.76(1H,m,H-6'),6.11–6.03(2H,m,-OCH2O-),5.50–5.44(1H,m,H-1”),5.44–5.40(2H,m,H-9),5.31(1H,br t,J=8.9Hz,H-3”),5.13(1H,dd,J=8.8,5.2Hz,H-2”),5.12(1H,dd,J=8.3,6.2Hz,H-4”),4.26(1H,dd,J=11.8,5.2Hz,H-5”a), 4.16–4.10(1H,m,H-5”b),4.07(3H,s,3-OCH3),3.80(3H,s,4-OCH3),2.12(3H,s,-OAc),2.10(3H,s,-OAc),2.04(3H,s,-OAc).

[0428] Fully acetylated patentiflorin A (25b, total yield 71%)

[0429] HR-EIMS m / z[M+H] + 653.1744 (calculated value 653.1870); 1 H NMR (400MHz, CDCl3) δ7.53(1H,d,J=1.9Hz,H-2),7.07(1H,s,H-5),6.96(1H,d,J=7.8Hz,H-5'),6.85–6.81(1H,m,H-2'),6. 81–6.77(1H,m,H-6'),6.12–6.04(2H,m,-OCH2O-),5.50–5.43(2H,m,H-9),5.39(1H,dd,J=14.7,2.4Hz,H-2”),5.27(1H,t,J =9.6Hz,H-3”),5.12(1H,d,J=7.9Hz,H-1”),5.00(1H,t,J=9.6Hz,H-4”),4.07(3H,s,3-OCH3),3.81(3H,s,4-OCH3),3.61(1H ,ddd,J=9.7,6.1,1.2Hz,H-5”),2.12(3H,s,-OAc),2.06(3H,s,-OAc),2.06(3H,s,-OAc),1.28(3H,dd,J=6.1,1.4Hz,H-6”).

[0430] 7β-D-Xylosyl-1,2-Dihydro-1-nitro-1-nitro-2 ...

[0431] HR-EIMS m / z[M+H] + 513.1389 (calculated value 513.1397); 1 H NMR(400MHz,methanol-d6)δ8.13(1H,s,H-2),7.09(1H,d,J=1.8Hz,H-5),6.97(1H,d,J=7.9Hz,H-5'),6.82(1 H,dd,J=3.1,1.3Hz,H-2'),6.79(1H,dt,J=7.9,1.8Hz,H-6'),6.08-6.04(2H,m,-OCH2O-),5.58(1H,dd,J=15.2 ,1.6Hz,H-9),5.46(1H,dd,J=15.2,2.0Hz,H-9),4.03(3H,s,3-OCH3),3.98(1H,d,J=6.5Hz,H-1”),3.98-3.92 (1H,m,H-5”),3.74(3H,s,4-OCH3),3.64(1H,m,H-2”),3.51-3.44(1H,m,H-4”),3.16-3.11(2H,m,H-3”,H-5”).

[0432] Patentiflorin A (26b, total yield 68%)

[0433] HR-EIMS m / z[M+H] + 527.1526 (calculated value 527.1553); 1 H NMR (400MHz, CD3OD) δ7.99-7.92(1H,m,H-2),6.86(1H,m,H-5),6.82-6.77(1H,m,H-5'),6.63(1H,m,H -2'),6.59(1H,m,H-6'),5.94(1H,d,J=1.2Hz,-OCH2O-),5.93(1H,dd,J=2.2,1.3Hz,-OCH2O-),5.50-5 .27(2H,m,H-9),4.67(1H,d,J=7.9Hz,H-1”),3.88(3H,s,3-OCH3),3.57(3H,s,4-OCH3),3.54(1H,m,H -2”), 3.33(1H,t,J=9.1Hz,H-3”), 3.05(1H,t,J=9.2Hz,H-4”), 3.170(1H,m,H-5”), 1.21(3H,m,H-6”).

[0434] 7-O-α-L-arabinosyl shanuolin (26c, total yield 45%)

[0435] HR-EIMS m / z[M+H] + 513.1305 (calculated value 513.1397); 1 H NMR (400MHz, acetone-d6) δ8.21(1H,s,H-2),7.07(1H,d,J=2.2,H-5),6.95(1H,d,J=7.9Hz,H-5'),6.85(1H,dd,J=5.8,1.7Hz,H-2') ,6.79(1H,dt,J=7.9,2.0Hz,H-6'),6.10-6.04(2H,m,-OCH2O-),5.62-5.34(3H,m,H-9,H-1”),4.98(1H,dt,J=4.2,1.9Hz,OH-3” ),4.87(1H,dd,J=7.1,2.0Hz,H-1”),4.24(1H,t,J=5.9Hz,OH-2”),4.03(1H,ddd,J=8.7,7.0,4.3Hz,H-2”),3.96(3H,s,3-OCH3) ,3.98-3.94(1H,m,H-5”),3.91-3.84(1H,m,H-4”),3.70(3H,s,4-OCH3),3.68-3.72(1H,m,H-3”),3.57(1H,d,J=12.4Hz,H-5”).

[0436] 7-O-β-L-fucopyranosyl shanuoyelin (26d, total yield 49%)

[0437] HR-EIMS m / z[M+H] + 527.1433 (calculated value 527.1553); 1H NMR (400MHz, DMSO-d6) δ8.20d(1.9Hz,H-2),7.05(1H,dd,J=7.9,1.4Hz,H-5'),6.99(1H,d,J=2.1Hz,H-5),6.94(1H,dd,J=11. 1,1.5Hz,H-2'),6.81(1H,ddd,J=7.8,6.0,1.6Hz,H-6'),6.13(2H,s,-OCH2O-),5.59-5.44(3H,m,H-9,OH-2”),4.89(1H,dd,J= 14.7,3.1Hz,OH-3”),4.70(1H,dd,J=7.7,4.9Hz,H-1”),4.20(1H,d,J=7.3Hz,OH-4”),3.95(3H,s,3-OCH3),3.75(dd,J=9.4,7 .7Hz,1H),3.67(3H,s,4-OCH3),3.62(1H,d,J=6.4Hz,H-2”),3.50-3.42(3H,m,H-3”,H-4”,H-5”),1.19(3H,d,J=6.2Hz,H-6”).

[0438] 7-O-β-D-fucopyranosyl shanuolin (26e, total yield 67%)

[0439] HR-EIMS m / z[M+H] + 527.1550 (calculated value 527.1553); 1 H NMR (400 MHz, acetone-d6) δ 8.29-8.08 (1H, m, H-2), 7.12-7.01 (1H, m, H-5), 6.96 (1H, q, J = 7.8 Hz, H-5'), 6.81 (2H, m, H-2', H-6'), 6.08 (2H, t, J = 7.5 Hz, -OCH2O-), 5.62-5.48 (1H, m, H-9), 5.50-5.35 (1H, m, H-9), 5.30-5.15 (1H,m,OH-2”),4.87(1H,dt,J=11.7,6.2Hz,H-1”),4.69(1H,s,OH-4”),4.02-3.95(2H,m,H-3”,H-4”),3.7 9(3H,d,J=7.4Hz,3-OCH3), 3.76-3.72(1H,m,H-2”), 3.70(4H,m,4-OCH3,H-5”), 1.29(q,J=8.2,7.7Hz,3H).

[0440] 7-O-β-D-pyranosylglucopyranosyl santhemol (26f, total yield 48%)

[0441] HR-EIMS m / z[M+H] + 543.1500 (calculated value 543.1503); 1 H NMR (400 MHz, acetone-d6) δ8.22 (1H, dq, J=9.0, 4.9 Hz, H-2), 7.05 (1H, m, H-5), 6.95 (1H, tq, J=8.2, 4.0 Hz, H-5'), 6.89-6.74 (2H, m, H-2', H-6'), 6.07 (2H, m, -OCH2O-), 5.73 (1H, m, H-9), 5.48-5.36 (1H, m, H-9), 5.22 (1H, q, J=4 .3Hz,OH-3”),4.91(1H,tt,J=7.6,3.9Hz,OH-4”),4.65(1H,d,J=4.6Hz,H-1”),4.43(1H,d,J=4.8Hz,OH-6”),3 .97(4H,m,3-OCH3,H-6”),3.70(5H,m,4-OCH3,H-6”,H-2”),3.61-3.43(2H,m,H-5”,H-3”),3.39(1H,m,H-4”).

[0442] 7-O-β-D-galactopyranosyl galactopyranosyl galactopyranoside (26 g, total yield 64%)

[0443] HR-EIMS m / z[M+H] + 543.1370 (calculated value 543.1503); 1 H NMR (400 MHz, acetone-d6) δ8.22 (1H, d, J = 1.0 Hz, H-2), 7.10 (1H, s, H-5), 6.98 (1H, dt, J = 7.9, 0.6 Hz, H-5'), 6.91-6.85 (1H, m, H-2'), 6.85-6.79 (1H, m, H-6'), 6.13-6.06 (2H, m, -OCH2O-), 5.84-5.35 (2H,m,H-9),4.96-4.83(1H,m,H-1”),4.34-4.19(1H,m,OH),4.08-4.01(2H,m,H-2”,H-4”),4.0 0(3H,s,3-OCH3),3.97-3.82(3H,m,H-5”,H-6”),3.73(3H,s,4-OCH3),3.54-3.69(1H,m,H-3”).

[0444] General Procedure B: Selective Modification of the 3"-Hydroxyl Group

[0445] In the presence of tetrabutylammonium acetate (TBOAc) (27 mg, 0.09 mmol), glycoside 26a or 26b (0.3 mmol) was allowed to react with anhydrous acetonitrile (MeCN) (1.5 mL) containing acetic anhydride (32 μL, 0.32 mmol) at 40° C. for 12 hours. The solution was concentrated in vacuo to give a mixture containing 27aa-27af (total mixture yield, obtained from 26a: 52%) or a mixture containing 27ba-27bf (total mixture yield, obtained from 26b: 50%) as a light yellow solid. The compound mixture containing 27aa-27af was purified by flash column chromatography (petroleum ether / EtOAc=1.5 / 1) to give six single compounds 27aa-27af (27aa, 27ab, 27ac, 27ad, 27ae and 27af). The compound mixture containing 27ba-27bf was purified by flash column chromatography (petroleum ether / EtOAc=1.5 / 1) to give six individual compounds 27ba-27bf (27ba, 27bb, 27bc, 27bd, 27be and 27bf).

[0446] Triethylamine (Et3N) (50 μL, 0.36 mmol) and allyl chloroformate (AllocOCl) (10.7 μL, 0.1 mmol) were added to a suspension of 27ab or 27bb (0.036 mmol) in CH2Cl2 (3 mL) at 0°C, and the reaction was allowed to slowly warm to room temperature. After 12 hours, the reaction mixture was poured into H2O and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to give a mixture of compounds containing 28ab1-28ab3 (total mixture yield, derived from 27ab: 45%) or a mixture of compounds containing 28bb1-28bb3 (total mixture yield, derived from 27bb: 52%) as a white solid. The compound mixture containing 28ab1-28ab3 was purified by flash column chromatography (petroleum ether / EtOAc=1 / 1) to obtain three single compounds 28ab1-28ab3 (28ab1, 28ab2 and 28ab3). The compound mixture containing 28bb1-28bb3 was purified by flash column chromatography (petroleum ether / EtOAc=1 / 1) to obtain three single compounds 28bb1-28bb3 (28bb1, 28bb2 and 28bb3).

[0447] To a solution of 28ab3 or 28bb3 (0.004 mmol) in 6 mL MeOH / CH2Cl2 (v / v=1 / 2) was added acetyl chloride (AcCl) (15 μL) at 0°C. The reaction mixture was stirred for 72 hours and then quenched with Et3N. The volatiles were removed in vacuo. The resulting residue was purified by silica gel column chromatography (petroleum ether / EtOAc 1 / 1) to give 29a or 29b (18.4 mg, 67%) as a white solid.

