Benzoheterocyclic compound, pharmaceutically acceptable salt or stereoisomer thereof, and preparation method and application thereof

Abstract

The invention relates to the technical field of medicinal chemistry, in particular to a benzoheterocycle compound, pharmaceutically acceptable salt or stereoisomer thereof, and a preparation method and application of the benzoheterocycle compound. The benzoheterocycle compound and the pharmaceutically acceptable salt or stereoisomer thereof have a structure as shown in a general formula (I): # imgabs0 #, and the compound and the pharmaceutically acceptable salt or stereoisomer thereof show very good inhibitory activity on STING, have an ideal prevention or treatment effect on STING-mediated diseases or symptoms, can be used as an STING inhibitor, and can be used for preparing an STING inhibitor for treating STING-mediated diseases or illness, such as STING, STING, STING, STING, STING, STING, STING, STING, STING, STING, STING, STING, STING, STING, STING, STING, STING, STING and STING. The compound is used for preventing or treating STING-mediated autoimmune diseases, inflammatory diseases, organ fibrosis diseases and other diseases or symptoms and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a benzoheterocyclic compound, a pharmaceutically acceptable salt or stereoisomer thereof, and a preparation method and application thereof. Background Art

[0002] The innate immune receptor interferon gene stimulator STING (Stimulator of interferon genes protein) located in the endoplasmic reticulum is widely expressed in a range of mammalian cells. STING can be activated by its natural ligands, such as cyclic dinucleotide CDN (cyclic dinucleotide) from bacteria or cyclic GMP-AMP (also known as 2'3'-cGAMP) produced by the DNA sensor cGAMP synthase cGAS (Cyclic GMP-AMP synthase) in the cytoplasm. The binding of agonists to the ligand binding pocket of the STING dimer will induce STING to translocate to the endoplasmic reticulum-Golgi intermediate zone. The activated STING induces the recruitment of TBK1 (TANK-binding kinase 1) and forms a STING-TBK1 complex. TBK1 will then mediate the phosphorylation of the transcription factor IRF3 (IFN-regulated transcription factor 3), and the phosphorylated IRF3 will dimerize and translocate to the nucleus, subsequently inducing the secretion of type I interferons IFN. Activation of STING can also activate the kinase IKK, which in turn phosphorylates IκB to activate NF-κB and induce the release of a series of inflammatory factors.

[0003] The dynamic activation of STING plays an important role in regulating innate and adaptive immune responses. Many evidences show that the dynamic activation of STING is crucial for pathogen infection resistance, vaccine development and cancer immunotherapy. However, the excessive release of IFN induced by abnormal overactivation of STING signaling has become a driving factor in the development of various autoimmune diseases, such as systemic lupus erythematosus (SLE), Aicardi-Goutières syndrome (AGS) and STING-associated vasculopathy in infancy (SAVI). TREX1 (DNase three prime repair exonuclease 1) is an exonuclease responsible for digesting cytoplasmic DNA. Its mutation or knockout will lead to excessive accumulation of free DNA in the cytoplasm, followed by activation of the cGAS-STING pathway and production of IFN and a series of proinflammatory cytokines, leading to the occurrence of SLE and AGS diseases. Similarly, gain-of-function mutations in the STING gene will also lead to persistent overactivation of STING, leading to the occurrence of SAVI disease in clinical practice. In addition, inflammatory bowel disease (IBD) is a type of chronic inflammatory gastrointestinal disease, including ulcerative colitis and Crohn's disease. In mice, STING has been shown to be an important regulator of intestinal damage or barrier disruption. Activation of STING can further aggravate colitis in mice induced by dextran sulfate sodium. Considering the important role of STING in regulating immune homeostasis, STING has quickly become an important biological target for the development of immune disease drugs since its discovery.

[0004] Classic STING agonists are CDNs and their analogs. However, due to the poor membrane permeability of CDNs (Dineret al, 2013) and phosphodiesterase-mediated degradation in vivo, their pharmacokinetic properties are poor, which in turn greatly hinders their potential clinical application. In order to circumvent the defects of natural CDNs in drug development, researchers have developed a series of new STING agonists and subsequent derivatives based on CDN and non-nucleotide chemical skeletons over the past few decades, such as diABZIs, PC7A, SR-717 and MSA-2. At the same time, studies have also confirmed that abnormal activation of STING is closely related to autoimmune diseases, and a variety of STING inhibitors have also been developed to try to treat autoinflammatory immune diseases. For example, C-176 and C-178 were identified as covalent inhibitors of murine STING, while the subsequently modified H-151 is a common inhibitor of mouse and human STING, which can block STING palmitoylation by covalently binding to STING's Cys91, thereby inhibiting STING-mediated IFN-β production and alleviating organ damage in Trex1 knockout mice. The natural product Astin C was identified as a STING inhibitor that can specifically block STING's recruitment of IRF3 and also alleviate inflammatory autoimmune diseases in Trex1 knockout mice in vivo. SN-011 was developed and identified as a selective inhibitor of STING, alleviating inflammatory lesions and death in Trex1 knockout mice. The CDK inhibitor Palbociclib was confirmed to be able to interact directly with STING, has a certain STING inhibitory activity, and can also alleviate the inflammatory response of Trex1 knockout mice, and alleviate IBD lesions in a STING-dependent manner in the DSS-induced ulcerative colitis mouse model. However, no STING modulators have been approved for clinical use so far, so the development of STING modulators for STING-related diseases and the development of small molecule drugs targeting STING remains an unmet clinical need. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides a benzoheterocyclic compound represented by the general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, which exhibits excellent inhibitory activity on STING and has an ideal preventive or therapeutic effect on STING-mediated diseases or conditions.

[0006] Specifically, the present invention includes the following technical solutions:

[0007] In the first aspect, the present invention first provides a benzoheterocyclic compound, a pharmaceutically acceptable salt or a stereoisomer thereof, which has a structure shown in the general formula (I):

[0008]

[0009] Wherein, A represents O, N, or a substituted or unsubstituted alkylamino group;

[0010] B represents CH2, CH, N, carbonyl, R a and R b R and R are each independently, the same or different, and represent one of hydrogen, deuterium, halogen, substituted or unsubstituted amino, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cyano-substituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or, R a With R b may be condensed or fused to form a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;

[0011] X represents C or N;

[0012] Y represents O, N, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted alkylamino;

[0013] R 1 , R 2 and R 3 each independently, the same or different, represents one of hydrogen, deuterium, halogen, substituted or unsubstituted amino, hydroxyl, cyano, carboxyl, substituted or unsubstituted carboxylate, substituted or unsubstituted phosphate, substituted or unsubstituted carbamate, substituted or unsubstituted alkylcarbonyloxy, acyloxy, amide, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;

[0014] R 4 independently represent substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or, Y and R 4 They may be condensed or fused to form a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

[0015] In the present invention, when X is C, In the case where both sides of X are not connected by double bonds at the same time; when X is N, Both sides of the middle X are connected by a single key.

[0016] In the present invention, unless otherwise specified, the following terms have the following meanings. A particular term should not be considered as uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient.

[0017] The term "alkyl" refers to a saturated aliphatic hydrocarbon radical which is a straight or branched chain radical containing from 1 to 20 carbon atoms; non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methyl 4-methylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof, etc. Preferably, the alkyl group contains 1 to 8 carbon atoms. More preferably, the alkyl group contains 1 to 6 carbon atoms; non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Most preferably, the alkyl group contains 1 to 3 carbon atoms.

[0018] In the present invention, the alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available connection point. The substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate; preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.

[0019] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be further substituted with other related groups, and the substituents may include: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0020] In the present invention, the alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0021] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0022] Wherein, the term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is 3 yuan / 6 yuan, 3 yuan / 5 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0023] wait;

[0024] It also includes spirocycloalkyl groups that share a spiro atom with a heterocycloalkyl group. Non-limiting examples include:

[0025] wait.

[0026] The term "condensed cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of condensed cycloalkyls include:

[0027]

[0028] wait.

[0029] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0030]

[0031] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0032] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O). m(wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring part of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; further preferably, it contains 1-3 nitrogen atoms, 3-8 membered heterocyclic groups, optionally substituted by 1-2 oxygen atoms, sulfur atoms, oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups, nitrogen-containing bridged heterocyclic groups or nitrogen-containing fused heterocyclic groups.

[0033] Among them, non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazacycloheptyl, pyranyl, etc., preferably pyrrolidinyl, morpholinyl, piperidinyl, azepanyl, 1,4-diazacycloheptyl and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, condensed ring and bridged heterocyclic groups; wherein the spirocyclic, condensed ring and bridged heterocyclic groups involved are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring.

[0034] The term "spiro heterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiral atoms between rings, spiral heterocyclic groups are divided into single spiral heterocyclic groups, double spiral heterocyclic groups or multi-spiro heterocyclic groups, preferably single spiral heterocyclic groups and double spiral heterocyclic groups. More preferably, it is 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic groups. Non-limiting examples of spiral heterocyclic groups include: wait.

[0035] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m(wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0036]

[0037] wait.

[0038] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system, and one or more of the ring atoms is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0039]

[0040] wait.

[0041] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0042] wait.

[0043] In the present invention, the heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0044] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, including benzo 5-10-membered heteroaryl, benzo 3-8-membered cycloalkyl and benzo 3-8-membered heteroalkyl, preferably benzo 5-6-membered heteroaryl, benzo 3-6-membered cycloalkyl and benzo 3-6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, and sulfur atoms; or further comprising a three-membered nitrogen-containing fused ring containing a benzene ring.

[0045] Wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0046] wait.

[0047] The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0048] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl is preferably 5 to 12 yuan, more preferably 5 yuan or 6 yuan, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidyl or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and its non-limiting examples include:

[0049] wait.

[0050] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0051] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0052] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0053] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0054] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0055] "Alkynyl" refers to -CH≡C-, wherein the alkynyl can be further substituted by other related groups, including: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0056] The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein the definition of alkenyl is as described above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. Alkenylcarbonyl can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0057] "Hydroxy" refers to an -OH group.

[0058] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0059] "Amino" refers to -NH2.

[0060] "Cyano" refers to -CN.

[0061] "Nitro" refers to -NO2.

[0062] "Carbonyl" refers to -C(O)-.

[0063] "Carboxy" refers to -C(O)OH.

[0064] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0065] "Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably Each hydrogen atom is independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0066] "Pharmaceutically acceptable salts" include, but are not limited to, inorganic salts selected from, for example, hydrochlorides, phosphates, hydrobromides, sulfates; and organic salts selected from, for example, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, benzoate, salicylate, stearate, alkanoates such as acetate, and salts of HOOC-(CH2)n-COOH, wherein n is selected from 0 to 4. Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0067] "Pharmaceutically acceptable salts" as defined herein include salts of the compounds, as well as salts of stereoisomers of the compounds, such as salts of enantiomers, and / or salts of diastereomers.

[0068] Preferably, in the general formula (I), A represents O, N or methylamino;

[0069] B represents CH2, CH, N, carbonyl,

[0070] Y represents O, N and methylamino;

[0071] R 1 Represents hydrogen, hydroxyl, methoxy, amino, cyano, carboxyl, methyl carboxylate, methylamino, acetamido, acetoxy

[0072] R 2 represents hydrogen, hydroxyl, F or Cl;

[0073] R 3 Represents hydrogen or Cl.

[0074] As a preference, R 4 for The benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer has a structure shown in general formula (II):

[0075]

[0076] R 5 represents hydrogen, deuterium, halogen, substituted or unsubstituted amino, hydroxy, cyano, carboxyl, substituted or unsubstituted carboxylate, substituted or unsubstituted phosphate, substituted or unsubstituted carbamate, substituted or unsubstituted alkylcarbonyloxy, amide, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0077] Preferably, R 5 represents hydrogen or Cl;

[0078] R 6 and R 7 each independently, the same or different, represents hydrogen, deuterium, halogen, substituted or unsubstituted amino, hydroxyl, cyano, carboxyl, substituted or unsubstituted carboxylate, substituted or unsubstituted phosphate, substituted or unsubstituted carbamate, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkylcarbonyl, amide, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or, R 6 With R 7 may be condensed or fused to form a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;

[0079] R 8 represents OH, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, or R 8 It can be condensed or fused with Y to form a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;

[0080] Y represents O, N, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted alkylamino;

[0081] Among them, the R 1 , R 2 , R 3 , A, B, and X are consistent with the definitions of general formula (I).

[0082] More preferably, the benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer has a structure represented by the general formula (III) or (IV):

[0083]

[0084] Among them, the R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , A, B, X, and Y are consistent with the definitions of general formula (II).

[0085] Preferably, the benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer has a structure shown in the general formula (V):

[0086]

[0087] L 1 represents O, N, NH or methylamino;

[0088] L 2 represents CH, CH2 or carbonyl;

[0089] W represents carbonyl, The R a and R b R and R are each independently, the same or different, and represent one of hydrogen, deuterium, halogen, substituted or unsubstituted amino, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cyano-substituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or, R a With R b may be condensed or fused to form a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group;

[0090] Preferably, W represents a carbonyl group,

[0091] Among them, the R 1 , R 2 , R 3 , A, B, and X are consistent with the definitions of general formula (I); the R 8 Consistent with the definition of general formula (II);

[0092] Y represents O, N, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted aryloxy group, or a substituted or unsubstituted alkylamino group.

[0093] More preferably, the benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer has a structure represented by the general formula (VI) or (VII):

[0094]

[0095] Among them, the R 1 , R 2 , R 3 , R 5 , A, B, X, and Y are consistent with the definitions of general formula (V).

[0096] As a preferred embodiment of the present invention,

[0097] Preferably, the benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer is any of the following compounds:

[0098]

[0099]

[0100]

[0101]

[0102] In a second aspect, the present invention further provides a method for preparing the benzoheterocyclic compound. In the compound of general formula (III), when A is O, B is CH2, X is C and Y is O, the synthesis route thereof is as follows, wherein R 1 , R 2 , R 3 , R 5 , R 6 , R 7 Part is as defined above.

[0103]

[0104] The preparation method comprises: compound 1 undergoes a condensation reaction to obtain compound 2, compound 2 undergoes ring-closing bromination to obtain compound 3, and then compound 3 undergoes a Miyaura borylation reaction to obtain compound 4; compound 4 undergoes a Suzuki coupling reaction with a corresponding halogenated aromatic hydrocarbon to obtain compound 5, and then compound 5 undergoes a reduction reaction to obtain compound 6; and finally compound 6 undergoes a tandem deprotection ring-closing reaction to obtain compound 7.

[0105] The specific steps of the preparation method are as follows:

[0106] Step 1: 1.0 equivalent of compound 1, 1.6-4.0 equivalents of N,N-dimethylformamide dimethyl acetal and N,N-dimethylformamide solution are mixed and reacted at 80-100° C.; after the reaction is completed, the mixture is diluted with water and extracted with ethyl acetate, and the combined organic layer is washed, dried, filtered and concentrated under reduced pressure in sequence to obtain a crude product of compound 2; the crude product is purified by silica gel column chromatography to obtain a pure product of compound 2; preferably, the reaction time is 1-2 hours;

[0107] Step 2: 1.0 equivalent of compound 2, chloroform solution and silica gel are mixed, and 1.1 to 1.5 equivalents of N-bromosuccinimide are added at 0°C, and then reacted at 0°C to room temperature; after the reaction is completed, the mixture is filtered and concentrated under reduced pressure, and then the residue is diluted with water and extracted with ethyl acetate, and the combined organic layer is washed, dried, filtered and concentrated under reduced pressure in sequence to obtain a crude product of compound 3; the crude product is purified by silica gel column chromatography to obtain a pure product of compound 3; preferably, the reaction time is 0.5 to 4 hours;

[0108] Step 3: 1.0 equivalent of compound 3, 1,4-dioxane solution, 3.0 equivalents of bis(pinacol)diboron, 3.0 equivalents of potassium acetate and 0.05-0.20 equivalents of tetrakistriphenylphosphine palladium are mixed at room temperature, and reacted at 90-100° C. under an inert gas atmosphere; after the reaction is completed, the mixture is filtered through diatomaceous earth, and the filtrate is concentrated under reduced pressure to obtain compound 4; preferably, the reaction time is 6-16 hours;

[0109] Step 4: Add 1.0 equivalent of compound 8 or 9, 3.0 equivalents of potassium carbonate and 0.05-0.20 equivalents of tetrakistriphenylphosphine palladium to 1.5-3.0 equivalents of 1,4-dioxane and aqueous solution of the compound 4 at room temperature, and react at 80-100° C. under an inert gas atmosphere; after the reaction, dilute with water and extract with ethyl acetate; wash, dry, filter and concentrate the combined organic layer in turn to obtain a crude product of compound 5; purify the crude product by a reverse phase column to obtain a pure product of compound 5; preferably, the reaction time is 3-12 hours;

[0110] Step 5: Mix 1.0 equivalent of compound 5, tetrahydrofuran solution, and 1.0 to 6.0 equivalents of 1.0 M hexane solution of diisobutylaluminum hydride at -10°C, and react at -20 to -10°C; quench with a saturated aqueous solution of Rochelle salt, and extract with ethyl acetate; wash, dry, filter, and concentrate under reduced pressure the combined organic layer to obtain a crude product of compound 6; purify the crude product by silica gel column chromatography to obtain a pure product of compound 6; preferably, the reaction time is 2 to 4 hours;

[0111] Step six: Mix 1.0 equivalent of compound 6, methanol, and 2.0 to 10.0 equivalents of toluenesulfonic acid, and react at 50 to 65°C; quench with aqueous sodium bicarbonate solution, and extract with ethyl acetate; wash, dry, filter and concentrate the combined organic layers in turn to obtain a crude product of compound 7; purify the crude product by silica gel column chromatography to obtain a pure compound 7; preferably, the reaction time is 2 to 12 hours.

[0112] Preferably, the combined organic layers are washed with saturated brine and dried over anhydrous sodium sulfate.

[0113] In the specific implementation process, for the preparation method of other benzoheterocyclic compounds except the compound of general formula (III), those skilled in the art can obtain them by using conventional synthesis techniques in the art.

[0114] In a third aspect, the present invention further provides a pharmaceutical composition comprising a therapeutically effective dose of the benzoheterocyclic compound, a pharmaceutically acceptable salt or a stereoisomer thereof.

[0115] Here, "effective amount" refers to an amount of at least one of the benzoheterocyclic compounds, pharmaceutically acceptable salts or stereoisomers thereof disclosed herein that is effective to "treat" (as defined below) a disease or disorder in a subject.

[0116] Preferably, the pharmaceutical composition further contains one or more pharmaceutically acceptable carriers, diluents or excipients.

[0117] "Pharmaceutical composition" means a mixture containing one or more benzoheterocyclic compounds of the present invention or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0118] In a fourth aspect, the present invention also provides the use of the benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer or the pharmaceutical composition in the preparation of a drug for preventing and treating STING-mediated diseases.

[0119] In a fifth aspect, the present invention also provides the use of the benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer or the pharmaceutical composition in the preparation of STING inhibitor drugs.

[0120] Preferably, the STING-mediated disease includes one or more of infectious diseases, inflammatory diseases, autoimmune diseases, organ fibrosis diseases, cancer and precancerous syndromes.

[0121] In the present invention, the benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer, or the composition can be used to prevent or treat infectious diseases, including: Mycobacterium tuberculosis infection, Chlamydia infection, herpes virus (herpes simplex virus) infection, adenovirus infection, hepatitis B virus infection, orthomyxovirus infection and coronavirus infection.

[0122] In the present invention, the benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer, or the composition can be used to prevent or treat inflammatory diseases, including: metabolic inflammation-related diseases (such as insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, obesity, atherosclerosis, myocardial ischemia, myocardial infarction, arrhythmia, coronary heart disease, hypertension, heart failure, myocardial hypertrophy, myocarditis, ischemic encephalopathy, stroke, hemorrhagic encephalopathy, cerebral hemorrhage, cerebral edema, diabetic cardiomyopathy, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy and diabetic ulcer, non-alcoholic fatty liver disease, non-alcoholic fatty hepatitis, alcoholic fatty liver disease, cirrhosis, gout, stroke or cerebral infarction, etc.), musculoskeletal muscle inflammation (inflammation of the hands, wrists, elbows, shoulders, neck, knees, ankles and feet, such as osteoarthritis, rheumatoid arthritis, Rheumatoid arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, etc.), eye inflammation (keratitis, scleritis, conjunctivitis, etc.), digestive system inflammation (colitis, hepatitis, cholangitis, cholecystitis, pancreatitis, gastritis, enteritis, inflammatory bowel disease, proctitis), nervous system inflammation (meningitis, neuromyotonia, multiple sclerosis, CNS vasculitis), vascular system or lymphatic system inflammation (vasculitis, lymphangitis, phlebitis), reproductive system inflammation (cervicitis, endometritis, epididymitis, orchitis, urethritis), respiratory system inflammation (pneumonia, asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiolitis obliterans, idiopathic pulmonary fibrosis, cystic fibrosis lung disease), other inflammatory diseases include appendicitis, myocarditis, mumps, gingivitis, prostatitis, peritonitis, pleurisy, vasculitis, phlebitis, edema.

[0123] In the present invention, the benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer, or the composition can be used to prevent or treat autoimmune diseases. The autoimmune diseases include: Aicardi syndrome (AGS), STING-associated vasculitis (SAVI) in infancy, retinal vasculopathy with cerebral protein dystrophy (RCVL), systemic lupus erythematosus (SLE), familial pernio lupus (CHBL), Behcet's disease, Chagas' disease, psoriasis, multiple sclerosis, scleroderma and Behcet's disease.

[0124] In the present invention, the benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer, or the composition can be used to prevent or treat T cell-mediated hypersensitivity reactions with inflammatory components, including urticaria, skin allergies, allergic rhinitis, contact dermatitis and respiratory allergies.

[0125] In the present invention, the benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer, or the composition can be used to treat cancers of various tissues and organs of the body, including but not limited to cancers of the lung, bone, pancreas, liver, kidney, head, uterus, ovary, stomach, colon, esophagus, small intestine, endocrine system, prostate, bladder, cervix, and vagina. For example, liver cancer, kidney cancer, cervical cancer, lung cancer, skin cancer, uterine cancer, adenocarcinoma, prostate cancer, sarcoma, osteosarcoma, thyroid cancer, non-small cell lung cancer, esophageal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and neuroblastoma.

[0126] The present invention also provides a method for treating the above-mentioned disease, which specifically comprises: administering an effective amount of the above-mentioned benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer, or the composition to the patient.

[0127] In specific applications, an effective amount of the above-mentioned benzoheterocyclic compounds, pharmaceutically acceptable salts or stereoisomers thereof are administered to patients to treat, alleviate or prevent the above-mentioned diseases. The specific form can adopt a variety of known means, and the present invention does not specifically limit this.

[0128] Here, "treatment" or "alleviation" refers to administering at least one of the benzoheterocyclic compounds disclosed herein, its pharmaceutically acceptable salt or stereoisomer, or the composition to a subject confirmed to need it, for example, the subject suffers from a tumor, etc.

[0129] In a sixth aspect, the present invention also provides the use of the benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer or the pharmaceutical composition in the preparation of an immune adjuvant drug.

[0130] In the present invention, the benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer, or the composition can be used alone or in combination with other therapeutic agents.

[0131] As immunomodulators, the benzoheterocyclic compounds, pharmaceutically acceptable salts or stereoisomers thereof, or the compositions can be used as monotherapy or in combination with other therapeutic agents to treat STING-mediated diseases, including infectious diseases, inflammatory diseases, autoimmune diseases, cardiovascular and cerebrovascular diseases, cancers and precancerous syndromes.

[0132] In a seventh aspect, the present invention provides a drug for preventing and treating STING-mediated diseases, which contains the benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer or the pharmaceutical composition.

[0133] Preferably, the drug for preventing and treating STING-mediated diseases is a STING inhibitor drug.

[0134] In an eighth aspect, the present invention provides an immune adjuvant drug, which contains the benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer or the pharmaceutical composition.

[0135] Based on the above technical solution, the beneficial effects of the present invention are:

[0136] The benzoheterocyclic compounds, pharmaceutically acceptable salts or stereoisomers thereof claimed in the present invention exhibit excellent inhibitory activity on STING, have ideal preventive or therapeutic effects on STING-mediated diseases or conditions, and can be used as STING inhibitors for preventing or treating STING-mediated autoimmune diseases, inflammatory diseases, organ fibrosis diseases and other diseases or conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0137] In order to more clearly illustrate the technical solutions in the present invention or the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0138] Figure 1 It is a pathological section diagram showing that the compound E1 prepared in Example 1 provided by the present invention alleviates the inflammatory response of the heart, muscle, tongue and stomach organs in Trex1 knockout mice.

[0139] Figure 2It is the histological score of the pathological sections of the inflammatory response of the heart, muscle, tongue and stomach organs of the compound E1 prepared in Example 1 provided by the present invention in Trex1 knockout mice.

[0140] Figure 3 This is a graph showing the results of the compound E1 prepared in Example 1 provided by the present invention regulating the mRNA levels of Ifnb, Cxcl10, Isg15 and Tnfa genes in the heart, muscle, tongue and stomach organs in Trex1 knockout mice.

[0141] Figure 4 This is the body weight change curve of the compound E1 prepared in Example 1 provided by the present invention in different treatment groups in the colitis mouse animal model.

[0142] Figure 5 This is a curve of disease activity index changes in different treatment groups of the compound E1 prepared in Example 1 provided by the present invention in a colitis mouse animal model.

[0143] Figure 6 These are pictures and quantitative values ​​of colon length of different treatment groups of compound E1 prepared in Example 1 provided by the present invention in a colitis mouse animal model.

[0144] Figure 7 The present invention provides compound E1 prepared in Example 1 of the present invention, and the pathological H&E staining sections and histological pathological scores of the colon of different treatment groups in a colitis mouse animal model.

[0145] Figure 8 This is a graph showing the mRNA levels of the interferon gene Ifnb and the interferon response genes Isg15 and Cxcl10 in different treatment groups of the compound E1 prepared in Example 1 of the present invention in a colitis mouse animal model.

[0146] Fig. 9 This is a graph showing the mRNA levels of inflammatory genes Il-6, Il-1β and Tnfa in different treatment groups of the compound E1 prepared in Example 1 provided by the present invention in a colitis mouse animal model.

[0147] Statistical parameters: n=6, *p<0.05, **p<0.01, ***p<0.001. DETAILED DESCRIPTION

[0148] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be clearly and completely described below in conjunction with the drawings of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0149] The compounds disclosed in the present invention or their pharmaceutically acceptable salts can be synthesized from commercially available starting materials together with the contents disclosed in the present invention. The following schemes describe the preparation methods of some of the compounds disclosed in the present invention.

[0150] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0151] In the following examples, "DCM" refers to dichloromethane. "PE" refers to petroleum ether. "THF" refers to tetrahydrofuran. "EtOAc" refers to ethyl acetate. "MeOH" refers to methanol. "DMF" refers to N,N-dimethylformamide. "TFA" refers to trifluoroacetic acid. "MeCN" refers to acetonitrile. "DMA" refers to N,N-dimethylacetamide. "Et2O" refers to diethyl ether.

[0152] Example 1

[0153] Preparation of 10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromene-3-ol (Compound E1)

[0154]

[0155]

[0156] Step 1: Preparation of 2,2-dimethylchroman-7-ol

[0157]

[0158] Resorcinol (20.0 g, 181.81 mmol) and 2-methylbut-3-en-2-ol (15.6 g, 90.90 mmol) were added to formic acid (100.00 mL). The mixed reaction solution was stirred at 90 ° C for 4 hours under argon protection. The reactant was diluted with water (100 mL) at room temperature, alkalized to pH = 7-8 with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (3x 60 mL). The combined organic layer was washed with saturated brine (2x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 10: 1) to obtain 2,2-dimethylchroman-7-ol (10.2 g, yield 31%) as a white solid. ESI-MS m / z = 179 [M+H] + .

[0159] Step 2: Preparation of 6-iodo-2,2-dimethylchroman-7-ol

[0160]

[0161] 2,2-Dimethylbenzodimethylchroman-7-ol (10.0 g, 56.18 mmol) and silver trifluoroacetate (15.6 g, 90.90 mmol) were added to chloroform (500.00 mL), then cooled to 0 ° C, and iodine solution (21.4 g, 84.27 mmol) of chloroform (500.00 mL) was added. The resulting mixture was stirred for 12 hours at room temperature under argon atmosphere. Then it was concentrated under reduced pressure, diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with 5% sodium thiosulfate solution (200 mL), 5% sodium bicarbonate aqueous solution (200 mL) and saturated brine (200 mL) in sequence, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 20: 1) to give 6-iodo-2,2-dimethylchroman-7-ol (5.2 g, yield 30%) as a white solid. ESI-MS m / z = 305 [M+H] + .

[0162] Step 3: Preparation of 6-iodo-7-(2-methoxyethoxy)methoxy)-2,2-dimethylchroman

[0163]

[0164] N,N-diisopropylethylamine (7.26 g, 56.25 mmol) was added to a solution of 6-iodo-2,2-dimethylchroman-7-ol (5.7 g, 18.75 mmol) in dichloromethane (50 mL) at room temperature. Then it was cooled to 0°C and 2-methoxyethoxymethyl chloride (3.5 g, 28.12 mmol) was added. The resulting mixture was stirred at room temperature under argon atmosphere for 12 hours. Then it was concentrated under reduced pressure, diluted with water (60 mL), and extracted with ethyl acetate (3 x 60 mL). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 5: 1) to give 6-iodo-7-((2-methoxyethoxy)methoxy)-2,2-dimethylchroman (5.7 g, yield 77%) as a white solid. ESI-MS m / z=393[M+H] + .

[0165] Step 4: Preparation of 6-iodo-7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromene

[0166]

[0167] To a solution of 6-iodo-7-((2-methoxyethoxy)methoxy)-2,2-dimethylchroman (5.7 g, 14.54 mmol) in 1,4-dioxane (50 mL) was added dichlorodicyanobenzoquinone (4.34 g, 19.10 mmol) at room temperature. The resulting mixture was stirred at 90°C for 12 hours under an argon atmosphere. It was then concentrated under reduced pressure, diluted with water (60 mL), and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 5: 1) to give 6-iodo-7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromene (3.0 g, yield 53%) as a white solid. ESI-MS m / z = 391 [M+H] + .

[0168] Step 5: Preparation of 1-(2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)ethan-1-one

[0169]

[0170] N,N-diisopropylethylamine (35.6 g, 276.04 mmol) was added to a solution of 1-(2,4-dihydroxyphenyl)ethane-1-one (14.0 g, 92.01 mmol) in dichloromethane (200 ml), then cooled to 0°C at room temperature and 2-methoxyethoxymethyl chloride (17.2 g, 138.02 mmol) was added. The resulting mixture was stirred at room temperature for 6 hours under an argon atmosphere. The mixture was washed with water (150 mL) and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 10: 1) to give 1-(2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)ethane-1-one (20.0 g, yield 90%) as a white solid. ESI-MS m / z = 241 [M+H] + .

[0171] Step 6: Preparation of (E)-3-dimethylamino-1-(2-hydroxy-4-(2-methoxyethoxy)methoxy)phenylprop-2-en-1-one

[0172]

[0173] To a solution of 1-(2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)ethan-1-one (20.0 g, 83.25 mmol) in N,N-dimethylformamide (100 ml) was added N,N-dimethylformamide dimethyl acetal (39.7 g, 332.98 mmol). The resulting mixture was stirred at 90°C for 1 hour under an argon atmosphere. It was then diluted with water (80 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with saturated brine (3 x 150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=1:1) to give (E)-3-(dimethylamino)-1-(2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)prop-2-en-1-one (24 g, yield 98%) as a white solid. ESI-MS m / z=296[M+H] + .

[0174] Step 7: Preparation of 3-bromo-7-(2-methoxyethoxy)methoxy-4H-chromen-4-one

[0175]

[0176] To a solution of (E)-3-(dimethylamino)-1-(2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)prop-2-en-1-one (24.0 g, 81.26 mmol) in chloroform (200 ml) was added silica gel (80.0 g) and N-bromosuccinimide (16.0 g, 89.39 mmol) was added at 0°C. The resulting mixture was stirred at 0°C for 0.5 hours under an argon atmosphere. After filtration, it was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layer was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 10: 1) to give 3-bromo-7-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (15 g, yield 28%) as a white solid. ESI-MS m / z = 329 [M+H] + .

[0177] Step 8: Preparation of 7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromene-3-boronic acid

[0178]

[0179] To a solution of 3-bromo-7-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (2.0 g, 6.07 mmol, 1.0 equiv) in 1,4-dioxane (20 mL) was added bis(pinacol)diboron (4.63 g, 18.23 mmol, 3.0 equiv), potassium acetate (1.8 g, 18.23 mmol, 3.0 equiv) and tetrakistriphenylphosphine palladium (1.40 g, 1.21 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 100 ° C for 6 hours under an argon atmosphere and then filtered through a small piece of celite. The filtrate was concentrated under reduced pressure and the crude product was used directly in the next step without further purification.

[0180] Step 9: Preparation of 7,7'-bis(2-methoxyethoxy)methoxy)-2,2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one

[0181]

[0182] To a solution of (7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-yl)boronic acid (crude) in 1,4-dioxane / water (4 / 1, 20 mL) was added 6-iodo-7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromene (608 mg, 1.56 mmol), potassium carbonate (645 mg, 4.68 mmol) and tetrakistriphenylphosphine palladium (360 mg, 0.31 mmol) at room temperature. The resulting mixture was stirred at 80° C. for 6 hours under an argon atmosphere. Diluted with water (50 mL) and extracted with ethyl acetate (3× 40 mL). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase column (acetonitrile / water 5% to 100%) to give 7,7'-bis((2-methoxyethoxy)methoxy)-2',2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one (537 mg, 17% yield) as a yellow oil. 1 H NMR (400MHz, Chloroform-d) δ8.17(d,J=8.8Hz,1H),7.87(d,J=0.7Hz,1H),7.10(d,J=2.4Hz,1H),7.08–7.04(m,1H),6.93(s,1H),6.70(s,1H),6. 25(d,J=9.8Hz,1H),5.49(d,J=9.8Hz,1H),5.39–5.25(m,4H),3.90–3.70 (m,4H),3.62–3.48(m,4H),3.38–3.32(m,6H),1.48–1.37(m,6H).ESI-MS m / z=513[M+H]+ .

[0183] Step 10: Preparation of 7-(2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)chroman-4-one

[0184]

[0185] At -10 ° C, diisobutylaluminum hydride (1.0M hexane solution, 1.57 mL) was added to a solution of 7,7'-bis((2-methoxyethoxy)methoxy)-2',2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one (537 mg, 1.05 mmol) in tetrahydrofuran (10 mL). The resulting mixture was stirred at -10 ° C for 4 hours under an argon atmosphere. It was quenched with a saturated aqueous solution of Rochelle salt (30 mL) and extracted with ethyl acetate (3x 30 mL). The combined organic layer was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 4: 1) to give 7-((2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)chroman-4-one (326.3 mg, yield 60%) as a yellow oil. ESI-MS m / z = 515 [M+H] + .

[0186] Step 11: Preparation of 10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromene-3-ol

[0187]

[0188] To a solution of 7-((2-methoxyethoxy)methoxy)-3-(7-(2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)chroman-4-one (326.3 mg, 0.63 mmol) in methanol (10 mL) was added p-toluenesulfonic acid (239.4 mg, 1.26 mmol). The resulting mixture was stirred at 50°C for 4 hours under an argon atmosphere. It was quenched with aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromen-3-ol (97.5 mg, 48% yield) as a yellow solid. 1H NMR(400MHz,Chloroform-d)δ7.33(d,J=8.1Hz,1H),6.96(s,1H),6.92(s,1H),6.47–6.42( m, 2H), 6.39 (d, J = 9.8Hz, 1H), 5.64 (d, J = 9.8Hz, 1H), 5.53 (s, 2H), 4.99 (s, 1H), 1.45 (s, 6H). ESI-MSm / z=320.99[M+H] + .

[0189] Example 2

[0190] Preparation of 3-hydroxy-8,11-dihydro-6H-benzopyrano[3,4:4,5]furano[3,2-g]quinolin-10(9H)one (Compound E2)

[0191]

[0192] Step 1: Preparation of 6-bromo-7-hydroxy-3,4-dihydroquinolin-2(1H)one

[0193]

[0194] N-bromosuccinimide (600 mg, 3.37 mmol, 1.10 equiv) was added to a solution of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (500 mg, 3.06 mmol, 1.00 equiv) in N,N-dimethylformamide (10 ml). The resulting mixture was stirred at 0 ° C for 1 hour under an argon atmosphere. Diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 4: 1) to give 6-bromo-7-hydroxy-3,4-dihydroquinolin-2(1H)-one (738 mg, 98% yield) as a white solid. ESI-MS m / z = 243 [M + H] +

[0195] Step 2: Preparation of 6-bromo-7-(2-methoxyethoxy)methoxy)-3,4-dihydroquinolin-2(1H)one

[0196]

[0197] N, N-diisopropylethylamine (1.51 mL, 9.15 mmol, 3.00 equiv) was added to a solution of 6-bromo-7-hydroxy-3,4-dihydroquinoline-2 (1H) -one (738 mg, 3.05 mmol, 1.00 equiv) in dichloromethane (12 mL) at room temperature. It was then cooled to 0 ° C and 2-methoxyethoxymethyl chloride (522.3 uL, 4.57 mmol, 1.50 equiv) was added. The resulting mixture was stirred at room temperature for 6 hours under an argon atmosphere. It was then concentrated under reduced pressure, diluted with water (15 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=2:1) ​​to give 1-(2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)ethan-1-one (883.6 mg, yield 87.8%) as a white solid. ESI-MS m / z=330.03 [M+H] + .

[0198] Step 3: Preparation of 7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromene-3-boronic acid

[0199]

[0200] To a solution of 3-bromo-7-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (2.0 g, 6.07 mmol, 1.0 equiv) in 1,4-dioxane (20 mL) was added bis(pinacol)diboron (4.63 g, 18.23 mmol, 3.0 equiv), potassium acetate (1.8 g, 18.23 mmol, 3.0 equiv) and tetrakistriphenylphosphine palladium (1.40 g, 1.21 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 100 ° C for 6 hours under an argon atmosphere and then filtered through a small piece of celite. The filtrate was concentrated under reduced pressure and the crude product was used directly in the next step without further purification.

[0201] Step 4: Preparation of 7-(2-methoxyethoxy)methoxy)-6-(7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-yl)-3,4-dihydroquinolin-2(1H)one

[0202]

[0203] To a solution of (7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-yl)boronic acid (1.2 g, 4.0 mmol, 4.0 equiv) in 1,4-dioxane / water (4:1, 50 mL) were added 6-bromo-7-((2-methoxyethoxy)methoxy)-3,4-dihydroquinolin-2(1H)-one (660 mg, 2.0 mmol, 1.00 equiv), potassium carbonate (828 mg, 6.0 mmol, 3.00 equiv) and tetrakistriphenylphosphine palladium (462 mg, 0.4 mmol, 0.20 equiv). The resulting mixture was stirred at 80° C. under an argon atmosphere for 6 hours. The mixture was concentrated under reduced pressure and extracted with ethyl acetate (30 mL). The combined organic layers were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give 7-((2-methoxyethoxy)methoxy)-6-(7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-yl)-3,4-dihydroquinolin-2(1H)-one (1.07 g, yield 66.6%) as a yellow oil. ESI-MS m / z = 500.18 [M+H] +

[0204] Step 5: Preparation of 7-(2-methoxyethoxy)methoxy)-6-(7-((2-methoxyethoxy)methoxy)-4-oxo-3-yl)-3,4-dihydroquinolin-2(1H)-one

[0205]

[0206] Diisobutylaluminum hydride (1.0M hexane solution, 2.80 mL, 2.80 mmol, 4.00 equiv) was added to a solution of 7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-yl)-3,4-dihydroquinolin-2(1H)-one (350 mg, 0.70 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) at -10 °C. The resulting mixture was stirred at -10 °C for 2 hours under an argon atmosphere. It was quenched with a saturated aqueous solution of Rochelle salt (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give 7-((2-methoxyethoxy)methoxy)-6-(7-((2-methoxyethoxy)methoxy)-4-oxoroma-3-yl)-3,4-dihydroquinolin-2(1H)-one (163.8 mg, yield 47%) as a yellow oil. ESI-MS m / z = 502.20 [M+H] + .

[0207] Step 6: Preparation of 3-hydroxy-8,11-dihydro-6H-benzopyrano[3,4:4,5]furano[3,2-g]quinolin-10(9H)one

[0208]

[0209] To a solution of 7-((2-methoxyethoxy)methoxy)-6-(7-(2-methoxyethoxy)methoxy)-4-oxo-3-yl)-3,4-dihydroquinolin-2(1H)-one (50 mg, 0.10 mmol, 1.00 equiv) in methanol (3 mL) was added p-toluenesulfonic acid (76.1 mg, 0.40 mmol, 4.00 equiv). The resulting mixture was stirred at 50 ° C for 4 hours under an argon atmosphere. It was quenched with aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=2:1) ​​to give 3-hydroxy-8,11-dihydro-6H-chromo[3',4':4,5]furo[3,2-g]quinolin-10(9H)-one (1.9 mg, 4% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),9.78(s,1H),7.26(s,1H),7.23(d,J=8.2Hz,1H),7.03(s,1H),6.39(dd, J=8.3,2.3Hz,1H),6.32(d,J=2.2Hz,1H),5.48(s,2H),2.89(dd,J=8.6,6.3Hz,2H),2.44–2.38(m,2H).ESI-MS m / z=308.05[M+H] + .

[0210] Example 3

[0211] Preparation of 6H-benzopyrano[3,4:4,5]furano[3,2-g]quinolin-3-ol (Compound E3)

[0212]

[0213]

[0214] Step 1: Preparation of 6-bromo-7-((2-methoxyethoxy)methoxy)quinoline

[0215]

[0216] N,N-diisopropylethylamine (486mg, 3.76mmol) was added to a DCM (5ml) solution of 6-bromoquinolin-7-ol (280mg, 1.25mmol) at room temperature. It was then cooled to 0°C and 2-methoxyethoxymethyl chloride (235mg, 1.88mmol) was added. The resulting mixture was stirred at room temperature for 2 hours under an argon atmosphere. It was then concentrated under reduced pressure, diluted with water (50mL), and extracted with ethyl acetate (50mL x 2). The combined organic layers were washed with saturated brine (50mL) and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give 6-bromo-7-((2-methoxyethoxy)methoxy)quinoline (204mg, yield 52%) as a brown oily liquid. ESI-MS m / z = 312 / 314 [M+H] + .

[0217] Step 2: Preparation of 7-((2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)quinolin-6-yl)-4H-chromen-4-one

[0218]

[0219] To a solution of 6-bromo-7-((2-methoxyethoxy)methoxy)quinoline (204 mg, 0.65 mmol) and (7-(((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-yl)boronic acid (289 mg, 0.98 mmol) in 1,4-dioxane / water (4:1, 10 mL) was added potassium carbonate (271 mg, 1.96 mmol) and tetrakistriphenylphosphine palladium (151 mg, 0.13 mmol) at room temperature. The resulting mixture was stirred at 80° C. for 12 hours under an argon atmosphere. After filtration, the filtrate was concentrated under reduced pressure. The residue was diluted with water (50 mL) and washed with ethyl acetate (50 mL x 40 mL). 2) Extraction. The combined organic layers were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give a brown solid 7-((2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)quinolin-6-yl)-4H-chromen-4-one (130 mg, yield 41%). ESI-MS m / z = 482 [M+H] + .

[0220] Step 3: Preparation of 7-((2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)quinolin-6-yl)chroman-4-one

[0221]

[0222] To a solution of 7-((2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)quinolin-6-yl)-4H-chromen-4-one (151.7 mg, 0.32 mmol, 1.00 equiv) in tetrahydrofuran (4 mL) was added diisobutylaluminum hydride (1.0 M in hexane, 1.28 mL, 1.28 mmol, 4.00 equiv). The resulting mixture was stirred at -10 °C for 2 hours under argon atmosphere. It was quenched with a saturated aqueous solution of Rochelle salt (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=2:1) ​​to give 7-((2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)quinolin-6-yl)chroman-4-one (31.4 mg, yield 21%) as a yellow oil. ESI-MS m / z=484.19 [M+H] + .

[0223] Step 4: Preparation of 6H-benzopyrano[3,4:4,5]furano[3,2-g]quinolin-3-ol

[0224]

[0225] To a solution of 7-((2-methoxyethoxy)methoxy)-3-(7-(((2-methoxyethoxy)methoxy)quinolin-6-yl)chroman-4-one (31.4 mg, 0.06 mmol, 1.00 equiv) in methanol (1 mL) was added p-toluenesulfonic acid (114 mg, 0.60 mmol, 10.00 equiv) at room temperature. The resulting mixture was stirred at 50 °C for 4 hours under argon atmosphere. It was quenched with aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=2:1) ​​to give 6H-benzopyrano[3',4':4,5]furo[3,2-g]quinolin-3-ol (2.0 mg, 10.6% yield) as a yellow solid. 1H NMR (400MHz, Methanol-d4) δ8.77(dd,J=4.3,1.7Hz,1H),8.42(d,J=8.3Hz,1H),8.05(s,1H),7.93(s,1H),7.47(dd ,J=8.3,4.2Hz,1H),7.44(d,J=8.3Hz,1H),6.48(dd,J=8.3,2.3Hz,1H),6.40(d,J=2.2Hz,1H),5.64(s,2H).ESI-MS m / z=290.07[M+H] + .

[0226] Example 4

[0227] Preparation of 10,10-dimethyl-10,11-dihydro-6H-chromeno[3',4':4,5]furan[3,2-g]quinolin-3-ol (Compound E4)

[0228]

[0229] Step 1: Preparation of 7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromene-3-boronic acid

[0230]

[0231] To a solution of 3-bromo-7-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (400 mg, 1.36 mmol, 1.00 equiv) in 1,4-dioxane (20 mL) was added bis(pinacol)diboron (1.4 g, 4.08 mmol, 3.0 equiv), potassium acetate (400.4 mg, 4.08 mmol, 3.0 equiv) and tetrakistriphenylphosphine palladium (314.45 mg, 0.27 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 100 ° C for 6 hours under an argon atmosphere and then filtered through a small piece of celite. The filtrate was concentrated under reduced pressure and the crude product was used directly in the next step without further purification.

[0232] Step 2: Preparation of 7-(2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-1,2-dihydroquinolin-6-yl)-4H-quinolin-4-one

[0233]

[0234] To a solution of (7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-yl)boronic acid (crude) in 1,4-dioxane / water (4:1, 20 mL) was added 6-iodo-7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromene (160 mg, 0.48 mmol, 1.00 equiv), potassium carbonate (200 mg, 1.45 mmol, 3.00 equiv) and tetrakistriphenylphosphine palladium (110 mg, 010 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 80° C. under an argon atmosphere for 6 hours. Diluted with water (50 mL) and extracted with ethyl acetate (3× 40 mL). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=2:1) ​​to give 7-((2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-1,2-dihydroquinolin-6-yl)-4H-chromen-4-one (307 mg, purity 60%, yield 74%) as a yellow oil. ESI-MS m / z=512[M+H] + .

[0235] Step 3: Preparation of 7-((2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-1,2-dihydroquinolin-6-yl)chroman-4-one

[0236]

[0237] To a solution of 7-((2-methoxyethoxy)methoxy)-3-(7-(2-methoxyethoxy)methoxy)-2,2-dimethyl-1,2-dihydroquinolin-6-yl)-4H-chromen-4-one (154 mg, 0.30 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) was added diisobutylaluminum hydride (1.0 M hexane solution, 1.2 mL, 1.20 mmol, 4.00 equiv) at -10 ° C. The resulting mixture was stirred at -10 ° C for 2 hours under an argon atmosphere. It was quenched with a saturated aqueous solution of Rochelle salt (30 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=1:1) to give 7-((2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-1,2-dihydroquinolin-6-yl)chroman-4-one (53.2 mg, yield 56%) as a yellow oil. ESI-MS m / z=514[M+H] + .

[0238] Step 4: Preparation of 10,10-dimethyl-10,11-dihydro-6H-chromeno[3',4':4,5]furan[3,2-g]quinolin-3-ol

[0239]

[0240] To a solution of 7-((2-methoxyethoxy)methoxy)-3-(7-(2-methoxyethoxy)methoxy)-2,2-dimethyl-1,2-dihydroquinolin-6-yl)chroman-4-one (53.2 mg, 0.10 mmol, 1.00 equiv) in methanol (5 mL) at room temperature was added p-toluenesulfonic acid (76.1 mg, 0.40 mmol, 4.00 equiv). The resulting mixture was stirred at 50 ° C for 4 hours under an argon atmosphere. It was quenched with aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=2:1) ​​to give 10,10-dimethyl-10,11-dihydro-6H-chromeno[3′,4′:4,5]furo[3,2-g]quinolin-3-ol (1.4 mg, yield 4%) as a yellow solid. 1 H NMR(400MHz,Chloroform-d)δ7.28–7.26(m,1H),6.83(s,1H),6.56(s,1H),6. 44–6.39(m,2H),6.32(d,J=9.7Hz,1H),5.52–5.48(m,3H),1.33(s,6H).ESI-MS m / z=320.12[M+H] + .

[0241] Example 5

[0242] Preparation of 10,10,11-trimethyl-10,11-dihydro-6H-benzopyrano[3',4':4,5]furano[3,2-g]quinolin-3-ol (Compound E5)

[0243]

[0244] Step 1: 7-(2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-1,2,2-trimethyl-1,2-dihydroquinolin-6-yl)-4H-chromen-4-one

[0245]

[0246] To a solution of 7-((2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-1,2-dihydroquinolin-6-yl)-4H-chromen-4-one (500 mg, 0.98 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.28 g, 3.91 mmol, 4.00 equiv) and iodomethane (833 mg, 5.87 mmol, 6.00 equiv) at 0°C. The resulting mixture was stirred at room temperature under argon atmosphere for 6 hours. Diluted with water (40 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=1:1) to give 7-((2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-1,2,2-trimethyl-1,2-dihydroquinolin-6-yl)-4H-chromen-4-one (440 mg, yield 95%) as a yellow oil. ESI-MS m / z=526[M+H] +

[0247] Step 2: 7-((2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-1,2,2-trimethyl-1,2-dihydroquinolin-6-yl)chroman-4-one

[0248]

[0249] Diisobutylaluminum hydride (1.0M hexane solution, 2.51 mL, 2.51 mmol, 4.0 equiv) was added to a solution of 7-((2-methoxyethoxy)methoxy)-1,2,2-trimethyl-1,2-dihydroquinolin-6-yl)-4H-chromen-4-one (440 mg, 0.84 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) at -10 °C. The resulting mixture was stirred at -10 °C for 4 hours under an argon atmosphere. It was quenched with a saturated aqueous solution of Rochelle salt (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give 7-((2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-1,2,2-trimethyl-1,2-dihydroquinolin-6-yl)chroman-4-one (44 mg, 20% yield) as a yellow oil. ESI-MS m / z = 528 [M+H] +

[0250] Step 3: Preparation of 10,10,11-trimethyl-10,11-dihydro-6H-benzopyrano[3',4':4,5]furano[3,2-g]quinolin-3-ol

[0251]

[0252] To a solution of 7-((2-methoxyethoxy)methoxy)-3-(7-(2-methoxyethoxy)methoxy)-1,2,2-trimethyl-1,2-dihydroquinolin-6-yl)chroman-4-one (44 mg, 0.08 mmol, 1.00 equiv) in methanol (5 mL) was added p-toluenesulfonic acid (31.7 mg, 0.17 mmol, 2.0 equiv). The resulting mixture was stirred at 50 ° C for 4 hours under an argon atmosphere. It was quenched with aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel preparative TLC (PE:EtOAc=2:1) ​​to give 10,10,11-trimethyl-10,11-dihydro-6H-benzopyrano[3',4':4,5]furano[3,2-g]quinolin-3-ol (11.0 mg, yield 39.5%) as a colorless oily liquid. 1 H NMR (400MHz, Methanol-d4) δ7.19 (d, J = 8.2 Hz, 1H), 6.85 (s, 1H), 6.67 (s, 1H), 6.38 (dd, J = 8.2, 2. 3Hz,1H),6.33–6.29(m,2H),5.46(d,J=9.8Hz,1H),5.43(s,2H),2.83(s,3H),1.32(s,6H).ESI-MS m / z=334.16[M+H] + .

[0253] Example 6

[0254] Preparation of 7-hydroxy-3-(7-hydroxy-2,2-dimethyl-2H-benzopyran-6-yl)chroman-4-one (Compound E6)

[0255]

[0256] Step 1: Preparation of 7-hydroxy-3-(7-hydroxy-2,2-dimethyl-2H-benzopyran-6-yl)chroman-4-one

[0257]

[0258] To a solution of 7-((2-methoxyethoxy)methoxy)-3-(7-(2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)chroman-4-one (74 mg, 0.144 mmol) in methanol (3 mL) was added p-toluenesulfonic acid (55 mg, 0.289 mmol) at room temperature. The resulting mixture was stirred at 50°C for 4 hours under an argon atmosphere. It was quenched with aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=1:1) to give 7-hydroxy-3-(7-hydroxy-2,2-dimethyl-2H-chromen-6-yl)chroman-4-one (4.0 mg, 8% yield) as a yellow solid. 1 H NMR(400MHz,Chloroform-d)δ7.81(d,J=8.7Hz,1H),7.08(s,1H),6.50(dd,J=8.7,2.4Hz,1H),6.42–6.36(m,2H),6.2 2(d,J=9.8Hz,1H),5.44(d,J=9.9Hz,1H),4.93–4.70(m,2H),3.89(t,J=4.1Hz,1H),1.39(s,3H),1.35(s,3H).ESI-MS m / z=338.99[M+H] + .

[0259] Example 7

[0260] Preparation of 10-methyl-6H-benzopyrano[3,4:4,5]furano[3,2-g]quinolin-3-ol (Compound E7)

[0261]

[0262] Step 1: Preparation of 6-bromo-7-methoxy-2-methylquinoline

[0263]

[0264] To a solution of 4-bromo-3-methoxyaniline (1.0 g, 4.95 mmol, 1.0 eq.) in 12N HCl (3 mL) was added chloranil (1.217 g, 4.95 mmol, 1.0 eq.). The resulting mixture was heated to 105 ° C, and a solution of (E)-butenal (451 mg, 6.34 mmol, 1.3 eq.) in tert-butyl alcohol (3.2 mL) was added. The resulting mixture was stirred at 105 ° C overnight. The reactants were filtered and diluted with water (10 mL), basified to pH 7-8 with sodium bicarbonate, and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with saturated brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 12: 1) to obtain 6-bromo-7-methoxy-2-methylquinoline (323.7 mg, yield 26%) as a white solid. ESI-MS m / z = 253 [M+H] + .

[0265] Step 2: Preparation of 6-bromo-2-methylquinolin-7-ol

[0266]

[0267] To a solution of 6-bromo-7-methoxy-2-methylquinoline (323.7 mg, 1.28 mmol, 1.0 equiv) in 75% sulfuric acid (4 mL) was added sodium iodide (2.5 mg, 0.017 mmol, 0.013 equiv) at room temperature. The resulting mixture was stirred at 140 ° C for 3 hours. The resulting mixture was basified to pH 7-8 with sodium hydroxide and extracted with ethyl acetate (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (300 mg) was used in the next step without further purification. ESI-MS m / z=238 [M+H] + .

[0268] Step 3: Preparation of 6-bromo-7-(2-methoxyethoxy)methoxy)-2-methylquinoline

[0269]

[0270] To a solution of 6-bromo-2-methylquinolin-7-ol (300 mg, 1.27 mmol, 1.0 equiv) in dichloromethane (5 mL) was added N,N-diisopropylethylamine (490 mg, 3.80 mmol, 3.0 equiv). Then cooled to 0 °C, 2-methoxyethoxymethyl chloride (230 mg, 1.89 mmol, 1.5 equiv) was added. The resulting mixture was stirred at room temperature under argon atmosphere for 12 hours. Then concentrated under reduced pressure, diluted with water (10 mL), and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 5: 1) to give 6-bromo-7-((2-methoxyethoxy)methoxy)-2-methylquinoline (210 mg, 51% yield) as a white solid. ESI-MS m / z = 326 [M+H] + .

[0271] Step 4: Preparation of 7-(2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2-methylquinolin-6-yl)-4H-chromen-4-one

[0272]

[0273] To a solution of 3-bromo-7-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (550 mg, 1.67 mmol, 1.0 equiv) in 1,4-dioxane (10 mL) was added bis(pinacol)diboron (1.24 g, 4.84 mmol, 3.0 equiv), potassium acetate (475 mg, 4.84 mmol, 3.0 equiv) and tetrakistriphenylphosphine palladium (373 mg, 0.32 mmol, 0.2 equiv) at room temperature. The resulting mixture was stirred at 100° C. for 2 hours under an argon atmosphere. It was then filtered through a small piece of celite and the filtrate was concentrated under reduced pressure. The crude product was redissolved in 1,4-dioxane / water (4 / 1, 10 mL). 6-Bromo-7-((2-methoxyethoxy)methoxy)-2-methylquinoline (210 mg, 0.71 mmol), potassium carbonate (294 mg, 2.13 mmol) and tetrakistriphenylphosphine palladium (164 mg, 0.14 mmol) were added at room temperature. The resulting mixture was stirred at 80°C for 6 hours under an argon atmosphere. Diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 4: 1) to give 7-((2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2-methylquinolin-6-yl)-4H-chromen-4-one (190 mg, yield 54%) as a yellow oil. ESI-MS m / z=495[M+H] + .

[0274] Step 5: Preparation of 7-(2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2-methylquinolin-6-yl)chroman-4-one

[0275]

[0276] Diisobutylaluminum hydride (1.0M hexane solution, 0.36mL, 0.36mmol, 1.0 equivalent) was added to a solution of 7-((2-methoxyethoxy)methoxy)-2-methylquinolin-6-yl)-4H-chromen-4-one (90mg, 0.18mmol, 1.0 equivalent) in tetrahydrofuran (4mL) at -10°C. The resulting mixture was stirred at -10°C for 4 hours under an argon atmosphere. It was quenched with a saturated aqueous solution of Rochelle salt (5mL) and extracted with ethyl acetate (3x 5mL). The combined organic layers were washed with saturated brine (5mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give 7-((2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2-methylquinolin-6-yl)chroman-4-one (20 mg, yield 22%) as a yellow oil. ESI-MS m / z = 497 [M+H] + .

[0277] Step 6: Preparation of 10-methyl-6H-benzopyrano[3,4:4,5]furano[3,2-g]quinolin-3-ol

[0278]

[0279] To a solution of 7-((2-methoxyethoxy)methoxy)-3-(7-(2-methoxyethoxy)methoxy)-2-methylquinolin-6-yl)chroman-4-one (20 mg, 0.04 mmol) in methanol (2 mL) was added p-toluenesulfonic acid (31 mg, 0.16 mmol). The resulting mixture was stirred at 50 °C for 4 hours under argon atmosphere. It was quenched with aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel preparative TLC (PE: EtOAc = 2: 1) to give 10-methyl-6H-benzopyrano[3',4':4,5]furano[3,2-g]quinolin-3-ol (4 mg, 33% yield) as a yellow solid. 1 H NMR(400MHz, Methanol-d4)δ8.27(d,J=8.7Hz,1H),7.95(s,1H),7.84(s,1H),7.43–7.39(m ,1H),7.34(d,J=8.4Hz,1H),6.49–6.44(m,1H),6.38(s,1H),2.70(d,J=3.7Hz,3H).ESI-MS m / z=304.05[M+H] + .

[0280] Example 8

[0281] Preparation of 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dichromen-3-ylphosphonic acid diethyl ester (Compound E8)

[0282]

[0283] Step 1: Preparation of diethyl 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dichromen-3-yl phosphate

[0284]

[0285] To a solution of 10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromene-3-ol (20 mg, 0.062 mmol, 1.00 equiv) in tetrahydrofuran (1.2 mL) was added 0.32 mL of triethylamine. Then, 0.32 mL of diethylphosphonate solution in carbon tetrachloride (25 uL, 0.187 mmol, 3.00 equiv) was slowly added at 0°C. The resulting mixture was stirred at room temperature overnight. Diluted with water (5 mL) and extracted with ethyl acetate (2 x 5 mL). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel preparative TLC (PE: EtOAc = 1: 1) to give diethyl 10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromen-3-yl phosphate (25.1 mg, yield 88%) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ7.39(dd,J=8.3,1.8Hz,1H),6.93(d,J=8.9Hz,2H),6.82(ddd,J=8.3,2.3,1.1Hz,1H),6.77(dd,J=2.3,1.1H z,1H),6.37(d,J=9.8Hz,1H),5.63(d,J=9.9Hz,1H),5.55(s,2H),4.27–4.16(m,4H),1.44(s,6H),1.36(td,J=6.6,6.0,2.3Hz,6H).ESI-MS m / z=457.15[M+H] +

[0286] Example 9

[0287] Preparation of 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dichromen-3-yl[1,4'-bipiperidinyl]-1'-carboxylate (Compound E9)

[0288]

[0289] Step 1: Preparation of 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dichromen-3-yl[1,4'-bipiperidinyl]-1'-carboxylate

[0290]

[0291] To a solution of 10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromene-3-ol (10 mg, 0.03 mmol, 1.00 equiv) in dichloromethane (0.3 ml) was added N,N-dimethylethylamine (16 mg, 0.22 mmol, 7.0 equiv) and [1,4'-bipiperidine]-1'-carbonyl chloride (10.1 mg, 0.04 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 2.5 hours. Diluted with water (5 mL) and extracted with ethyl acetate (2 x 5 mL). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel preparative TLC (PE: EtOAc = 1: 1) to give 10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromen-3-yl[1,4'-bipiperidine]-1'-carboxylate (12.6 mg, yield 79%) as a yellow solid. 1 H NMR(400MHz,Chloroform-d)δ7.41(d,J=8.2Hz,1H),6.95(s,1H),6.93(s,1H),6.71 (dd,J=8.2,2.2Hz,1H),6.66(d,J=2.2Hz,1H),6.38(d,J=9.8Hz,1H),5.63(d,J=9.8H z,1H),5.54(s,2H),4.30(d,J=12.7Hz,2H),2.99–2.76(m,2H),2.60–2.46(m,5H),1 .89(d,J=12.9Hz,4H),1.61(q,J=5.5Hz,4H),1.57–1.45(m,2H),1.44(s,6H).ESI-MS m / z=515.29[M+H] +

[0292] Example 10

[0293] Preparation of 3-methoxy-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromene (Compound E10)

[0294]

[0295] Step 1: Preparation of 2,2-dimethyl-7-(oxiran-2-ylmethoxy)chromane

[0296]

[0297] Potassium carbonate (4.65 g, 33.708 mmol, 3.00 equiv) and 2-(chloromethyl)oxirane (1.55 g, 16.854 mmol, 1.50 equiv) were added to a solution of 2,2-dimethylbenzopyran-7-ol (2 g, 11.236 mmol, 1.00 equiv) in acetonitrile (6.00 mL) at 0°C. The resulting mixture was stirred at 90°C for 24 hours under an argon atmosphere. The reactants were cooled to room temperature, filtered through a small piece of celite, and extracted with EtOAc (30 mL). The organic phase was washed with saturated brine (20 mL) and dried (Na2SO4). The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 5: 1) to give 2,2-dimethyl-7-(oxiran-2-ylmethoxy)chromane (1.5 g, yield 57%) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ6.93(dt,J=8.3,1.0Hz,1H),6.44(dd,J=8.4,2.6Hz,1H),6.33(d,J=2.6Hz,1H),4.13(dd,J=11.0,3.3 Hz,1H),3.90(dd,J=11.0,5.6Hz,1H),3.37–3.28(m,1H),2.95–2.82(m,1H),2.78–2.61(m,3H),1.76(t,J=6.8Hz,2H),1.31(s,6H).

[0298] Step 2: Preparation of 2,2-dimethyl-7-oxirane-2-methoxy-2H-dibenzopyran

[0299]

[0300] 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.75 g, 7.692 mmol, 1.20 equiv) was added to a solution of 2,2-dimethyl-7-(oxiran-2-ylmethoxy)chromane (1.5 g, 6.410 mmol, 1.00 equiv) in 1,4-dioxane (20 mL) at 0°C. The resulting mixture was stirred overnight at 100°C under an argon atmosphere. The reactants were cooled to room temperature, filtered through a small piece of celite, and extracted with EtOAc (30 mL). The organic phase was washed with saturated brine (20 mL) and dried (Na2SO4). The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=7:1) to give 2,2-dimethyl-7-oxirane-2-methoxy-2H-dibenzopyran (980 mg, yield 66%) as a yellow oil. 1 H NMR(400MHz,Chloroform-d)δ6.87(d,J=8.2Hz,1H),6.41(dd,J=8.2,2.5Hz,1H),6 .36(dd,J=2.5,0.7Hz,1H),6.26(dd,J=9.8,0.7Hz,1H),5.47(d,J=9.8Hz,1H),4.16 (dd,J=11.0,3.2Hz,1H),3.91(dd,J=11.0,5.6Hz,1H),3.33(dddd,J=5.8,4.1,3.2 ,2.6Hz,1H),2.89(dd,J=4.9,4.1Hz,1H),2.73(dd,J=4.9,2.7Hz,1H),1.40(s,6H).