[0448] 29a or 29b (0.05mmol), Et3N (20.8 μL, 0.15mmol) and 4-dimethylaminopyridine (DMAP) (catalytic amount) are dissolved in 2mL of anhydrous CH2Cl2. At 0°C, selected acyl chloride (0.15mmol) is added to the mixture. The reaction mixture is allowed to warm to 25°C and kept stirring at 25°C for 2 hours. The desired products 30a-30k are given by preparative TLC (petroleum ether / EtOAc=1 / 1) purification of the mixture.

[0449] To a solution of 29a (20 mg, 0.036 mmol) in anhydrous THF (2 mL) were added fresh powdered KOH (3.6 mg, 0.0648 mmol), 18-crown-6 (0.4 mg, 0.0014 mmol) and benzyl bromide (11 μL, 0.09 mmol) in succession. The mixture was stirred at room temperature and the reaction was monitored by TLC; at the end of the reaction, the mixture was diluted with CH2Cl2 and washed several times with water. The combined organic phases were dried over Na2SO4 and concentrated. The obtained residue was purified by preparative TLC (petroleum ether / EtOAc=1 / 1) to give the desired product 301.

[0450] To a solution of 30a-301 (0.045 mmol) in anhydrous THF (4 ml) was added triphenylphosphine (PPh3) (5.9 mg, 0.023 mmol), Et3N (31.2 μL, 0.225), HCOOH (17 μL, 0.45 mmol) and tetrakis (triphenylphosphino) palladium (0) [Pd (PPh3) 4] (5 mg, 0.0025 mmol) in sequence. Under nitrogen, the solution was stirred at 55 ° C for 4 hours and concentrated in vacuo to give a mixture. The mixture was chromatographed on preparative TLC (petroleum ether / EtOAc=1 / 1) to give the desired products 31a-311.

[0451] 4"-Acetyl-7-O-β-D-xylosyl feroxanthin (27aa)

[0452] HR-EIMS m / z[M+H] + 555.1406 (calculated value 555.1503);1 H NMR (400 MHz, acetone-d6) δ7.63 (1H, d, J = 1.0 Hz, H-2), 7.07 (1H, d, J = 2.3 Hz, H-5), 7.01–6.94 (1H, m, H-5′), 6.85 (1H, d, J = 1.6 Hz, H-2′), 6.80 (1H, ddd, J = 7.9, 1.6, 0.4 Hz, H-6′), 6.10 (2H, dt, J =4.9,1.0Hz,-OCH2O-),5.60–5.45(2H,m,H-9),5.33(1H,d,J=7.8Hz,H-1”),5.22(1H,dd,J=9 .1,7.8Hz,H-2”),4.08(1H,dd,J=11.4,5.2Hz,H-5”a),4.03(3H,s,3-OCH3),3.70-3.80(1H,m H-3”), 3.70-3.80 (1H, m H-4”), 3.73 (3H, s, 4-OCH3), 3.46 (1H, dd, J = 11.3, 10.1 Hz, H-5” b), 2.09 (3H, s, OAc).

[0453] 3"-Acetyl-7-O-β-D-xylosyl shanuolin (27ab)

[0454] HR-EIMS m / z[M+H] + 555.1439 (calculated value 555.1503); 1 H NMR (400MHz, acetone-d6) δ8.08(1H,d,J=3.3Hz,H-2),7.05(1H,br s,H-5),6.99-6.93(1H,m,H-5'),6.89(1H,m,H-2'),6.79(1H dd,J=1.8,6.0Hz,H-6'),6.13-6.07(2H,m,-OCH2O-),5.53(1H,d,J=15.0Hz,H-1”),5.41(1H d,J=15.1Hz,H-3”),5.11-5.01(2H,m,br s,H-9),4.04(1H,m,H-5”),3.94(3H,s,3-OCH3),3.91-3.82(1H,m,H-2”), 3.69(3H,d,J=6.5Hz,4-OCH3),3.47-3.35(1H,m,H-5”),2.10(3H,s,OAc); 13C NMR (100 MHz, acetone-d6) δ 171.0 (OAc), 169.8 (C-9'), 153.0 (C-3), 151.5 (C-4), 148.4 (C-3'), 148.3 (C-4'), 145.8 (C-7), 136.7 (C-7'), 131.4 (C-1), 129.7 (C-6), 128.1 (C-1'), 124.6 (C-6'), 120.0 (C-8), 111. 8(C-8'),111.7(C-2'),108.7(C-5'),106.7(C-5),106.6(C-1”),102.4(C-2),102.2(-OCH2O-),78.8( C-3”),73.2(C-2”),69.1(C-4”),67.8(C-9),66.8(C-5”),56.4(3-OCH3),55.8(4-OCH3),21.2(-OAc).

[0455] 3”,4”-Diacetyl-7-O-β-D-xylosyl shanhuoyexin (27ad)

[0456] HR-EIMS m / z[M+H] + 597.1533 (calculated value 597.1608); 1 H NMR (400MHz, acetone-d6) δ7.53 (1H, d, J = 0.8Hz, H-2), 7.02 (1H, d, J = 2.1Hz, H-5), 6. 91(1H,d,J=7.9Hz,H-5'),6.79(1H,dd,J=3.3,1.4Hz,H-2'),6.74(1H,ddd,J=7. 9,2.7,1.7Hz,H-6'),6.03(2H,dt,J=4.8,0.9Hz,-OCH2O-),5.59–5.45(2H,m,H- 9),5.42(1H,d,J=7.6Hz,H-1''),5.23(1H,dd,J=9.8,7.6Hz,H-2''),5.14(1H,br t,J=9.3Hz,H-3”),4.06(1H,dd,J=11.5,5.6Hz,H-5”a),3.95(3H,s,3-O CH3),3.94(1H,br td,J=10.3,5.3Hz,H-4”),3.66(3H,s,4-OCH3),3.51(1H,br t,J=10.8Hz,H-5”b),2.03(3H,s,-OAc),1.98(3H,s,-OAc).

[0457] 2”,4”-Diacetyl-7-O-β-D-xylosyl-shanyaenoyl (27ae)

[0458] HR-EIMS m / z[M+H] + 597.1509 (calculated value 597.1608); 1 H NMR (400MHz, acetone-d6) δ7.62(1H,d,J=1.8Hz,H-2),7.03(1H,d,J=2.1Hz,H-5),6.92(1H,dd,J=7.9,1.1Hz,H-5'),6.80(1H,d,J=1.6Hz,H-2'),6.77 –6.71(1H,m,H-6'),6.07–6.00(2H,m,-OCH2O-),5.54–5.40(2H,m,H-9), 5.43(1H,d,J=7.1,H-1”),5.27(1H,dd,J=8.8,7.2Hz,H-2”),4.90(1H,br td,J=9.0,5.2Hz,H-4”),4.15(1H,dd,J=11.6,5.1Hz,H-5”a),4.04–3.99(1H,br t,J=8.7Hz,H-3”),3.98(3H,s,3-OCH3),3.67(3H,s,4-OCH3),3.50(1H,dd,J=11.6,9.5Hz,H-5”b),2.10(3H,s,-OAc),2.03(3H,s,-OAc).

[0459] 2",3"-Diacetyl-7-O-β-D-xylosyl-shanyaminol (27af)

[0460] HR-EIMS m / z[M+H] + 597.1505 (calculated value 597.1608); 11H NMR (400 MHz, acetone-d6) δ 8.10 (1H, d, J = 1.5 Hz, H-2), 7.10 (1H, d, J = 4.5 Hz, H-5), 6.98 (1H, dd, J = 7.9, 1.2 Hz, H-5’), 6.88 (1H, br d, J = 1.3 Hz, H-2’), 6.81 (1H, dd, J = 7.9, 1.7 Hz, H-6’), 6.10 (2H, ddd, J = 4.8, 1.6, 1.1 Hz, -OCH2O-), 5.58–5.41 (2H, m, H-9), 5.25 (1H, br t, J = 9.5 Hz, H-3”), 5.13 (1H, d, J = 7.6 Hz, H-1”), 5.00 (1H, br td, J = 9.6, 5.5 Hz, H-4”), 4.16 (1H, dd, J = 11.5, 5.5 Hz, H-5”a), 4.02 (1H, d, J = 9.6, 7.7 Hz, H-2”), 3.97 (3H, s, 3-OCH3), 3.72 (3H, s, 4-OCH3), 3.54 (1H, dd, J = 11.5, 9.9 Hz, H-5”b), 2.06 (3H, s, -OAc), 1.98 (3H, s, -OAc).

[0461] 4”-Acetyl-7-O-β-D-patentiflorin A (27ba)

[0462] HR-EIMS m / z [M+H] + 569.1612 (calcd 569.1659); 1 1H NMR (400 MHz, CDCl3) δ 7.58 (1H, d, J = 1.5 Hz, H-2), 7.07 (1H, s, H-5), 6.96 (1H, d, J = 7.8 Hz, H-5’), 6.86–6.81 (1H, m, H-2’), 6.81–6.77 (1H, m, H-6’), 6.12–6.01 (2H, m, -OCH2O-), 5.51–5.37 (2H, m, H-9), 5.272 (1H, dd, J = 9.8, 7.9 Hz, H-2”), 5.06 (1H, d, J = 7.8 Hz, H-1”), 4.07 (3H, s, 3-OCH3), 3.81 (3H, s, 4-OCH3), 3.67 (1H, t, J = 9.2 Hz, H-3”), 3.44 (1H, m, H-4”), 3.43 (1H, m, H-5”), 2.20 (3H, s, OAc), 1.39 (3H, d, J = 4.0 Hz, H-6”).

[0463] 3”-Acetyl-7-O-β-D-patentiflorin A(27bb)

[0464] HR-EIMS m / z[M+H] + 569.1602 (calculated value 569.1659); 1 H NMR (400MHz, CDCl3) δ7.93(1H,s,H-2),7.02(1H,d,J=3.6Hz,H-5),6.91(1H,dd,J=9.2,8.0Hz,H-5'),6.82-6 .67(2H,m,H-2',6'),6.11-5.99(2H,m,-OCH2O-),5.55-5.34(2H,m,H-9),4.86(1H,t,J=9.2Hz,H-3”),4.82( 1H,d,J=7.8Hz,H-1”),3.99(3H,s,3-OCH3),3.93(1H,dd,J=9.5,7.8Hz,H-2”),3.77(3H,d,J=2.3Hz,4-OCH3) ,3.42(1H,t,J=9.2Hz,H-4”),3.37-3.28(1H,m,H-5”),2.20(3H,s,-OAc),1.34(3H,dd,J=6.0,1.2Hz,H-6”); 13 C NMR(100MHz, CDCl3)δ173.5(OAc),170.3(C-9'),152.1(C-3),150.3(C-4),147.6(C-3'),147.6(C-4'),1 44.5(C-7),136.8(C-7'),131.2(C-8),130.8(C-6),128.3(C-1'),127.4(C-1),123.7(C-6'),119.1(C-8' ),110.8(C-2'),108.3(C-5'),106.2(C-1”),104.7(C-5),101.4(C-2),101.1(-OCH2O-),79.4(C-3”),73 .9(C-4”),73.0(C-2”),72.4(C-5”),67.7(C-9),56.4(3-OCH3),55.9(4-OCH3),21.20(C-6”),17.7(OAc).