[0301] Step 3: Preparation of 1-(2,2-dimethyl-2H-dihydropyran-7-yl)oxy)-3-(2-iodo-5-methoxyphenoxy)propanol

[0302]

[0303] Potassium carbonate (821 mg, 5.948 mmol, 2.00 equiv) and 2-iodo-5-methoxyphenol (818 mg, 3.272 mmol, 1.10 equiv) were added to a solution of 2,2-dimethyl-7-oxirane-2-methoxy-2H-dibenzopyran (690 mg, 2.974 mmol, 1.00 equiv) in acetonitrile (10 mL) at 0°C. The resulting mixture was stirred at 90°C overnight under an argon atmosphere. The reactants were cooled to room temperature and then filtered through a small piece of celite, and the resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 5: 1) to give 1-(2,2-dimethyl-2H-dihydropyran-7-yl)oxy)-3-(2-iodo-5-methoxyphenoxy)propanol (1 g, yield 70%) as a yellow oil. 1 H NMR(400MHz,Chloroform-d)δ7.60(dd,J=8.5,0.7Hz,1H),6.87(d,J=8.2Hz,1H),6.47–6.32(m,4H),6.26(d,J= 9.8Hz,1H),5.47(d,J=9.8Hz,1H),4.19–4.08(m,5H),3.78(d,J=0.8Hz,3H),2.65(d,J=5.8Hz,1H),1.40(s,6H).

[0304] Step 4: Preparation of 1-(2,2-dimethyl-2H-benzoyl)oxy)-3-(2-iodo-5-methoxyphenoxy)-2-propanone

[0305]

[0306] To a solution of 1-(2,2-dimethyl-2H-dihydropyran-7-yl)oxy)-3-(2-iodo-5-methoxyphenoxy)propanol (1 g, 2.075 mmol, 1.00 equiv) in dichloromethane (20 mL) at 0°C was added Dess-Martin periodinane (1.23 g, 2.905 mmol, 1.40 equiv). The resulting mixture was stirred at room temperature under argon for 3 hours. The reaction was filtered through a small piece of celite and eluted with EtOAc (30 mL). The filtrate was washed with saturated brine (20 mL) and dried (Na2SO4). The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=10:1) to give 1-(2,2-dimethyl-2H-benzoyl)oxy)-3-(2-iodo-5-methoxyphenoxy)-2-propanone (700 mg, yield 70%) as a yellow oil. 1H NMR(400MHz,Chloroform-d)δ7.65(d,J=8.5Hz,1H),6.89(d,J=8.3Hz,1H),6.48–

[0307] 6.22(m,5H),5.49(d,J=9.8Hz,1H),5.06(s,2H),4.78(s,2H),3.78(s,3H),1.40(s,6H).

[0308] Step 5: Preparation of 3-(2-iodo-5-methoxyphenoxy)methyl-7,7-dimethyl-7H-furo[3,2-g]chromene

[0309]

[0310] Boron trichloride (1M in dichloromethane, 2.2 ml, 2.187 mmol, 1.50 equiv) was added dropwise to a solution of 1-(2,2-dimethyl-2H-benzoyl)oxy)-3-(2-iodo-5-methoxyphenoxy)-2-propanone (700 mg, 1.458 mmol, 1.00 equiv) in dichloromethane (10 mL) at -78 °C. The resulting mixture was stirred at -78 °C under an argon atmosphere for 30 minutes and then quenched with water (10 mL). The reaction solution was warmed to room temperature and extracted with DCM (2 x 40 mL). The organic phase was washed with saturated brine (50 mL) and dried (Na2SO4). The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=20:1) to give 3-(2-iodo-5-methoxyphenoxy)methyl-7,7-dimethyl-7H-furo[3,2-g]chromene (160 mg, yield 24%) as a colorless oil. 1 H NMR(400MHz,Chloroform-d)δ7.69–7.54(m,2H),7.34(s,1H),6.91(s,1H),6.54(d,J=2.7Hz,1H),6.43(d,J= 9.7Hz,1H),6.34(dd,J=8.6,2.6Hz,1H),5.69–5.57(m,1H),5.17(d,J=1.1Hz,2H),3.77(s,3H),1.43(s,6H).

[0311] Step 6: Preparation of 3-methoxy-10,10-dimethyl-6H,10H-furano[3,2-c:4,5-g']dichromene

[0312]

[0313] Tetrabutylammonium bromide (111 mg, 0.346 mmol, 2.0 equiv), potassium acetate (85 mg, 0.866 mmol, 5.0 equiv) and palladium acetate (4 mg, 0.017 mmol, 0.2 equiv) were added to a solution of 3-(2-iodo-5-methoxyphenoxy)methyl-7,7-dimethyl-7H-furo[3,2-g]chromene (80 mg, 0.173 mmol, 1.00 equiv) in DMF (4 mL) at room temperature. The resulting mixture was stirred at 90°C for 3 hours under an argon atmosphere. The reaction solution was cooled to room temperature, then diluted with water (15 mL), extracted with EtOAc (2×15 mL), and the organic layer was washed with saturated brine (2×25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=20:1) to give 3-methoxy-10,10-dimethyl-6H,10H-furano[3,2-c:4,5-g']dichromene (17 mg, yield 29.4%) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ7.37(d,J=8.4Hz,1H),7.01–6.89(m,2H),6.55–6.45(m,2H), 6.38(d,J=9.8Hz,1H),5.63(d,J=9.8Hz,1H),5.53(s,2H),3.79(s,3H),1.44(s,6H).ESI-MS m / z=334.98[M+H] + .

[0314] Embodiment 11

[0315] Preparation of 10,10-dimethyl-9,10-dihydro-6H,8H-furan[3,2-c:4,5-g']dibenzopyran-3-ol (Compound E11)

[0316]

[0317] Step 1: Preparation of 4-bromo-7-hydroxy-2H-dihydrobenzopyran-2-one

[0318]

[0319] 48% aqueous hydrobromic acid solution (2 mL) was added to a solution of 4-bromo-7-methoxy-2H-dihydrobenzopyran-2-one (500 mg, 1.97 mmol, 1.00 equiv) in acetic acid (2.00 mL) at room temperature. The resulting mixture was heated to 110 degrees Celsius under an argon atmosphere and stirred for 48 hours. The reaction solution was cooled to room temperature, poured into ice water with saturated sodium bicarbonate to quench the reaction, and the aqueous phase was extracted with ethyl acetate (3 x 80 mL). The organic phase was washed with saturated brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography PE / EtOAc (2:1) to obtain 4-bromo-7-hydroxy-2H-dihydrobenzopyran-2-one (350 mg, yield 74%) as a yellow oil. ESI-MS m / z=240.74[M+H] + .

[0320] Step 2: Preparation of 7-benzyloxy-4-bromo-2H-dihydrobenzopyran-2-one

[0321]

[0322] Potassium carbonate (115.00 mg, 0.83 mmol, 2.00 equiv) and benzyl bromide (107.00 mg, 0.62 mmol, 1.50 equiv) were added to a DMF (2.00 mL) solution of 4-bromo-7-hydroxy-2H-dihydrobenzopyran-2-one (100.00 mg, 0.42 mmol, 1.00 equiv) under ice bath. The resulting reaction solution was stirred at room temperature for 16 hours under argon atmosphere and diluted with water (30 mL). The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The organic phase was washed with saturated brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography PE / EtOAc (4:1) to obtain 7-benzyloxy-4-bromo-2H-dihydrobenzopyran-2-one (70.0 mg, yield 50%) as a yellow solid. ESI-MS m / z=330.82[M+H] + .

[0323] Step 3: Preparation of 7-benzyloxy-4-(2,2-dimethylbenzopyran-7-oxy)-2H-chromen-2-one

[0324]

[0325] Potassium carbonate (59.00 mg, 0.83 mmol, 2.00 equiv) and 2,2-dimethylbenzopyran-7-ol (45.00 mg, 0.25 mmol, 1.20 equiv) were added to a solution of 7-benzyloxy-4-bromo-2H-dihydrobenzopyran-2-one (70.00 mg, 0.21 mmol, 1.00 equiv) in DMF (2.00 mL) at room temperature. The resulting mixture was heated to 80 degrees Celsius under an argon atmosphere and stirred for 3 hours. The reaction solution was cooled to room temperature, diluted with water (30 mL), and the aqueous phase was extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography with PE / EtOAc (4:1) to give 7-benzyloxy-4-(2,2-dimethylbenzopyran-7-oxy)-2H-chromen-2-one (75.00 mg, yield 82%) as a yellow solid. ESI-MS m / z = 428.98 [M+H] + .

[0326] Step 4: Preparation of 3-benzyloxy-10,10-dimethyl-9,10-dihydro-6H,8H-furan[3,2-c:4,5-g']dibenzopyran-6-one

[0327]

[0328] Pivalic acid (2.00 mL), palladium acetate (4.00 mg, 0.017 mmol, 0.10 equiv), silver acetate (41.00 mg, 0.35 mmol, 2.00 equiv) and cesium acetate (67.00 mg, 0.35 mmol, 2.00 equiv) were added to 7-benzyloxy-4-(2,2-dimethylbenzopyran-7-oxy)-2H-chromen-2-one (75.00 mg, 0.17 mmol, 1.00 equiv) at room temperature. The resulting mixture was heated to 100 degrees Celsius under an argon atmosphere and stirred for 3 hours. The reaction solution was cooled to room temperature and poured into saturated sodium bicarbonate ice water to quench the reaction. The aqueous phase was extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 4: 1) to obtain benzyloxy-10,10-dimethyl-9,10-dihydro-6H,8H-furan[3,2-c:4,5-g']dibenzopyran-6-one (50.00 mg, yield 69%) as a yellow solid. ESI-MS m / z = 426.97 [M+H] + .

[0329] Step 5: Preparation of 3-hydroxy-10,10-dimethyl-9,10-dihydro-6H,8H-furan[3,2-c:4,5-g']dibenzopyran-6-one

[0330]

[0331] To a solution of benzyloxy-10,10-dimethyl-9,10-dihydro-6H,8H-furan[3,2-c:4,5-g']dibenzopyran-6-one (50.00 mg, 0.12 mmol, 1.00 equiv) in methanol (2.00 mL) was added ammonium formate (74.00 mg, 1.17 mmol, 10.00 equiv) and 10% wet palladium on carbon (20.00 mg) at room temperature. The reaction solution was stirred at room temperature for 16 hours under a hydrogen atmosphere and then filtered. The residue was washed with methanol (3 x 10 mL) and the filtrate was concentrated under reduced pressure to obtain 3-hydroxy-10,10-dimethyl-9,10-dihydro-6H,8H-furan[3,2-c:4,5-g']dibenzopyran-6-one (50.00 mg, crude product) as a yellow solid, which was directly used in the next step without purification. ESI-MS m / z=336.92[M+H] + .

[0332] Step 6: Preparation of 10,10-dimethyl-9,10-dihydro-6H,8H-furan[3,2-c:4,5-g']dibenzopyran-3-ol

[0333]

[0334] Add 2M borane dimethyl sulfide tetrahydrofuran solution (2.00mL, 4.00mmol) to 3-hydroxy-10,10-dimethyl-9,10-dihydro-6H,8H-furan[3,2-c:4,5-g']dibenzopyran-6-one (65.00mg, 0.19mmol) under ice bath, and react the reaction solution at room temperature for 16 hours. Add methanol (1mL) to the reaction solution under ice bath, add water (20mL) after quenching the reaction, and extract with ethyl acetate (3x 20mL). Wash the organic phase with saturated brine (2x 30mL), dry over anhydrous sodium sulfate, filter, and concentrate the organic solvent under reduced pressure. The crude product was purified by preparative silica gel plate PE / EtOAc (4:1) to obtain 10,10-dimethyl-9,10-dihydro-6H,8H-furan[3,2-c:4,5-g']dibenzopyran-3-ol (4.5 mg, yield 7%) as a yellow solid. ESI-MS m / z=321.95[M+H] + ; 1H NMR(400MHz,Chloroform-d)δ7.33(d,J=8.0Hz,1H),7.00(s,1H),6.92(s,1H),6.47– 6.39(m,2H),5.52(s,2H),2.86(t,J=6.8Hz,2H),1.83(t,J=6.8Hz,2H),1.35(s,6H).

[0335] Example 12

[0336] Preparation of 10,10-dimethyl-9,10-dihydro-6H,8H-furan[3,2-c:4,5-g']dichromene (Compound E12)

[0337]

[0338] Step 1: Preparation of 1-(2,2-dimethylbenzopyran-7-yl)oxy)-3-(2-iodophenoxy)propan-2-ol

[0339]

[0340] Potassium carbonate (2.01 g, 14.530 mmol, 2.00 equiv) and 2-iodo-5-methoxyphenol (1.76 g, 7.991 mmol, 1.10 equiv) were added to a solution of 2,2-dimethyl-7-(oxiran-2-ylmethoxy)chromene (1.7 g, 7.265 mmol, 1.00 equiv) in acetonitrile (20 mL) at 0°C. The resulting mixture was stirred at 90°C overnight under an argon atmosphere. The reaction solution was cooled to room temperature and then filtered through a small piece of celite. The resulting filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 6: 1) to give 1-(2,2-dimethylbenzopyran-7-yl)oxy)-3-(2-iodophenoxy)propan-2-ol (2.77 g, yield 84%) as a yellow oil. 1 H NMR(400MHz,Chloroform-d)δ7.75(dd,J=7.8,1.6Hz,1H),7.33–7.24(m,1H),6 .98–6.89(m,1H),6.83(dd,J=8.2,1.4Hz,1H),6.73(td,J=7.6,1.4Hz,1H),6.4 5(dd,J=8.4,2.6Hz,1H),6.38(d,J=2.6Hz,1H),5.29(s,1H),4.38(p,J=5.3Hz, 1H), 4.21–4.13 (m, 4H), 2.70–2.66 (m, 2H), 1.77 (t, J = 6.8Hz, 2H), 1.31 (s, 6H).

[0341] Step 2: Preparation of 1-(2,2-dimethylbenzopyran-7-yl)oxy)-3-(2-iodophenoxy)-2-propanone

[0342]

[0343] To a solution of 1-(2,2-dimethylbenzopyran-7-yl)oxy)-3-(2-iodophenoxy)propan-2-ol (2.77 g, 6.101 mmol, 1.00 equiv) in dichloromethane (30 mL) at 0°C, Dess-Martin periodinane (3.36 g, 7.932 mmol, 1.30 equiv) was added. The resulting mixture was stirred at room temperature overnight under an argon atmosphere. The reactants were filtered through a small piece of celite and eluted with EtOAc (30 mL). The filtrate was washed with saturated brine (20 mL) and dried (Na2SO4). The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 6: 1) to give 1-(2,2-dimethylbenzopyran-7-yl)oxy)-3-(2-iodophenoxy)-2-propanone (2.2 g, 80% yield) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ7.80(dd,J=7.8,1.6Hz,1H),7.34–7.25(m,1H),6.96(dt,J=8.4,1.0Hz,1H),6.78(td,J=7.6,1.3Hz,1H),6.70(dd,J=8.2,1 .3Hz,1H),6.47(dd,J=8.4,2.6Hz,1H),6.33(d,J=2.6Hz,1H),5.03(s,2H),4 .83(s,2H),2.70(td,J=6.8,1.0Hz,2H),1.77(t,J=6.8Hz,2H),1.31(s,6H).

[0344] Step 3: Preparation of 3-(2-iodophenoxy)methyl-7,7-dimethyl-6,7-dihydro-5H-furo[3,2-g]dibenzopyran

[0345]

[0346] Boron trichloride (1M in dichloromethane, 2.88 ml, 2.876 mmol, 1.30 equiv) was added dropwise to a solution of 1-(2,2-dimethylbenzopyran-7-yl)oxy)-3-(2-iodophenoxy)-2-propanone (1 g, 2.212 mmol, 1.00 equiv) in dichloromethane (100 mL) at -78°C. The resulting mixture was stirred at -78°C under an argon atmosphere for 30 minutes and then quenched with water (10 mL). The reaction solution was warmed to room temperature and extracted with DCM (2 x 40 mL). The organic phase was washed with saturated brine (50 mL) and dried (Na2SO4). The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=10:1) to give 3-(2-iodophenoxy)methyl-7,7-dimethyl-6,7-dihydro-5H-furo[3,2-g]dibenzopyran (320 mg, yield 33%) as a colorless oil. 1 H NMR(400MHz,Chloroform-d)δ7.84–7.73(m,1H),7.65–7.50(m,1H),7.43(s,1H),7.29(ddd,J=8.1,7.4,1.6Hz,1H ),7.00–6.84(m,2H),6.79–6.66(m,1H),5.20(d,J=1.1Hz,2H),2.99–2.81(m,2H),1.91–1.75(m,2H),1.35(s,6H).

[0347] Step 4: Preparation of 10,10-dimethyl-9,10-dihydro-6H,8H-furan[3,2-c:4,5-g']dichromene

[0348]

[0349] Tetrabutylammonium bromide (237 mg, 0.737 mmol, 2.0 equiv), potassium acetate (181 mg, 1.843 mmol, 5.0 equiv) and palladium acetate (8 mg, 0.037 mmol, 0.1 equiv) were added to a solution of 3-(2-iodophenoxy)methyl-7,7-dimethyl-6,7-dihydro-5H-furo[3,2-g]dibenzopyran (160 mg, 0.369 mmol, 1.00 equiv) in DMF (8 mL) at room temperature. The resulting mixture was stirred at 90 ° C for 3 hours under an argon atmosphere. The reaction solution was cooled to room temperature, then diluted with water (15 mL), extracted with EtOAc (2×15 mL), and the organic layer was washed with saturated brine (3×15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=20:1) to give 10,10-dimethyl-9,10-dihydro-6H,8H-furano[3,2-c:4,5-g']dichromene (80 mg, yield 71%) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ7.50–7.43(m,1H),7.13(ddd,J=8.1,7.5,1.7Hz,1H),7.04(d,J=1.1Hz,1H),6.99– 6.92(m,2H),6.87(dd,J=8.2,1.1Hz,1H),5.56(s,2H),2.95–2.82(m,2H),1.91–1.79(m,2H),1.35(s,6H).ESI-MS m / z=304.92[MH] - .

[0350] Embodiment 13

[0351] Preparation of 10,10-dimethyl-9,10-dihydro-6H,8H-furan[3,2-c:4,5-g']dibenzopyran-6-one (Compound E13)

[0352]

[0353] Step 1: Preparation of 10,10-dimethyl-9,10-dihydro-6H,8H-furan[3,2-c:4,5-g']dibenzopyran-6-one

[0354]

[0355] 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (5 mg, 0.020 mmol, 1.20 equiv) was added to a solution of 10,10-dimethyl-9,10-dihydro-6H,8H-furan[3,2-c:4,5-g']dichromene (5 mg, 0.016 mmol, 1.00 equiv) in 1,4-dioxane (0.5 mL) at 0°C. The resulting mixture was stirred overnight at 100°C under an argon atmosphere. The reaction was cooled to room temperature and filtered through a small piece of celite. The filtrate was diluted with water (15 mL) and extracted with EtOAc (20 mL). The organic phase was washed with saturated brine (20 mL) and dried (Na2SO4). The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=10:1) to give 10,10-dimethyl-9,10-dihydro-6H,8H-furan[3,2-c:4,5-g']dibenzopyran-6-one (2.8 mg, yield 54%) as a light yellow solid. 1 H NMR(400MHz,Chloroform-d)δ7.99(dd,J=7.8,1.6Hz,1H),7.87–7.74(m,1H),7.56(ddd,J=8.7,7.2,1.6Hz,1H),7.48(dd,J=8.4,1 .2Hz,1H),7.39(ddd,J=8.3,7.2,1.2Hz,1H),7.07(s,1H),2.96(td,J=6.8,1.1Hz,2H),1.87(t,J=6.8Hz,2H),1.38(s,6H).ESI-MS m / z=320.90[M+H] + .

[0356] Embodiment 14

[0357] Preparation of 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dibenzopyran-6-one (Compound E14)

[0358]

[0359] Step 1: Preparation of 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dibenzopyran-6-one

[0360]

[0361] 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (18 mg, 0.082 mmol, 5.00 equiv) was added to a solution of 10,10-dimethyl-9,10-dihydro-6H,8H-furan[3,2-c:4,5-g']dichromene (5 mg, 0.016 mmol, 1.00 equiv) in 1,4-dioxane (0.5 mL) at 0°C. The resulting mixture was stirred at 100°C for 2 days under an argon atmosphere. The reaction was cooled to room temperature and filtered through a small piece of celite. The filtrate was diluted with water (15 mL) and extracted with EtOAc (20 mL). The organic phase was washed with saturated brine (20 mL) and dried (Na2SO4). The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC (PE:EtOAc=10:1) to give 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g′]dibenzopyran-6-one (3.8 mg, yield 73%) as a yellow solid. 1 H NMR(400MHz,Chloroform-d)δ7.98(ddd,J=7.8,1.7,0.5Hz,1H),7.70(s,1H),7.61–7.53(m,1H),7.48(ddd,J=8.4,1.2,0.5 Hz,1H),7.39(ddd,J=7.8,7.2,1.2Hz,1H),7.08(t,J=0.6Hz,1H),6.54–6.41(m,1H),5.77–5.64(m,1H),1.47(s,6H).ESI-MS m / z=318.89[M+H] + .

[0362] Embodiment 15

[0363] Preparation of 7,7'-dihydroxy-2',2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one (Compound E15)

[0364]

[0365] Step 1: Preparation of 7,7'-dihydroxy-2',2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one

[0366]

[0367] To a solution of 7,7'-bis((2-methoxyethoxy)methoxy)-2',2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one (35 mg, 0.068 mmol, 1.00 equiv) in methanol (2 mL) was added p-toluenesulfonic acid (25.9 mg, 0.136 mmol, 2.00 equiv). The mixture was stirred at 50°C for 5 hours. The reactant was diluted with ethyl acetate (20 mL), washed with water (2 x 20 mL), and the organic phase was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:3) to give 7,7'-dihydroxy-2',2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one (4 mg, 17.4% yield) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ8.23(d,J=8.7Hz,1H),8.02(s,1H),6.97(d,J=8.4Hz,1 H),6.91(s,1H),6.75(s,1H),6.52(s,1H),6.27(d,J=9.8Hz,1H),1.43(s,6H).ESI-MS m / z=336.97[M+H] + .

[0368] Example 16

[0369] Preparation of 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dichromene-3-carbonitrile (Compound E16)

[0370]

[0371]

[0372] Step 1: Preparation of 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dibenzopyran-3-yl trifluoromethanesulfonate

[0373]

[0374] Triethylamine (39.5 mg, 0.39 mmol) and pyridine (24.7 mg, 0.31 mmol) were added to a stirred solution of 10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromene-3-ol (25 mg, 0.078 mmol) in DCM (2 mL) at room temperature, then cooled to -10°C and trifluoromethanesulfonic anhydride (44 mg, 0.16 mmol) was added. The resulting mixture was stirred at -10°C for 3 hours under an argon atmosphere, then diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM) to give 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dibenzopyran-3-yl trifluoromethanesulfonate (17.5 mg, 50% yield) as a yellow solid. ESI-MS m / z = 453 [M+H] +

[0375] Step 2: Preparation of 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dichromene-3-carbonitrile

[0376]

[0377] Zinc cyanide (3.9 mg, 0.022 mmol) and methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (0.9 mg, 0.001 mmol) were added to a stirred solution of 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dibenzopyran-3-yl trifluoromethanesulfonate (5 mg, 0.011 mmol) in THF / water (0.2 mL / 0.2 mL) at room temperature. The resulting mixture was stirred at 50°C overnight under an argon atmosphere. Dilute with water (5 mL) and extract with ethyl acetate (3×5 mL). The combined organic layers were washed with saturated brine (10 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC (PE:EtOAc=2:1) ​​to give 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g′]dichromene-3-carbonitrile (3.6 mg, 99% yield) as a brown solid. 1H NMR(400MHz,Chloroform-d)δ7.48(d,J=7.7Hz,1H),7.22(d,J=1.5Hz,1H),7.09(d,J=1.5Hz,1H),6 .97(d,J=5.2Hz,2H),6.39(d,J=9.8Hz,1H),5.67(d,J=9.8Hz,1H),5.63(s,2H),1.45(s,6H).ESI-MS m / z=329.93[M+H] +

[0378] Embodiment 17

[0379] Preparation of 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dichromene-3-carboxylic acid methyl ester (Compound E17)

[0380]

[0381]

[0382] Step 1: Preparation of 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dichromene-3-carboxylic acid methyl ester

[0383]

[0384] Triethylamine (20.1 mg, 0.20 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (9.7 mg, 0.013 mmol) were added to a solution of 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dibenzopyran-3-yl trifluoromethanesulfonate (30 mg, 0.066 mmol) in MeOH (4 mL) at room temperature. The resulting mixture was stirred at 60°C for 4 hours under an argon atmosphere. The reaction solution was filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (PE: EtOAc = 1: 1) to give 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dichromene-3-carboxylic acid methyl ester (21 mg, 87.5% yield) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ7.65(dd,J=7.9,1.6Hz,1H),7.53–7.47(m,2H),6.97(d,J=3.0Hz, 2H),6.39(d,J=9.8Hz,1H),5.66(d,J=9.9Hz,1H),5.60(s,2H),3.90(s,3H),1.45(s,6H).ESI-MS m / z=362.93[M+H]+

[0385] Embodiment 18

[0386] Preparation of 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dichromene-3-carboxylic acid (Compound E18)

[0387]

[0388] Step 1: Preparation of 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dichromene-3-carboxylic acid

[0389]

[0390] To a stirred solution of 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dichromene-3-carboxylate (10 mg, 0.028 mmol) in THF / water (0.6 mL / 0.2 mL) was added LiOH (6.6 mg, 0.28 mmol) at room temperature. The resulting mixture was stirred at 45°C overnight under an argon atmosphere. The reaction solution was diluted with water (3 mL) and acidified to pH 5 with 1N HCl. Extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with saturated brine (10 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Xbridge BEH C18 OBD column, 5uM, 10mm×250mm; mobile phase: [water (0.5% formic acid)-acetonitrile]; b%: 10%-90% within 20 minutes) to obtain 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g′]dichromene-3-carboxylic acid (4.7 mg, 49% yield) as a brown solid. 1 H NMR(400MHz, Methanol-d4)δ7.64–7.59(m,1H),7.50–7.42(m,2H),7.13(s,1H),6.93( s,1H),6.45(d,J=9.9Hz,1H),5.72(d,J=9.8Hz,1H),5.60(s,2H),1.41(s,6H).ESI-MS m / z=348.93[M+H] +

[0391] Embodiment 19

[0392] Preparation of 10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-3-acetate (Compound E19)

[0393]

[0394] Step 1: Preparation of 10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-3-acetate

[0395]

[0396] Triethylamine (79 mg, 0.078 mmol) was added to a stirred solution of 10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromene-3-ol (5 mg, 0.016 mmol) in DCM (0.5 mL) at room temperature, then cooled to 0°C and acetic anhydride (3.2 mg, 0.031 mmol) was added. The resulting mixture was stirred at room temperature overnight under an argon atmosphere. Diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC (PE:EtOAc=2:1) ​​to give 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g′]dibenzopyran-3-acetate (4.7 mg, 83% yield) as a white solid. 1 HNMR(400MHz,Chloroform-d)δ7.44(d,J=8.2Hz,1H),7.25(s,1H),6.95(d,J=6.4Hz,2H),6.69(dd,J=8.3,2.3Hz,1H),6.64(d ,J=2.3Hz,1H),6.38(d,J=9.8Hz,1H),5.64(d,J=9.8Hz,1H),5.56(s,2H),2.29(d,J=1.0Hz,3H),1.44(d,J=1.0Hz,6H).ESI-MS m / z=362.93[M+H] +

[0397] Embodiment 20

[0398] Preparation of N-(10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dichromen-3-yl)acetamide (Compound E20)

[0399]

[0400]

[0401] Step 1: Preparation of N-(4-acetyl-3-hydroxyphenyl)acetamide

[0402]

[0403] To a stirred solution of 1-(4-amino-2-hydroxyphenyl)ethane-1-one (3 g, 19.85 mmol, 1.00 equiv) in DCM (30 mL) at 0°C, acetic anhydride (5.07 g, 49.62 mmol, 2.50 equiv) and triethylamine (10.05 g, 99.24 mmol, 5.00 equiv) were added. The mixture was then concentrated under reduced pressure, diluted with water (20 mL), and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with 5% NaHCO3 (30 mL) and saturated brine (30 mL), and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc=1:1) to give N-(4-acetyl-3-hydroxyphenyl)acetamide (3.63 g, 95% yield) as a white solid. ESI-MS m / z=194[M+H] +

[0404] Step 2: Preparation of (E)-N-(4-(3-(dimethylamino)acryloyl)-3-hydroxyphenyl)acetamide

[0405]

[0406] Under argon atmosphere, a solution of N-(4-acetyl-3-hydroxyphenyl)acetamide (3.63 g, 18.8 mmol, 1.00 equiv) in N,N-dimethylformamide dimethyl acetal (12 mL) was stirred at 100°C for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give (E)-N-(4-(3-(dimethylamino)acryloyl)-3-hydroxyphenyl)acetamide (3.4 g, 73% yield) as a yellow solid. ESI-MS m / z = 249 [M+H] +

[0407] Step 3: Preparation of N-(3-bromo-4-oxo-4H-chromen-7-yl)acetamide

[0408]

[0409] To a stirred solution of (E)-N-(4-(3-(dimethylamino)acryloyl)-3-hydroxyphenyl)acetamide (1.7 g, 6.855 mmol, 1.00 equiv) in chloroform (120 mL) at 0°C were added silica gel (5 g) and N-bromosuccinimide (1.83 g, 10.282 mmol, 1.50 equiv). The resulting mixture was stirred at 0°C for 4 hours under an argon atmosphere. After filtration, the filter cake was washed with PE / EtOAc (1:1, 100 mL) and DCM / MeOH (1:1, 100 mL). All the filtrate was concentrated under reduced pressure. The residue was washed with DCM (6 mL) to give N-(3-bromo-4-oxo-4H-chromen-7-yl)acetamide (990 mg, 51% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.75(s,1H),8.04(d,J=1.9Hz,1H),7.98(d,J=8.8Hz,1H),7.47(dd,J=8.8,2.0Hz,1H),2.08(s,3H).ESI-MS m / z=282[M+H] +

[0410] Step 4: Preparation of 7-acetylamino-4-oxo-4H-chromene-3-boronic acid

[0411]

[0412] To a stirred solution of N-(3-bromo-4-oxo-4H-chromen-7-yl)acetamide (800 g, 2.85 mmol, 1.00 equiv) in 1,4-dioxane (20 mL) was added bis(pinacolato)diboron (17 g, 8.54 mmol, 3.0 equiv), potassium acetate (838 mg, 8.54 mmol, 3.0 equiv) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (241 mg, 0.285 mmol, 0.10 equiv) and then filtered through a small piece of celite. The filtrate was concentrated under reduced pressure and the crude product was used directly in the next step without further purification.

[0413] Step 5: Preparation of N-(7'-((2-methoxyethoxy)methoxy)-2',2'-dimethyl-4-oxo-2'H,4H-[3,6'-bichromene]-7-yl)-acetamide

[0414]

[0415] To a stirred solution of 7-acetylamino-4-oxo-4H-chromene-3-boronic acid in 1,4-dioxane / water (4:1, 20 mL) was added 6-iodo-7-(2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromene (333 mg, 0.854 mmol, 0.50 equiv), potassium carbonate (705 mg, 5.10 mmol, 3.00 equiv) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (144 mg, 0.17 mmol, 0.10 equiv). The resulting mixture was stirred at 80° C. overnight under an argon atmosphere. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (2×40 mL). The organic layer was washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give N-(7'-((2-methoxyethoxy)methoxy)-2',2'-dimethyl-4-oxo-2'H,4H-[3,6'-bichromene]-7-yl)-acetamide (440 mg, 79% yield) as a brown solid. ESI-MS m / z = 466 [M+H] +

[0416] Step 6: Preparation of N-(3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)-4-oxo-7-yl)acetamide

[0417]

[0418] To a stirred solution of N-(7'-((2-methoxyethoxy)methoxy)-2',2'-dimethyl-4-oxo-2'H,4H-[3,6'-bichromene]-7-yl)-acetamide (200 mg, 0.43 mmol, 1.00 equiv) in THF (5 mL) at -10°C was added diisobutylaluminum hydride (1.0 M hexane solution, 880 μL, 0.86 mmol, 2.00 equiv). The resulting mixture was stirred at -10°C for 2 hours under an argon atmosphere. The mixture was quenched with sodium potassium tartrate solution (5 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was washed with saturated brine (5 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give N-(3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)-4-oxo-7-yl)acetamide (47 mg, 23% yield) as a pink solid. ESI-MS m / z = 468 [M+H] +

[0419] Step 7: Preparation of N-(10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dichromen-3-yl)acetamide

[0420]

[0421] To a stirred solution of N-(3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)-4-oxo-7-yl)acetamide (40 mg, 0.086 mmol, 1.00 equiv) in MeOH (1 mL) at room temperature was added p-toluenesulfonic acid (33 mg, 0.171 mmol, 2.0 equiv). The resulting mixture was stirred at 50°C for 4 hours under an argon atmosphere. The reaction solution was diluted with water (3 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with saturated brine (3 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM) to give N-(10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g′]dichromen-3-yl)acetamide (4 mg, 13% yield) as a yellow solid. 1 HNMR(400MHz,Chloroform-d)δ7.38(d,J=8.2Hz,1H),7.19–7.11(m,2H),7.05(d,J=8.2Hz,1H),6.94(d,J =8.8Hz,2H),6.38(d,J=9.8Hz,1H),5.63(d,J=9.8Hz,1H),5.54(s,2H),2.17(s,3H),1.44(s,6H).ESI-MS m / z=362.11[M+H] +

[0422] Embodiment 21

[0423] Preparation of 10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-3-amine (Compound E21)

[0424]

[0425] Step 1: Preparation of 10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-3-amine

[0426]

[0427] To a stirred solution of N-(3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)-4-oxo-7-yl)acetamide (40 mg, 0.086 mmol, 1.00 equiv) in MeOH (1 mL) at room temperature was added p-toluenesulfonic acid (33 mg, 0.171 mmol, 2.00 equiv). The resulting mixture was stirred at 50°C for 4 hours under an argon atmosphere. The reaction solution was diluted with water (3 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with saturated brine (3 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM) to give N-(10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dichromen-3-yl)acetamide (4 mg, 13% yield) as a yellow solid and 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dibenzopyran-3-amine (10 mg, 36% yield) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ7.27(s,1H),6.91(d,J=15.3Hz,2H),6.38(d,J=9.8Hz,1H),6.28(d,J=8.1H z,1H),6.24(d,J=2.1Hz,1H),5.61(d,J=9.7Hz,1H),5.48(d,J=1.1Hz,4H),1.43(d,J=1.0Hz,6H).ESI-MS m / z=320.08[M+H] +

[0428] Embodiment 22

[0429] Preparation of 10,10-diethyl-6H,10H-furan[3,2-c:4,5-g']dichromene-3-ol (Compound E22)

[0430]

[0431] Step 1: Preparation of 2,2-diethyl-7-(2-methoxyethoxy)methoxy)chroman-4-one

[0432]

[0433] To a solution of 1-(2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)ethane-1-one (1.0 g, 4.1623 mmol, 1.00 equiv) in methanol (6.00 mL) was added pentan-3-one (6.00 mL), pyrrolidine (0.30 mL, 3.7461 mmol, 0.90 equiv). The resulting mixture was stirred at 75 °C for 12 hours under argon atmosphere. The reaction was diluted with water (10 mL) at room temperature, the aqueous phase was acidified to pH 7-8 with 1N HCl, and extracted with EtOAc (3×20 mL). The organic phase was washed with saturated brine (250 mL) and dried (Na2SO4). The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 4: 1) to give 2,2-diethyl-7-(2-methoxyethoxy)methoxy)chroman-4-one (529 mg, yield 53%) as a yellow oil. ESI-MS m / z = 309 [M+H] + .

[0434] Step 2: Preparation of 6-bromo-2,2-diethyl-7-((2-methoxyethoxy)methoxy)chroman-4-one

[0435]

[0436] N-bromosuccinimide (419.8 mg, 2.3586 mmol, 1.50 equiv) was added to a solution of 2,2-diethyl-7-(2-methoxyethoxy)methoxy)chroman-4-one (484.3 mg, 1.5724 mmol, 1.00 equiv) in acetonitrile (10.00 mL) at 0°C. The mixture was stirred at room temperature for 4 hours, then diluted with water (20 mL), extracted with EtOAc (3×20 mL), and the organic layer was washed with saturated brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 25: 1) to obtain the preparation of 6-bromo-2,2-diethyl-7-((2-methoxyethoxy)methoxy)chroman-4-one (455.3 mg, yield 94%) as a colorless oily liquid. ESI-MS m / z=387[M+H] + .

[0437] Step 3: Preparation of 7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromene-3-boronic acid

[0438]

[0439] To a solution of 3-bromo-7-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (682.2 mg, 2.0725 mmol, 1.00 equiv) in 1,4-dioxane (20 mL) was added bis(pinacol)diboron (1.58 g, 6.2175 mmol, 3.0 equiv), potassium acetate (610.19 g, 6.2175 mmol, 3.0 equiv) and tetrakis(triphenylphosphine)palladium (479 g, 0.4145 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 100° C. under an argon atmosphere for 6 hours and then filtered through a small piece of celite. The filtrate was concentrated under reduced pressure and the crude product was used directly in the next step without further purification.

[0440] Step 4: Preparation of 3-(2,2-diethyl-7-(2-methoxyethoxy)methoxy)-4-oxacyclohexan-6-yl)-7-(2-methoxyethoxy)methoxy)-4H-chromen-4-one

[0441]

[0442] To a solution of (7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-ylboronic acid (crude) in 1,4-dioxane / water (5:1, 20 mL) was added 6-bromo-2,2-diethyl-7-((2-methoxyethoxy)methoxy)chroman-4-one (400 g, 1.0363 mmol, 1.00 equiv), potassium carbonate (429.7 g, 3.1089 mmol, 3.00 equiv) and tetrakis(triphenylphosphine)palladium (239.5 g, 0.2073 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred under argon. Stir at 80 ° C for 12 hours under atmosphere. After filtration, concentrate under reduced pressure and extract with ethyl acetate (50 mL). Wash the combined organic layer with saturated brine (50 mL) and dry over anhydrous Na2SO4. The resulting mixture is concentrated under reduced pressure. The crude product is purified by reverse phase HPLC (acetonitrile / water 5% to 100%) to give 3-(2,2-diethyl-7-((2-methoxyethoxy)methoxy)-4-oxo-6-yl)-7-((2-methoxyethoxy)methoxy)-4H-chromene-4-one (270 mg, yield 67%) as a yellow oil. ESI-MS m / z=557[M+H] + .

[0443] Step 5: Preparation of 2',2'-diethyl-4'-hydroxy-7,7'-bis((2-methoxyethoxy)methoxy)-[3,6'-bichroman]-4-one

[0444]

[0445] To a solution of 3-(2,2-diethyl-7-((2-methoxyethoxy)methoxy)-4-oxo-6-yl)-7-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (150.0 mg, 0.265 mmol, 1.00 equiv) in THF (3.00 mL) was added diisobutylaluminum hydride (1.0 M hexane solution, 1.06 mL, 1.06 mmol, 4 equiv) at -10°C. The resulting mixture was stirred at -10°C for 4 hours under an argon atmosphere. The mixture was quenched with potassium sodium tartrate solution (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with saturated brine (50 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain 2',2'-diethyl-4'-hydroxy-7,7'-bis((2-methoxyethoxy)methoxy)-[3,6'-bichroman]-4-one (57.1 mg, yield 38%) as a yellow oil. ESI-MS m / z=561[M+H] + .

[0446] Step 6: Preparation of 10,10-diethyl-6H,10H-furan[3,2-c:4,5-g']dichromen-3-ol

[0447]

[0448] To a solution of 2',2'-diethyl-4'-hydroxy-7,7'-bis((2-methoxyethoxy)methoxy)-[3,6'-bichroman]-4-one (51 mg, 0.091 mmol, 1.00 equiv) in MeOH (2.00 mL) at room temperature was added p-toluenesulfonic acid (69.3 mg, 0.3641 mmol, 4.0 equiv). The resulting mixture was stirred at 50 ° C for 2 hours under an argon atmosphere. It was then diluted with saturated aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (PE:EtOAc=4:1) to give 10,10-diethyl-6H,10H-furan[3,2-c:4,5-g']dichromen-3-ol (16.5 mg, yield 32%) as a yellow oil. 1H NMR(400MHz,Chloroform-d)δ7.32(d,J=8.1Hz,1H),6.91(s,1H),6.87(s,1H),6.47(d,J=10.0Hz,1H),6.45–6.41(m,2H ),5.51(s,2H),5.49(d,J=10.0Hz,1H),4.91(s,1H),1.79–1.71(m,2H),1.67–1.60(m,2H),0.94(t,J=7.4Hz,6H).ESI-MS m / z=349.14[M+H] + .

[0449] Embodiment 23

[0450] Preparation of 2',3',5',6'-tetrahydro-6H-spiro[furan[3,2-c:4,5-g']dichromene-10,4'-pyran]-3-ol (Compound E23)

[0451]

[0452] Step 1: Preparation of 7-(2-methoxyethoxy)methoxy-2',3',5',6'-tetrahydrospiro[chroman-2,4'-pyran]-4-one

[0453]

[0454] To a solution of 1-(2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)ethane-1-one (500 mg, 2.0833 mmol, 1.00 equiv) in methanol (10.00 mL) was added tetrahydro-4H-pyran-4-one (2.08 g, 20.8 mmol, 10.00 equiv), pyrrolidine (0.43 mL, 5.2083 mmol, 2.50 equiv). The resulting mixture was stirred at 75 °C for 12 hours under argon atmosphere. The reaction was diluted with water (10 mL) at room temperature, the aqueous phase was acidified to pH 7-8 with 1N HCl, and extracted with EtOAc (3 x 20 mL). The organic phase was washed with saturated brine (2 x 50 mL) and dried (Na2SO4). The resulting mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE: EtOAc = 4: 1) to obtain 7-((2-methoxyethoxy)methoxy)-2',3',5',6'-tetrahydrospiro[chroman-2,4'-pyran]-4-one (400 mg, yield 80%) as a yellow oil. ESI-MS m / z = 323 [M+H] + .

[0455] Step 2: Preparation of 6-bromo-7-((2-methoxyethoxy)methoxy)-2',3',5',6'-tetrahydrospiro[chromane-2,4'-pyran]-4-one

[0456]

[0457] To a solution of 7-((2-methoxyethoxy)methoxy)-2',3',5',6'-tetrahydrospiro[chroman-2,4'-pyran]-4-one (506.3 mg, 1.5724 mmol, 1.00 equiv) in acetonitrile (10.00 mL) was added N-bromosuccinimide (419.8 mg, 2.3586 mmol, 1.50 equiv) at 0° C. The mixture was stirred at room temperature for 4 hours, then diluted with water (20 mL), extracted with EtOAc (3×20 mL), and the organic layer was washed with saturated brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 25: 1) to give 6-bromo-7-((2-methoxyethoxy)methoxy)-2',3',5',6'-tetrahydrospiro[chromane-2,4'-pyran]-4-one (591.3 mg, yield 94%) as a colorless oil. ESI-MS m / z = 401 [M+H] + .

[0458] Step 3: Preparation of (7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromene-3-boronic acid

[0459]

[0460] To a solution of 3-bromo-7-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (682.2 mg, 2.0725 mmol, 1.00 equiv) in 1,4-dioxane (20 mL) was added bis(pinacol)diboron (1.58 g, 6.2175 mmol, 3.0 equiv), potassium acetate (610.19 mg, 6.2175 mmol, 3.0 equiv) and tetrakis(triphenylphosphine)palladium (479 mg, 0.4145 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 100° C. for 6 hours under an argon atmosphere. It was then filtered through a small piece of celite, the filtrate was concentrated under reduced pressure, and the crude product was used directly in the next step without further purification.

[0461] Step 4: Preparation of 7-((2-methoxyethoxy)methoxy)-6-(7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-yl)-2',3',5',6'-tetrahydrospiro[chroman-2,4'-pyran]-4-one

[0462]

[0463] 6-Bromo-7-((2-methoxyethoxy)methoxy)-2',3',5',6'-tetrahydrospiro[chromene-2,4'-pyran]-4-one (288.5 mg, 0.7213 mmol, 1.00 equiv), potassium carbonate (299.1 mg, 2.1638 mmol, 3.00 equiv) and tetrakis(triphenylphosphine)palladium (166.7 mg, 0.1443 mmol, 0.20 equiv) were added to a solution of (7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-yl)boronic acid (crude) in 1,4-dioxane / water (5:1, 15 mL) at room temperature. The resulting mixture was stirred at 80° C. for 12 hours under an argon atmosphere. After filtration, the mixture was concentrated under reduced pressure and extracted with ethyl acetate (50 mL). The combined organic layers were washed with saturated brine (50 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (acetonitrile / water 5% to 100%) to give 7-((2-methoxyethoxy)methoxy)-6-(7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-yl)-2',3',5',6'-tetrahydrospiro[chroman-2,4'-pyran]-4-one (304.5 mg, yield 72%) as a yellow oil. ESI-MS m / z=571[M+H] + .

[0464] Step 5: Preparation of 3-(4-hydroxy-7-((2-methoxyethoxy)methoxy)-2',3',5',6'-tetrahydrospiro[chroman-2,4'-pyran]-6-yl)-7-((2-methoxyethoxy)methoxy)chroman-4-one

[0465]

[0466] To a solution of 7-((2-methoxyethoxy)methoxy)-6-(7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-yl)-2',3',5',6'-tetrahydrospiro[chroman-2,4'-pyran]-4-one (102.0 mg, 0.1789 mmol, 1.00 equiv) in THF (2.00 mL) was slowly added diisobutylaluminum hydride (1.0 M hexane solution, 0.90 mL, 0.90 mmol, 5.00 equiv) at -10°C. The resulting mixture was stirred at -10°C for 2 hours under an argon atmosphere. The mixture was quenched with sodium potassium tartrate solution (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain 3-(4-hydroxy-7-((2-methoxyethoxy)methoxy)-2',3',5',6'-tetrahydrospiro[chroman-2,4'-pyran]-6-yl)-7-((2-methoxyethoxy)methoxy)chroman-4-one (50.8 mg, yield 50%) as a yellow oil. ESI-MS m / z=575[M+H] + .

[0467] Step 6: Preparation of 2',3',5',6'-tetrahydro-6H-spiro[furan[3,2-c:4,5-g']dichromene-10,4'-pyran]-3-ol

[0468]

[0469] To a solution of 3-(4-hydroxy-7-((2-methoxyethoxy)methoxy)-2',3',5',6'-tetrahydrospiro[chroman-2,4'-pyran]-6-yl)-7-((2-methoxyethoxy)methoxy)chroman-4-one (51 mg, 0.091 mmol, 1.00 equiv) in MeOH (2.00 mL) was added p-toluenesulfonic acid (69.3 mg, 0.3641 mmol, 4.0 equiv) at room temperature. The reaction solution was stirred at 50°C for 2 hours, then diluted with saturated aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=4:1) to give 2',3',5',6'-tetrahydro-6H-spiro[furan[3,2-c:4,5-g']dichromene-10,4'-pyran]-3-ol (16.5 mg, yield 32%) as a white solid. 1H NMR (400MHz, DMSO-d6) δ9.79(s,1H),7.25–7.14(m,2H),7.11(s,1H),6.52(d,J=9.9Hz,1H),6.39(dd,J=8.3,2.3Hz,1H),6.32(d,J=2.3H z,1H),5.79(d,J=11.1Hz,1H),5.47(s,2H),3.74(ddd,J=11.3,9.2,3.6Hz,2H),3.62(dt,J=11.4,4.3Hz,2H),1.85–1.65(m,4H).ESI-MS m / z=363.10[M+H] + .

[0470] Embodiment 24

[0471] Preparation of 3-hydroxy-10,10-dimethyl-9,10-dihydro-6H,8H-furan[3,2-c:4,5-g']dibenzopyran[3,2-c:4,5-g']dibenzopyran-8-one (Compound E24)

[0472]

[0473] Step 1: Preparation of 1-(2,4-bis((2-methoxyethoxy)methoxy)phenyl)ethan-1-one

[0474]

[0475] To a stirred solution of 1-(2,4-dihydroxyphenyl)ethane-1-one (1 g, 6.57 mmol, 1.00 equiv) in THF (10 mL) at 0°C were added 2-methoxyethoxymethyl chloride (2.05 g, 16.43 mmol, 2.50 equiv) and NaH (60%, 473 mg, 19.70 mmol, 3.00 equiv). The resulting mixture was stirred at room temperature overnight, then quenched with ice water (10 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc=1:1) to give 1-(2,4-bis((2-methoxyethoxy)methoxy)phenyl)ethane-1-one (930 mg, 43% yield) as a colorless transparent oil. ESI-MS m / z=329[M+H] +

[0476] Step 2: Preparation of 1-(5-bromo-2,4-bis(2-methoxyethoxy)methoxy)phenyl)ethan-1-one

[0477]

[0478] N-bromosuccinimide (605 mg, 3.40 mmol, 1.20 equiv) was added to a stirred solution of 1-(2,4-bis((2-methoxyethoxy)methoxy)phenyl)ethane-1-one (930 mg, 2.835 mmol, 1.00 equiv) in DMF (10 mL). The resulting mixture was stirred at room temperature overnight under an argon atmosphere. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 3: 1) to give 1-(5-bromo-2,4-bis(2-methoxyethoxy)methoxy)phenyl)ethane-1-one (500 mg, 43% yield) as a brown oil. ESI-MS m / z = 407 [M+H] +

[0479] Step 3: Preparation of 7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromene-3-boronic acid

[0480]

[0481] To a stirred solution of 3-bromo-7-(2-methoxyethoxy)methoxy-4H-benzopyran-4-one (800 mg, 2.43 mmol, 1.00 equiv) in 1,4-dioxane (20 mL) was added bis(pinacol)diboron (1.85 g, 7.29 mmol, 3.0 equiv), potassium acetate (718 mg, 7.29 mmol, 3.0 equiv) and tetrakis(triphenylphosphine)palladium (562 mg, 0.486 mmol, 0.20 equiv). The resulting mixture was stirred at 100 ° C for 2 hours under an argon atmosphere. It was then filtered through a small piece of celite. The filtrate was concentrated under reduced pressure and the crude product was used directly in the next step without further purification.

[0482] Step 4: Preparation of 3-(5-acetyl-2,4-bis(2-methoxyethoxy)methoxy)phenyl)-7-(2-methoxyethoxy)methoxy)-4H-chromen-4-one

[0483]

[0484] To a stirred solution of 7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromene-3-boronic acid in 1,4-dioxane / water (4:1, 25 mL) were added 1-(5-bromo-2,4-bis(2-methoxyethoxy)methoxy)phenyl)ethane-1-one (483 mg, 1.36 mmol, 0.7 equiv), potassium carbonate (704 mg, 5.1 mmol, 3.00 equiv) and tetrakis(triphenylphosphine)palladium (393 mg, 0.34 mmol, 0.20 equiv). The resulting mixture was stirred at 80° C. overnight under an argon atmosphere. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was washed with saturated brine (10 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give 3-(5-acetyl-2,4-bis(2-methoxyethoxy)methoxy)phenyl)-7-(2-methoxyethoxy)methoxy)-4H-chromen-4-one (620 mg, 76% yield) as a black solid. ESI-MS m / z = 577 [M+H] +

[0485] Step 5: Preparation of 3-(5-(1-hydroxyethyl)-2,4-bis(2-methoxyethoxy)methoxy)phenyl)-7-(2-methoxyethoxy)methoxy)chroman-4-one

[0486]

[0487] To a stirred solution of 3-(5-acetyl-2,4-bis(2-methoxyethoxy)methoxy)phenyl)-7-(2-methoxyethoxy)methoxy)-4H-chromen-4-one (310 mg, 0.538 mmol, 1.00 equiv) in THF (10 mL) at -20°C was added diisobutylaluminum hydride (2.33 mL, 2.153 mmol, 4.0 equiv). The resulting mixture was stirred at -20°C for 2 hours under an argon atmosphere. The mixture was quenched with sodium potassium tartrate solution (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine (10 mL) and dried over anhydrous Na2SO4 to obtain 3-(5-(1-hydroxyethyl)-2,4-bis(2-methoxyethoxy)methoxy)phenyl)-7-(2-methoxyethoxy)methoxy)chroman-4-one (384 mg) as a yellow oil. The crude product was used directly in the next step without further purification. ESI-MS m / z = 581 [M+H] +

[0488] Step 6: Preparation of 3-(5-acetyl-2,4-bis(2-methoxyethoxy)methoxy)phenyl)-7-(2-methoxyethoxy)methoxy)chroman-4-one

[0489]

[0490] To a stirred solution of 3-(5-(1-hydroxyethyl)-2,4-bis(2-methoxyethoxy)methoxy)phenyl)-7-(2-methoxyethoxy)methoxy)chroman-4-one (384 mg, 0.662 mmol, 1.00 equiv) in DCM (7 mL) was added sodium bicarbonate (167 mg, 1.99 mmol, 3.00 equiv) and Dess-Martin periodinane (384 mg, 0.993 mmol, 1.50 equiv). The resulting mixture was stirred at room temperature under argon atmosphere for 1 hour. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with saturated aqueous Na2S2O3 solution (10 mL), saturated aqueous NaHCO3 solution (10 mL) and saturated brine (10 mL) in that order. The organic phase was dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM: MeOH = 100: 1) to obtain 3-(5-acetyl-2,4-bis(2-methoxyethoxy)methoxy)phenyl)-7-(2-methoxyethoxy)methoxy)chroman-4-one (55 mg) as a brown oil. ESI-MS m / z = 579 [M+H] +

[0491] Step 7: Preparation of 1-(3,9-dihydroxy-6H-benzofurano[3,2-c]chromen-8-yl)ethan-1-one

[0492]

[0493] To a stirred solution of 3-(5-acetyl-2,4-bis(2-methoxyethoxy)methoxy)phenyl)-7-(2-methoxyethoxy)methoxy)chroman-4-one (50 mg, 0.087 mmol, 1.00 equiv) in MeOH (1 mL) at room temperature was added p-toluenesulfonic acid (66 mg, 0.35 mmol, 4.0 equiv). The resulting mixture was stirred at 65°C overnight under an argon atmosphere. The reaction solution was diluted with water (3 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with saturated brine (3 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give 1-(3,9-dihydroxy-6H-benzofurano[3,2-c]chromen-8-yl)ethan-1-one (7 mg, 27% yield) as a yellow solid. ESI-MS m / z=297[M+H] +

[0494] Step 8: Preparation of 3-hydroxy-10,10-dimethyl-9,10-dihydro-6H,8H-furan[3,2-c:4,5-g']dibenzopyran[3,2-c:4,5-g']dibenzopyran-8-one

[0495]

[0496] To a stirred solution of 1-(3,9-dihydroxy-6H-benzofurano[3,2-c]chromen-8-yl)ethan-1-one (7 mg, 0.024 mmol, 1.00 equiv) in MeOH (1 mL) at room temperature, acetone (7 mg, 0.118 mmol, 5.0 equiv) and pyrrolidine (3.4 mg, 0.048 mmol, 2.0 equiv) were added. The resulting mixture was stirred at room temperature overnight under an argon atmosphere. The reaction solution was diluted with water (2 mL) and extracted with ethyl acetate (3 mL). The organic layer was washed with saturated brine (3 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give 3-hydroxy-10,10-dimethyl-9,10-dihydro-6H,8H-furano[3,2-c:4,5-g']dibenzopyrano[3,2-c:4,5-g']dibenzopyran-8-one (1 mg, 12% yield) as a colorless oil. 1H NMR (400MHz, Chloroform-d) δ7.86 (s, 1H), 7.34 (d, J = 8.0Hz, 1H), 7.01 (s, 1H), 6.47 ( d,J=2.3Hz,1H),6.44(t,J=2.6Hz,1H),5.54(s,2H),2.75(s,2H),1.45(s,6H).ESI-MS m / z=337.06[M+H] +

[0497] Embodiment 25

[0498] Preparation of 2-fluoro-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-3-ol (Compound E25)

[0499]

[0500] Step 1: Preparation of 1-(5-fluoro-2,4-dihydroxyphenyl)ethane-1-one

[0501]

[0502] To a stirred solution of 4-fluorobenzene-1,3-diol (1 g, 7.8 mmol, 1.00 equiv) in boron trifluoride etherate (10 mL) was added acetic acid (937 mg, 15.6 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred at 90°C overnight under an argon atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 5: 1) to give 1-(5-fluoro-2,4-dihydroxyphenyl)ethane-1-one (1 g, 75% yield) as a brown powdery solid. ESI-MS m / z = 171 [M+H] +

[0503] Step 2: Preparation of 1-(5-fluoro-2-hydroxy-4-(2-methoxyethoxy)methoxy)phenyl)ethan-1-one

[0504]

[0505] To a stirred solution of 1-(5-fluoro-2,4-dihydroxyphenyl)ethane-1-one (1 g, 5.88 mmol, 1.00 equiv) in DCM (50 mL) at room temperature was added N,N-diisopropylethylamine (2.28 g, 17.64 mmol, 3.00 equiv), then cooled to 0°C and 2-methoxyethoxymethyl chloride (806 mg, 6.47 mmol, 1.10 equiv) was added. The resulting mixture was stirred at room temperature for 4 hours under an argon atmosphere. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 5: 1) to give 1-(5-fluoro-2-hydroxy-4-(2-methoxyethoxy)methoxy)phenyl)ethan-1-one (1.5 g, 99% yield) as a white solid. ESI-MS m / z = 259 [M+H] +

[0506] Step 3: Preparation of (E)-3-dimethylamino-1-(5-fluoro-2-hydroxy-4-(2-methoxyethoxy)methoxy)phenyl)prop-2-en-1-one

[0507]

[0508] A solution of 1-(5-fluoro-2-hydroxy-4-(2-methoxyethoxy)methoxy)phenyl)ethane-1-one (1.5 g, 5.814 mmol, 1.00 equiv) in N,N-dimethylformamide dimethyl acetal (10 mL) was stirred at 80°C for 2 hours under an argon atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give (E)-3-dimethylamino-1-(5-fluoro-2-hydroxy-4-(2-methoxyethoxy)methoxy)phenyl)prop-2-en-1-one (1.378 g, 76% yield) as a yellow solid. ESI-MS m / z = 314 [M+H] +

[0509] Step 4: Preparation of 6-fluoro-3-iodo-7-(2-methoxyethoxy)methoxy)-4H-benzopyran-4-one

[0510]

[0511] To a stirred solution of (E)-3-dimethylamino-1-(5-fluoro-2-hydroxy-4-(2-methoxyethoxy)methoxy)phenyl)prop-2-en-1-one (626 mg, 2.0 mmol, 1.00 equiv) in chloroform (10 mL) was added a solution of iodine (1.016 g, 4.0 mmol, 2.00 equiv) in chloroform (120 mL). The resulting mixture was stirred at room temperature overnight under an argon atmosphere. The reaction mixture was washed with 10% Na2S2O3 (20 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 3: 1) to give 6-fluoro-3-iodo-7-(2-methoxyethoxy)methoxy)-4H-benzopyran-4-one (408 mg, 52% yield) as a white solid. ESI-MS m / z=395[M+H] +

[0512] Step 5: Preparation of 6-fluoro-7-(2-methoxyethoxy)methoxy)-4-oxo-4H-benzopyran-3-boronic acid

[0513]

[0514] To a stirred solution of 6-fluoro-3-iodo-7-(2-methoxyethoxy)methoxy)-4H-benzopyran-4-one (408 mg, 1.03 mmol, 1.00 equiv) in 1,4-dioxane (15 mL) was added bis(pinacol)diboron (789 mg, 3.11 mmol, 3.0 equiv), potassium acetate (305 mg, 3.11 mmol, 3.0 equiv) and tetrakis(triphenylphosphine)palladium (239 mg, 0.21 mmol, 0.20 equiv). The resulting mixture was stirred at 100° C. for 2 days under an argon atmosphere. It was then filtered through a small piece of celite. The filtrate was concentrated under reduced pressure and the crude product was used directly in the next step without further purification. ESI-MS m / z=313 [M+H] +

[0515] Step 6: Preparation of 6-fluoro-7,7'-bis(2-methoxyethoxy)methoxy)-2,2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one

[0516]

[0517] To a stirred solution of 6-fluoro-7-(2-methoxyethoxy)methoxy)-4-oxo-4H-benzopyran-3-boronic acid in 1,4-dioxane / water (10:1, 20 mL / 2 mL) were added 6-iodo-7-(2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromene (124 mg, 0.318 mmol, 0.50 equiv), potassium carbonate (264 mg, 1.91 mmol, 3.00 equiv) and tetrakis(triphenylphosphine)palladium (147 mg, 0.127 mmol, 0.20 equiv). The resulting mixture was stirred at 80° C. overnight under an argon atmosphere. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with saturated brine (10 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give 6-fluoro-7,7'-bis(2-methoxyethoxy)methoxy)-2,2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one (100 mg, 40% yield) as a yellow oil. ESI-MS m / z = 531 [M+H] +

[0518] Step 7: Preparation of 6-fluoro-7-(2-methoxyethoxy)methoxy)-3-(7-(2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)chroman-4-one

[0519]

[0520] To a stirred solution of 6-fluoro-7,7'-bis(2-methoxyethoxy)methoxy)-2,2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one (50 mg, 0.094 mmol, 1.00 equiv) in THF (1 mL) at -10°C was added diisobutylaluminum hydride (1.0 M hexane solution, 0.57 mL, 0.565 mmol, 6.0 equiv). The resulting mixture was stirred at -10°C for 2 hours under an argon atmosphere. The mixture was quenched with potassium sodium tartrate solution (2 mL) and extracted with ethyl acetate (2 x 5 mL). The organic layer was washed with saturated brine (3 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give 6-fluoro-7-(2-methoxyethoxy)methoxy)-3-(7-(2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)chroman-4-one (29 mg, 58% yield) as a yellow oil. ESI-MS m / z = 533 [M+H] +

[0521] Step 8: Preparation of 2-fluoro-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-3-ol

[0522]

[0523] To a stirred solution of 6-fluoro-7-(2-methoxyethoxy)methoxy)-3-(7-(2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)chroman-4-one (29 mg, 0.055 mmol, 1.00 equiv) in MeOH (1 mL) at room temperature was added p-toluenesulfonic acid (41.5 mg, 0.218 mmol, 4.0 equiv). The resulting mixture was stirred at 65° C. for 2 hours under an argon atmosphere. The reaction solution was diluted with water (3 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with saturated brine (2 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 2-fluoro-10,10-dimethyl-6H,10H-furano[3,2-c:4,5-g']dibenzopyran-3-ol (10 mg, 54% yield) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ7.18(d,J=10.0Hz,1H),6.93(d,J=7.3Hz,2H),6.57(d,J=7 .4Hz,1H),6.38(d,J=9.8Hz,1H),5.63(d,J=9.8Hz,1H),5.49(s,2H),1.44(s,6H).ESI-MS m / z=339.12[M+H] +

[0524] Embodiment 26

[0525] Preparation of N,10,10-trimethyl-6H,10H-furo[3,2-c:4,5-g']dichromene-3-amine (Compound E26)

[0526]

[0527]

[0528] Step 1: Preparation of N-(7'-((2-methoxyethoxy)methoxy)-2',2'-dimethyl-4-oxo-2'H,4H-[3,6'-bichromene]-7-yl)-N-methylacetamide

[0529]

[0530] To a stirred solution of N-(7'-((2-methoxyethoxy)methoxy)-2',2'-dimethyl-4-oxo-2'H,4H-[3,6'-bichromene]-7-yl)-acetamide (340 mg, 0.731 mmol, 1.00 equiv) in DMF (8 mL) were added NaH (60%, 88 mg, 3.656 mmol, 5.0 equiv) and iodomethane (519 mg, 3.656 mmol, 5.0 equiv). The resulting mixture was stirred under argon atmosphere for 4 hours. The mixture was quenched with water (5 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with saturated brine (10 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give N-(7'-((2-methoxyethoxy)methoxy)-2',2'-dimethyl-4-oxo-2'H,4H-[3,6'-bichromene]-7-yl)-N-methylacetamide (147 mg, 42% yield) as a white solid. ESI-MS m / z = 480 [M+H] +

[0531] Step 2: Preparation of 3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)-7-methylaminochroman-4-one

[0532]

[0533] To a stirred solution of N-(7'-((2-methoxyethoxy)methoxy)-2',2'-dimethyl-4-oxo-2'H,4H-[3,6'-bichromene]-7-yl)-N-methylacetamide (74 mg, 0.154 mmol, 1.00 equiv) in THF (3 mL) at -10°C was added diisobutylaluminum hydride (1.0 M hexane solution, 772 μL, 0.772 mmol, 5.00 equiv). The resulting mixture was stirred at -10°C for 2 hours under an argon atmosphere. The mixture was quenched with sodium potassium tartrate solution (5 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was washed with saturated brine (5 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was redissolved in MeOH / water (0.8 mL / 0.8 mL) and KOH (43 mg, 0.772 mmol, 5.0 equiv.) was added at room temperature. The resulting mixture was stirred under an argon atmosphere for 1 hour. The reaction solution was diluted with water (3 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with saturated brine (2 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give 3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)-7-methylaminochroman-4-one (19 mg, 28% yield) as a white solid. ESI-MS m / z = 440 [M+H] +

[0534] Step 3: Preparation of N,10,10-trimethyl-6H,10H-furo[3,2-c:4,5-g']dichromene-3-amine

[0535]

[0536] To a stirred solution of 3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)-7-methylaminochroman-4-one (18 mg, 0.041 mmol, 1.00 equiv) in MeOH (1 mL) at room temperature was added p-toluenesulfonic acid (15.6 mg, 0.082 mmol, 2.0 equiv). The resulting mixture was stirred at 50°C for 5 hours under an argon atmosphere. The reaction solution was diluted with water (3 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with saturated brine (3 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=20:1) to give N,10,10-trimethyl-6H,10H-furo[3,2-c:4,5-g']dichromen-3-amine (7 mg, 51% yield) as a white solid. 1H NMR (400MHz, Methanol-d4) δ7.18(d,J=8.2Hz,1H),7.17(s,1H),6.97(s,1H),6.84(s,1H),6.42(d,J=9.8Hz,1H),6.22(dd, J=8.3,2.2Hz,1H),6.15(d,J=2.2Hz,1H),5.66(d,J=9.8Hz.1H),5.41(s,2H),2.74(s,3H),1.33(s,3H),1.31(s,3H).ESI-MS m / z=334.14[M+H] +

[0537] Embodiment 27

[0538] Preparation of 10,10,13-trimethyl-10,13-dihydro-6H-chromeno[4,3-b]pyrano[3,2-f]indol-3-ol (Compound E27)

[0539]

[0540] Step 1: Preparation of 1-bromo-4-(2-methylbut-3-yn-2-oxy)-2-nitrobenzene

[0541]

[0542] To a stirred solution of 4-bromo-3-nitrophenol (2 g, 9.174 mmol, 1.00 equiv) in acetone (100 mL) at room temperature, potassium carbonate (1.52 g, 11.01 mmol, 1.20 equiv) and potassium iodide (2.437 g, 14.68 mmol, 1.60 equiv) were added. The resulting mixture was refluxed at 90 °C overnight under an argon atmosphere. The mixture was filtered, the insoluble solid was washed with acetone (2×50 mL), and the combined filtrate was concentrated under reduced pressure. The residual oil was dissolved in ether (20 mL), washed with aqueous sodium hydroxide solution (1 M, 2×20 mL), saturated brine (20 mL), and dried over anhydrous Na2SO4. The crude product was purified by silica gel column chromatography (PE:EtOAc=10:1) to give 1-bromo-4-(2-methylbut-3-yn-2-oxy)-2-nitrobenzene (2.6 g, 99% yield) as a colorless oil. 1 H NMR (400MHz, Chloroform-d) δ7.74(d,J=2.8Hz,1H),7.59(d,J=8.8Hz,1H),7.27(d,J=2.8Hz,1H),2.66(s,1H),1.67(s,6H).