[0465] 2”-Acetyl-7-O-β-D-patentiflorin A(27bc)

[0466] HR-EIMS m / z[M+H] +569.1596 (calculated value 569.1659); 1 H NMR (400MHz, CDCl3) δ7.96(1H,s,H-2),7.09(1H,s,H-5),6.96(1H,d,J=7.9Hz,H-5'),6.84(1H,dd,J=3.1,1.4 Hz,H-2'),6.83–6.78(1H,m,H-6'),6.12–6.03(2H,m,-OCH2O-),5.54-5.39(2H,m,H-9),4.83(1H,dt,J=8.7,1 .4Hz,H-4”),4.74(1H,t,J=9.5Hz,H-1”),4.04(3H,s,3-OCH3),3.92(1H,dd,J=9.3,7.9Hz,H-2”),3.81(3H,s, 4-OCH3), 3.67 (1H, t, J = 9.3Hz, H-3”), 3.51–3.44 (1H, m, H-5”), 2.15 (3H, s, OAc), 1.27 (3H, d, J = 1.5Hz, H-6”).

[0467] 3”,4”-Diacetyl-7-O-β-D-patentiflorin A(27bd)

[0468] HR-EIMS m / z[M+H] + 611.1705 (calculated value 609.1972); 1 H NMR (400MHz, CDCl3) δ7.53(1H,d,J=1.5Hz,H-2),7.07(1H,s,H-5),6.98–6.94(1H,m,H-5'),6.84–6.80(1H,m,H-2' ),6.81–6.76(1H,m,H-6'),6.11–6.02(2H,m,-OCH2O-),5.50–5.43(2H,m,H-9),5.42–5.36(1H,m,H-2”),5.12(1H,d ,J=7.9Hz,H-1”),5.06(1H,t,J=9.8Hz,H-3”),4.06(3H,s,3-OCH3),3.80(3H,s,4-OCH3),3.54(1H,t,J=9.1Hz,H-4” ), 3.48(1H,ddd,J=8.8,5.6,1.1Hz,H-5”),2.14(3H,s,-OAc),2.11(3H,s,-OAc),1.40(3H,dd,J=5.8,1.2Hz,H-6”).

[0469] 2”,4”-Diacetyl-7-O-β-D-patentiflorin A(27be)

[0470] HR-EIMS m / z[M+H] + 611.1721 (calculated value 609.1972); 1 H NMR (400MHz, CDCl3) δ7.58(1H,d,J=1.7Hz,H-2),7.07(1H,s,H-5),6.96(1H,d,J=7.9Hz,H-5'),6.83(1H,dd,J=3.0,1. 5Hz,H-2'),6.80(1H,ddd,J=7.9,3.0,1.7Hz,H-6'),6.12–6.03(2H,m,-OCH2O-),5.50–5.38(2H,m,H-9),5.38–5.29(1H ,m,H-2”),5.05(1H,d,J=7.9Hz,H-1”),4.84(1H,t,J=9.5Hz,H-4”),4.07(3H,s,3-OCH3),3.81(3H,s,4-OCH3),3.77(1 H,t,J=9.6Hz,H-3”),3.60–3.50(1H,m,H-5”),2.20(3H,s,-OAc),2.15(3H,s,-OAc),1.29(3H,dd,J=6.2,1.4Hz,H-6”).

[0471] 2”,3”-Diacetyl-7-O-β-D-patentiflorin A(27bf)

[0472] HR-EIMS m / z[M+H] + 611.1699 (calculated value 609.1972); 1H NMR (400 MHz, chloroform-d) δ7.93 (1H, s, H-2), 7.08 (1H, s, H-5), 6.97–6.93 (1H, m, H-5'), 6.86–6.81 (1H, m, H-2'), 6.80–6.76 (1H, m, H-6'), 6.11–6.02 (2H, m, -OCH2O-), 5.53–5.37 (2H, m, H-9), 5.08 (1H, t, J = 9.5 Hz, H-3'), 4.92 (1 H,t,J=9.6Hz,H-4”),4.88(1H,d,J=7.8Hz,H-1”),4.04(1H,dd,J=9.3,7.9Hz,H-2”),4.02(3H,s,3-OCH3),3.8 0(3H,s,4-OCH3),3.55–3.46(1H,m,H-5”),2.15(3H,s,-OAc),2.06(3H,s,-OAc),1.24(3H,d,J=5.6Hz,H-6”).

[0473] 4"-O-allyloxycarbonyl-3"-acetyl-7-O-β-D-xylosyl feroxanthin (28ab1)

[0474] HR-EIMS m / z[M+H] + 639.1514 (calculated value 639.1714); 1H NMR (400MHz, acetone-d6) δ7.66 (1H, s, H-2), 7.10 (1H, d, J = 3.3 Hz, H-5), 6.98 (1H, dd, J=7.9,1.8Hz,H-5'),6.92–6.77(2H,m,H-2',H-6'),6.10(2H,dt,J=4.8,1.3Hz, -OCH2O-),5.96(1H,ddt,J=16.2,10.9,5.6Hz,O-Alloc),5.63–5.46(2H,m,H-9) ,5.44(1H,d,J=7.6Hz,H-1”),5.34(1H,dq,J=17.2,1.6Hz,O-Alloc),5.24(1H,bt t,J=9.4Hz,H-3”)5.29–5.20(1H,m,O-Alloc),5.08(1H,dd,J=9.8,7.8Hz,H-2”),4.85(1H,dd,J=5.1,2.1H z,O-Alloc),4.71(1H,m,O-Alloc),4.10(1H,dd,J=11.2,5.5Hz,H-5”a),4.02(3H,s,3-OCH3),3.99(1H,br td,J=10.2,5.5Hz,H-4”),3.72(3H,s,4-OCH3),3.51(1H,br t,J=10.9Hz,H-5”b),2.08(3H,s,OAc).

[0475] 2"-O-allyloxycarbonyl-3"-acetyl-7-O-β-D-xylosyl feroxanthin (28ab2)

[0476] HR-EIMS m / z[M+H] + 639.1514 (calculated value 639.1714); 1H NMR (400MHz, acetone-d6) δ8.09(1H,s,H-2),7.10(1H,dd,J=4.1,1.6Hz,H-5),6.98( 1H,dd,J=7.9,1.6Hz,H-5'),6.91–6.85(1H,m,H-2'),6.85–6.78(1H,m,H-6'), 6.10(2H,dt,J=5.2,1.3Hz,-OCH2O-),5.93(1H,ddt,J=16.2,10.8,5.6Hz,O-Al loc),5.76(1H,dt,J=5.0,2.4Hz,O-Alloc),5.60–5.41(2H,m,H-9),5.29(1H,bt t,J=9.5Hz,H-3”),5.25–5.20(1H,m,O-Alloc),5.14(1H,d,J=7.6Hz,H-1”),4.88(1H,br td,J=9.5,5.5Hz,H-4”),4.68–4.54(2H,m,O-Alloc),4.26(1H,dd,J=11.6,5.5Hz,H-5”a) ,4.03(1H,dd,J=9.5,7.6Hz,H-2”),3.96(3H,s,3-OCH3),3.72(3H,s,4-OCH3),3.61(1H,br t,J=11.2Hz,H-5”b),2.06(3H,s,OAc).

[0477] 2”,4”-O-diallyloxycarbonyl-3”-acetyl-7-O-β-D-xylosyl feroxanthin (28ab3)

[0478] HR-EIMS m / z[M+H] + 723.1703 (calculated value 723.1925); 1H NMR (400MHz, CDCl3) δ7.55(1H,s,H-2),7.09(1H,s,H-5),6.96(1H,dd,J=8.2,1.0Hz,H-2'),6.87-6.77 (2H,m,H-5',6'),6.12-6.04(2H,m,-OCH2O-),5.90(2H,m,H-9),5.52-5.20(8H,m,O-alloc),5.05(1H, d,J=7.7Hz,H-1”),5.04-4.95(1H,m,H-3”),4.75-4.59(4H,m,O-alloc),4.24(1H,dd,J=11.8,5.5Hz,H -5”),4.06(3H,s,3-OCH3),3.81(3H,s,4-OCH3),3.36(1H,dd,J=11.7,10.1Hz,H-5”),2.11(3H,s,OAc); 13 C NMR (100MHz, acetone-d6) δ170.2(OAc),169.6(C-9'),155.3(O-alloc),155.1(O-alloc),153.2(C-3),151.5(C-4),148.4(C-3'),148.3(C- 4'),144.7(C-7),132.9(O-alloc),132.8(O-alloc),136.7(C-7'),131.4(C-1),129.6(C-6),127.2(C-1'),124.6(C-6'),120.1(C-8), 119.2(O-alloc),118.9(O-alloc),111.7(C-2'),111.7(C-8'),108.7(C-1”,C-5'),106.9(C-5),102.5(C-2),102.2(-OCH2O-),79.1(C -3”),75.7(C-2”),72.1(C-4”),69.6(O-alloc),69.3(Alloc),67.5(C-9),63.4(C-5”),56.5(3-OCH3),55.8(4-OCH3),21.2(O-alloc).

[0479] 2”,4”-O-diallyloxycarbonyl-3”-acetyl-7-O-β-D-patentiflorin A(28bb3)

[0480] HR-EIMS m / z[M+H] + 737.1950 (calculated value 737.2082); 1H NMR(400MHz,CDCl3)δ7.56(1H,s,H-2),7.08(1H,s,H-5),7.00-6.91(1H,m,H-5'),6.86-6.73(2H,m,H-2',6'),6.08(1H,br s,OCH2O)6.04(1H,br s,-OCH2O-),5.90(2H,m,H-9),5.53-5.20(9H,m,O-alloc,2”,4”),5.08(1H ,dd,J=8.5,4.4Hz,H-1”),4.78(1H,td,J=9.4,4.5Hz,H-3”),4.65(4H,dt,J =22.0,5.1Hz,O-alloc),4.04(3H,s,3-OCH3),3.79(3H,s,4-OCH3),3.58(1 H,dq,J=10.5,5.0Hz,H-5”),2.06(3H,s,OAc),1.27(3H,d,J=25.1Hz,H-6”); 13 C NMR (100MHz, CDCl3) δ170.1(OAc),169.6(C-9'),154.1(O-alloc),152.2(C-3),150.3(C-4),147.6(C-3'),147.5(C-4'),143.3(C- 7),137.0(C-7'),131.5(C-6),131.2(C-8),131.0(C-1),130.8(O-alloc),128.1(C-1'),123.6(C-6'),119.9(O-alloc),119.4(O- alloc),118.9(C-8'),110.6(C-2'),108.2(C-5'),106.3(C-1”),101.5(C-5),101.3(C-2),100.0(-OCH2O-),75.9(C-3”),72.3(C- 2”),70.4(C-4”),69.4(O-alloc),69.1(O-alloc),68.5(C-5”),67.2(C-9),56.6(3-OCH3),55.9(4-OCH3),20.7(C-6”),17.4(OAc).

[0481] 2",4"-O-diallyloxycarbonyl-7-O-β-D-xylosyl feroxanthin (29a, yield 92%)

[0482] HR-EIMS m / z[M+H] +681.1696 (calculated value 681.1819); H NMR (400MHz, acetone-d6) δ7.58(1H,s,H-2),6.99(1H,s,H-5),6.86(1H,m,H-5' ),6.72(2H,m,H-2',6'),5.98(2H,m,H-9),5.85(9H,m,O-alloc,-OCH2O-,H -1”,H-2”,H-4”),4.73(1H,d,J=7.7Hz,H-5”),4.56(4H,m,O-alloc),4.12( 1H,m,H-3”),3.92(3H,s,3-OCH3),3.61(3H,s,4-OCH3),3.42(1H,m,H-5”); 13 C NMR (100MHz, acetone-d6) δ169.6(C-9'),155.4(O-alloc),155.2(O-alloc),153.2(C-3),151.6(C-4),148.4(C-3'),148.3(C-4'),14 4.7(C-7),138.1(C-7'),132.9(O-alloc),132.8(O-alloc),131.4(C-1),129.1(C-6),127.2(C-1'),124.6(C-8),124.5(C-6'), 120.1(O-alloc),119.2(O-alloc),118.9(C-8'),111.7(C-2'),108.7(C-1”,C-5'),106.9(C-5),102.6(C-2),102.2(-OCH2O-), 78.7(C-3”),75.7(C-2”),72.1(C-4”),69.6(O-alloc),69.3(O-alloc),67.5(C-9),63.4(C-5”),56.5(3-OCH3),55.8(4-OCH3).