[0543] Step 2: Preparation of 6-bromo-2,2-dimethyl-7-nitro-2H-dihydrobenzopyran

[0544]

[0545] A solution of 1-bromo-4-(2-methylbut-3-yn-2-oxy)-2-nitrobenzene (2.6 g, 9.19 mmol, 1.00 equiv) in anhydrous DMF (60 mL) and N,N-dimethylaniline (445 mg, 3.68 mmol, 0.40 equiv) was stirred overnight at 140° C. under argon. After cooling, the reaction mixture was poured into water (100 mL) and the mixture was extracted with n-hexane (2×100 mL). The combined extracts were washed with 2N NaOH (2×50 mL), 2N HCl (2×50 mL), and water (50 mL) before drying (Na2SO4). The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE: EtOAc = 10: 1) to obtain 6-bromo-2,2-dimethyl-7-nitro-2H-dihydrobenzopyran (660 mg, 25.4% yield) as a brown oil. ESI-MS m / z = 284 [M+H] +

[0546] Step 3: Preparation of 6-bromo-2,2-dimethyl-7-benzopyranamine

[0547]

[0548] Zinc (1.525 g, 23.3 mmol, 10.0 equiv) was added to a solution of 6-bromo-2,2-dimethyl-7-nitro-2H-dihydrobenzopyran (660 mg, 2.33 mmol, 1.00 equiv) in MeOH / THF (10 mL / 10 mL) and saturated aqueous ammonium chloride (10 mL) at room temperature. The resulting mixture was stirred overnight under an argon atmosphere. The solid was then filtered off. The filtrate was concentrated under reduced pressure to remove MeOH and THF and extracted with ethyl acetate (3×10 mL). The combined extracts were washed with water (10 mL) before drying (Na2SO4). The organic phase was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (PE: EtOAc=10:1) to give 6-bromo-2,2-dimethyl-7-benzopyranamine (421 mg, 71% yield) as a yellow solid. ESI-MS m / z=254[M+H] +

[0549] Step 4: Preparation of 7'-amino-7-((2-methoxyethoxy)methoxy)-2',2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one

[0550]

[0551] To a stirred solution of 3-bromo-7-(2-methoxyethoxy)methoxy-4H-benzopyran-4-one (400 mg, 1.22 mmol, 1.00 equiv) in 1,4-dioxane (12 mL) was added bis(pinacol)diboron (926 mg, 3.65 mmol, 3.0 equiv), potassium acetate (358 mg, 3.65 mmol, 3.0 equiv) and tetrakis(triphenylphosphine)palladium (281 mg, 0.24 mmol, 0.20 equiv). The resulting mixture was stirred at 100° C. for 2 hours under an argon atmosphere. It was then filtered through a small piece of celite. The filtrate was concentrated under reduced pressure and the crude product was redissolved in 1,4-dioxane / water (4:1, 15 mL). 6-Bromo-2,2-dimethyl-7-benzopyranamine (145 mg, 0.57 mmol, 0.70 equiv), potassium carbonate (339 mg, 2.45 mmol, 3.00 equiv) and tetrakis(triphenylphosphine)palladium (189 mg, 0.163 mmol, 0.20 equiv) were added at room temperature. Under an argon atmosphere, the resulting mixture was stirred at 80 ° C overnight. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (2×30 mL). The organic layer was washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give 7'-amino-7-((2-methoxyethoxy)methoxy)-2',2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one (330 mg, 93% yield) as a black oil. ESI-MS m / z = 424 [M+H] +

[0552] Step 5: Preparation of 3-(2-methoxyethoxy)methoxy)-10,10-dimethyl-10,13-dihydro-6H-benzopyrano[4,3-b]pyrano[3,2-f]indole

[0553]

[0554] To a stirred solution of 7'-amino-7-((2-methoxyethoxy)methoxy)-2',2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one (210 mg, 0.496 mmol, 1.00 equiv) in THF (5 mL) was added diisobutylaluminum hydride (1.0 M n-hexane solution, 1.98 mL, 1.98 mmol, 4.0 equiv) at -10°C. The reaction solution was stirred at -10°C for 2 hours, quenched with potassium sodium tartrate solution (10 mL), and extracted with ethyl acetate (2×10 mL). The organic layer was washed with saturated brine (10 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give 3-(2-methoxyethoxy)methoxy)-10,10-dimethyl-10,13-dihydro-6H-benzopyrano[4,3-b]pyrano[3,2-f]indole (19 mg, 9% yield) as a yellow oil. ESI-MS m / z = 408 [M+H] +

[0555] Step 6: Preparation of 3-(2-methoxyethoxy)methoxy)-10,10,13-trimethyl-10,13-dihydro-6H-benzopyrano[4,3-b]pyrano[3,2-f]indole

[0556]

[0557] Cesium carbonate (46 mg, 0.141 mmol, 3.00 equivalents) and iodomethane (34 mg, 0.24 mmol, 5.10 equivalents) were added to a stirred DMF (1 mL) solution of 3-(2-methoxyethoxy)methoxy)-10,10-dimethyl-10,13-dihydro-6H-benzopyrano[4,3-b]pyrano[3,2-f]indole (19 mg, 0.047 mmol, 1.00 equivalents). The resulting mixture was stirred for 2 hours under an argon atmosphere. It was quenched with water (3 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with saturated brine (2 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give 3-(2-methoxyethoxy)methoxy)-10,10,13-trimethyl-10,13-dihydro-6H-benzopyrano[4,3-b]pyrano[3,2-f]indole (11 mg, 56% yield) as a brown solid. ESI-MS m / z = 422 [M+H] +

[0558] Step 7: Preparation of 10,10,13-trimethyl-10,13-dihydro-6H-chromeno[4,3-b]pyrano[3,2-f]indol-3-ol

[0559]

[0560] To a stirred solution of 3-(2-methoxyethoxy)methoxy)-10,10,13-trimethyl-10,13-dihydro-6H-benzopyrano[4,3-b]pyrano[3,2-f]indole (11 mg, 0.026 mmol, 1.00 equiv) in MeOH (1 mL) at room temperature was added p-toluenesulfonic acid (10 mg, 0.052 mmol, 2.0 equiv). The resulting mixture was stirred at 50°C for 3 hours under an argon atmosphere. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with saturated brine (5 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give 10,10,13-trimethyl-10,13-dihydro-6H-chromeno[4,3-b]pyrano[3,2-f]indol-3-ol (6 mg, 69% yield) as a brown oil. 1 H NMR(400MHz,Chloroform-d)δ7.44(d,J=8.4Hz,1H),7.00(s,1H),6.75(s,1H),6.53(d,J=2.6Hz,1H),6.49(d,J=8.7Hz, 1H),6.43(d,J=9.8Hz,1H),5.60(d,J=9.7Hz,1H),5.39(s,2H),4.85(s,1H),3.88(s,3H),1.44(d,J=0.8Hz,6H).ESI-MS m / z=334.12[M+H] +

[0561] Embodiment 28

[0562] Preparation of 8-(3-aminophenyl)-9-methoxy-6H-benzofurano[3,2-c]chromen-3-ol (Compound E28)

[0563]

[0564] Step 1: Preparation of 2-methoxy-3'-nitro-[1,1'-biphenyl]-4-ol

[0565]

[0566] To a stirred solution of 4-bromo-3-methoxyphenol (1 g, 4.93 mmol) in 1,4-dioxane / water (6:1, 35 mL) at room temperature were added (3-nitrophenyl)boric acid (1.64 g, 9.85 mmol), potassium carbonate (2.04 g, 14.78 mmol) and tetrakis(triphenylphosphine)palladium (1.14 g, 0.985 mmol). The resulting mixture was stirred at 80°C overnight under an argon atmosphere. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=8:1) to give 2-methoxy-3'-nitro-[1,1'-biphenyl]-4-ol (813 mg) as an orange solid. 1 H NMR(400MHz,Chloroform-d)δ8.36(t,J=2.0Hz,1H),8.12(dq,J=8.3,1.0Hz,1H),7.80(dt,J=7.8,1.4Hz,1H),7.5 2(t,J=8.0Hz,1H),7.19(d,J=8.1Hz,1H),6.53(d,J=2.3Hz,1H),6.51(dd,J=8.1,2.4Hz,1H),3.81(s,3H).ESI-MS m / z=244[MH] +

[0567] Step 2: Preparation of 5-bromo-2-methoxy-3-nitro-1,1-biphenyl-4-ol

[0568]

[0569] To a stirred solution of 2-methoxy-3'-nitro-[1,1'-biphenyl]-4-ol (411 mg, 1.68 mmol) in chloroform (20 mL) was added N-bromosuccinimide (299 mg, 1.68 mmol) at 0°C. After filtration, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with saturated brine (15 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give 5-bromo-2-methoxy-3-nitro-1,1-biphenyl-4-ol (408 mg, 75% yield) as a yellow solid. 1H NMR(400MHz,Chloroform-d)δ8.33(t,J=2.0Hz,1H),8.15(ddd,J=8.2,2.3,1.1Hz,1H), 7.82–7.73(m,1H),7.54(t,J=8.0Hz,1H),7.40(s,1H),6.71(s,1H),3.80(s,3H).ESI-MS m / z=324[M+H] +

[0570] Step 3: Preparation of 3-(4-hydroxy-6-methoxy-3'-nitro-[1,1'-biphenyl]-3-yl)-7-(2-methoxyethoxy)methoxy)-4H-benzopyran-4-one

[0571]

[0572] To a stirred solution of 3-bromo-7-(2-methoxyethoxy)methoxy-4H-benzopyran-4-one (1 g, 3.04 mmol) in 1,4-dioxane (25 mL) was added bis(pinacol)diboron (2.32 g, 9.113 mmol), potassium acetate (894 mg, 9.11 mmol) and tetrakis(triphenylphosphine)palladium (702 mg, 0.61 mmol) at room temperature. The resulting mixture was stirred at 100° C. overnight under an argon atmosphere. It was then filtered through a small piece of celite. The filtrate was concentrated under reduced pressure and the crude product was redissolved in 1,4-dioxane / water (4:1, 35 mL). 5-Bromo-2-methoxy-3-nitro-1,1-biphenyl-4-ol (400 mg, 1.24 mmol), potassium carbonate (513 mg, 3.72 mmol) and tetrakis(triphenylphosphine)palladium (286 mg, 0.25 mmol) were added at room temperature. Under an argon atmosphere, the resulting mixture was stirred at 80°C overnight. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 3-(4-hydroxy-6-methoxy-3'-nitro-[1,1'-biphenyl]-3-yl)-7-(2-methoxyethoxy)methoxy)-4H-benzopyran-4-one (736 mg) as a yellow oil. ESI-MS m / z=494[M+H] +

[0573] Step 4: Preparation of 3-(3'-amino-4-hydroxy-6-methoxy-[1,1'-biphenyl]-3-yl)-7-(2-methoxyethoxy)methoxy)-4H-benzopyran-4-one

[0574]

[0575] To a stirred solution of 3-(4-hydroxy-6-methoxy-3'-nitro-[1,1'-biphenyl]-3-yl)-7-(2-methoxyethoxy)methoxy)-4H-benzopyran-4-one (736 mg, 1.49 mmol) in MeOH / THF (12 mL / 4 mL) at room temperature, saturated ammonium chloride (4 mL) and zinc powder (976 mg, 14.93 mmol) were added. The resulting mixture was stirred overnight under an argon atmosphere. The reaction solution was filtered. The filtrate was concentrated under reduced pressure to remove MeOH and THF, and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated brine (25 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give 3-(3'-amino-4-hydroxy-6-methoxy-[1,1'-biphenyl]-3-yl)-7-(2-methoxyethoxy)methoxy)-4H-benzopyran-4-one (177 mg) as a brown solid. ESI-MS m / z = 464 [M+H] +

[0576] Step 5: Preparation of 3-(3'-amino-4-hydroxy-6-methoxy-[1,1'-biphenyl]-3-yl)-7-(2-methoxyethoxy)methoxy)chroman-4-one

[0577]

[0578] Pd / C (140 mg) and ammonium formate (95 mg, 1.51 mmol) were added to a stirred solution of 3-(3'-amino-4-hydroxy-6-methoxy-[1,1'-biphenyl]-3-yl)-7-(2-methoxyethoxy)methoxy)-4H-benzopyran-4-one (70 mg, 0.15 mmol) in MeOH (3 mL) at room temperature. The resulting mixture was stirred under an argon atmosphere for 2 hours. The reaction liquid was filtered and dried in vacuo. The crude product was purified by preparative TLC (PE: EtOAc = 1: 1) to give 3-(3'-amino-4-hydroxy-6-methoxy-[1,1'-biphenyl]-3-yl)-7-(2-methoxyethoxy)methoxy)chroman-4-one (30 mg, 43% yield) as a brown solid. ESI-MS m / z = 466 [M+H] +

[0579] Step 6: Preparation of 8-(3-aminophenyl)-9-methoxy-6H-benzofurano[3,2-c]chromen-3-ol

[0580]

[0581] To a stirred solution of 3-(3'-amino-4-hydroxy-6-methoxy-[1,1'-biphenyl]-3-yl)-7-(2-methoxyethoxy)methoxy)chroman-4-one (30 mg, 0.06 mmol) in MeOH (2 mL) at room temperature was added p-toluenesulfonic acid (64.4 mg, 0.32 mmol). The resulting mixture was stirred at 50°C for 4 hours under an argon atmosphere. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with saturated brine (5 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give 8-(3-aminophenyl)-9-methoxy-6H-benzofurano[3,2-c]chromen-3-ol (3.8 mg, 16% yield) as a brown oil. 1 H NMR (400MHz, Methanol-d4) δ7.27(d,J=8.2Hz,1H),7.24(d,J=1.2Hz,1H),7.22(d,J=1.2Hz,1H),7.10(t,J=7.7Hz,1H),6.86(s,1H),6.79(d,J=7.6 Hz,1H),6.68(d,J=8.4Hz,1H),6.41(dt,J=8.2,1.8Hz,1H),6.36-6.34m,1 H),5.49(d,J=1.1Hz,2H),3.80(d,J=1.2Hz,3H).ESI-MSm / z=360.12[M+H] +

[0582] Embodiment 29

[0583] Preparation of 6H-spirofurano[3,2-c:4,5-g']dichromene-10,4'-piperidin]-3-ol (Compound E29)

[0584]

[0585] Step 1: Preparation of tert-butyl 7-((2-methoxyethoxy)methoxy)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate

[0586]

[0587] Pyrrolidine (133.33 mg, 1.8747 mmol, 0.90 equiv) and 4-N-Boc-aminocyclohexanone (456.6 mg, 2.291 mmol, 1.1 equiv) were added to a methanol solution (10.00 mL) of 1-(2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)ethane-1-one (500 mg, 2.083 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred at 70 ° C for 24 hours under an argon atmosphere. It was concentrated under reduced pressure, diluted with water (30 mL) and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (2 x 50 mL) and dried (Na2SO4). The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give tert-butyl 7-((2-methoxyethoxy)methoxy)-4-oxospiro[chromane-2,4'-piperidine]-1'-carboxylate (780 mg, yield 89%) as a yellow solid. ESI-MS m / z = 422 [M+H]+.

[0588] Step 2: Preparation of tert-butyl 6-bromo-7-((2-methoxyethoxy)methoxy)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate

[0589]

[0590] N-bromosuccinimide (177.58 mg, 0.9976 mmol, 1.20 equiv) was added to a DMF (5 mL) solution of tert-butyl 7-((2-methoxyethoxy)methoxy)-4-oxospiro[chromane-2,4'-piperidine]-1'-carboxylate (350 mg, 0.8314 mmol, 1.0 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 hours under an argon atmosphere. Diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with saturated brine (40 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give tert-butyl 6-bromo-7-((2-methoxyethoxy)methoxy)-4-oxospiro[chromane-2,4'-piperidine]-1'-carboxylate (373 mg, yield 90%) as a yellow oil. ESI-MS m / z = 500 [M+H]+.

[0591] Step 3: Preparation of tert-butyl 7-((2-methoxyethoxy)methoxy)-6-(7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-yl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate

[0592]

[0593] To a mixed solution of (7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-yl)boronic acid (282 mg, 0.960 mmol, 2.00 equiv) in 1,4-dioxane / water (4:1, 20 mL) were added tert-butyl (7-((2-methoxyethoxy)methoxy)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (240 mg, 0.480 mmol, 1.00 equiv), potassium carbonate (199 mg, 1.443 mmol, 3.00 equiv) and tetrakis(triphenylphosphine)palladium (111.16 mg, 0.0962 mmol, 0.20 equiv). The resulting mixture was stirred at 80° C. under argon atmosphere for 6 h. The mixture was diluted with water (30 mL) and washed with EtOAc (3×10% MgSO). 30mL) was extracted. The combined organic layers were washed with saturated brine (50mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=1:2) to give tert-butyl 7-((2-methoxyethoxy)methoxy)-6-(7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-yl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (292.6 mg, yield 90%) as a yellow oil. ESI-MS m / z=670[M+H] + .

[0594] Step 4: Preparation of tert-butyl 4-hydroxy-7-((2-methoxyethoxy)methoxy)-6-(7-((2-methoxyethoxy)methoxy)-4-oxan-3-yl)spiro[chromane-2,4'-piperidine]-1'-carboxylate

[0595]

[0596] To a solution of tert-butyl 7-((2-methoxyethoxy)-6-(7-((2-methoxyethoxy)methoxy-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (49.4 mg, 0.0738 mmol, 1.0 equiv) in THF (1.00 mL) was added diisobutylaluminum hydride (1.0 M in hexanes, 0.37 mL, 0.37 mmol, 5.00 equiv) at -10 °C. The resulting mixture was stirred at -10 °C under argon atmosphere for 4 h. The mixture was quenched with sodium potassium tartrate solution (10 mL) and washed with ethyl acetate (3x 20mL) extraction. The combined organic layer was washed with saturated brine (40mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 2) to give 4-hydroxy-7-((2-methoxyethoxy)methoxy)-6-(7-((2-methoxyethoxy)methoxy)-4-oxacyclooxy-3-yl)spiro[chromane-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (12.2 mg, yield 25%) as a yellow oil. ESI-MS m / z = 674 [M+H] + .

[0597] Step 5: Preparation of 6H-spirofurano[3,2-c:4,5-g']dichromene-10,4'-piperidin]-3-ol

[0598]

[0599] To a solution of tert-butyl 4-hydroxy-7-((2-methoxyethoxy)methoxy)-6-(7-((2-methoxyethoxy)methoxy)-4-oxotrichloro-3-yl)spiro[chromane-2,4'-piperidine]-1'-carboxylate (12.2 mg, 0.0182 mmol, 1.0 equiv) in methanol (1 mL) was added p-toluenesulfonic acid (13.79 mg, 0.0725 mmol, 4.0 equiv). The resulting mixture was stirred at 50 °C for 4 hours under argon atmosphere. It was then diluted with saturated aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. The crude product was purified by silica gel chromatography to give 6H-spiro[furan[3,2-c:4,5-g']dichromene-10,4'-piperidin]-3-ol (1.6 mg, 24% yield) as a white solid. 1H NMR (400MHz, Methanol-d4) δ7.24(dd,J=8.3,2.7Hz,1H),7.07(s,1H),7.04(s,1H),6.57(d,J=9.6Hz,1H),6.40(dt,J=8.5,2.6Hz,1H),6.33( d,J=2.8Hz,1H),5.67(d,J=9.9Hz,1H),5.46(s,2H),3.40–3.30(m,2H),3.21–2.99(m,2H),2.11(d,J=14.0Hz,2H),1.88–1.81(m,2H).ESI-MS m / z=362.10[M+H] + .

[0600] Embodiment 30

[0601] Preparation of 10-hydroxymethyl-10-methoxymethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-3-ol (Compound E30)

[0602]

[0603] Step 1: Preparation of 7-((2-methoxyethoxy)methoxy)spiro[chroman-2,3'-oxetane]-4-one

[0604]

[0605] Pyrrolidine (133.33 mg, 1.8747 mmol, 0.90 equiv) and 3-oxetanone (165.1 mg, 2.2917 mmol, 1.1 equiv) were added to a solution of 1-(2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)ethane-1-one (500 mg, 2.083 mmol, 1.00 equiv) in methanol (10.00 mL) at room temperature. The resulting mixture was stirred at 70 ° C for 24 hours under an argon atmosphere. It was concentrated under reduced pressure, diluted with water (30 mL) and extracted with ethyl acetate (50 mL). The organic phase was washed with saturated brine (2 x 50 mL) and dried (Na2SO4). The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give 7-((2-methoxyethoxy)methoxy)spiro[chroman-2,3'-oxetane]-4-one (130 mg, yield 21%) as a yellow oil. ESI-MS m / z = 295 [M+H] + .

[0606] Step 2: Preparation of 6-bromo-7-((2-methoxyethoxy)methoxy)spiro[chroman-2,3'-oxetane]-4-one

[0607]

[0608] To a solution of 7-((2-methoxyethoxy)methoxy)spiro[chromane-2,3'-oxetane]-4-one (130 mg, 0.4421 mmol, 1.0 equiv) in DMF (3 mL) was added N-bromosuccinimide (102.3 mg, 0.5748 mmol, 1.30 equiv) and the resulting mixture was stirred at room temperature under an argon atmosphere for 2 hours. Diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated brine (40 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give 6-bromo-7-((2-methoxyethoxy)methoxy)spiro[chroman-2,3'-oxetane]-4-one (105 mg, yield 64%) as a yellow oil. ESI-MS m / z = 373 [M+H] + .

[0609] Step 3: Preparation of (7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromene-3-boronic acid

[0610]

[0611] To a solution of 3-bromo-7-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (350 mg, 1.063 mmol, 1.00 equiv) in 1,4-dioxane (5 mL) was added bis(pinacol)diboron (810.1 mg, 3.190 mmol, 3.0 equiv), potassium acetate (313.07 mg, 3.190 mmol, 3.0 equiv) and tetrakis(triphenylphosphine)palladium (245.76 mg, 0.213 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 100 ° C for 6 hours under an argon atmosphere. It was then filtered through a small piece of celite. The filtrate was concentrated under reduced pressure and the crude product was used directly in the next step without further purification.

[0612] Step 4: Preparation of 7-((2-methoxyethoxy)methoxy)-6-(7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-yl)spiro[chroman-2,3'-oxetane]-4-one

[0613]

[0614] To a mixed solution of (7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-yl)boronic acid (crude) in 1,4-dioxane / water (4:1, 20 mL) was added 6-bromo-7-((2-methoxyethoxy)methoxy)spiro[chroman-2,3'-oxetane]-4-one (105 mg, 0.283 mmol, 1.00 equiv), potassium carbonate (116.86 mg, 0.9468 mmol, 3.00 equiv) and tetrakis(triphenylphosphine)palladium (65.24 mg, 0.0565 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 80° C. under argon atmosphere for 6 hours. Diluted with water (30 mL) and extracted with EtOAc (3× 30 mL). The combined organic layers were washed with saturated brine (50 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 2) to give 7-((2-methoxyethoxy)methoxy)-6-(7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-yl)spiro[chromene-2,3'-oxetane]-4-one (110 mg, yield 72%) as a yellow oil. ESI-MS m / z = 543 [M+H] + .

[0615] Step 5: Preparation of 3-(4-hydroxy-7-((2-methoxyethoxy)methoxy)spiro[chroman-2,3'-oxetane]-6-yl)-7-((2-methoxyethoxy)methoxy)chroman-4-one

[0616]

[0617] To a solution of 7-((2-methoxyethoxy)methoxy)-4-oxo-4-hydroxybenzopyran (110 mg, 0.203 mmol, 1.0 equivalent) in THF (2.00 mL) at -10 ° C, diisobutylaluminum hydride (hexane solution, 1.0 mL, 1.0 mmol, 5.00 equivalent) was added. The resulting mixture was stirred at -10 ° C for 4 hours under an argon atmosphere. It was quenched with sodium potassium tartrate solution (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was washed with saturated brine (60 mL) and dried over anhydrous Na2SO4. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 2) to give 3-(4-hydroxy-7-((2-methoxyethoxy)methoxy)spiro[chroman-2,3'-oxetane]-6-yl)-7-((2-methoxyethoxy)methoxy)chroman-4-one (20 mg, yield 18%) as a yellow oil. ESI-MS m / z = 547 [M+H] + .

[0618] Step 6: Preparation of 10-hydroxymethyl-10-methoxymethyl-6H,10H-furan[3,2-c:4,5-g']dichromene-3-ol

[0619]

[0620] To a solution of 3-(4-hydroxy-7-((2-methoxyethoxy)methoxy)spiro[chroman-2,3'-oxetane]-6-yl)-7-((2-methoxyethoxy)methoxy)chroman-4-one (10 mg, 0.018 mmol, 1.0 equiv) in methanol (1 mL) at room temperature was added p-toluenesulfonic acid (13.9 mg, 0.0731 mmol, 4.0 equiv). The resulting mixture was stirred at 50 ° C for 4 hours under an argon atmosphere. It was then diluted with saturated aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. The crude product was purified by silica gel chromatography (DCM:MeOH=30:1) to give 10-(hydroxymethyl)-10-(methoxymethyl)-6H,10H-furan[3,2-c:4,5-g']dichromen-3-ol (1.6 mg, yield 23%) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ7.30(d,J=8.2Hz,1H),7.00(s,1H),6.92(s,1H),6.60(d,J=10.0Hz,1H),6. 45–6.37(m,2H),5.65(d,J=10.0Hz,1H),5.50(s,2H),3.82(s,2H),3.66–3.59(m,3H),3.40(s,3H).ESI-MS m / z=367.10[M+H] + .

[0621] Embodiment 31

[0622] Preparation of 6,6,10,10-tetramethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-3-ol (Compound E31)

[0623]

[0624]

[0625] Step 1: Preparation of 3-(2-methoxyethoxy)methoxy)-10,10-dimethyl-6H,10H-furano[3,2-c:4,5-g']dichromene

[0626]

[0627] To a solution of 10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromene-3-ol (20 mg, 0.062 mmol, 1.00 equiv) in DCM (1 mL) at room temperature was added N,N-diisopropylethylamine (24.2 mg, 0.18 mmol, 3.00 equiv). Then cooled to 0°C, 2-methoxyethoxymethyl chloride (11.6 mg, 0.09 mmol, 2.00 equiv) was added. The resulting mixture was stirred at room temperature for 3 hours under an argon atmosphere. Then it was concentrated under reduced pressure, diluted with water (10 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with saturated brine (40 mL) and dried over anhydrous Na2SO4. The resulting organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 3: 1) to give 3-((2-methoxyethoxy)methoxy)-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromene (24 mg, 94% yield) as a white solid. ESI-MS m / z = 409 [M+H] + .

[0628] Step 2: Preparation of 3-(2-methoxyethoxy)methoxy)-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromene-6-one

[0629]

[0630] 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (26 mg, 0.11 mmol, 2.00 equiv) was added to a solution of 3-((2-methoxyethoxy)methoxy)-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromene (24 mg, 0.058 mmol, 1.00 equiv) in THF (2 mL). The resulting mixture was stirred at room temperature for 2 hours. It was then concentrated under reduced pressure, diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated brine (40 mL) and dried over anhydrous Na2SO4. The resulting organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 5: 1) to give 3-((2-methoxyethoxy)methoxy)-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromene-6-one (22 mg, 88% yield) as a white solid. ESI-MS m / z = 423 [M+H] + .

[0631] Step 3: Preparation of 3-(2-methoxyethoxy)methoxy)-6,6,10,10-tetramethyl-6H,10H-furano[3,2-c:4,5-g']dichromene

[0632]

[0633] To a solution of 3-((2-methoxyethoxy)methoxy)-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromene-6-one (22 mg, 0.052 mmol, 1.00 equiv) in THF (2 mL) was added 1.3 M methyllithium in THF (0.14 mL, 0.41 mmol, 7.88 equiv) under argon atmosphere. The resulting mixture was stirred at room temperature for 16 hours under argon atmosphere. The reaction was quenched with saturated ammonium chloride solution (30 mL). It was then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated brine (40 mL) and dried over anhydrous Na2SO4. The resulting organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 4: 1) to give 3-((2-methoxyethoxy)methoxy)-6,6,10,10-tetramethyl-6H,10H-furan[3,2-c:4,5-g']dichromene (16 mg, yield 70%) as a white solid. ESI-MS m / z = 437 [M+H] + .

[0634] Step 4: Preparation of 6,6,10,10-tetramethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-3-ol

[0635]

[0636] To a solution of 3-((2-methoxyethoxy)methoxy)-6,6,10,10-tetramethyl-6H,10H-furan[3,2-c:4,5-g']dichromene (16 mg, 0.036 mmol, 1.00 equiv) in MeOH (2 mL) was added p-toluenesulfonic acid (28 mg, 0.147 mmol, 4.00 equiv). The resulting mixture was stirred at 50 °C for 4 hours under an argon atmosphere. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. The resulting organic phase was concentrated under reduced pressure. The crude product was purified by preparative TLC (PE:EtOAc=3:1) to give 6,6,10,10-tetramethyl-6H,10H-furan[3,2-c:4,5-g′]dichromen-3-ol (2.5 mg, yield 19%) as a white solid. 1H NMR(400MHz,Chloroform-d)δ7.35-7.31(d,J=8.1Hz,1H),6.98(s,1H),6.93(s,1H ),6.45-6.36(m,3H),5.66-5.60(d,J=9.8Hz,1H),1.74(s,6H),1.44(s,6H).ESI-MS m / z=349.14[M+H] + .

[0637] Embodiment 32

[0638] Preparation of 3-hydroxy-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-6-one (Compound E32)

[0639]

[0640] Step 1: Preparation of 3-hydroxy-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-6-one

[0641]

[0642] To a solution of 3-((2-methoxyethoxy)methoxy)-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromene-6-one (4.6 mg, 0.0109 mmol, 1.0 equiv) in toluene (1 mL) was added Lawesson's reagent (8.8 mg, 0.0218 mmol, 2.0 equiv). The reaction mixture was stirred at 110°C for 12 hours. Diluted with water (10 mL) and extracted with EtOAc (3x10 mL). The combined organic layers were washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=4:1) to give 3-hydroxy-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-6-one (1.6 mg, yield 44%) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ7.70(dd,J=8.6,3.4Hz,1H),7.49(dd,J=6.7,3.1Hz,1H),6.93(d,J=3.8Hz,1 H),6.83–6.76(m,2H),6.35(dd,J=10.2,3.7Hz,1H),5.58(dd,J=9.9,3.5Hz,1H),1.37–1.32(s,6H).ESI-MS m / z=333.06[MH]- .

[0643] Embodiment 33

[0644] Preparation of 6,6-diethyl-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-3-ol (Compound E33)

[0645]

[0646] Step 1: Preparation of 2-(3-(3-hydroxypentan-3-yl)-7,7-dimethyl-7H-furan[3,2-g]furan[3,2-g]furan-2-yl)-5-((2-methoxyethoxy)methoxy)phenol

[0647]

[0648] Ethylmagnesium bromide (2.0M THF solution, 0.12mL, 0.237mmol) was dissolved in THF (1mL) at -78°C under argon protection, and a solution of 3-((2-methoxyethoxy)methoxy)-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromene-6-one (10mg, 0.024mmol) in THF (0.5mL) was slowly added. The solution was warmed to room temperature within 2 hours under stirring. Saturated aqueous ammonium chloride solution (5mL) was added at 0°C to quench the reaction, and the reaction solution was extracted with ethyl acetate (10mL). The organic layer was washed with saturated brine (2x 5mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative silica gel plate (PE: EtOAc = 3: 1) to give 2-(3-(3-hydroxypentan-3-yl)-7,7-dimethyl-7H-furan[3,2-g]furan[3,2-g]furan-2-yl)-5-((2-methoxyethoxy)methoxy)phenol (10 mg, yield 87.7%) as a colorless oily liquid. ESI-MS m / z = 483 [M+H] + .

[0649] Step 2: Preparation of 6,6-diethyl-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-3-ol

[0650]

[0651] To a solution of 2-(3-(3-hydroxypentan-3-yl)-7,7-dimethyl-7H-furan[3,2-g]furan[3,2-g]furan-2-yl)-5-((2-methoxyethoxy)methoxy)phenol (10 mg, 0.021 mmol, 1.00 equiv) in MeOH (1 mL) at room temperature was added p-toluenesulfonic acid (12 mg, 0.062 mmol, 3.0 equiv). The resulting mixture was stirred at 50°C under argon atmosphere for 2 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with saturated brine (5 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (PE:EtOAc=2:1) ​​to give 6,6-diethyl-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-3-ol (3.5 mg, yield 45%) as a white solid. 1 H NMR (400MHz, Methanol-d4) δ7.21(d,J=8.3Hz,1H),7.04(s,1H),6.86(s,1H),6.43(d,J=9.8Hz,1H),6.33(dd,J=8.3,2.3Hz,1H),6.2 8(d,J=2.2Hz,1H),5.67(d,J=9.8Hz,1H),2.09(m,J=14.4,7.4Hz,2H),2.00–1.93(m,2H),1.40(s,6H),0.86(t,J=7.4Hz,6H).ESI-MS m / z=377.19[M+H] + .

[0652] Embodiment 34

[0653] Preparation of 4-chloro-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-3-ol (Compound E34)

[0654]

[0655]

[0656] Step 1: Preparation of 7-hydroxy-2,2-dimethylchroman-4-one

[0657]

[0658] Acetone (49.1 mL, 657.80 mmol) and pyrrolidine (13.6 mL, 164.4 mmol) were added to a stirred solution of 1-(2,4-dihydroxyphenyl)ethane-1-one (10.0 g, 65.78 mmol) in MeOH (100 mL) at room temperature. The resulting mixture was stirred at 75°C for 24 hours and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was washed with 1M hydrochloric acid solution (100 mL), saturated ammonium chloride solution (2×50 mL) and saturated brine (100 mL), and dried over anhydrous Na2SO4. The organic phase was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give 7-hydroxy-2,2-dimethylchroman-4-one (7.1 g, 56% yield) as a brown oil. ESI-MS m / z=193[M+H] +

[0659] Step 2: Preparation of 7-((2-methoxyethoxy)methoxy)-2,2-dimethylchroman-4-one

[0660]

[0661] To a stirred solution of 7-hydroxy-2,2-dimethylchroman-4-one (7.1 g, 36.40 mmol) in DCM (70 mL) was added N,N-diisopropylethylamine (18.1 mL, 109.20 mmol) at room temperature. It was then cooled to 0°C and 2-methoxyethoxymethyl chloride (6.2 mL, 54.60 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours under an argon atmosphere. It was then concentrated under reduced pressure, diluted with water (100 mL), and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated brine (100 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 3: 1) to give 7-((2-methoxyethoxy)methoxy)-2,2-dimethylchroman-4-one (8.8 g, 85% yield) as a brown oil. ESI-MS m / z=281[M+H] +

[0662] Step 3: Preparation of 7-((2-methoxyethoxy)methoxy)-2,2-dimethylbenzopyran-4-ol

[0663]

[0664] Sodium borohydride (4.2 g, 111.44 mmol) was added to a stirred solution of 7-((2-methoxyethoxy)methoxy)-2,2-dimethylchroman-4-one (7.8 g, 27.86 mmol) in EtOH (80 mL) at 0°C, and the resulting mixture was stirred at room temperature for 16 hours. It was then quenched with water (100 mL) at 0°C and extracted with ethyl acetate (3×100 mL). The organic phase was concentrated under reduced pressure to give 7-((2-methoxyethoxy)methoxy)-2,2-dimethylbenzopyran-4-ol (7.4 g, 94% yield) as a yellow oil. The crude product was used in the next step without further purification. ESI-MS m / z=283[M+H] +

[0665] Step 4: Preparation of 6-bromo-7-(2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromene

[0666]

[0667] To a stirred solution of 7-((2-methoxyethoxy)methoxy)-2,2-dimethylbenzopyran-4-ol (7.0 g, 24.82 mmol) in chloroform (70 mL) at 0°C was added N-bromosuccinimide (4.86 g, 27.30 mmol), and the mixture was stirred at room temperature for 4 hours, then diluted with water (100 mL) and extracted with EtOAc (200 mL). The organic layer was washed with saturated brine (2×100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc=2:1) ​​to give 6-bromo-7-(2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromene (6.0 g, 70% yield) as a brown oil. ESI-MS m / z=345[M+H] +

[0668] Step 5: Preparation of 1-(3-chloro-2,4-dihydroxyphenyl)ethan-1-one

[0669]

[0670] To a stirred solution of 1-(2,4-dihydroxyphenyl)ethane-1-one (12 g, 7.89 mmol, 1.00 equiv) in water (400 mL) and 1N NaOH (84 mL) was added 10% NaOCl (75 mL) at room temperature over 1 hour. The resulting mixture was stirred at room temperature overnight under an argon atmosphere. The reaction solution was adjusted to pH 2-3 with concentrated hydrochloric acid and extracted with ethyl acetate (2×300 mL). The organic layer was washed with saturated brine (250 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc=1:1) to give 1-(3-chloro-2,4-dihydroxyphenyl)ethane-1-one (8.5 g, 58% yield) as a white solid. ESI-MS m / z=187[M+H] +

[0671] Step 6: Preparation of 1-(3-chloro-2-hydroxy-4-(2-methoxyethoxy)methoxy)phenyl)ethan-1-one

[0672]

[0673] To a stirred solution of 1-(3-chloro-2,4-dihydroxyphenyl)ethane-1-one (4 g, 21.4 mmol, 1.00 equiv) in DCM (50 mL) at room temperature was added N,N-diisopropylethylamine (8.3 g, 64.3 mmol, 3.00 equiv). It was then cooled to 0°C and 2-methoxyethoxymethyl chloride (4.0 g, 32.2 mmol, 1.50 equiv) was added. The resulting mixture was stirred at room temperature for 6 hours under an argon atmosphere. The reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (2×40 mL). The organic layer was washed with saturated brine (40 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give 1-(3-chloro-2-hydroxy-4-(2-methoxyethoxy)methoxy)phenyl)ethan-1-one (3.64 g, 62% yield) as a white solid. ESI-MS m / z = 275 [M+H] +

[0674] Step 7: Preparation of (E)-1-(3-chloro-2-hydroxy-4-(2-methoxyethoxy)methoxy)phenyl)-3-dimethylaminoprop-2-en-1-one

[0675]

[0676] To a stirred solution of 1-(3-chloro-2-hydroxy-4-(2-methoxyethoxy)methoxy)phenyl)ethane-1-one (1.5 g, 5.46 mmol, 1.00 equiv) in DMF (15 mL) at room temperature was added N,N-dimethylformamide dimethyl acetal (2.6 g, 21.82 mmol, 1.60 equiv). The resulting mixture was stirred at 80°C for 1 hour under an argon atmosphere. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with saturated brine (50 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give 6: (E)-1-(3-chloro-2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)-3-(dimethylamino)prop-2-en-1-one (1.19 g, 66% yield) as a white solid. ESI-MS m / z = 330 [M+H] +

[0677] Step 8: Preparation of 3-bromo-8-chloro-7-(2-methoxyethoxy)methoxy-4H-benzopyran-4-one

[0678]

[0679] To a stirred solution of 6:(E)-1-(3-chloro-2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)-3-(dimethylamino)prop-2-en-1-one (587 mg, 1.78 mmol, 1.00 equiv) in chloroform (20 mL) at 0°C were added silica gel (1.8 g) and N-bromosuccinimide (348 mg, 1.96 mmol, 1.1 equiv). The resulting mixture was stirred at 0°C for 4 hours under an argon atmosphere. After filtration, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 10: 1) to give 3-bromo-8-chloro-7-(2-methoxyethoxy)methoxy-4H-benzopyran-4-one (470 mg, 70% yield) as a yellow solid. ESI-MS m / z = 363 [M+H] +

[0680] Step 9: Preparation of 8-chloro-7-(2-methoxyethoxy)methoxy-4-oxo-4H-benzopyran-3-boronic acid

[0681]

[0682] To a stirred solution of 3-bromo-8-chloro-7-(2-methoxyethoxy)methoxy-4H-benzopyran-4-one (470 mg, 1.29 mmol, 1.00 equiv) in 1,4-dioxane (20 mL) was added bis(pinacol)diboron (985 mg, 3.88 mmol, 3.0 equiv), potassium acetate (380 mg, 3.88 mmol, 3.0 equiv) and tetrakis(triphenylphosphine)palladium (1.40 g, 0.258 mmol, 0.20 equiv). The resulting mixture was stirred at 100 ° C for 3 hours under an argon atmosphere. It was then filtered through a small piece of celite. The filtrate was concentrated under reduced pressure and the crude product was used in the next step. ESI-MS m / z=329[M+H] +

[0683] Step 10: Preparation of 8-chloro-7,7'-bis(2-methoxyethoxy)methoxy)-2,2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one

[0684]

[0685] To a stirred solution of 8-chloro-7-(2-methoxyethoxy)methoxy-4-oxo-4H-benzopyran-3-boronic acid in 1,4-dioxane / water (4:1, 24 mL) were added 6-bromo-7-(2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromene (222 mg, 0.646 mmol, 1.00 equiv), potassium carbonate (268 mg, 1.944 mmol, 3.00 equiv) and tetrakis(triphenylphosphine)palladium (150 mg, 0.13 mmol, 0.20 equiv). The resulting mixture was stirred at 80° C. for 6 hours under an argon atmosphere. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give 8-chloro-7,7'-bis(2-methoxyethoxy)methoxy)-2,2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one (610 mg) as a black oil. ESI-MS m / z = 547 [M+H] +

[0686] Step 11: Preparation of 8-chloro-7-(2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)chroman-4-one

[0687]

[0688] To a stirred solution of 8-chloro-7,7'-bis(2-methoxyethoxy)methoxy)-2,2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one (200 mg, 0.366 mmol, 1.00 equiv) in THF (5 mL) was added diisobutylaluminum hydride (1.0 M in n-hexane, 732 uL, 0.732 mmol, 2.0 equiv) at -10°C. The resulting mixture was stirred at -10°C under an argon atmosphere for 3 hours. The mixture was quenched with potassium sodium tartrate solution (10 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give 8-chloro-7-(2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)chroman-4-one (66 mg, 33% yield) as a yellow oil. ESI-MS m / z = 549 [M+H] +

[0689] Step 12: Preparation of 4-chloro-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-3-ol

[0690]

[0691] To a stirred solution of 8-chloro-7-(2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)chroman-4-one (66 mg, 0.12 mmol, 1.00 equiv) in MeOH (3 mL) at room temperature was added p-toluenesulfonic acid (68.7 mg, 0.36 mmol, 3.0 equiv). The resulting mixture was stirred at 50° C. for 4 hours under an argon atmosphere. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with saturated brine (5 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 4-chloro-10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dibenzopyran-3-ol (5.7 mg, 13% yield) as a brown solid. 1H NMR (400MHz, Chloroform-d) δ7.30 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 4.2 Hz, 2H), 6.66 (d, J = 8. 4Hz,1H),6.38(d,J=9.8Hz,1H),5.67(s,2H),5.64(d,J=9.8Hz,1H),1.44(s,6H).ESI-MS m / z=355.01[M+H] +

[0692] Embodiment 35

[0693] Preparation of 6,10,10-trimethyl-6H,10H-furo[3,2-c:4,5-g']dibenzopyran-3-ol (Compound E35)

[0694]

[0695]

[0696] Step 1: Preparation of 2-(2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)-7,7-dimethyl-7H-furan[3,2-g]furan[3,2-g]benzopyran-3-carbaldehyde

[0697]

[0698] To a stirred solution of 3-(2-methoxyethoxy)methoxy)-10,10-dimethyl-6H,10H-furano[3,2-c:4,5-g']dichromene (42 mg, 0.103 mmol) in DCM / pH 9.2 buffer (10:1, 1.1 mL) at 0°C was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.6 mg, 0.103 mmol) in portions. The resulting mixture was stirred for 1.5 hours, then the mixture was diluted with water (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were washed successively with water (until the aqueous layer became colorless) and saturated brine (5 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by preparative TLC (PE:EtOAc=1:1) to give 2-(2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)-7,7-dimethyl-7H-furano[3,2-g]furano[3,2-g]benzopyran-3-carbaldehyde (26 mg, 60% yield) as a yellow solid. 1H NMR (400MHz, Chloroform-d) δ10.13(s,1H),7.79(s,1H),7.46(d,J=8.5Hz,1H),7.03(s,1H),6.95(s,1H),6.79(d,J=2.3Hz,1H),6.76(dd,J=8. 5,2.4Hz,1H),6.46(d,J=9.9Hz,1H),5.67(d,J=9.9Hz,1H),5.31(s,2H) ,3.86–3.82(m,2H),3.58–3.56(m,2H),3.38(s,3H),1.45(s,6H).ESI-MS m / z=425[M+H] +

[0699] Step 2: Preparation of 4-(3-hydroxyethyl)-7,7-dimethylfuran[3,2-g]furan[3,2-g]phenyl-2-yl)benzene-1,3-diol

[0700]

[0701] Methyllithium (1.6M in diethoxymethane, 529uL, 0.873mmol, 10.0equiv) was added to a stirred solution of 2-(2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)-7,7-dimethyl-7H-furan[3,2-g]furan[3,2-g]benzopyran-3-carbaldehyde (37mg, 0.0.087mmol, 1.00equiv) in THF (2mL) at 0°C. The resulting reaction mixture was stirred for 2 hours and the crude product was purified by preparative TLC (PE:EtOAc=1:1) to give 4-(3-hydroxyethyl)-7,7-dimethylfuran[3,2-g]furan[3,2-g]ben-2-yl)benzene-1,3-diol (14mg, 37% yield) as a brown oil. ESI-MS m / z=441[M+H] +

[0702] Step 3: Preparation of 6,10,10-trimethyl-6H,10H-furo[3,2-c:4,5-g']dibenzopyran-3-ol

[0703]

[0704] To a stirred solution of 4-(3-hydroxyethyl)-7,7-dimethylfuran[3,2-g]furan[3,2-g]benzene-2-yl)benzene-1,3-diol (14 mg, 0.032 mmol, 1.00 equiv) in toluene (1 mL) at 50°C was added p-toluenesulfonic acid (1.2 mg, 0.0064 mmol, 0.2 equiv). The resulting mixture was concentrated under reduced pressure. It was then dissolved in MeOH (2 mL), p-toluenesulfonic acid (12 mg, 0.064 mmol, 2 equiv) was added, and the resulting reaction mixture was stirred at 50°C for 2 hours. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with saturated brine (5 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 6,10,10-trimethyl-6H,10H-furo[3,2-c:4,5-g′]dibenzopyran-3-ol (6 mg, 57% yield) as a brown oil. 1 H NMR(400MHz,Chloroform-d)δ7.33(d,J=7.9Hz,1H),6.94(d,J=2.6Hz,2H),6.46–6.34(m,3 H),5.80(q,J=6.5Hz,1H),5.63(d,J=9.9Hz,1H),1.72(d,J=6.5Hz,3H),1.44(s,6H).ESI-MS m / z=335.09[M+H] +

[0705] Embodiment 36

[0706] Preparation of 9-isopropoxy-6H-benzofurano[3,2-c]furan-3-ol (Compound E36)

[0707]

[0708] Step 1: Preparation of 4-bromo-3-hydroxyphenyl 4-methylbenzenesulfonate

[0709]

[0710] Potassium carbonate (657 mg, 4.76 mmol) and p-toluenesulfonyl chloride (333 mg, 1.75 mmol) were added to a stirred solution of 4-bromobenzene-1,3-diol (300 mg, 1.59 mmol) in acetone (13 mL) at room temperature. The resulting mixture was stirred at 65°C overnight. The mixture was concentrated under reduced pressure to give 4-bromo-3-hydroxyphenyl 4-methylbenzenesulfonate (600 mg, crude product) as a brown oil. The crude product was used in the next step. ESI-MS m / z=343[M+H] +

[0711] Step 2: Preparation of 4-bromo-3-methoxymethoxyphenyl 4-methylbenzenesulfonate

[0712]

[0713] To a stirred solution of 4-bromo-3-hydroxyphenyl 4-methylbenzenesulfonate (600 mg, crude product) in DCM (12.00 mL) was added bromomethyl methyl ether (595 mg, 4.76 mmol) at room temperature. The resulting mixture was stirred for 0.25 hours. The reaction was diluted with water (50 mL) at room temperature and extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc=3:1) to give 4-bromo-3-methoxymethoxyphenyl 4-methylbenzenesulfonate (449 mg, 73% yield) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ7.72–7.68(m,2H),7.42(d,J=8.7Hz,1H),7.33–7.29(m,2H),6.7 5(d,J=2.6Hz,1H),6.55(dd,J=8.7,2.6Hz,1H),5.09(s,2H),3.42(s,3H),2.44(s,3H).ESI-MS m / z=388[M+H] + .

[0714] Step 3: Preparation of 4-bromo-3-methoxymethoxyphenol

[0715]

[0716] 4M KOH (1.46 mL, 5.82 mmol) was added to a stirred solution of 4-bromo-3-methoxymethoxyphenyl 4-methylbenzenesulfonate (449 mg, 1.16 mmol) in ethanol (2.00 mL). The reaction mixture was stirred at 60°C overnight, then cooled to room temperature, the aqueous phase was acidified to pH 6 with 1M HCl, and extracted with DCM (3×40 mL). The organic layer was dried over Na2SO4. The resulting mixture was concentrated under reduced pressure to give 4-bromo-3-methoxymethoxyphenol (257 mg, 95% yield) as a yellow solid. ESI-MS m / z=234[M+H] +

[0717] Step 4: Preparation of 1-bromo-4-isopropoxy-2-methoxymethoxybenzene

[0718]

[0719] To a stirred solution of 4-bromo-3-methoxymethoxyphenol (257 mg, 1.10 mmol) in DMF (5 mL) was added NaH (60%, 53 mg, 2.20 mmol), and 2-iodopropane (281 mg, 1.65 mmol) was added 12 minutes later. The resulting mixture was stirred at room temperature for 2.5 hours. Water (10 mL) was then added at 0°C to quench the NaH. It was then extracted with DCM (2×30 mL). The combined organic layers were washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc=5: 1) to give 1-bromo-4-isopropoxy-2-methoxymethoxybenzene (252 mg, 83% yield) as a yellow liquid. 1 H NMR(400MHz,Chloroform-d)δ7.37(d,J=8.7Hz,1H),6.72(d,J=2.7Hz,1H),6.44(dd,J=8.8 ,2.7Hz,1H),5.20(s,2H),4.48(p,J=6.0Hz,1H),3.50(s,3H),1.31(d,J=6.1Hz,6H).ESI-MS m / z=276[M+H] + .

[0720] Step 5: Preparation of 3-(4-isopropoxy-2-methoxymethoxy)phenyl-7-(2-methoxyethoxy)methoxy)-4H-benzopyran-4-one

[0721]

[0722] To a stirred solution of 3-bromo-7-(2-methoxyethoxy)methoxy-4H-benzopyran-4-one (250 mg, 0.76 mmol) in 1,4-dioxane (10 mL) was added bis(pinacol)diboron (508 mg, 2.28 mmol), potassium acetate (224 mg, 2.28 mmol) and tetrakis(triphenylphosphine)palladium (176 mg, 0.15 mmol) at room temperature. The resulting mixture was stirred at 100° C. overnight under an argon atmosphere. It was then filtered through a small piece of celite. The filtrate was concentrated under reduced pressure and the crude product was redissolved in 1,4-dioxane / water (4:1, 15 mL). 1-Bromo-4-isopropoxy-2-methoxymethoxybenzene (98 mg, 0.38 mmol), potassium carbonate (315 mg, 2.28 mmol) and tetrakis(triphenylphosphine)palladium (176 mg, 0.15 mmol) were added at room temperature. Under an argon atmosphere, the resulting mixture was stirred at 80°C overnight. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (2×30 mL). The organic layer was washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc=2:1) ​​to give 3-(4-isopropoxy-2-methoxymethoxy)phenyl-7-(2-methoxyethoxy)methoxy)-4H-benzopyran-4-one (143 mg, 85% yield) as a yellow oil. ESI-MS m / z=445[M+H] +

[0723] Step 6: Preparation of 3-(4-isopropoxy-2-methoxymethoxy)phenyl)-7-(2-methoxyethoxy)methoxy)chroman-4-one

[0724]

[0725] To a stirred solution of 3-(4-isopropoxy-2-methoxymethoxy)phenyl-7-(2-methoxyethoxy)methoxy)-4H-benzopyran-4-one (50 mg, 0.11 mmol) in THF (3 mL) was added diisobutylaluminum hydride (1.0 M in n-hexane, 225 uL, 0.225 mmol) at -10°C. The mixture was quenched with 3 mL of sodium potassium tartrate solution and extracted with 5 mL of ethyl acetate. The organic layer was washed with saturated brine (5 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC to give 3-(4-isopropoxy-2-methoxymethoxy)phenyl)-7-(2-methoxyethoxy)methoxy)chroman-4-one (10 mg, 20% yield) as a colorless oil. ESI-MS m / z=515[M+H] +

[0726] Step 7: Preparation of 9-isopropoxy-6H-benzofurano[3,2-c]furan-3-ol

[0727]

[0728] To a stirred solution of 3-(4-isopropoxy-2-methoxymethoxy)phenyl)-7-(2-methoxyethoxy)methoxy)chroman-4-one (10 mg, 0.022 mmol) in MeOH (2 mL) at room temperature was added p-toluenesulfonic acid (12.8 mg, 0.067 mmol). The resulting mixture was stirred at 60°C for 3 hours under an argon atmosphere. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with saturated brine (5 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC (PE: EtOAc = 2: 1) to give 9-isopropoxy-6H-benzofurano[3,2-c]furan-3-ol (2 mg, 30% yield) as a brown solid. 1 H NMR (400MHz, Methanol-d4) δ7.25(dd,J=8.4,1.8Hz,2H),7.07(d,J=2.2Hz,1H),6.82(dd,J=8.5,2.2Hz,1H),6.40(dt,J=8.3,2.1 Hz,1H),6.33(d,J=2.3Hz,1H),5.48(d,J=1.9Hz,2H),4.59(d,J=6.1Hz,1H),1.32(d,J=1.9Hz,3H),1.30(d,J=1.8Hz,3H).ESI-MS m / z=297.09[M+H] + .

[0729] Embodiment 37

[0730] Preparation of 12-chloro-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-3-ol (Compound E37)

[0731]

[0732] Step 1: Preparation of 8-chloro-7-(2-methoxyethoxy)methoxy)-2,2-dimethylchroman-4-one

[0733]

[0734] Acetone (4.36 mL, 59.334 mmol, 1.00 equiv) and pyrrolidine (1.06 g, 14.832 mmol, 2.50 equiv) were added to a solution of 1-(3-chloro-2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)ethan-1-one (1.63 g, 5.933 mmol, 1.00 equiv) in methanol (25.00 mL) at room temperature. The resulting mixture was stirred at 75 °C for 17 hours under an argon atmosphere. It was then concentrated under reduced pressure and extracted with ethyl acetate (20.00 mL), and the organic phase was washed with 1N HCl (5.00 mL) and saturated aqueous NH4Cl (10.00 mL) in sequence and dried (Na2SO4). The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give 8-chloro-7-((2-methoxyethoxy)methoxy)-2,2-dimethylchroman-4-one (1.8 g, yield 92%) as a yellow oil. ESI-MS m / z = 315 [M+H] + .

[0735] Step 2: Preparation of 8-chloro-7-(2-methoxyethoxy)methoxy)-2,2-dimethylchroman-4-ol

[0736]

[0737] Sodium borohydride (869 mg, 22.872 mmol, 4.00 equiv) was added to a solution of 8-chloro-7-((2-methoxyethoxy)methoxy)-2,2-dimethylchroman-4-one (1.8 g, 5.718 mmol, 1.00 equiv) in ethanol (25.00 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. It was quenched with ice water (25.00 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (30 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE: EtOAc = 3: 1) to give 8-chloro-7-((2-methoxyethoxy)methoxy)-2,2-dimethylchroman-4-ol (1.7 g, yield 94%) as a yellow oil. ESI-MS m / z = 317 [M+H] +

[0738] Step 3: Preparation of 6-bromo-8-chloro-7-(2-methoxyethoxy)methoxy)-2,2-dimethylchroman-4-ol

[0739]

[0740] N-bromosuccinimide (843 mg, 4.734 mmol, 1.10 equiv) was added to a solution of 8-chloro-7-((2-methoxyethoxy)methoxy)-2,2-dimethylchroman-4-ol (1.7 g, 4.304 mmol, 1.00 equiv) in DMF (17.00 mL) at 0 ° C. The resulting mixture was stirred at 0 ° C for 1 hour under an argon atmosphere. Diluted with water (20.00 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with saturated brine (20.00 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give 6-bromo-8-chloro-7-((2-methoxyethoxy)methoxy)-2,2-dimethylchroman-4-ol (1000 mg, yield 70%) as a yellow oil. ESI-MS m / z = 395 [M+H] +

[0741] Step 4: Preparation of 3-(8-chloro-4-hydroxy-7-(2-methoxyethoxy)methoxy)-2,2-dimethylbenzopyran-6-yl)-7-(2-methoxyethoxy)methoxy)-4H-benzopyran-4-one

[0742]

[0743] To a solution of (7-((2-methoxyethoxy)methoxy)-4H-chromen-3-ylboronic acid (100 mg, 0.292 mmol, 1.00 equiv) in 1,4-dioxane / water (4:1, 10 mL) was added 6-bromo-8-chloro-7-((2-methoxyethoxy)methoxy)-2,2-dimethylchroman-4-ol (114 mg, 0.292 mmol, 1.00 equiv), potassium carbonate (120 mg, 0.876 mmol, 3.00 equiv) and tetrakis(triphenylphosphine)palladium (67 mg, 0.058 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 80° C. under argon atmosphere for 4 hours. The mixture was concentrated under reduced pressure and washed with ethyl acetate (10 mL x 40 mL). 3) Extraction. The combined organic layers were washed with saturated brine and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=1:1) to obtain 3-(8-chloro-4-hydroxy-7-((2-methoxyethoxy)methoxy)-2,2-dimethylchroman-6-yl)-7-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (180 mg, yield 70%) as a yellow oil. ESI-MSm / z=565[M+H] +

[0744] Step 5: Preparation of 8-chloro-4-hydroxy-7,7-bis(2-methoxyethoxy)methoxy)-2,2-dimethyl-[3,6-bichroman]-4-one

[0745]

[0746] To a solution of 3-(8-chloro-4-hydroxy-7-((2-methoxyethoxy)methoxy)-2,2-dimethylbenzopyran-6-yl)-7-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (150 mg, 0.265 mmol, 1.00 equiv) in THF (2.00 mL) was added diisobutylaluminum hydride (1.0 M hexane solution, 0.7 mL, 0.7 mmol) at -10°C. The resulting mixture was stirred at -10°C for 2 hours under an argon atmosphere. The mixture was quenched with potassium sodium tartrate solution (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (1:1) to obtain 8'-chloro-4'-hydroxy-7,7'-bis((2-methoxyethoxy)methoxy)-2',2'-dimethyl-[3,6'-bichroman]-4-one (10.5 mg, yield 12%) as a yellow oil. ESI-MS m / z = 567 [M+H] + .

[0747] Step 6: Preparation of 12-chloro-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-3-ol

[0748]

[0749] To a solution of 8'-chloro-4'-hydroxy-7,7'-bis((2-methoxyethoxy)methoxy)-2',2'-dimethyl-[3,6'-bichroman]-4-one (6 mg, 0.011 mmol, 1.00 equiv) in MeOH (0.50 mL) at room temperature was added p-toluenesulfonic acid (8 mg, 0.042 mmol, 3.80 equiv). The resulting mixture was stirred at 50 ° C for 4 hours under an argon atmosphere. It was then diluted with saturated aqueous NaHCO3 (5 mL) and extracted with ethyl acetate (5 mL×3). The combined organic layer was washed with saturated brine and dried over anhydrous Na2SO4, and the resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=1:1) to give 12-chloro-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromen-3-ol (1 mg, yield 24%) as a white solid. 1H NMR(400MHz, Methanol-d4)δδ7.30(d,J=8.3Hz,1H),7.00(s,1H),6.47–6.41(m,2 H),6.35(d,J=2.3Hz,1H),5.74(d,J=9.8Hz,1H),5.46(s,2H),1.28(s,6H).ESI-MS m / z=355.04[M+H] + .

[0750] Embodiment 38

[0751] Preparation of 9-methoxy-6H-benzofurano[3,2-c]furan-3-ol (Compound E38)

[0752]

[0753]

[0754] Step 1: Preparation of (7-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromene-3-boronic acid

[0755]

[0756] To a solution of 3-bromo-7-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (500 mg, 1.519 mmol, 1.0 equiv) in 1,4-dioxane (20.00 mL) was added bis(pinacol)diboron (1157 mg, 4.558 mmol, 3.00 equiv), tetrakis(triphenylphosphine)palladium (350 mg, 0.304 mmol, 0.20 equiv) and potassium acetate (450 mg, 4.558 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at 100 ° C for 17 hours under an argon atmosphere. It was then filtered through celite, the filtrate was concentrated under reduced pressure, and the crude product was used directly in the next step without further purification.