[0483] 2",4"-O-diallyloxycarbonyl-7-O-β-D-patentiflorin A (29b, yield 83%)

[0484] HR-EIMS m / z[M+H] + 695.1911 (calculated value 695.1976); 1H NMR (400MHz, CDCl3) δ7.62(1H,s,H-2),7.09(1H,s,H-5),6.95(1H,dd,J=8.2,1.4Hz,H-5'),6.84-6.77(2H,m,H- 2',6'),6.12-6.01(2H,m,-OCH2O-),5.93(2H,m,O-alloc),5.50-5.25(6H,m,H-9,O-alloc),5.15(1H,dd,J=9.7, 8.1Hz,H-1”),4.99(1H,d,J=8.1Hz,H-2”),4.74-4.63(5H,m,H-4”,O-alloc),4.06(3H,s,3-OCH3),3.88(1H,t,J =9.5Hz,H-3”),3.80(3H,s,4-OCH3),3.49(1H,ddt,J=12.7,6.6,4.9Hz,H-5”),1.31(3H,dd,J=6.1,1.7Hz,H-6”); 13 C NMR(100MHz, CDCl3)δ169.8(C-9'),155.0(O-alloc),154.9(O-alloc),152.3(C-3),150.4(C-4),147.7(C-3'),147.7(C-4') ,143.7(C-7),137.0(C-7'),131.1(C-8),130.9(C-1),128.3(C-6),126.9(C-1'),123.7(C-6'),120.2(O-alloc),119.7(O-a lloc),119.3(C-8'),110.8(C-2'),108.3(C-5'),106.4(C-1”),101.6(C-5),101.4(C-2),100.2(-OCH2O-),79.3(C-3”),78. 2(C-1”),73.5(C-4”),70.5(C-5”),69.7(O-alloc),69.4(O-alloc),67.3(C-9),56.7(3-OCH3),56.0(4-OCH3),17.5(C-6”).

[0485] 2”,4”-O-diallyloxycarbonyl-3”-O-dimethylcarbamoyl-7-O-β-D-xylosyl feroxanthin (30a, yield 99%)

[0486] HR-EIMS m / z[M+H] + 752.2133 (calculated value 752.2191); 1H NMR (400MHz, CDCl3) δ7.56(1H,s,H-2),7.07(1H,d,J=1.8Hz,H-5),6.93(1H,dd,J=8.1,1.1Hz,H-5'),6.83–6.74(2H,m,H-2',H-6'),6.05(2 H,dt,J=17.9,1.5Hz,-OCH2O-),5.89(2H,ddtd,J=17.6,10.4,5.8,1.5Hz,O-Alloc),5.52–5.39(2H,m,H-9),5.35(1H,m,H-1”),5.31(1H,br t,J=1.6Hz,H-3”),5.27–5.23(4H,m,O-Alloc),5.10–5.06(1H,m,H-2”),5 .02(1H,tdd,J=9.7,4.8,2.1Hz,H-4”),4.73–4.59(4H,m,O-Alloc),4.20(1 H,ddd,J=11.8,5.4,1.1Hz,H-5”a),4.04(3H,s,3-OCH3),3.78(3H,s,4-OCH 3),3.40(1H,ddd,J=11.9,9.9,0.9Hz,H-5”b),2.91[6H,s,OC(O)N(CH3)2].

[0487] 2”,4”-O-diallyloxycarbonyl-3”-O-(3,5-dinitrobenzoyl)-7-O-β-D-xylosyl shanhuoyelin (30b, yield 90%)

[0488] HR-EIMS m / z[M+H] + 889.1763 (calculated value 889.1940); 1H NMR (400 MHz, CDCl3) δ9.26 (1H, t, J = 2.1 Hz, 3,5-dinitrobenzoyl), 9.15 (2H, d, J = 2.1 Hz, 3,5-dinitrobenzoyl), 7.59 (1H, s, H-2), 7.09 (1H, d, J = 1.2 Hz, H-5), 6.94 (1H, dd, J = 7.9, 3.8 Hz, H-5'), 6. 81(1H,dd,J=9.7,1.6Hz,H-2'),6.78–6.72(1H,m,H-6'),6.10–6.01(2H,m,-OCH2O-),5.7 6(2H,ddt,J=17.2,16.1,5.7Hz,O-Alloc),5.61(1H,t,J=9.4Hz,O-Alloc),5.54–5.48(1H ,m,O-Alloc),5.48–5.43(2H,m,H-9),5.24(1H,d,J=8.2Hz,H-1”),5.20(2H,ddd,J=8.0, 2.8,1.4Hz,O-Alloc),5.14(1H,dd,J=6.4,1.2Hz,H-2”),5.11(1H,dd,J=6.5,1.2Hz,H-3” ),5.02(1H,t,J=9.5Hz,H-4”),4.55(4H,ddt,J=20.0,5.7,1.4Hz,O-Alloc),4.06(3H,s,3 -OCH3),3.79(3H,s,4-OCH3),3.73–3.67(1H,m,H-5”),1.37(3H,dd,J=6.1,1.7Hz,H-6”).

[0489] 3"-O-dimethylcarbamoyl-7-O-β-D-xylosyl shanuolin (31a, two-step yield 69%)

[0490] HR-EIMS m / z[M+H] + 584.1723 (calculated value 584.1768); 1H NMR (400MHz, acetone-d6) δ8.15(1H,d,J=1.6Hz,H-2),7.10(1H,d,J=4.4Hz,H-5),6.98(1H,dd,J=7.9,1.5Hz,H-5'),6.88(1H,dd,J=15.7 ,1.6Hz,H-2'),6.83(1H,td,J=7.9,1.7Hz,H-6'),6.10(2H,dt,J=4.8,1.3Hz,-OCH2O-),5.56-5.38(3H,m,H-9,H-1”),5.02(1H,d,J =7.6Hz,H-3”),4.79-4.67(2H,m,OH-2”,OH-4”),4.05(1H,ddd,J=11.5,5.5,1.9Hz,H-2”),3.97(3H,s,3-OCH3),3.89(2H,m,H-4”,H -5”),3.73(3H,d,J=1.4Hz,4-OCH3),3.39(1H,ddd,J=11.4,10.0,1.1Hz,H-5”),3.02(3H,s,OCON(CH3)2),2.93(3H,s,OCON(CH3)2); 13 C NMR (100 MHz, acetone-d6) δ 169.8 (C-9'), 158.3 (OCON (CH3)2), 153.0 (C-3), 151.5 (C-4), 148.4 (C-3'), 148.3 (C-4'), 145.9 (C-7), 136.7 (C-7'), 131.5 (C-1), 131.4 (C-6), 129.7 (C-1'), 128.1 (C-8), 124.6 (C-6'), 120.0 (C-8'), 111.8(C-2'),111.7(C-5'),108.7(C-1”),106.8(C-2),102.4(C-5),102.2(-OCH2O-),81.5(C-3”),73.5(C-2” ),69.3(C-4”),67.8(C-9),66.7(C-5”),56.3(3-OCH3),55.8(4-OCH3),36.7(OCON(CH3)2),36.2(OCON(CH3)2).

[0491] 3"-O-(3,5-dinitrobenzoyl)-7-O-β-D-patentiflorin A (31b, yield 77% in two steps)

[0492] HR-EIMS m / z[M+H] + 721.1337 (calculated value 721.1517);1 H NMR (400 MHz, acetone-d6) δ9.17 (3H, m, 3,5-dinitrobenzoyl), 8.11 (1H, dt, J = 6.9, 3.1 Hz, H-2), 7.13-7.05 (1H, m, H-5), 6.99 (1H, dd, J = 7.7, 1.7 Hz, H-5'), 6.89 (1H, dd, J = 11.2, 1.5 Hz, H-2'), 6.83 (1H, ddd, J = 9.4, 5.5, 1.6 Hz, H-6'), 6.16-6.08 (2H, m,-OCH2O-),5.75-5.41(4H,m,H-9,OH-2”,OH-4”),5.18(1H,d,J=7.8Hz,H-1”),4.95(1H,d,J=4.9Hz,H-2”),4.21(1 H,ddd,J=9.7,7.8,5.3Hz,H-4”),3.95(3H,s,3-OCH3),3.71(5H,m,4-OCH3,H-3”,H-5”),1.41(3H,d,J=5.1Hz,H-6”); 13 C NMR (100 MHz, acetone-d6) δ 169.8 (C-9'), 163.4 (3,5-dinitrobenzoyl), 152.9 (C-3), 151.4 (3,5-dinitrobenzoyl), 151.3 (3,5-dinitrobenzoyl), 149.7 (C-4), 148.3 (C-3'), 148.3 (C-4'), 145.8 (C-7), 136.7 (C-7'), 134.8 (3,5-dinitrobenzoyl), 131.4 (C-1), 130.1 (3,5-dinitrobenzoyl), 129.6 (C-8), 128.1 (C -6), 124.6 (C-1'), 123.3 (C-6'), 120.0 (3,5-dinitrobenzoyl), 111.7 (C-8'), 111.7 (C-2'), 108.7 (C-5'), 106.7 (C-2), 105.5 (C-1"), 102.3 (C-5), 102.2 (-OCH2O-), 81.4 (C-3"), 74.1 (C-2"), 73.4 (C-4"), 73.0 (C-5"), 67.8 (C-9), 56.3 (3-OCH3), 55.8 (4-OCH3), 18.1 (C-6").

[0493] 3"-O-Butyryl-7-O-β-D-patentiflorin A (31c, yield 77% in two steps)

[0494] HR-EIMS m / z[M+H] +597.1968 (calculated value 597.1972); 1 H NMR (400MHz, acetone-d6) δ8.12(1H,s,H-2),7.08(1H,t,J=4.7Hz,H-5),6.98(1 H,ddd,J=8.0,3.6,1.3Hz,H-5'),6.93-6.75(2H,m,H-2',H-6'),6.14-6.0 5(2H,m,H-9),5.64-5.39(2H,m,-OCH2O-),5.31(1H,ddt,J=6.2,4.6,1.8H z,H-1”),5.13-5.02(2H,m,OH),4.52(1H,d,J=6.0Hz,H-3”),3.96(3H,d,J =2.9 Hz, 3-OCH3), 3.91-3.82 (1H, m, H-2"), 3.71 (3H, dd, J = 5.5, 3.1 Hz, 4-OCH3), 3.55 (1H, dd, J = 9.7, 5.9 Hz, H-4"), 3.37 (1H, ddd, J = 9.6, 5.6, 3.8 Hz, H-5"), 2.38 (2H, td, J = 7.4, 1.6 Hz, O-butyryl), 1.66 (2H, dd, J = 7.5, 1.6 Hz, O-butyryl), 1.35 (3H, dd, J = 5.9, 1.8 Hz, O-butyryl), 0.97 (3H, td, J = 7.4, 1.7 Hz, H-6"); 13 C NMR (100 MHz, acetone-d6) δ 173.6 (O-butyryl), 169.8 (C-9'), 152.9 (C-3), 151.4 (C-4), 148.3 (C-3'), 148.3 (C-4'), 145.9 (C-7), 136.6 (C-7'), 131.4 (C-1), 131.3 (C-6), 129.7 (C-1'), 128.2 (C-8), 124.6 (C-6'), 111.8 (C-8'), 111.7 (C-2 '), 108.6 (C-5'), 106.6 (C-2), 105.8 (C-1"), 102.4 (C-5), 102.2 (-OCH2O-), 78.3 (C-3"), 74.5 (C-2"), 73.7 (C-4"), 73.1 (C-5"), 67.9 (C-9), 56.3 (3-OCH3), 55.7 (4-OCH3), 36.7 (O-butyryl), 19.0 (C-6"), 18.1 (O-butyryl), 13.9 (O-butyryl).

[0495] 3"-O-Benzoyl-7-O-β-D-patentiflorin A (31d, yield 72% in two steps)

[0496] HR-EIMS m / z[M+H] + 631.1810 (calculated value 631.1816); 1 H NMR (400 MHz, acetone-d6) δ8.13 (1H, dt, J = 6.2, 3.0 Hz, H-2), 8.11-8.04 (2H, m, O-benzoyl), 8.01 (1H, dd, J = 8.3, 2.7 Hz, O-benzoyl), 7.51 (2H, d, J = 6.1 Hz, O-benzoyl), 7.05 (1H, dq, J = 10.2, 3.4 Hz, H-5), 6.95 (1H, dq, J = 6.9, 3.8 Hz, H-5'), 6.90-6.73 (2H, m, H-2', H-6'), 6.07 ( 2H,q,J=2.9,2.2Hz,-OCH2O-),5.62-5.28(4H,m,H-9,OH),5.12(1H,dd,J=7.8,2.1Hz,H-1”),4.07(1H,q,J=9.1,6.1Hz,H-3”),3 .91(3H,q,J=2.9,2.5Hz,3-OCH3),3.67(3H,dt,J=7.1,3.5Hz,4-OCH3),3.64-3.53(3H,m,H-2”,4” and 5”),1.42-1.32(3H,m,H-6”); 13C NMR (100 MHz, acetone-d6) δ 169.9 (C-9'), 166.6 (O-benzoyl), 152.9 (C-3), 151.4 (C-4), 148.3 (C-3'), 148.3 (C-4'), 146.0 (C-7), 136.6 (C-7'), 133.8 (O-benzoyl), 133.7 (O-benzoyl), 131.6 (C-1), 131.5 (C-6), 131.3 (C-8), 130.5 (O-benzoyl), 130.4 (O-benzoyl), 129.3 (O-benzoyl) ,129.3(O-benzoyl),128.2(C-1'),124.6(C-6'),111.8(C-8'),111.7(C-2'),108.7(C-5'),106.6(C-2),105.8(C-1"),102.4(C-5),102.2(-OCH2O-),79.5(C-3"),74.5(C-2"),73.8(C-4"),73.1(C-5"),67.9(C-9),56.3(3-OCH3),55.7(4-OCH3),18.2(C-6").

[0497] 3"-Op-dimethylaminobenzoyl-7-O-β-D-patentiflorin A (31e, yield 51% in two steps)

[0498] HR-EIMS m / z[M+H] + 674.2099 (calculated value 674.2238); 1H NMR (400 MHz, acetone-d6) δ8.21 (1H, d, J = 1.7 Hz, H-2), 7.95-7.90 (2H, m, Op-dimethylaminobenzoyl), 7.11 (1H, d, J = 2.9 Hz, H-5), 7.01-6.96 (1H, m, H-5'), 6.93-6.81 (2H, m, H-2', 6'), 6.79-6.75 (m, 2H, Op-dimethylaminobenzoyl), 6.10 (2H, ddd, J = 4.4, 1.7, 1.1 Hz, -OCH2O-), 5.60 (1H, d, J = 15.0 Hz, H-1''), 5.50-5.42 (2H, m, H -9), 5.24 (1H, t, J = 9.3 Hz, OH), 5.11 (1H, d, J = 7.8 Hz, OH), 4.67 (1H, dd, J = 5.7, 1.0 Hz, H-3"), 4.07-3.99 (1H, m, H-2"), 3.96 (3H, s, 3-OCH3), 3.73 (3H, d, J = 1.2 Hz, 4-OCH3), 3.65-3.57 (1H, m, H-5"), 3.52 (1H, td, J = 9.2, 5.5 Hz, H-4"), 3.07 (6H, s, Op-dimethylaminobenzoyl), 1.39 (3H, dd, J = 6.0, 1.5 Hz, H-6"); 13 C NMR (100 MHz, acetone-d6) δ 169.9 (C-9'), 167.4 (Op-dimethylaminobenzoyl), 154.6 (Op-dimethylaminobenzoyl), 153.0 (C-3), 151.5 (C-4), 148.4 (C-3'), 148.3 (C-4'), 146.1 (C-7), 136.6 (C-7'), 132.3 (Op-dimethylaminobenzoyl), 132.1 (Op-dimethylaminobenzoyl), 131.4 (C-1), 131.4 (C-6), 129.7 (C-8), 128.2 (C-1'), 124.6 (C-6'), 120.0 (Op- 9.8 (C-1-), 116.7 (C-2-), 114.7 (C-3-), 116.7 (C-4-), 116.6 (C-5-), 115.9 (C-1”), 114.7 (C-2”), 116.7 (C-4”), 116.6 (C-5”), 116.7 (C-6”).

[0499] 3"-O-dimethylcarbamoyl-7-O-β-D-patentiflorin A (31f, yield 66% in two steps)

[0500] HR-EIMS m / z[M+H] + 674.2099 (calculated value 598.1925); 1 H NMR (400MHz, acetone-d6) δ8.16(1H,d,J=2.7Hz,H-2),7.07(1H,d,J=4.9Hz,H-5),6.97(1H,dd,J=7.9,2.7Hz,H-5'),6.92-6.78(2H,m, H-2',6'),6.13-6.07(2H,m,-OCH2O-),5.59-5.47(2H,m,H-9),5.42(1H,dd,J=15.0,0.8Hz,H-1”),5.02(1H,d,J=7.8Hz,H-3”),4. 80-4.72 (2H, m, OH), 3.95 (3H, s, 3-OCH3), 3.90 (1H, ddd, J = 9.4, 7.8, 4.5 Hz, H-2"), 3.70 (3H, d, J = 2.6 Hz, 4-OCH3), 3.56-3.45 (1H, m, H-4"), 3.39 (1H, td, J = 9.2, 4.4 Hz, H-5"), 3.02 (3H, s, O-dimethylcarbamoyl), 2.92 (3H, s, O-dimethylcarbamoyl), 1.35 (3H, dd, J = 6.0, 1.5 Hz, H-6"); 13C NMR (100 MHz, acetone-d6) δ 169.9 (C-9'), 158.4 (O-dimethylcarbamoyl), 152.9 (C-3), 151.4 (C-4), 148.3 (C-3'), 148.2 (C-4'), 146.0 (C-7), 136.6 (C-7'), 131.6 (C-1), 131.5 (C-6), 129.7 (C-8), 128.2 (C-1'), 124.6 (C-6'), 111.8 (C-8'), 111.7 ( C-2'), 108.6 (C-5'), 106.6 (C-2), 105.9 (C-1"), 102.5 (C-5), 102.2 (-OCH2O-), 81.4 (C-3"), 74.7 (C-2"), 74.0 (C-4"), 73.0 (C-5"), 67.9 (C-9), 56.3 (3-OCH3), 55.7 (4-OCH3), 36.7 (O-dimethylcarbamoyl), 36.2 (O-dimethylcarbamoyl), 18.1 (C-6").

[0501] 3"-O-cyclopropanecarbonyl-7-O-β-D-patentiflorin A (31 g, yield 62% in two steps)

[0502] HR-EIMS m / z[M+H] + 595.1808 (calculated value 595.1816); 1 H NMR (400 MHz, acetone-d6) δ8.15 (1H, d, J = 2.1 Hz, H-2), 7.09 (1H, d, J = 4.2 Hz, H-5), 6.98 (1H, dd, J = 7.9, 2.8 Hz, H-5'), 6.91-6.79 (2H, m, H-2', 6'), 6.12-6.07 (2H, m, -OCH2O-), 5.61-5.40 (3H, m, H-9, 1"), 5.10-5.01 (2H, m, OH), 4.69-4.61 (1H, m, H-3"), 3.95 ( 3H, s, 3-OCH3), 3.89 (1H, ddd, J = 12.2, 8.3, 4.1 Hz, H-2"), 3.71 (3H, d, J = 2.3 Hz, 4-OCH3), 3.59-3.49 (1H, m, H-4"), 3.38 (1H, dd, J = 10.7, 7.7 Hz, H-5"), 1.69 (1H, tt, J = 7.9, 4.7 Hz, O-cyclopropanecarbonyl), 1.35 (3H, dd, J = 6.1, 1.5 Hz, H-6"), 0.90-0.83 (4H, m, O-cyclopropanecarbonyl); 13C NMR (100 MHz, acetone-d6) δ 175.1 (O-cyclopropanecarbonyl), 169.8 (C-9'), 152.9 (C-3), 151.4 (C-4), 148.3 (C-3'), 148.3 (C-4'), 146.0 (C-7), 136.6 (C-7'), 131.4 (C-1), 131.3 (C-6), 129.7 (C-8), 128.2 (C-1'), 124.6 (C-6'), 111.7 (C-8'), 111.7 (C-2' ),108.6(C-5'),106.6(C-2),105.8(C-1"),102.5(C-5),102.2(-OCH2O-),78.7(C-3"),74.5(C-2"),73.7(C-4"),73.1(C-5"),67.9(C-9),56.3(3-OCH3),55.7(4-OCH3),18.1(c-6"),13.6(O-cyclopropanecarbonyl),8.7(O-cyclopropanecarbonyl),8.2(O-cyclopropanecarbonyl).

[0503] 3"-Op-chlorobenzoyl-7-O-β-D-patentiflorin A (31 h, yield 80% in two steps)

[0504] HR-EIMS m / z[M+H] + 665.1413 (calculated value 665.1426); 1 H NMR (400 MHz, acetone-d6) δ8.15 (1H, d, J = 2.4 Hz, H-2), 8.14-8.08 (2H, m, Op-chlorobenzoyl), 7.61-7.55 (2H, m, Op-chlorobenzoyl), 7.08 (1H, d, J = 6.3 Hz, H-5), 7.00-6.95 (1H, m, H-5'), 6.93-6.78 (2H, m, H-2', 6'), 6.13-6.08 (2H, m, -OCH2O-), 5.61-5.42 (3H, m, H-5, 1''), 5 .35(1H,t,J=9.2Hz,OH),5.15(1H,dd,J=7.8,1.2Hz,OH),4.80(1H,dd,J=5.7,1.1Hz,H-3”),4.09(1H,ddd,J=9.5,7.8,5.4Hz ,H-2”),3.94(3H,s,3-OCH3),3.70(3H,d,J=3.7Hz,4-OCH3),3.68-3.54(2H,m,H-4”,5”),1.40(3H,dd,J=5.9,1.2Hz,H-6”); 13C NMR (100 MHz, acetone-d6) δ 169.9 (C-9'), 165.8 (Op-chlorobenzoyl), 152.9 (C-3), 151.4 (C-4), 148.3 (C-3'), 148.3 (C-4'), 145.9 (C-7), 139.5 (Op-chlorobenzoyl), 136.7 (C-7'), 132.2 (Op-chlorobenzoyl), 131.4 (C-1), 131.3 (C-6), 130.4 (C-8), 129.5 (Op-chlorobenzoyl), 12 8.2(C-1'),124.6(C-6'),111.8(C-8'),111.7(C-2'),108.7(C-5'),106.6(C-2),105.7(C-1”),102.4(C-5),102.2(- OCH2O-),79.8(C-3”),74.4(C-2”),73.7(C-4”),73.1(C-5”),67.9(C-9),56.3(3-OCH3),55.7(4-OCH3),18.2(C-6”).