[0757] Step 2: Preparation of 3-(2-hydroxy-4-methoxyphenyl)-7-((2-methoxyethoxy)methoxy)-4H-benzopyran-4-one

[0758]

[0759] To a solution of (7-((2-methoxyethoxy)methoxy)-4H-chromen-3-yl)boronic acid (268 mg, 0.912 mmol, 1.00 equiv) in 1,4-dioxane / water (4:1, 15 mL) at room temperature were added 2-bromo-5-methoxyphenol (185 mg, 0.912 mmol, 1.00 equiv), potassium carbonate (377 mg, 2.736 mmol, 3.00 equiv) and tetrakis(triphenylphosphine)palladium (200 mg, 0.182 mmol, 0.20 equiv). The resulting mixture was stirred at 80° C. for 17 hours under an argon atmosphere. The mixture was concentrated under reduced pressure and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=1:1) to give 3-(2-hydroxy-4-methoxyphenyl)-7-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (300 mg, yield 66%) as a yellow oil. ESI-MS m / z=373[M+H] +

[0760] Step 3: Preparation of 3-(4-methoxy-2-methoxymethoxy)phenyl-7-(2-methoxyethoxy)methoxy)-4H-benzopyran-4-one

[0761]

[0762] To a solution of 3-(2-hydroxy-4-methoxyphenyl)-7-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (220 mg, 0.593 mmol, 1.00 equiv) in DCM (5.00 mL) was added bromomethyl methyl ether (0.054 mL, 0.652 mmol, 1.10 equiv) and N,N-diisopropylethylamine (0.3 mL, 1.779 mmol, 3.00 equiv) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. It was then diluted with water (20 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EtOAc=3:1) to give 3-(4-methoxy-2-(methoxymethoxy)phenyl)-7-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (80 mg, yield 36%) as a yellow solid. ESI-MS m / z=417 [M+H] + .

[0763] Step 4: Preparation of 3-(4-methoxy-2-(methoxymethoxy)phenyl)-7-((2-methoxyethoxy)methoxy)chroman-4-one

[0764]

[0765] To a solution of 3-(4-methoxy-2-(methoxymethoxy)phenyl)-7-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (80 mg, 0.192 mmol, 1.00 equiv) in THF (2.00 mL) was added diisobutylaluminum hydride (hexane solution, 0.4 mL, 0.4 mmol) at -10 °C. The resulting mixture was stirred at -10 °C for 2 hours under an argon atmosphere. The mixture was quenched with potassium sodium tartrate solution (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saturated brine (10 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (1:1) to give 3-(4-methoxy-2-(methoxymethoxy)phenyl)-7-((2-methoxyethoxy)methoxy)chroman-4-one (15 mg, yield 19%) as a yellow oil. ESI-MS m / z = 419 [M+H] + .

[0766] Step 5: Preparation of 9-methoxy-6H-benzofurano[3,2-c]benzofuran-3-ol

[0767]

[0768] To a solution of 3-(4-methoxy-2-(methoxymethoxy)phenyl)-7-((2-methoxyethoxy)methoxy)chroman-4-one (15 mg, 0.036 mmol, 1.00 equiv) in MeOH (1 mL) was added p-toluenesulfonic acid (27.3 mg, 0.144 mmol, 4.00 equiv). The resulting mixture was stirred at 60 ° C for 4 hours under an argon atmosphere. It was then diluted with saturated aqueous NaHCO3 solution (10 mL) and extracted with ethyl acetate (5 mL×3). The combined organic layers were washed with saturated brine (10 mL) and dried over Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=1:1) to give 9-methoxy-6H-benzofurano[3,2-c]benzofuran-3-ol (4 mg, yield 42%) as a white solid. 1 H NMR (400MHz, Methanol-d4) δ7.28–7.23(m,2H),7.08(s,1H),6.83(d,J=8.3Hz,1H),6.42–6.37(m,1H),6.33(s,1H),5.47(s,2H),3.81(s,3H).ESI-MS m / z=269.06[M+H] + .

[0769] Embodiment 39

[0770] Preparation of 2-chloro-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-3-ol (Compound E39)

[0771]

[0772]

[0773] Step 1: Preparation of 1-(5-chloro-2,4-dihydroxyphenyl)ethan-1-one

[0774]

[0775] To a solution of 1-(2,4-dihydroxyphenyl)ethane-1-one (5.00 g, 32.89 mmol, 1.00 equiv) in chloroform (50.00 mL) at 0°C was added N-chlorosuccinimide (5.27 g, 39.47 mmol, 1.20 equiv) and a drop of concentrated hydrochloric acid. The resulting mixture was stirred at room temperature for 2 hours. The reactants were diluted with water (100 mL) at room temperature and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated brine (2x 50 mL) and dried (Na2SO4). The resulting organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 3: 1) to give 1-(5-chloro-2,4-dihydroxyphenyl)ethane-1-one (1.80 g, yield 29%) as a white solid. ESI-MS m / z = 187 [M+H] + .

[0776] Step 2: Preparation of 1-(5-chloro-2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)ethan-1-one

[0777]

[0778] 2-Methoxyethoxymethyl chloride (1.81 g, 14.50 mmol, 1.50 equiv) and N,N-diisopropylethylamine (3.75 g, 29.00 mmol, 3.00 equiv) were added to a solution of 1-(5-chloro-2,4-dihydroxyphenyl)ethane-1-one (1.80 g, 9.67 mmol, 1.00 equiv) in DCM (20.00 mL) at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The reactant was diluted with water (100 mL) at room temperature and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with saturated brine (2 x 50 mL) and dried (Na2SO4). The obtained organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to obtain 1-(5-chloro-2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)ethan-1-one (2.15 g, yield 81%) as a white solid. ESI-MS m / z = 275 [M+H] + .

[0779] Step 3: Preparation of (E)-1-(5-chloro-2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)-3-(dimethylamino)prop-2-en-1-one

[0780]

[0781] To a solution of 1-(5-chloro-2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)ethane-1-one (2.15 g, 7.85 mmol, 1.00 equiv) in DMF (22.00 mL) was added N,N-dimethylformamide dimethyl acetal (3.74 g, 31.39 mmol, 4.00 equiv). The resulting mixture was stirred at 80 °C for 1 hour. The reactants were diluted with water (200 mL) at room temperature and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with saturated brine (2 x 50 mL) and dried (Na2SO4). The resulting organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give (E)-1-(5-chloro-2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)-3-(dimethylamino)prop-2-en-1-one (1.90 g, yield 73%) as a white solid. ESI-MS m / z = 330 [M+H] + .

[0782] Step 4: Preparation of 3-bromo-6-chloro-7-(2-methoxyethoxy)methoxy-4H-benzopyran-4-one

[0783]

[0784] To a solution of (E)-1-(5-chloro-2-hydroxy-4-((2-methoxyethoxy)methoxy)phenyl)-3-(dimethylamino)prop-2-ene-1-one (1.90 g, 5.77 mmol, 1.00 equiv) in chloroform (20.00 mL) was added N-bromosuccinimide (1.13 g, 6.35 mmol, 1.10 equiv) and silica gel (5.70 g). The resulting mixture was stirred at room temperature for 1 hour. The mixture was filtered, the filtrate was diluted with water (100 mL) at room temperature, and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with saturated brine (2 x 50 mL) and dried (Na2SO4). The obtained organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE: EtOAc = 7: 3) to obtain 3-bromo-6-chloro-7-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (2.01 g, 96% yield) as a brown solid. ESI-MS m / z = 363 / 365 [M+H] + .

[0785] Step 5: Preparation of 6-chloro-7-(2-methoxyethoxy)methoxy)-3-trimethylstannyl-4H-benzopyran-4-one

[0786]

[0787] To a solution of 3-bromo-6-chloro-7-((2-methoxyethoxy)methoxy)-4H-chromene-4-one (0.80 g, 2.20 mmol, 1.00 equiv) in dioxane (10.00 mL) was added hexamethylditin (1.44 g, 4.40 mmol, 2.00 equiv) and tetrakis(triphenylphosphine)palladium (0.51 g, 0.44 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 90° C. for 12 hours under an argon atmosphere. The resulting mixture was filtered, and the filtrate was diluted with water (20 mL) at room temperature and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated brine (2×50 mL) and dried (Na2SO4). The resulting organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 3: 1) to give 6-chloro-7-((2-methoxyethoxy)methoxy)-3-(trimethylstannyl)-4H-chromen-4-one (0.38 g, yield 38%) as a brown oil. ESI-MS m / z = 449 [M+H] + .

[0788] Step 6: Preparation of 6-chloro-7,7-bis(2-methoxyethoxy)methoxy-2,2-dimethyl-2-H,4H-[3,6-bichromene]-4-one

[0789]

[0790] To a solution of 6-chloro-7-((2-methoxyethoxy)methoxy)-3-(trimethylstannyl)-4H-chromen-4-one (380.00 mg, 0.85 mmol, 1.00 equiv) and 6-iodo-7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromene (330.00 mg, 0.85 mmol, 1.00 equiv) in dioxane (5.00 mL) was added tetrakis(triphenylphosphine)palladium (196.00 mg, 0.17 mmol, 0.20 equiv) and cuprous iodide (8.00 mg, 0.04 mmol, 0.05 equiv) at room temperature. The resulting mixture was stirred at 80° C. for 2 hours under an argon atmosphere. The resulting mixture was filtered, and the filtrate was diluted with water (20 mL) at room temperature and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated brine (2 x 50 mL) and dried (Na2SO4). The resulting organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give 6-chloro-7,7'-bis((2-methoxyethoxy)methoxy)-2',2'-dimethyl-2'H,4H-[3,6'-bichromatic]-4-one (160.00 mg, 34% yield) as a white solid. ESI-MS m / z = 547 [M+H] + .

[0791] Step 7: Preparation of 6-chloro-7-(2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)chroman-4-one

[0792]

[0793] To a solution of 6-chloro-7,7'-bis((2-methoxyethoxy)-2',2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one (160.00 mg, 0.29 mmol, 1.00 equiv) in THF (3.00 mL) was added dropwise a 1 M solution of diisobutylaluminum hydride in n-hexane (0.87 mL, 0.87 mmol, 3.00 equiv) at -10°C under argon atmosphere. The mixture was stirred at -10°C for 2 hours under argon atmosphere. The resulting reaction solution was quenched with sodium potassium tartrate solution (10 mL) at 0°C. The mixture was diluted with water (20 mL) at room temperature and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with saturated brine (2 x 30 mL). 50mL) and dried (Na2SO4). The resulting organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=2:1) ​​to give 6-chloro-7-((2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)chroman-4-one (68.00 mg, yield 42%) as a white solid. ESI-MS m / z=549[M+H] + .

[0794] Step 8: Preparation of 2-chloro-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dibenzopyran-3-ol

[0795]

[0796] To a solution of 6-chloro-7-((2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)chroman-4-one (68.00 mg, 0.12 mmol, 1.00 equiv) in MeOH (2.00 mL) was added p-toluenesulfonic acid hydrate (94.00 mg, 0.48 mmol, 4.00 equiv). The resulting mixture was stirred at 50° C. for 2 hours under argon atmosphere. The resulting mixture was quenched with sodium bicarbonate solution (10 mL) at 0° C. The mixture was diluted with water (20 mL) at room temperature and extracted with ethyl acetate (2× 30 mL). The combined organic layers were washed with saturated brine (2× 50 mL) and dried (Na2SO4). The resulting organic phase was concentrated under reduced pressure. The crude product was purified by HPLC (chromatographic column: Xbridge BEHC18 OBD column, 5uM, 10mm*250mm; mobile phase: [water (0.5% formic acid)-acetonitrile]; B%: 10%-90% over 20 minutes) to give 2-chloro-10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromene-3-ol (7.40 mg, yield 16%) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ7.39(s,1H),6.93(d,J=9.6Hz,2H),6.59(s,1H),6.37( d,J=9.9Hz,1H),5.63(d,J=9.7Hz,1H),5.58(s,1H),5.52(s,2H),1.44(s,6H).ESI-MS m / z=355.07[M+H] + .

[0797] Embodiment 40

[0798] Preparation of 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dibenzopyran-2-ol (Compound E40)

[0799]

[0800]

[0801] Step 1: Preparation of 1-(2-hydroxy-5-((2-methoxyethoxy)methoxy)phenyl)ethan-1-one

[0802]

[0803] 2-Methoxyethoxymethyl chloride (2.45 g, 19.73 mmol, 1.50 equiv) and N,N-diisopropylethylamine (5.09 g, 39.47 mmol, 3.00 equiv) were added to a solution of 1-(2,5-dihydroxyphenyl)ethane-1-one (2.00 g, 13.15 mmol, 1.00 equiv) in dichloromethane (20.00 mL) at 0 ° C. The resulting mixture was stirred at room temperature for 2 hours. The reactant was diluted with water (100 mL) at room temperature and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with saturated brine (2 x 50 mL) and dried (Na2SO4). The resulting organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 3: 1) to give 1-(2-hydroxy-5-((2-methoxyethoxy)methoxy)phenyl)ethan-1-one (2.02 g, yield 64%) as a brown oil. ESI-MS m / z = 241 [M+H] + .

[0804] Step 2: Preparation of (E)-3-(dimethylamino)-1-(2-hydroxy-5-((2-methoxyethoxy)methoxy)phenyl)prop-2-en-1-one

[0805]

[0806] To a solution of 1-(2-hydroxy-5-((2-methoxyethoxy)methoxy)phenyl)ethane-1-one (2.02 g, 8.41 mmol, 1.00 equiv) in DMF (21.00 mL) was added N,N-dimethylformamide dimethyl acetal (4.01 g, 33.67 mmol, 4.00 equiv). The resulting mixture was stirred at 80 °C for 1 hour. The reactants were diluted with water (200 mL) at room temperature and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with saturated brine (2 x 50 mL) and dried (Na2SO4). The resulting organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 1: 1) to give (E)-3-(dimethylamino)-1-(2-hydroxy-5-((2-methoxyethoxy)methoxy)phenyl)prop-2-en-1-one (2.20 g, yield 88%) as a brown oil. ESI-MS m / z = 296 [M+H] + .

[0807] Step 3: Preparation of 3-bromo-6-(2-methoxyethoxy)methoxy-4H-chromen-4-one

[0808]

[0809] To a solution of (E)-3-(dimethylamino)-1-(2-hydroxy-5-((2-methoxyethoxy)methoxy)phenyl)prop-2-ene-1-one (1.00 g, 3.39 mmol, 1.00 equivalent) in chloroform (20.00 mL) was added N-bromosuccinimide (0.66 g, 3.72 mmol, 1.10 equivalent) and silica gel (3.00 g). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was filtered, and the solution was diluted with water (100 mL) at room temperature and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with saturated brine (2 x 50 mL) and dried (Na2SO4). The resulting organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give 3-bromo-6-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (0.68 g, yield 61%) as a white solid. ESI-MS m / z = 329 [M+H] + .

[0810] Step 4: Preparation of 6-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromene-3-boronic acid

[0811]

[0812] To a solution of 3-bromo-6-((2-methoxyethoxy)methoxy)-4H-chromen-4-one (0.50 g, 1.52 mmol, 1.00 equiv) in 1,4-dioxane (10.00 mL) was added bis(pinacol)diboron ester (1.12 g, 4.57 mmol, 3.00 equiv) and potassium acetate (0.43 g, 4.57 mmol, 3.00 equiv) and tetrakis(triphenylphosphine)palladium (0.34 g, 0.30 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 100 ° C for 8 hours under an argon atmosphere. The resulting mixture was filtered and used directly in the next step without further purification. ESI-MS m / z=295[M+H] + .

[0813] Step 5: Preparation of 6,7'-bis(2-methoxyethoxy)methoxy)-2,2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one

[0814]

[0815] To a solution of (6-((2-methoxyethoxy)methoxy)-4-oxo-4H-chromen-3-ylboronic acid (crude) in dioxane (8.00 mL) and water (2.00 mL) were added 6-iodo-7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromene (300 mg, 0.76 mmol, 0.50 equiv), tetrakis(triphenylphosphine)palladium (352.00 mg, 0.30 mmol, 0.20 equiv) and potassium carbonate (631.00 mg, 4.57 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred at 80° C. for 3 hours under an argon atmosphere. The mixture was filtered, the filtrate was diluted with water (20 mL), and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated brine (2×10 mL). 50mL) and dried (Na2SO4). The obtained organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 5: 2) to obtain 6,7'-bis (2-methoxyethoxy) methoxy)-2,2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one (320.00 mg, yield 81%) as a brown solid. ESI-MS m / z = 513 [M+H] + .

[0816] Step 6: Preparation of 6-(2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)chroman-4-one

[0817]

[0818] A 1M solution of diisobutylaluminum hydride in n-hexane (0.27 mL, 0.27 mmol, 3.00 equiv.) was added dropwise to 6,7'-bis(2-methoxyethoxy)methoxy)-2,2'-dimethyl-2'H,4H-[3,6'-bichromene]-4-one in THF (2.00 mL) at -10°C under argon atmosphere. The resulting mixture was stirred at -10°C for 2 hours under argon atmosphere. The resulting mixture was quenched with potassium sodium tartrate solution (20 mL) at 0°C. The mixture was diluted with water (20 mL) at room temperature and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with saturated brine (2 x 50 mL) and dried (Na2SO4). The resulting organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 2: 1) to give 6-(2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)chroman-4-one (24.00 mg, yield 47%) as a white solid. ESI-MS m / z = 515 [M+H] + .

[0819] Step 7: Preparation of 10,10-dimethyl-6H,10H-furo[3,2-c:4,5-g']dibenzopyran-2-ol

[0820]

[0821] To a solution of 6-((2-methoxyethoxy)methoxy)-3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)chroman-4-one (24.00 mg, 0.04 mmol, 1.00 equiv) in MeOH (2.00 mL) was added p-toluenesulfonic acid hydrate (36.00 mg, 0.16 mmol, 4.00 equiv). The resulting mixture was stirred at 50 °C for 2 hours under argon atmosphere. The reaction was quenched with sodium bicarbonate solution (10 mL) at 0 °C. The mixture was diluted with water (20 mL) at room temperature and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with saturated brine (2 x 50 mL) and dried (Na2SO4). The resulting mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (PE:EtOAc=2:1) ​​to give 10,10-dimethyl-6H,10H-furan[3,2-c:4,5-g']dichromen-2-ol (8.0 mg, yield 53%) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ6.96(d,3H),6.77(d,J=8.6Hz,1H),6.65–6.58(m,1 H),6.39(d,J=9.8Hz,1H),5.64(d,J=9.7Hz,1H),5.47(s,2H),1.44(s,6H).ESI-MS m / z=321.10[M+H] + .

[0822] Embodiment 41

[0823] Preparation of 9-methoxy-6-phenylindazolo[2,3-a]quinoxalin-3-ol (Compound E41)

[0824]

[0825] Step 1: Preparation of 1-fluoro-4-methoxymethoxy-2-nitrobenzene

[0826]

[0827] Bromomethyl methyl ether (590 mg, 4.721 mmol, 1.10 equiv) and N,N-diisopropylethylamine (0.393 mL, 12.794 mmol, 3.00 equiv) were added to a solution of 4-fluoro-3-nitrophenol (670 mg, 4.264 mmol, 1.00 equiv) in DCM (12.00 mL) at 0 ° C. The resulting mixture was stirred at room temperature for 2 hours under an argon atmosphere. Diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with saturated brine (40 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 4: 1) to give 1-fluoro-4-(methoxymethoxy)-2-nitrobenzene (710 mg, 83% yield) as a white oil. 1 H NMR (400MHz, Chloroform-d) δ7.73–7.69 (m, 1H), 7.27 (s, 1H), 7.20 (d, J = 9.8Hz, 1H), 5.18 (s, 2H), 3.48 (s, 3H).

[0828] Step 2: Preparation of 6-methoxy-2-(4-(methoxymethoxy)-2-nitrophenyl-2H-indazole

[0829]

[0830] To a solution of 1-fluoro-4-(methoxymethoxy)-2-nitrobenzene (500 mg, 2.488 mmol, 1.00 equiv) in DMF (5.00 mL) was added 60% NaH (120 mg, 2.986 mmol, 1.22 equiv) at 0°C. After the mixture was stirred for 10 minutes, 6-methoxy-1H-indazole (406 mg, 2.737 mmol, 1.10 equiv) was added. The resulting mixture was stirred at 60°C for 17 hours. Diluted with water (40 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated brine (40 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=1:1) to give 6-methoxy-2-(4-(methoxymethoxy)-2-nitrophenyl)-2H-indazole (160 mg, yield 18%) as a yellow solid. ESI-MS m / z=330[M+H] +

[0831] Step 3: Preparation of 2-(6-methoxy-2H-indazol-2-yl)-5-(methoxymethoxy)aniline

[0832]

[0833] To a solution of 6-methoxy-2-(4-(methoxymethoxy)-2-nitrophenyl)-2H-indazole (150 mg, 0.456 mmol, 1.00 equiv) in MeOH / THF (3:1, 2 mL) at 0°C, reduced zinc powder (300 mg, 4.560 mmol, 10.0 equiv) and saturated aqueous ammonium chloride solution (1 mL) were added in sequence. The resulting mixture was stirred at room temperature for 17 hours. It was then filtered and the filtrate was concentrated to half volume under reduced pressure. It was diluted with water (15 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=1:1) to give 2-(6-methoxy-2H-indazol-2-yl)-5-(methoxymethoxy)aniline (35 mg, yield 25.2%) as a yellow solid. ESI-MS m / z=300[M+H] +

[0834] Step 4: Preparation of 9-methoxy-3-(methoxymethoxy)-6-phenylindazolo[2,3-a]quinoxaline

[0835]

[0836] To a solution of 2-(6-methoxy-2H-indazol-2-yl)-5-(methoxymethoxy)aniline (33 mg, 0.110 mmol, 1.00 equiv) in acetonitrile (1 mL) was added benzylamine (0.02 mL, 0.166 mmol, 1.50 equiv) and iodine (28 mg, 0.110 mmol, 1.00 equiv). The resulting mixture was stirred at 90 °C for 17 hours. It was then diluted with saturated aqueous Na2S2O3 solution (15 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=3:1) to give 9-methoxy-3-(methoxymethoxy)-6-phenylindazolo[2,3-a]quinoxaline (16 mg, yield 37%) as a yellow solid. ESI-MS m / z=386[M+H] +

[0837] Step 5: Preparation of 9-methoxy-6-phenylindazolo[2,3-a]quinoxalin-3-ol

[0838]

[0839] Trifluoroacetic acid (0.50 mL) was added to a solution of 9-methoxy-3-(methoxymethoxy)-6-phenylindazolo[2,3-a]quinoxaline (16 mg, 0.043 mmol, 1.00 equiv) in DCM (1.50 mL). The resulting mixture was stirred at room temperature for 4 hours under an argon atmosphere. It was then diluted with saturated aqueous NaHCO3 solution (10 mL) and extracted with ethyl acetate (5 mL×3). The combined organic layers were washed with saturated brine (10 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EtOAc=1:1) to give 9-methoxy-6-phenylindazolo[2,3-a]quinoxaline-3-ol (4 mg, yield 28%) as a yellow solid. 1 H NMR(400MHz, Methanol-d4)δ8.59(d,J=9.1Hz,1H),7.88–7.79(m,2H),7.72–7.61(m,3H),7.48(d,J=2.6 Hz,1H),7.40–7.31(m,1H),7.28(dd,J=5.7,3.4Hz,2H),6.84(dd,J=9.2,2.2Hz,1H),3.90(s,3H).ESI-MS m / z=342.20[M+H] + .

[0840] Embodiment 42

[0841] Preparation of 9-methoxybenzo[5,6][1,2,4]triazine[4,3-b]indazol-3-ol (Compound E42)

[0842]

[0843] Step 1: Preparation of 9-methoxy-3-(methoxymethoxy)benzo[5,6][1,2,4]triazine[4,3-b]indazole

[0844]

[0845] To a stirred solution of 2-(6-methoxy-2H-indazol-2-yl)-5-methoxymethoxyaniline (50 mg, 0.17 mmol) in acetic acid (2.5 mL) was added a solution of sodium nitrite (11.5 mg, 0.17 mmol) in water (1 mL) at room temperature. The resulting mixture was stirred under an argon atmosphere for 4 hours. The reaction solution was neutralized with 5% NaOH and then extracted with ethyl acetate (3×5 mL). The organic layer was washed with saturated brine (5 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM) to give 9-methoxy-3-(methoxymethoxy)benzo[5,6][1,2,4]triazine[4,3-b]indazole (20 mg, 39% yield) as an orange solid. 1 H NMR(400MHz,Chloroform-d)δ8.63(d,J=9.2Hz,1H),8.48(d,J=9.0Hz,1H),8.28(d,J=2.6Hz,1H),7.72(dd,J =9.2,2.6Hz,1H),7.33(d,J=2.1Hz,1H),7.22(d,J=2.1Hz,1H),5.41(s,2H),3.99(s,3H),3.57(s,3H).ESI-MS m / z=311[M+H] +

[0846] Step 2: Preparation of 9-methoxybenzo[5,6][1,2,4]triazine[4,3-b]indazol-3-ol

[0847]

[0848] To a stirred solution of 9-methoxy-3-(methoxymethoxy)benzo[5,6][1,2,4]triazine[4,3-b]indazole (19 mg, 0.06 mmol) in MeOH (2 mL) at room temperature was added p-toluenesulfonic acid (23.3 mg, 0.12 mmol). The resulting mixture was stirred at 60°C for 4 hours under an argon atmosphere. The reaction solution was diluted with water (3 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with saturated brine (5 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Xbridge BEH C18 OBD column, 5uM, 10mm×250mm; mobile phase: [water (0.5% formic acid)-acetonitrile]; b%: 10%-90% in 20 minutes) to give 9-methoxybenzo[5,6][1,2,4]triazine[4,3-b]indazole-3-ol (6.3 mg, 37% yield) as an orange solid. 1H NMR (400MHz, DMSO-d6) δ10.72(s,1H),8.54(d,J=9.1Hz,1H),8.40(d,J=8.9Hz,1H),7.87(d,J=2.6Hz,1 H),7.67(dd,J=9.1,2.6Hz,1H),7.44(d,J=2.1Hz,1H),7.20(dd,J=8.9,2.1Hz,1H),3.92(s,3H).ESI-MS m / z=267.09[M+H] +

[0849] Embodiment 43

[0850] Preparation of 10,10-dimethyl-10H-benzopyrano[6,7:4,5]furano[3,2-c]quinolin-3-ol (Compound E43)

[0851]

[0852] Step 1: Preparation of 5-((3-(benzyloxy)phenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0853]

[0854] To a solution of 3-(benzyloxy)aniline (2.00 g, 10.05 mmol, 1.00 equiv) in ethanol (20.00 mL) was added 2,2-dimethyl-1,3-dioxane-4,6-dione (1.71 g, 11.86 mmol, 1.18 equiv), trimethoxymethane (1.25 g, 11.86 mmol, 1.18 equiv). The resulting mixture was stirred at 75 °C for 1 hour. The reaction solution was cooled to room temperature and stirred for 0.5 hours. Filtered, the solid was washed with EtOH (30.00 mL) to give 5-(((benzyloxy)phenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.41 g, 96% yield) as a white solid. ESI-MS m / z=354 [M+H] +

[0855] Step 2: Preparation of 7-(benzyloxy)quinolin-4(1H)one

[0856]

[0857] A solution of 5-((benzyloxy)phenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.41 g, 9.66 mmol, 1.00 equiv) in Dowtherm A (8 mL) was stirred at 220°C for 2 hours. It was then cooled to room temperature and diluted with n-hexane (30.00 mL), filtered, and the resulting solid was washed with n-hexane (50.00 mL) to give 7-(benzyloxy)quinolin-4(1H)-one (1.72 g, 71% yield) as a brown solid. ESI-MS m / z=252 [M+H] + .

[0858] Step 3: Preparation of 7-benzyloxy-3-bromoquinolin-4(1H)one

[0859]

[0860] N-bromosuccinimide (0.97 g, 5.48 mmol, 0.80 equiv) was added to a solution of 7-(benzyloxy)quinoline-4(1H)-one (1.72 g, 6.85 mmol, 1.00 equiv) in DMF (20 mL) at 0°C. The resulting mixture was stirred at room temperature for 3 hours. It was then diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was concentrated under reduced pressure. The residue was slurried with petroleum ether (200 mL) and filtered to give 7-(benzyloxy)-3-bromoquinoline-4(1H)-one (1.34 g, 60% yield) as a brown solid. ESI-MS m / z=330 / 332[M+H] + .

[0861] Step 4: Preparation of 7-benzyloxy-3-bromo-4-chloroquinoline

[0862]

[0863] To a solution of 7-(benzyloxy)-3-bromoquinolin-4(1H)-one (1.34 g, 4.07 mmol, 1.00 equiv) in POCl3 (15 mL) was added N,N-diisopropylethylamine (660 mg, 10.18 mmol, 2.50 equiv) at room temperature. The resulting mixture was stirred at 110°C for 2 hours. It was concentrated under reduced pressure and the pH was adjusted to 8 with sodium bicarbonate solution (100 mL). The resulting mixture was extracted with DCM (100 mL) and dried over anhydrous Na2SO4. The resulting organics were concentrated under reduced pressure. The crude product was purified by preparative TLC (PE: EtOAc = 10: 1) to give 7-(benzyloxy)-3-bromo-4-chloroquinoline (0.83 g, 67% yield) as a yellow oil. ESI-MS m / z = 348 / 350 [M+H] +

[0864] Step 5: Preparation of 7-(Benzyloxy)-4-chloroquinoline-3-boronic acid

[0865]

[0866] To a solution of 7-(benzyloxy)-3-bromo-4-chloroquinoline (160 mg, 0.45 mmol, 1.00 equiv) in 1,4-dioxane (5 mL) was added bis(pinacol)diboron ester (350 mg, 1.38 mmol, 3.00 equiv), potassium acetate (135 mg, 1.38 mmol, 3.00 equiv) and tetrakis(triphenylphosphine)palladium (106 mg, 0.09 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 100 °C for 16 hours under an argon atmosphere. The filtrate was filtered and concentrated under reduced pressure, and the crude product was used directly in the next step without further purification. ESI-MS m / z=314 [M+H] + .

[0867] Step 6: Preparation of 7-benzyloxy-4-chloro-3-(7-(2-methoxyethoxy)methoxy)-2,2-dimethyl-6-ylquinoline

[0868]

[0869] To a solution of (7-(benzyloxy)-4-chloroquinolin-3-yl)boronic acid (141 mg, 0.45 mmol, 1.00 equiv) in 1,4-dioxane / water (4:1, 6 mL) was added 6-bromo-7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromene (169 mg, 0.49 mmol, 1.08 equiv), potassium carbonate (828 mg, 1.35 mmol, 3.00 equiv) and tetrakis(triphenylphosphine)palladium (104 mg, 0.09 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 80°C for 3 hours under an argon atmosphere. The mixture was concentrated under reduced pressure, diluted with water (20 mL), and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with saturated brine (40 mL) and dried over anhydrous Na2SO4. The resulting organic phase was concentrated under reduced pressure. The crude product was purified by preparative TLC (PE: EtOAc = 3: 1) to give 7-(benzyloxy)-4-chloro-3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)quinoline (65 mg, yield 26%) as a white solid. ESI-MS m / z = 532 [M+H] + .

[0870] Step 7: Preparation of 6-(7-benzyloxy)-4-chloroquinolin-3-yl)-2,2-dimethyl-2H-benzopyran-7-ol

[0871]

[0872] To a solution of 7-(benzyloxy)-4-chloro-3-(7-(((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)quinoline (65 mg, 0.12 mmol, 1.00 equiv) in MeOH (2 mL) was added p-toluenesulfonic acid (93 mg, 0.48 mmol, 4.00 equiv) at room temperature. The resulting mixture was stirred at 50°C for 4 hours under an argon atmosphere. The resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. The resulting organic phase was concentrated under reduced pressure. The crude product was purified by preparative TLC (PE:EtOAc=2:1) ​​to give 6-(7-(benzyloxy)-4-chloroquinolin-3-yl)-2,2-dimethyl-2H-chromen-7-ol (48 mg, 88% yield) as a white solid. ESI-MS m / z=444[M+H] + .