[0505] 3"-O-pyrazinecarbonyl-7-O-β-D-patentiflorin A (31i, yield 52% in two steps)

[0506] HR-EIMS m / z[M+H] + 633.1709 (calculated value 633.1720); 1H NMR (400 MHz, acetone-d6) δ8.89 (1H, d, J = 1.5 Hz, O-pyrazinecarbonyl), 8.49 (1H, d, J = 2.4 Hz, O-pyrazinecarbonyl), 8.43 (1H, dd, J = 2.5, 1.5 Hz, O-pyrazinecarbonyl), 7.62 (1H, d, J = 2.1 Hz, H-2), 6.60 (1H, dd, J = 7.9, 2.4 Hz, H-5'), 6.55 (1H, d, J = 2.7 Hz, H-5), 6.49 (1H, dd, J = 12.2, 1.7 Hz, H-6'), 6.36 (1H, ddd, J = 8.6, 7.9, 1.7 Hz, H- -2'),5.89(1H,dd,J=5.6,3.3Hz,H-3”),5.68(2H,q,J=1.2Hz,-OCH2O-),5.16-5.01(3H,m,H-9,1”),4.76(1H,t,J=9.3Hz,OH),4.60(1H,dd, J=7.8,4.9Hz,OH),3.47(3H,s,3-OCH3),3.45-3.39(1H,m,H-2”),3.22(3H,s,4-OCH3),3.16-3.07(2H,m,H-4”,5”),0.86-0.80(3H,m,H-6”); 13 C NMR (100 MHz, acetone-d6) δ 169.9 (C-9'), 168.6 (O-pyrazinecarbonyl), 153.0 (C-3), 151.5 (C-4), 149.7 (C-3'), 148.3 (C-4'), 146.2 (O-pyrazinecarbonyl), 145.9 (O-pyrazinecarbonyl), 145.5 (C-7), 144.8 (O-pyrazinecarbonyl), 144.2 (O-pyrazinecarbonyl), 136.8 (C-7'), 131.5 (C-1), 131.4 (C-6), 130.1 (C-8),128.2(C-1'),124.6(C-6'),111.8(C-8'),111.7(C-2'),108.7(C-5'),105.6(C-1”),102.4(C-5),102.2,(-O CH2O-),81.5(C-3”),74.2(C-2”),73.5(C-4”),73.0(C-5”),67.9(C-9),56.3(3-OCH3),55.8(4-OCH3),18.2(C-6”).

[0507] 3"-O-cyanoacetyl-7-O-β-D-patentiflorin A (31j, yield 49% in two steps)

[0508] HR-EIMS m / z[M+H]+ 594.1609 (calculated value 594.1612); 1 H NMR (400 MHz, acetone-d6) δ 7.85 (1H, s, H-2), 7.09 (1H, m, H-5), 6.98 (1H, dd, J = 7.9, 2.5 Hz, H-5'), 6.89 (1H, dd, J = 12.2, 1.6 Hz, H-2'), 6.85-6.79 (1H, m, H-6'), 6.15-6.02 (2H, m, -OCH2O-), 5.70-5.37 (2H, m, H-9), 5.12-4.98 (2H, m, H-1", H-3"), 3.96 (3H, d, J = 1.6 Hz, 3-OCH3), 3.91 (1H, dd, J = 9.5, 7.8 Hz, H-2"), 3.78-3.66 (3H, m, 4-OCH3), 3.55 (1H, ddd, J = 9.5, 6.1, 1.2 Hz, H-4"), 3.35 (3H, m, O-cyanoacetyl, H-5"), 1.36 (3H, dd, J = 6.0, 1.3 Hz, H-6"); 13 C NMR (100 MHz, acetone-d6) δ 169.9 (C-9'), 167.8 (O-cyanoacetyl), 153.0 (C-3), 151.5 (C-4), 148.4 (C-3'), 148.3 (C-4'), 146.0 (C-7), 136.6 (C-7'), 131.4 (C-1), 131.3 (C-6) 129.7 (C-8), 128.2 (C-1'), 124.6 (C-6'), 113.8 (O-cyanoacetyl), 11 1.8 (C-2'), 111.8 (C-8'), 108.7 (C-5'), 106.7 (C-2), 105.8 (C-1"), 102.5 (C-5), 102.2 (-OCH2O-), 79.2 (C-3"), 74.6 (C-2"), 73.9 (C-4"), 73.1 (C-5"), 67.9 (C-9), 56.4 (3-OCH3), 55.8 (4-OCH3), 25.1 (O-cyanoacetyl), 18.2 (C-6").

[0509] 3"-O-trichloroacetyl-7-O-β-D-patentiflorin A (31k, 53% yield in two steps)

[0510] HR-EIMS m / z[M+H] + 671.0325 (calculated value 671.0490); 1H NMR (400MHz, acetone-d6) δ8.15(1H,d,J=1.5Hz,H-2),7.11(1H,t,J=2.4Hz,H-5),6.98(1H,dd,J=7.9,2.5Hz,H-5'),6.90(1H,d,J=1.6Hz,H-2 '),6.88-6.80(1H,m,H-6'),6.10(2H,dt,J=4.7,1.2Hz,-OCH2O-),5.74-5.66(1H,m,4”-OH),5.61-5.41(2H,m,H-9),5.12-5.02(1H,m,2 ”-OH),4.92(1H,t,J=9.3Hz,H-1”),4.84(1H,d,J=8.7Hz,H-3”),3.97(3H,d,J=1.3Hz,3-OCH3),3.91(1H,ddd,J=9.5,7.8,5.4Hz,H-2”), 3.73(3H,d,J=1.6Hz,4-OCH3), 3.56(1H,dq,J=12.2,6.2Hz,H-4”), 3.42(1H,td,J=9.3,5.9Hz,H-5”), 1.36(3H,dd,J=6.1,1.5Hz,H-6”); 13 CNMR (100 MHz, acetone-d6) δ 169.8 (C-9'), 162.5 (O-trichloroacetyl), 153.0 (C-3), 151.5 (C-4), 148.4 (C-3'), 148.3 (C-4'), 145.9 (C-7), 136.7 (C-7'), 131.5 (C-1), 131.4 (C-6), 129.7 (C-8), 128.2 (C-1'), 124.6 (C-6'), 111.8 (C-8 '), 111.7(C-2'), 108.7(C-5'), 106.7(C-2), 105.7(C-1"), 102.5(C-5), 102.2(-OCH2O-), 91.4(O-trichloroacetyl), 79.6(C-3"), 74.1(C-2"), 73.3(C-4"), 73.1(C-5"), 67.9(C-9), 56.4(3-OCH3), 55.8(4-OCH3), 18.1(C-6").

[0511] 3"-O-benzyl-7-O-β-D-xylosyl shanuolin (31l, yield 59% in two steps)

[0512] HR-EIMS m / z[M+H] + 603.1676 (calculated value 603.1866); 1H NMR(400MHz, CDCl3)δ7.85(1H,s,H-2),7.30(5H,m,O-Bn),7.01(1H,m,H-5),6.89(1 H,m,H-5'),6.74(1H,m,H-2'),6.74(1H,m,H-6'),5.99(2H,m,-OCH2O-),5.38(2H,m ,H-9),4.96(1H,m,H-1”),4.69(2H,m,O-Bn),3.96(3H,s,3-OCH3),3.81(1H,ddJ=8. 6,7.2Hz,H-3”),3.73(3H,s,4-OCH3),3.60(3H,m,H-2”,4”,5”),3.12(1H,m,H-5”); 13 C NMR(100MHz, CDCl3)δ169.9(C-9'),152.0(C-3),150.2(C-4),147.6(C-3'),147.5(C-4'),144.3(C-7),137.6(C-7'),13 6.6(O-Bn),130.8(C-1),130.7(C-6),128.8(C-8),128.8(O-Bn),128.5(O-Bn),128.3(O-Bn),128.3(C-1'),127.9(O-Bn ),127.0(O-Bn),123.6(C-6'),119.2(C-8'),110.7(C-2'),108.2(C-5'),106.4(C-2),104.8(C-1”),101.3(C-5),100.9 (-OCH2O-),81.1(C-3”),75.6(C-2”),75.3(C-4”),73.4(C-5”),73.04(O-Bn),67.4(C-9),56.3(3-OCH3),55.9(4-OCH3).

[0513] 3”,4”-acetonide-4-O-β-D-glucopyranosyl shanhuoyexin (32a)

[0514] To a solution of compound 26f (54.2 mg, 0.1 mmol) in 3 mL of 2,2-dimethylpropane (DMP) was added a catalytic amount of TsOH (0.19 mg, 0.001 mmol) (as Figure 6 The reaction was stirred at room temperature for 12 hours, and then the excess DMP was removed by evaporation under reduced pressure. The residue was purified by silica gel column separation (n-hexane: ethyl acetate = 1: 1) to give 32a (11.4 mg, 20%) as a white solid: HR-EIMS m / z [M+H] +583.1656 (calculated value 583.1816); 1 H NMR (400MHz, acetone-d6) δ8.22(1H,s,H-2),7.09(1H,s,H-5),6.97(1H,dd,J=7.8,2.2Hz,H-5'),6.87(1H,dd,J=6.8,2.2Hz,H-2' ),6.81(1H,q,J=7.4Hz,H-6'),6.10(2H,d,J=3.6Hz,-OCH2O-),5.52–5.34(2H,m,H-9),5.32(1H,s,-OH),5.03(1H,dd,J=7.7 , 2.8Hz, H-1"), 4.66(1H, s, -OH), 3.98(3H, s, 3-OCH3), 3.96-3.82(2H, m, H-2", H-3"), 3.79(1H, td, J=7.9, 3.3Hz, H-6"), 3.72(3H, s, 4-OCH3), 3.68-3.64(2H, m, H-5", H-6"), 3.34(1H, q, J=7.9, 6.8Hz, H-4"), 1.52(3H, s, O-isopropylidene), 1.32(3H, s, O-isopropylidene).

[0515] To a solution of compound 26g (50 mg, 0.09 mmol) in 3 mL of DMP was added a catalytic amount of TsOH (0.19 mg, 0.001 mmol) (as Figure 6 After the reaction was stirred at room temperature for 12 hours, excess DMP was removed by evaporation under reduced pressure. The residue was purified by silica gel column separation (containing 45-52% ethyl acetate in n-hexane) to give 32b (18 mg, 34%), 32c (20 mg, 38%) and 32d (2 mg, 4%) as white solids.

[0516] 3”,4”-acetonide-4-O-β-D-galactopyranosyl shanhuoyexin (32b)

[0517] HR-EIMS m / z[M+H] + 583.1666 (calculated value 583.1816); 1H NMR (400MHz, acetone-d6) δ8.21(1H,s,H-2),7.09(1H,s,H-5),6.97(1H,d,J=7.4Hz,H-5'),6.90–6.75(2H,m,H-2' ,H-6'),6.10(2H,d,J=4.5Hz,-OCH2O-),5.78(1H,d,J=15.6Hz,-OH),5.48–5.39(2H,m,H-9),4.88(1H,d,J=9. 5Hz, H-1"), 4.28 (1H, d, J=5.9Hz, H-3"), 4.23 (1H, t, J=6.0Hz, H-4"), 4.07 (1H, q, J=5.7, 5.2Hz, H-2"), 4.00 (3H, s, 3-OCH3), 3.96-3.83 (3H, m, H-5"), H-6"), 3.73 (3H, s, 4-OCH3), 1.53 (3H, s, O-isopropylidene), 1.33 (3H, s, O-isopropylidene).

[0518] 4”,6”-acetonide-4-O-β-D-galactopyranosyl shanhuoyelin (32c)

[0519] HR-EIMS m / z[M+H] + 583.1688 (calculated value 583.1816); 1 H NMR (400 MHz, acetone-d6) δ 8.28–8.19 (1H, m, H-2), 7.09 (1H, s, H-5), 6.98 (1H, dt, J = 8.0, 1.1 Hz, H-5'), 6.90–6.78 (2H, m, H-2', H-6'), 6.10 (2H, dt, J = 5.0, 1.1 Hz, -OCH2O-), 5.84–5.32 (2H, m, H-9), 4.94–4.83 (1H, m, H-1'), 4.32–4.20 (1H, m, H-6”), 4.04 (1H, dt, J=9.6, 7.6 Hz, H-2”), 4.00 (3H, s, 3-OCH3), 3.97–3.81 (3H, m, H-3”, H-4”, H-6”), 3.73 (3H, s, 4-OCH3), 3.66 (1H, tt, J=6.7, 4.3 Hz, H-5”), 1.53 (3H, s, O-isopropylidene), 1.33 (3H, s, O-isopropylidene).

[0520] 2”,3”-acetonide-4-O-β-D-galactopyranosyl shanhuoyexin (32d)

[0521] HR-EIMS m / z[M+H] +583.1648 (calculated value 583.1816); 1 H NMR (400MHz, acetone-d6) δ8.25(1H,s,H-5),7.11(1H,s,H-5),6.98(1H,dd,J=7.8,1.0Hz,H-5'),6.90–6.86(1H,m,H-2'),6. 83(1H,dd,J=7.9,1.7Hz,H-6'),6.10(2H,dd,J=4.3,1.0Hz,-OCH2O-),5.65–5.45(2H,m,H-9),4.96–4.90(1H,m,H-1”),4 .26 (1H, d, J = 3.5 Hz, H-3"), 4.15 (1H, dt, J = 12.8, 2.1 Hz, H-2"), 4.01 (3H, s, 3-OCH3), 3.93–3.83 (2H, m, H-6"), 3.73 (3H, s, 4-OCH3), 3.68 (1H, ddd, J = 9.5, 7.9, 3.6 Hz, H-4"), 3.57–3.50 (1H, m, H-5"), 1.47 (3H, s, O-isopropylidene), 1.41 (3H, s, O-isopropylidene).

[0522] Having now fully described the present invention in some detail by way of illustration and example for the purpose of clear understanding, it will be apparent to those skilled in the art that the same may be performed by modifying or changing the present invention within a wider and equivalent range of conditions, formulations and other parameters without affecting the scope of the present invention or any specific embodiment thereof, and such modifications or changes are intended to be covered within the scope of the appended claims. The terms and expressions employed are used as descriptive and non-limiting terms, and it is not intended that any equivalents or portions thereof of the features shown and described be excluded by the use of such terms and expressions, but it should be recognized that various modifications are possible within the scope of the invention claimed. Therefore, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modifications and changes of the concepts disclosed herein may be adopted by those skilled in the art, and such modifications and changes are considered to be within the scope of the present invention.

[0523] As used herein, "comprising" is synonymous with "including". "Containing" or "characterized by" are inclusive or open-ended and do not exclude additional unlisted elements or method steps. As used herein, "consisting of excludes any element, step, or ingredient not specified in the claim elements. As used herein, "consisting essentially of does not exclude materials or steps that do not substantially affect the basic and novel characteristics of the claim. In each case herein, any of the terms "comprising", "consisting essentially of", and "consisting of" may be replaced by any of the other two terms.

[0524] When a group of materials, compositions, components or compounds are disclosed herein, it is understood that all individual members of those groups and all subgroups thereof are disclosed individually. When Markush groups or other groupings are used herein, all individual members of the group and all possible combinations and subcombinations of the group are intended to be included individually in the present disclosure. Unless otherwise indicated, each formulation or combination of components described or illustrated herein can be used to practice the present invention. Whenever a range is given in the specification, such as a temperature range, a time range, or a composition range, all intermediate ranges and subranges, and all individual values ​​included in the given range are intended to be included in the present disclosure. In the present disclosure and claims, "and / or" means in addition to or alternatively. In addition, any singular term used also encompasses plural forms.

[0525] All references cited herein are hereby incorporated by reference in their entirety, to the extent that there is no inconsistency with the disclosure of this specification. Some references provided herein are incorporated by reference to provide details about the source of starting materials, additional starting materials, additional reagents, additional synthesis methods, additional analytical methods, additional biological materials, additional cells and additional uses of the present invention. All titles used herein are for convenience only. All patents and publications mentioned in the specification indicate the technical level of the technical personnel in the field to which the present invention belongs, and are incorporated herein by reference to the extent that each publication, patent or patent application is specifically and individually indicated to be incorporated by reference. The references cited herein are incorporated herein by reference in their entirety to indicate the state of the art as disclosed or applied for, and it is intended that the information can be adopted herein as needed to exclude specific embodiments in the prior art. For example, when claiming a composition of matter, it should be understood that compounds known and available in the art before the applicant's invention (including compounds permitted to be disclosed provided in the references cited herein) are not intended to be included in the composition of matter claims herein.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt or prodrug thereof, wherein X is oxygen; R 1 For R 15 ; R 2 , R 5 , R 6 , R 7 , R 10 , R 13 and R 14 Each is hydrogen; R 3 and R 4 Each independently selected from -OC 1-6 alkyl; R 8 and R 9 Together with the carbon atoms to which they are attached, they form a methylenedioxy ring; R 11 and R 12 Together they form an oxo group; R 15 is independently selected at each occurrence from -OCH2-C(O)OR 17 、-O-CH2-R 16 , -O-heteroaryl, -OC(O)phenyl, optionally substituted by 1, 2, 3, or 4 independently C 1-6 1,3,2-dioxaborolane substituted with alkyl, heteroaryl, heterocyclic, -C(O)-C 1-6 Alkyl, -CH(OH)C 1-6 alkyl, alkynyl optionally substituted by trialkylsilane, -N=C(phenyl)phenyl, amino, -N(H)phenyl, -N(H)alkynyl, -N(H)C(O)C 1-6 An alkyl group; a glycosidic group; wherein the glycosidic group is a monosaccharide group; wherein the heteroaryl is a monocyclic ring having 5 or 6 ring atoms, at least one of which is selected from nitrogen or oxygen; wherein the phenyl is optionally substituted with halogen or trifluoromethyl; wherein the heterocyclyl has 5 or 6 ring atoms, at least one of which is selected from nitrogen or oxygen, and is optionally substituted with -C(O)OC 1-6 alkyl; wherein the 1,3,2-dioxaborolane is a pinacol boryl group; R 16 is independently selected at each occurrence from alkynyl, cyano; and R 17 is independently at each occurrence hydrogen or alkyl; wherein the glycoside group is a glycoside group represented by formula (V): Where R 19 , R 21 , R 23 and R 25 Each is hydrogen; R 20 , R 22 and R 24 Each independently selected from hydroxyl, -OC(O)R 27 、-OC(O)OC 2-6 Alkenyl, -OC(O)OR 27 and -OCH2-phenyl; And R 26 is hydrogen or C optionally substituted by 1 independently selected from hydroxy 1-6 alkyl; or R 20 and R 22 Together with the carbon atoms to which they are attached, they form a 5-membered heterocyclic group, the 5-membered heterocyclic group is optionally substituted by 1 or 2 independently selected 1-6 alkyl, wherein the heterocyclyl is a monocyclic ring, wherein at least one of the ring atoms is selected from oxygen; or R 22 and R 24 Together with the carbon atoms to which they are attached, they form a 5-membered heterocyclic group, the 5-membered heterocyclic group is optionally substituted by 1 or 2 independently selected 1-6 alkyl, wherein the heterocyclyl is a monocyclic ring, wherein at least one of the ring atoms is selected from oxygen; or R 24 and R 26 Together with the carbon atoms to which they are attached, they form a 6-membered heterocyclic group, the 6-membered heterocyclic group is optionally substituted by 1 or 2 independently selected 1-6 alkyl radicals, wherein the heterocyclyl radical is a monocyclic ring, wherein at least one of the ring atoms is selected from oxygen; R 27 independently selected at each occurrence from trichloromethyl, optionally substituted with 1 group independently selected from cyano 1-6 Alkyl, -N(R 29 )R 30 , optionally substituted by 1 or 2 independently selected from halogen, nitro, -N(R 29 )R 30 substituted phenyl, cyclopropyl, and heteroaryl having 6 ring atoms, wherein the heteroaryl is a monocyclic ring, wherein at least one of the ring atoms is selected from nitrogen; and R 29 and R 30 Each time it occurs, it is independently C 1-6 alkyl, Provided that the compound of formula (I) is not selected from the group consisting of 25a-25g and 26a-26g:

2. The compound according to claim 1, wherein R 3 and R 4 Each of them is -O-methyl.

3. The compound according to claim 1 or 2, wherein the heteroaryl group has 5 or 6 ring atoms, wherein at least one ring atom is selected from nitrogen or oxygen.

4. A compound according to any one of claims 1 to 3, wherein R 1 is an alkynyl group or a pinacol boron group; -N(R 17 )R 18 , -OCH2-cyano, -OCH2-alkynyl.

5. The compound of claim 1, wherein the compound is selected from 12a, 12b, 13, 17a, 17c, 17d, 17g, 19a, 19c, 19e, 19i, 19k, 191, 19m, 19n, 19o, 19p, 20, 21, 22, 23 and 24: The compound according to claim 1 , wherein the glycoside is a monosaccharide selected from the group consisting of an α-L isomer and a β-L isomer.

7. The compound of claim 1, wherein the compound is selected from 27ab, 27ba, 27bb, 27bc, 27bd, 27be, 27bf, 28ab1, 28ab2, 28ab3, 29a, 29b, 30a, 31a, 31b, 31c, 31d, 31e, 31g, 31h, 31i, 31j, 31k, 311, 32a, 32b, 32c and 32d:

8. A pharmaceutical composition comprising: the compound according to claim 1 and at least one pharmaceutically acceptable excipient.