[0873] Step 8: Preparation of 3-benzyloxy-10,10-dimethyl-10H-benzopyrano[6,7:4,5]furo[3,2-c]quinoline

[0874]

[0875] To a solution of 7-(benzyloxy)-4-chloro-3-(7-((2-methoxyethoxy)methoxy)-2,2-dimethyl-2H-chromen-6-yl)quinoline (48 mg, 0.10 mmol, 1.00 equiv) in DMF (2 mL) was added potassium tert-butoxide (60 mg, 0.54 mmol, 5.40 equiv). The resulting mixture was stirred at 60° C. for 8 hours. The resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated brine (40 mL) and dried over anhydrous Na2SO4. The resulting organic phase was concentrated under reduced pressure. The crude product was purified by preparative TLC (PE: EtOAc = 2: 1) to give 3-(benzyloxy)-10,10-dimethyl-10H-benzopyrano[6',7':4,5]furo[3,2-c]quinoline (30 mg, 68% yield) as a white solid. ESI-MS m / z = 408 [M+H] + .

[0876] Step 9: Preparation of 10,10-dimethyl-10H-benzopyrano[6,7:4,5]furano[3,2-c]quinolin-3-ol

[0877]

[0878] To a solution of 3-(benzyloxy)-10,10-dimethyl-10H-benzopyrano[6',7':4,5]furano[3,2-c]quinoline (25 mg, 0.06 mmol, 1.00 equiv) in DCM (2 mL) was added 1 M boron trichloride in DCM (0.12 mL, 0.12 mmol, 2.00 equiv) at -78°C under argon atmosphere. The resulting mixture was stirred at -78°C for 0.5 hours. The reaction was quenched with NaHCO3(aq) / MeOH (1:1, 40 mL) at -78°C and the mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated brine (40 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure and the crude product was purified by preparative TLC (PE:EtOAc=1:1) to give 10,10-dimethyl-10H-benzopyrano[6',7':4,5]furano[3,2-c]quinolin-3-ol (2.0 mg, 10% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),9.37(s,1H),8.15(d,J=8.9Hz,1H),7.88(s,1H),7.39(d,J=2.3Hz ,1H),7.29-7.25(m,2H),7.24(s,1H),6.56(d,J=9.9Hz,1H),5.82(d,J=9.8Hz,1H),1.40(s,6H).ESI-MS m / z=318.12[M+H] + .

[0879] Embodiment 44

[0880] Preparation of 10,10-dimethyl-10H-benzo[5,6][1,2,4]triazine[4,3-b]pyrano[3,2-f]indazol-3-ol (Compound E44)

[0881]

[0882] Step 1: Preparation of 2-fluoro-4-(2-methylbut-3-ynyl)oxy)benzaldehyde

[0883]

[0884] To a stirred solution of 2-fluoro-4-hydroxybenzaldehyde (4.2 g, 30.0 mmol) in acetone (80 mL) was added potassium carbonate (8.3 g, 60.0 mmol), potassium iodide (7.5 g, 45.0 mmol), cuprous iodide (57 mg, 0.3 mmol) and 3-chloro-3-methylbut-1-yne (4.6 g, 45.0 mmol) at reflux temperature. The resulting mixture was stirred overnight under an argon atmosphere. The reaction solution was diluted with 1N NaOH (50 mL) and then extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (50 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 2-fluoro-4-(2-methylbut-3-ynyl)oxy)benzaldehyde (5.3 g, 86% yield) as a yellow oil. 1 H NMR(400MHz,Chloroform-d)δ10.21(s,1H),7.78(t,J=8.2Hz,1H),7.07–7.04(m,1H),7.03–7.01(m,1H),2.69(s,1H),1.71(s,6H).ESI-MS m / z=207[M+H] +

[0885] Step 2: Preparation of 7-fluoro-2,2-dimethyl-2H-chromene-6-carbaldehyde

[0886]

[0887] At 140°C, N,N-dimethylaniline (293 mg, 2.41 mmol) was added to a stirred solution of 7-fluoro-2,2-dimethyl-2H-chromene-6-carboxaldehyde (1.24 g, 6.04 mmol) in DMF (20 mL), and the resulting mixture was stirred overnight under an argon atmosphere. The reaction solution was diluted with water (20 mL), and then extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 7-fluoro-2,2-dimethyl-2H-chromene-6-carboxaldehyde (1.35 g, crude product) as a yellow oily liquid. ESI-MS m / z=207[M+H] +

[0888]

[0889] To a stirred solution of 7-fluoro-2,2-dimethyl-2H-chromene-6-carboxaldehyde (1.35 g, 6.55 mmol) in DMSO (15 mL) at 120°C was added hydrazine hydrate (1.05 g, 32.75 mmol). The reaction solution was diluted with water (20 mL) and then extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 7,7-dimethyl-1,7-dihydropyrano[3,2-f]indazole (128 mg) as a yellow oil. 1 H NMR (400MHz, Chloroform-d) δ7.91(s,1H),7.30(s,1H),6.82(s,1H),6.43(d,J=9.9Hz,1H),5.68(d,J=9.9Hz,1H),1.44(s,6H).ESI-MS m / z=201[M+H] +

[0890] Step 4: Preparation of 2-(4-methoxymethoxy)-2-nitrophenyl)-7,7-dimethyl-2,7-dihydropyrano[3,2-f]indazole

[0891]

[0892] 7,7-dimethyl-1,7-dihydropyrano[3,2-f]indazole (100 mg, 0.50 mmol) and NaH (36 mg, 1.50 mmol) were added to a stirred solution of 1-fluoro-4-methoxymethoxy-2-nitrobenzene (100 mg, 0.50 mmol) in DMF (5 mL) at room temperature. The resulting mixture was stirred at 60 ° C for 3 hours under an argon atmosphere. The reaction solution was diluted with water (5 mL) and then extracted with ethyl acetate (10 mL). The organic layer was washed with saturated brine (5 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 2-(4-methoxymethoxy)-2-nitrophenyl)-7,7-dimethyl-2,7-dihydropyrano[3,2-f]indazole (32 mg, yield 17%) as a brown solid. 1H NMR(400MHz,Chloroform-d)δ8.01(d,J=1.0Hz,1H),7.67(d,J=2.8Hz,1H),7.59–7.56(m,1H),7.35(dd,J=8.8,2.8Hz,1H),7. 33(s,1H),6.72(d,J=0.9Hz,1H),6.44(d,J=9.9Hz,1H),5.69(d,J=9.9Hz,1H),5.27(s,2H),3.51(s,3H),1.43(s,6H).ESI-MS m / z=382[M+H] +

[0893]

[0894] Saturated ammonium chloride (0.5 mL) and zinc powder (55 mg, 0.84 mmol) were added to a stirred solution of 2-(4-methoxymethoxy)-2-nitrophenyl)-7,7-dimethyl-2,7-dihydropyrano[3,2-f]indazole (32 mg, 0.084 mmol) in MeOH / THF (1.5 mL / 0.5 mL) at room temperature. The resulting mixture was stirred overnight under an argon atmosphere. The reaction solution was filtered, diluted with ethyl acetate (10 mL), washed with saturated brine (5 mL), and the organic layer was dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC (PE: EtOAc = 1: 1) to give 2-(7,7-dimethylpyrano[3,2-f]indazole-2(7H)yl)-5-methoxymethoxyaniline (16 mg, 54% yield) as a brown solid. ESI-MS m / z=352[M+H] +

[0895] Step 6: Preparation of 3-methoxymethoxy-10,10-dimethyl-10H-benzo[5,6][1,2,4]triazine[4,3-b]pyrano[3,2-f]indazole

[0896]

[0897] To a stirred solution of 2-(7,7-dimethylpyrano[3,2-f]indazole-2(7H)yl)-5-methoxymethoxyaniline (16 mg, 0.045 mmol) in acetic acid (1 mL) was added a solution of sodium nitrite (3.1 mg, 0.045 mmol) in water (0.4 mL) at room temperature. The resulting mixture was stirred under an argon atmosphere for 4 hours. The reaction solution was neutralized with 5% NaOH and then extracted with ethyl acetate (10 mL). The organic layer was washed with saturated brine (5 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC (PE: EtOAc = 1: 1) to give 3-methoxymethoxy-10,10-dimethyl-10H-benzo[5,6][1,2,4]triazine[4,3-b]pyrano[3,2-f]indazole (10 mg, 61% yield) as an orange solid. ESI-MS m / z=363[M+H] +

[0898] Step 7: Preparation of 10,10-dimethyl-10H-benzo[5,6][1,2,4]triazine[4,3-b]pyrano[3,2-f]indazol-3-ol

[0899]

[0900] To a stirred solution of 9-methoxy-3-(methoxymethoxy)benzo[5,6][1,2,4]triazine[4,3-b]indazole (10 mg, 0.028 mmol) in MeOH (2 mL) at room temperature was added p-toluenesulfonic acid (10.6 mg, 0.056 mmol). The resulting mixture was stirred at 60°C for 4 hours under an argon atmosphere. The reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with saturated brine (5 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC (PE: EtOAc = 1: 1) to give 10,10-dimethyl-10H-benzo[5,6][1,2,4]triazine[4,3-b]pyrano[3,2-f]indazole-3-ol (5.3 mg, 60% yield) as an orange solid. 1 H NMR (400MHz, DMSO-d6) δ8.50(d,J=9.1Hz,1H),8.22(s,1H),7.84(d,J=2.6Hz,1H),7.63(dd,J= 9.1,2.6Hz,1H),7.25(s,1H),6.75(d,J=9.9Hz,1H),5.99(d,J=9.9Hz,1H),1.44(s,6H).ESI-MS m / z=319.16[M+H] + .

[0901] Embodiment 45

[0902] Preparation of 5,10,10-trimethyl-10H-chromeno[6',7':4,5]furo[3,2-c]quinolin-3(5H)-one (Compound E45)

[0903]

[0904]

[0905] Step 1: Preparation of 7-benzyloxy-4-chloroquinoline

[0906]

[0907] Potassium carbonate (414 mg, 3.0 mmol) and benzyl bromide (257 mg, 1.5 mmol) were added to a stirred solution of 4-chloroquinoline-7-ol (180 mg, 1.0 mmol) in DMF (7 mL) at room temperature. The resulting mixture was stirred at room temperature overnight under an argon atmosphere. The reaction solution was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The organic layer was washed with saturated brine (10 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 3: 1) to give 7-benzyloxy-4-chloroquinoline (210 mg, yield 78%) as a white solid. ESI-MS m / z = 270 [M+H] +

[0908] Step 2: Preparation of 7-benzyloxy-4-(6-bromo-2,2-dimethyl-2H-chromene-7-oxy)quinoline

[0909]

[0910] A solution of 7-benzyloxy-4-chloroquinoline (200 mg, 0.741 mmol), 6-bromo-2,2-dimethyl-2H-chromen-7-ol (188 mg, 0.741 mmol) and 4-dimethylaminopyridine (136 mg, 0.112 mmol) in chlorobenzene (8 mL) was stirred at 130°C until the reaction was complete as shown by thin layer chromatography. The cooled reaction mixture was diluted with 10% NaOH (5 mL). Stirred at room temperature for 1 h. The aqueous phase was extracted with DCM (3×5 mL). The combined organic layers were washed with 3N NaOH (3×5 mL), 1N HCl (2×5 mL), water (10 mL) and saturated brine (10 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography (PE: EtOAc = 3: 1) to give 7-benzyloxy-4-(6-bromo-2,2-dimethyl-2H-chromene-7-oxy)quinoline (335 mg, yield 92%) as a white solid. ESI-MS m / z = 488 [M+H] +

[0911] Step 3: Preparation of 3-benzyloxy-10,10-dimethyl-10H-benzopyrano[6',7':4,5]furo[3,2-c]quinoline

[0912]

[0913] To a stirred solution of 7-benzyloxy-4-(6-bromo-2,2-dimethyl-2H-chromene-7-oxy)quinoline (310 mg, 0.637 mmol) in N-methylpyrrolidone (5 mL) were added cesium carbonate (415 mg, 1.273 mmol) and palladium acetate (7.1 mg, 0.03 2 mmol). The resulting mixture was stirred at 135°C for 6 hours under an argon atmosphere. The reaction solution was diluted with DCM (5 mL) and filtered. The resulting filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 3: 1) to give 3-benzyloxy-10,10-dimethyl-10H-benzopyrano[6',7':4,5]furo[3,2-c]quinoline (108 mg, yield 42%) as a yellow solid. ESI-MS m / z = 408 [M+H] +

[0914] Step 4: Preparation of 3-benzyloxy-5,10,10-trimethyl-10H-benzopyrano[6',7':4,5]furo[3,2-c]quinolin-5-ium

[0915]

[0916] To a stirred solution of 3-benzyloxy-10,10-dimethyl-10H-benzopyrano[6',7':4,5]furano[3,2-c]quinoline (108 mg, 0.27 mmol) in acetone (10 mL) was added iodomethane (753 mg, 5.3 mmol) at reflux temperature. The resulting mixture was stirred overnight under an argon atmosphere. The reaction solution was filtered to give the product 3-benzyloxy-5,10,10-trimethyl-10H-benzopyrano[6',7':4,5]furano[3,2-c]quinolin-5-ium (130 mg) as a yellow solid. ESI-MS m / z=422[M] +

[0917] Step 5: Preparation of 3-benzyloxy-5,10,10-trimethyl-5,6-dihydro-10H-chromeno[6',7':4,5]furo[3,2-c]quinoline

[0918]

[0919] At 0°C, lithium aluminum hydride (0.331 mL, 1.0 M, in THF, 0.331 mmol) was added to a stirred solution of 3-benzyloxy-5,10,10-trimethyl-10H-benzopyrano[6',7':4,5]furano[3,2-c]quinolin-5-ium (70 mg, 0.166 mmol) in THF (10 mL). The reaction mixture was stirred at 0°C for 2 hours, ice water (5 mL) was added to quench the reaction, and extracted with EtOAc (2×15 mL). The combined organic layers were washed with saturated brine (20 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative TLC (PE:EtOAc=2:1) ​​to give 3-benzyloxy-5,10,10-trimethyl-5,6-dihydro-10H-chromeno[6',7':4,5]furo[3,2-c]quinoline (29 mg, yield 41%) as a yellow solid. ESI-MS m / z=424[M+H] +

[0920] Step 6: Preparation of 5,10,10-trimethyl-10H-chromeno[6',7':4,5]furo[3,2-c]quinolin-3(5H)-one

[0921]

[0922] To a stirred solution of 3-benzyloxy-5,10,10-trimethyl-5,6-dihydro-10H-chromeno[6',7':4,5]furo[3,2-c]quinoline (24 mg, 0.057 mmol) in DCM (2 mL) was added boron trichloride (0.171 mL, 1.0 M DCM solution, 0.171 mmol) at -78°C under argon atmosphere. The mixture was reacted for 5 minutes, then quenched by adding ice water (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with saturated brine (10 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Xbridge BEH C18 OBD column, 5uM, 10mm×250mm; mobile phase: [water (0.5% ammonia)-acetonitrile]; b%: 10%-90% within 20 minutes) to give 5,10,10-trimethyl-10H-chromeno[6',7':4,5]furo[3,2-c]quinolin-3(5H)-one (1.5 mg, yield 5%) as a white solid. 1 H NMR(400MHz, Methanol-d4)δ9.48(s,1H),8.38(d,J=9.2Hz,1H),7.73(s,1H),7.39(dd,J=9.1,2.0Hz, 1H),7.26–7.17(m,2H),6.55(d,J=9.9Hz,1H),5.83(d,J=9.9Hz,1H),4.39(s,3H),1.47(s,6H).ESI-MS m / z=332.20[M+H] + .

[0923] Test Example 1

[0924] Evaluation of the inhibitory activity of compounds on the STING signaling pathway in human cells

[0925] Experimental principle: 2'3'-cGAMP can specifically bind to STING and induce the multimerization activation of STING protein. The activated STING protein translocates from the endoplasmic reticulum to the Golgi apparatus. During this process, STING will recruit the kinase protein TBK1 and the transcription factor IRF3. The recruited IRF3 will then be phosphorylated by TBK1. The phosphorylated IRF3 dimerizes into the nucleus and induces the transcriptional expression of downstream type I interferon genes. Therefore, by detecting the effect of the compound on the phosphorylation level of IRF3 (p-IRF3 / IRF3) after 2'3'-cGAMP stimulation of HeLa cells (with complete STING pathway components), the inhibitory activity of the compound on STING can be indirectly characterized.

[0926] Experimental method: HeLa cells were cultured in a culture plate with DMEM complete medium (10% FBS, 1% streptomycin / penicillin) (37 degrees, 5% carbon dioxide incubator). The cells were passaged the day before the experiment, and when the cell density reached 80%, they were incubated overnight with the test compound at a working concentration of 10μM. The blank control was added with an equal amount of DMSO (final concentration 0.1%). After the incubation, the cells were treated with a digitonin solution containing 2'3'-cGAMP (1.5μg / mL) to promote the smooth entry of 2'3'-cGAMP into the cells. After 2 hours, the cells were lysed and collected with RIPA lysis buffer, and the supernatant was collected after centrifugation. Protein loading buffer was added, and SDS-PAGE electrophoresis was performed after boiling. After the electrophoresis, the SDS-PAGE gel, PVDF membrane and filter paper were made into a "sandwich" style, and electrophoresis was performed at 100V for 1 hour using the wet transfer method. After the electrophoresis, the PVDF membrane was blocked with skim milk powder for 1 hour to reduce nonspecific background. After blocking, use TBST to wash and remove the remaining blocking solution, and add the corresponding primary antibody to incubate it to fully bind to the target protein. After the primary antibody incubation is completed, wash it with TBST three times, then add the corresponding species and HRP-coupled secondary antibody, incubate for 1 hour, and wash it with TBST three times after the secondary antibody incubation is completed. Mix the A solution and B solution of the BCL reagent in equal proportions and incubate with the PVDF membrane for 30 seconds, then expose and develop it with an ultra-sensitive multifunctional imager (GE Healthcare, AI600) and analyze the results. Anti-IRF3 (CST, 4302), Anti-p-IRF3 (S386) (Abcam, ab76493), GAPDH (Proteintech, 10494-1-AP), Goat-anti-Rabbit-HRP (CST, 7074).

[0927] The experimental results are shown in Table 1.

[0928] Table 1. Inhibitory effects of compounds on IRF3 phosphorylation levels downstream of the STING signaling pathway in HeLa cells

[0929] Compound No. Inhibition rate (%) Compound No. Inhibition rate (%) Compound No. Inhibition rate (%) DMSO 0±0 E39 53±9 E8 42±13 E1 78±5 E2 63±11 E43 54±11 E11 27±2 E3 35±13 E9 17±4 E10 28±4 E24 63±16 E33 46±11 E12 22±3 E7 40±9 E32 47±21 E13 34±9 E4 43±11 E34 19±9 E14 21±5 E25 24±7 E35 13±3 E15 26±11 E22 45±13 E37 26±11 E6 37±9 E29 37±10 E41 28±4 E18 17±4 E5 45±21 E36 40±11 E17 48±15 E26 47±17 E38 23±9 E16 48±17 E40 5±2 E42 17±6 E19 67±14 E27 13±3 E44 18±9 E21 69±22 E23 13±5 E45 28±12 E31 67±10 E28 48±15 E20 56±11 E30 44±11

[0930] The experimental results show that the benzoheterocyclic compounds of the present invention can significantly inhibit the phosphorylation level of IRF3 downstream of the STING signaling pathway induced by 2'3'-cGAMP stimulation in human HeLa cells. This shows that the compounds of the present invention or their pharmaceutically acceptable salts or esters or solvent compounds can be used as new small molecule inhibitors targeting STING, which can effectively inhibit the activation of the STING signaling pathway and downstream signal transmission.

[0931] Test Example 2

[0932] Compound E1 alleviates autoinflammatory response in Trex1 knockout mice

[0933] In order to verify the effect of the compound of the present invention on autoinflammatory immune diseases, Trex1 knockout mice with spontaneous autoimmune diseases were used to verify the efficacy of the compound.

[0934] Experimental animals: Trex1 knockout mice and wild-type control mice of the same litter, 5 weeks old, were purchased from Guangzhou Saiye Experimental Animal Co., Ltd.

[0935] Drug preparation and modeling administration: After one week of exposure to the test environment, Trex1 knockout mice were randomly divided into a model group and an E1 compound intervention group, and a healthy control group of wild mice of the same litter was set up (n=6). The healthy control group and the model group were treated with Vehicle (10% DMSO + 10% solutol HS-50 + 80% saline) by intraperitoneal injection, and the E1 compound intervention group was treated with the set concentration of the test compound (E1, 10 mg / kg and 30 mg / kg), once a day for 14 consecutive days. After reaching the experimental endpoint, the mice were euthanized by cervical dislocation, and the heart, muscle, tongue and stomach of the same part were taken for dehydration and paraffin embedding to make sections and H&E staining to observe tissue pathological changes. At the same time, another part of the organ tissue of the same part of each mouse was taken for RNA extraction for gene level testing.

[0936] Experimental results: Trex1 knockout mice showed severe inflammatory responses in heart, muscle, tongue and stomach tissues. Compared with the placebo group, pathological section results showed that both 10mg / kg and 30mg / kg doses of E1 could significantly alleviate the symptoms of autoinflammatory diseases ( Figure 1 ) and histological scoring of pathological sections ( Figure 2 ). The mice were euthanized and their tissues were collected to test the expression of STING downstream effector genes and inflammatory genes in the tissues. Consistent with the results of pathological sections, E1 treatment was able to significantly reverse the abnormally elevated mRNA levels of Ifnβ, Cxcl10, Isg15, and Tnfα in Trex1 knockout mice ( Figure 3 ). The above data indicate that E1 has the potential to alleviate autoinflammatory diseases caused by excessive and abnormal activation of STING in vivo. Other compounds of the present invention also have similar in vivo therapeutic effects, which are not listed one by one due to space limitations.

[0937] Test Example 3

[0938] Compound E1 alleviates intestinal inflammation in IBD mice

[0939] In order to verify the effect of the compound of the present invention on intestinal inflammatory immune diseases, DSS-induced IBD disease mice were used to verify the efficacy of the compound.

[0940] Experimental animals: SPF-grade C57 male mice, 7 weeks old, were purchased from Beijing Weitonglihua Experimental Animal Co., Ltd.

[0941] Drug preparation and modeling and administration: After one week of adaptation, mice were randomly divided into healthy group, model group and E1 compound intervention group (n=6). Day0-day3, the healthy group and model group were treated with intraperitoneal vehicle (10% DMSO + 10% solutol HS-50 + 80% saline), and the drug intervention group was treated with the set concentration of the test compound (E1, 10 mg / kg and 30 mg / kg); day4-day13, while giving vehicle and drug treatment, the healthy group was given normal drinking water, and the model group and drug intervention group were given drinking water containing 2.5% DSS (MP biomedicals, MV36000-50000). The weight, stool shape and stool blood of each mouse were monitored once a day and scored. The scores of weight change, stool shape and stool occult blood were recorded as the disease activity index DAI (disease activity index) score. After reaching the experimental endpoint, the mice were euthanized by cervical dislocation and the serum was collected by centrifugation. The colon of the mice was removed, and the intestinal contents were removed after measuring the length. The intestines of the same part were dehydrated and embedded in paraffin to make sections and stained with H&E to observe intestinal pathological changes and score the degree of intestinal lesions. Another part of the colon of the same part of each mouse was taken for RNA extraction for gene level testing.

[0942] The above test method adopts the method in the document "Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease" (DOI: 10.1136 / gut.2010.212159).

[0943] Experimental results: Compared with the control group, 10mg / kg and 30mg / kg E1 could significantly alleviate the weight loss caused by DSS treatment ( Figure 4 ) and DAI rises ( Figure 5 DSS treatment significantly reduced colon length, and E1 intervention at 10 mg / kg and 30 mg / kg was able to reverse the pathological shortening of the colon ( Figure 6 ). Pathological section results showed that E1 treatment could reverse the intestinal tissue lesions induced by DSS treatment, including the fragmentation of intestinal villi, the loss of goblet cells and the infiltration of inflammatory cells ( Figure 7). Activation of the cGAS-STING pathway can induce the release of IFNβ, which is further accompanied by the production of interferon-stimulating factors such as Isg15 and Cxcl10. Consistent with literature reports, DSS treatment can significantly increase the mRNA levels of IFNβ, Isg15 and Cxcl10, while E1 treatment can reduce the transcription levels of these genes in a concentration-dependent manner ( Figure 8 ). At the same time, DSS stimulation can promote the production of various inflammatory factors including IL-6, IL-1β and TGF-β. The mRNA results showed that E1 intervention can alleviate the transcriptional levels of these inflammatory factors ( Fig. 9 The above results show that E1 has a good effect of relieving enteritis in vivo. Other compounds of the present invention and their pharmaceutically acceptable salts and stereoisomers also have similar in vivo therapeutic effects, which are not listed one by one due to space limitations.

[0944] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A benzoheterocyclic compound, a pharmaceutically acceptable salt or a stereoisomer thereof, characterized in that: It has the structure shown in general formula (I): Wherein, A represents O, N, or a substituted or unsubstituted alkylamino group; B represents CH2, CH, N, carbonyl, R a and R b R and R are each independently, the same or different, and represent one of hydrogen, deuterium, halogen, substituted or unsubstituted amino, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cyano-substituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or, R a With R b may be condensed or fused to form a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; X represents C or N; Y represents O, N, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted alkylamino; R 1 , R 2 and R 3 each independently, the same or different, represents one of hydrogen, deuterium, halogen, substituted or unsubstituted amino, hydroxyl, cyano, carboxyl, substituted or unsubstituted carboxylate, substituted or unsubstituted phosphate, substituted or unsubstituted carbamate, substituted or unsubstituted alkylcarbonyloxy, acyloxy, amide, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R 4 represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; or, Y and R 4 They may be condensed or fused to form a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

2. The benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer according to claim 1, characterized in that: In the general formula (I), A represents O, N or methylamino; B represents CH2, CH, N, carbonyl, Y represents O, N and methylamino; R 1 Represents hydrogen, hydroxyl, methoxy, amino, cyano, carboxyl, methyl carboxylate, methylamino, acetamido, acetoxy R 2 represents hydrogen, hydroxyl, F or Cl; R 3 Represents hydrogen or Cl.

3. The benzoheterocyclic compound, or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1 or 2, characterized in that: R 4 for It has a structure shown in general formula (II): R 5 represents hydrogen, deuterium, halogen, substituted or unsubstituted amino, hydroxyl, cyano, carboxyl, substituted or unsubstituted carboxylate, substituted or unsubstituted phosphate, substituted or unsubstituted carbamate, substituted or unsubstituted alkylcarbonyloxy, amide, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; preferably, R 5 represents hydrogen or Cl; R 6 and R 7 each independently, the same or different, represents hydrogen, deuterium, halogen, substituted or unsubstituted amino, hydroxyl, cyano, carboxyl, substituted or unsubstituted carboxylate, substituted or unsubstituted phosphate, substituted or unsubstituted carbamate, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkylcarbonyl, amide, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or, R 6 With R 7 may be condensed or fused to form a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; R 8 represents OH, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, or R 8 It can be condensed or fused with Y to form a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; Y represents one of O, N, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, and substituted or unsubstituted alkylamino; Among them, the R 1 , R 2 , R 3 , A, B, and X are consistent with the definitions of general formula (I); Preferably, the benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer has a structure shown in general formula (III) or (IV): Among them, the R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , A, B, X, and Y are consistent with the definitions of general formula (II).

4. The benzoheterocyclic compound, or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 3, characterized in that: It has a structure shown in general formula (V): L 1 represents O, N, NH or methylamino; L 2 represents CH, CH2 or carbonyl; W represents carbonyl, The R a and R b R and R are each independently, the same or different, and represent one of hydrogen, deuterium, halogen, substituted or unsubstituted amino, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cyano-substituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or, R a With R b may be condensed or fused to form a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; Preferably, W represents a carbonyl group, Among them, the R 1 , R 2 , R 3 , R 5 , A, B, and X are consistent with the definitions of general formula (I); the R 8 Consistent with the definition of general formula (II); Y represents O, N, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted alkylamino; Preferably, the benzoheterocyclic compound, its pharmaceutically acceptable salt or stereoisomer has a structure shown in the general formula (VI) or (VII): Among them, the R 1 , R 2 , R 3 , R 5 , A, B, X, and Y are consistent with the definitions of general formula (V).

5. The benzoheterocyclic compound, or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 4, characterized in that: It is any of the following compounds:

6. The method for preparing the benzoheterocyclic compound, the pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 5, characterized in that: In the structure represented by the general formula (III), when A is O, B is CH2, X is C and Y is O, the compound represented by the general formula (III) has the following synthesis route: The preparation method comprises the following steps: Step 1: 1.0 equivalent of compound 1, 1.6-4.0 equivalents of N,N-dimethylformamide dimethyl acetal and N,N-dimethylformamide solution are mixed and reacted at 80-100° C.; after the reaction is completed, the mixture is diluted with water and extracted with ethyl acetate, and the combined organic layer is washed, dried, filtered and concentrated under reduced pressure in sequence to obtain a crude product of compound 2; the crude product is purified by silica gel column chromatography to obtain a pure product of compound 2; preferably, the reaction time is 1-2 hours; Step 2: 1.0 equivalent of compound 2, chloroform solution and silica gel are mixed, and 1.1 to 1.5 equivalents of N-bromosuccinimide are added at 0°C, and then reacted at 0°C to room temperature; after the reaction is completed, the mixture is filtered and concentrated under reduced pressure, and then the residue is diluted with water and extracted with ethyl acetate, and the combined organic layer is washed, dried, filtered and concentrated under reduced pressure in sequence to obtain a crude product of compound 3; the crude product is purified by silica gel column chromatography to obtain a pure product of compound 3; preferably, the reaction time is 0.5 to 4 hours; Step 3: 1.0 equivalent of compound 3, 1,4-dioxane solution, 3.0 equivalents of bis(pinacol)diboron, 3.0 equivalents of potassium acetate and 0.05-0.20 equivalents of tetrakistriphenylphosphine palladium are mixed at room temperature, and reacted at 90-100° C. under an inert gas atmosphere; after the reaction is completed, the mixture is filtered through diatomaceous earth, and the filtrate is concentrated under reduced pressure to obtain compound 4; preferably, the reaction time is 6-16 hours; Step 4: Add 1.0 equivalent of compound 8 or 9, 3.0 equivalents of potassium carbonate and 0.05-0.20 equivalents of tetrakistriphenylphosphine palladium to 1.5-3.0 equivalents of 1,4-dioxane and aqueous solution of the compound 4 at room temperature, and react at 80-100° C. under an inert gas atmosphere; after the reaction, dilute with water and extract with ethyl acetate; wash, dry, filter and concentrate the combined organic layer in turn to obtain a crude product of compound 5; purify the crude product by a reverse phase column to obtain a pure product of compound 5; preferably, the reaction time is 3-12 hours; Step 5: Mix 1.0 equivalent of compound 5, tetrahydrofuran solution, and 1.0 to 6.0 equivalents of 1.0 M hexane solution of diisobutylaluminum hydride at -10°C, and react at -20 to -10°C; quench with a saturated aqueous solution of Rochelle salt, and extract with ethyl acetate; wash, dry, filter, and concentrate under reduced pressure the combined organic layer to obtain a crude product of compound 6; purify the crude product by silica gel column chromatography to obtain a pure product of compound 6; preferably, the reaction time is 2 to 4 hours; Step six: Mix 1.0 equivalent of compound 6, methanol, and 2.0 to 10.0 equivalents of toluenesulfonic acid, and react at 50 to 65°C; quench with aqueous sodium bicarbonate solution, and extract with ethyl acetate; wash, dry, filter and concentrate the combined organic layers in turn to obtain a crude product of compound 7; purify the crude product by silica gel column chromatography to obtain a pure compound 7; preferably, the reaction time is 2 to 12 hours.

7. A pharmaceutical composition, characterized in that It contains the benzoheterocyclic compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or stereoisomer thereof; Preferably, the pharmaceutical composition further contains one or more pharmaceutically acceptable carriers, diluents or excipients.

8. Use of the benzoheterocyclic compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt or stereoisomer, or the pharmaceutical composition according to claim 7 in the preparation of a STING inhibitor drug, a drug for preventing and treating STING-mediated diseases, or an immune adjuvant drug.

9. A drug for preventing and treating STING-mediated diseases, characterized in that: A pharmaceutical composition comprising the benzoheterocyclic compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt or stereoisomer thereof, or claim 7; Preferably, the drug for preventing and treating STING-mediated diseases is a STING inhibitor drug.

10. An immune adjuvant drug, characterized in that: A pharmaceutical composition comprising the benzoheterocyclic compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition according to claim 7.

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