9. Use of a compound in the preparation of a medicament for treating viral infection, wherein the compound has formula (I): or a pharmaceutically acceptable salt or prodrug thereof, wherein X is oxygen; R 1 For R 15 ; R 2 , R 5 , R 6 , R 7 ,R 10 , R 13 and R 14 Each is hydrogen; R 3 and R 4 Each independently selected from -OC 1-6 alkyl; R 8 and R 9 Together with the carbon atoms to which they are attached, they form a methylenedioxy ring; R 11 and R 12 Together they form an oxo group; R 15 is independently selected at each occurrence from hydrogen, hydroxy, C substituted with 1 hydroxy 1-6 Alkyl, -OC 1-6 Alkyl, -OCH2-C(O)OR 17 , -O-CH2-R 16 , -O-heteroaryl, -OC(O)phenyl, optionally substituted by 1, 2, 3, or 4 independently C 1-6 1,3,2-dioxaborolane substituted with alkyl, heteroaryl, heterocyclic, -C(O)-C 1-6 Alkyl, -CH(OH)C 1-6 alkyl, alkynyl optionally substituted by trialkylsilane, -N=C(phenyl)phenyl, amino, -N(H)phenyl, -N(H)alkynyl, -N(H)C(O)C 1-6 An alkyl group; a glycosidic group; wherein the glycosidic group is a monosaccharide group; wherein the heteroaryl is a monocyclic ring having 5 or 6 ring atoms, at least one of which is selected from nitrogen or oxygen; wherein the phenyl is optionally substituted with halogen or trifluoromethyl; wherein the heterocyclyl has 5 or 6 ring atoms, at least one of which is selected from nitrogen or oxygen, and is optionally substituted with -C(O)OC 1-6 alkyl; wherein the 1,3,2-dioxaborolane is a pinacol boryl group; R 16 is independently selected at each occurrence from alkynyl, cyano; and R 17 is independently at each occurrence hydrogen or alkyl; The glycoside group is a glycoside group represented by formula (V): Where R 19 , R 21 , R 23 and R 25 Each is hydrogen; R 20 , R 22 and R 24 Each independently selected from hydroxyl, -OC(O)R 27 、-OC(O)OC 2-6 Alkenyl, -OC(O)OR 27 and -OCH2-phenyl; And R 26 is hydrogen or C optionally substituted by 1 independently selected from hydroxy 1-6 alkyl; or R 20 and R 22 Together with the carbon atoms to which they are attached, they form a 5-membered heterocyclic group, the 5-membered heterocyclic group is optionally substituted by 1 or 2 independently selected 1-6 alkyl, wherein the heterocyclyl is a monocyclic ring, wherein at least one of the ring atoms is selected from oxygen; or R 22 and R 24 Together with the carbon atoms to which they are attached, they form a 5-membered heterocyclic group, the 5-membered heterocyclic group is optionally substituted by 1 or 2 independently selected 1-6 alkyl, wherein the heterocyclyl is a monocyclic ring, wherein at least one of the ring atoms is selected from oxygen; or R 24 and R 26 Together with the carbon atoms to which they are attached, they form a 6-membered heterocyclic group, the 6-membered heterocyclic group is optionally substituted by 1 or 2 independently selected 1-6 alkyl radicals, wherein the heterocyclyl radical is a monocyclic ring, wherein at least one of the ring atoms is selected from oxygen; R 27 independently selected at each occurrence from trichloromethyl, optionally substituted with 1 group independently selected from cyano 1-6 Alkyl, -N(R 29 )R 30 , optionally substituted by 1 or 2 independently selected from halogen, nitro, -N(R 29 )R 30 substituted phenyl, cyclopropyl, and heteroaryl having 6 ring atoms, wherein the heteroaryl is a monocyclic ring, wherein at least one of the ring atoms is selected from nitrogen; and R 29 and R 30 Each time it occurs, it is independently C 1-6 alkyl; The viral infection is HIV; wherein, The condition is, When the viral infection is selected from HIV, the compound of formula (I) is not selected from the group consisting of 5, 16, 17b, 19d, 25a, 25b, 25c, 25d, 25e, 25f, 25g, 26a, 26b, 26c, 26cl, 26d, 26e, 26f and 26g:

10. The use according to claim 9, wherein R 3 and R 4 wherein each of the heteroaryl groups is -O-methyl; wherein the heteroaryl group has 5 or 6 ring atoms, wherein at least one ring atom is selected from nitrogen or oxygen.

11. The use according to claim 10, wherein the compound is selected from 12a, 12b, 13, 15a, 15b, 17a, 17c, 17d, 17g, 19a, 19c, 19e, 19i, 19k, 19l, 19m, 19n, 19o, 19p, 20, 21, 22, 23 and 24:

12. The use according to claim 9, wherein the glycoside is a monosaccharide selected from the group consisting of α-L isomer and β-L isomer.

13. The method of claim 9, wherein the compound is selected from 26d, 26e, 26f, 26g, 27ab, 27ba, 27bb, 27bc, 27bd, 27be, 27bf, 28ab1, 28ab2, 28ab3, 29a, 29b, 30a, 31a, 31b, 31c, 31d, 31e, 31g, 31h, 31i, 31j, 31k, 311, 32a, 32b, 32c and 32d:

14. Use of a compound for preparing a medicament for treating a viral infection, wherein the virus is HIV, wherein the compound is selected from the group consisting of: 12a, 12b, 13, 15a, 15b, 17a, 17c, 17d, 17g, 19a, 19c, 19e, 19i, 19k, 19l, 19m, 19n, 19o, 19p, 20, 21, 22, 23 and 24; 27ba, 27bb, 27bc, 27bd, 27be, 27bf, 28ab2, 28ab3, 29b, 31b, 31c, 31d, 31e, 31i and 31j:

15. Use of a compound in the preparation of a medicament for treating a viral infection, wherein the virus is an influenza virus, wherein the compound has formula (I): or a pharmaceutically acceptable salt or prodrug thereof, wherein X is oxygen; R 1 For R 15 ; R 2 , R 5 , R 6 , R 7 ,R 10 , R 13 and R 14 Each is hydrogen; R 3 and R 4 Each independently selected from -OC 1-6 alkyl; R 8 and R 9 Together with the carbon atoms to which they are attached, they form a methylenedioxy ring; R 11 and R 12 Together they form an oxo group; R 15 is independently selected at each occurrence from -N=C(phenyl)phenyl or a glycosidic group; The glycoside group is a glycoside group represented by formula (V): Where R 19 , R 21 , R 23 and R 25 Each is hydrogen; R 20 , R 22 and R 24 Each independently selected from hydroxyl, -OC(O)R 27 、-OC(O)OC 2-6 Alkenyl, -OC(O)OR 27 and -OCH2-phenyl; And R 26 is hydrogen or C optionally substituted by 1 independently selected from hydroxy 1-6 alkyl; or R 20 and R 22 Together with the carbon atoms to which they are attached, they form a 5-membered heterocyclic group, the 5-membered heterocyclic group is optionally substituted by 1 or 2 independently selected 1-6 alkyl, wherein the heterocyclyl is a monocyclic ring, wherein at least one of the ring atoms is selected from oxygen; or R 22 and R 24 Together with the carbon atoms to which they are attached, they form a 5-membered heterocyclic group, the 5-membered heterocyclic group is optionally substituted by 1 or 2 independently selected 1-6 alkyl, wherein the heterocyclyl is a monocyclic ring, wherein at least one of the ring atoms is selected from oxygen; or R 24 and R 26 Together with the carbon atoms to which they are attached, they form a 6-membered heterocyclic group, the 6-membered heterocyclic group is optionally substituted by 1 or 2 independently selected 1-6 alkyl radicals, wherein the heterocyclyl radical is a monocyclic ring, wherein at least one of the ring atoms is selected from oxygen; R 27 is independently selected at each occurrence from trichloromethyl, C 1-6 Alkyl, -N(R 29 )R 30 , phenyl optionally substituted by 1 or 2 groups independently selected from halogen, cyclopropyl, and heteroaryl having 6 ring atoms, wherein the heteroaryl is a monocyclic ring, wherein at least one of the ring atoms is selected from nitrogen; and R 29 and R 30 Each time it occurs, it is independently C 1-6 alkyl.

16. Use of a compound in the preparation of a medicament for treating a viral infection, wherein the virus is an influenza virus, wherein the compound is selected from the group consisting of: 19p, 26g, 27ab, 28ab1, 28ab2, 28ab3, 29a, 30a, 31a, 31e, 31g, 31h, 31j, 31k, 311, 32a, 32b, 32c and 32d:

17. Use of a compound in the preparation of a medicament for treating a viral infection, wherein the virus is a coronavirus, and wherein the compound has formula (I): or a pharmaceutically acceptable salt or prodrug thereof, wherein X is oxygen; R 1 For R 15 ; R 2 , R 5 , R 6 , R 7 ,R 10 , R 13 and R 14 Each is hydrogen; R 3 and R 4 Each independently selected from -OC 1-6 alkyl; R 8 and R 9 Together with the carbon atoms to which they are attached, they form a methylenedioxy ring; R 11 and R 12 Together they form an oxo group; R 15 is independently selected at each occurrence from -OH or a glycosidic group; The glycoside group is a glycoside group represented by formula (V): Where R 19 , R 21 , R 23 and R 25 Each is hydrogen; R 20 , R 22 and R 24 Each independently selected from hydroxyl, -OC(O)R 27 、-OC(O)OC 2-6 alkenyl; And R 26 is hydrogen or C optionally substituted by 1 independently selected from hydroxy 1-6 alkyl; or R 20 and R 22 Together with the carbon atoms to which they are attached, they form a 5-membered heterocyclic group, the 5-membered heterocyclic group is optionally substituted by 1 or 2 independently selected 1-6 alkyl, wherein the heterocyclyl is a monocyclic ring, wherein at least one of the ring atoms is selected from oxygen; or R 22 and R 24 Together with the carbon atoms to which they are attached, they form a 5-membered heterocyclic group, the 5-membered heterocyclic group is optionally substituted by 1 or 2 independently selected 1-6 alkyl, wherein the heterocyclyl is a monocyclic ring, wherein at least one of the ring atoms is selected from oxygen; or R 24 and R 26 Together with the carbon atoms to which they are attached, they form a 6-membered heterocyclic group, the 6-membered heterocyclic group is optionally substituted by 1 or 2 independently selected 1-6 alkyl radicals, wherein the heterocyclyl radical is a monocyclic ring, wherein at least one of the ring atoms is selected from oxygen; R 27 In each occurrence, independently selected from C 1-6 Alkyl, which is optionally substituted with 1 group independently selected from cyano.

18. Use of a compound in the preparation of a medicament for treating a viral infection, wherein the virus is a coronavirus, wherein the compound is selected from: 5, 26b, 26e, 28ab1, 31j, 32a, 32b, 32c and 32d:

19. Use of a compound in the preparation of a medicament for treating a viral infection, wherein the virus is Ebola virus, wherein the compound has formula (I): or a pharmaceutically acceptable salt or prodrug thereof, wherein X is oxygen; R 1 For R 15 ; R 2 , R 5 , R 6 , R 7 ,R 10 , R 13 and R 14 Each is hydrogen; R 3 and R 4 Each independently selected from -OC 1-6 alkyl; R 8 and R 9 Together with the carbon atoms to which they are attached, they form a methylenedioxy ring; R 11 and R 12 Together they form an oxo group; R 15 is independently selected at each occurrence from -N=C(phenyl)phenyl or a glycosidic group; The glycoside group is a glycoside group represented by formula (V): Where R 19 , R 21 , R 23 and R 25 Each is hydrogen; R 20 , R 22 and R 24 Each independently selected from hydroxyl, -OC(O)R 27 、-OC(O)OC 2-6 Alkenyl, -OC(O)OR 27 and -OCH2-phenyl; And R 26 is hydrogen or C optionally substituted by 1 independently selected from hydroxy 1-6 alkyl; or R 20 and R 22 Together with the carbon atoms to which they are attached, they form a 5-membered heterocyclic group, the 5-membered heterocyclic group is optionally substituted by 1 or 2 independently selected 1-6 alkyl, wherein the heterocyclyl is a monocyclic ring, wherein at least one of the ring atoms is selected from oxygen; or R 22 and R 24 Together with the carbon atoms to which they are attached, they form a 5-membered heterocyclic group, the 5-membered heterocyclic group is optionally substituted by 1 or 2 independently selected 1-6 alkyl, wherein the heterocyclyl is a monocyclic ring, wherein at least one of the ring atoms is selected from oxygen; or R 24 and R 26 Together with the carbon atoms to which they are attached, they form a 6-membered heterocyclic group, the 6-membered heterocyclic group is optionally substituted by 1 or 2 independently selected 1-6 alkyl radicals, wherein the heterocyclyl radical is a monocyclic ring, wherein at least one of the ring atoms is selected from oxygen; R 27 is independently selected at each occurrence from C optionally substituted with 1 group independently selected from cyano 1-6 Alkyl, -N(R 29 )R 30 , optionally 1 or 2 independently selected from -N(R 29 )R 30 phenyl, cyclopropyl substituted with R 29 and R 30 Each time it occurs, it is independently C 1-6 alkyl.

20. Use of a compound in the preparation of a medicament for treating a viral infection, wherein the virus is Ebola virus, wherein the compound is selected from the group consisting of: 19p, 26b, 26f, 26g, 28ab1, 28ab2, 28ab3, 29a, 30a, 31a, 31e, 31g, 31j, 311, 32a, 32b, 32c and 32d:

21. The use according to claim 15 or 16, wherein the influenza virus is an H5N1 virus.

22. The use of claim 17 or 18, wherein the coronavirus is SARS-CoV-2 virus.

Images