Aromatic hydrocarbon receptor modulator compound as well as preparation method and application thereof

Abstract

The invention relates to aromatic hydrocarbon receptor modulator compounds represented by the following formula I, respective optical isomers, deuterated compounds, prodrugs or pharmaceutically acceptable salts thereof, and a preparation method and application of the aromatic hydrocarbon receptor modulator compounds and the optical isomers, the deuterated compounds, the prodrugs or the pharmaceutically acceptable salts thereof. The compound can be used as an aromatic hydrocarbon receptor regulator for regulating the activity of an aromatic hydrocarbon receptor in a body, and has very important significance on treatment of related diseases such as immunity, inflammation, infection, skin diseases, osteoporosis, cancers and neurodegenerative diseases.

Description

Aryl hydrocarbon receptor modulator compounds and their preparation methods and applications

[0001] This application claims the priority benefit of the Chinese invention patent application with application number 202311351389.X filed with the State Intellectual Property Office of China on October 18, 2023, entitled “Aryl hydrocarbon receptor modulator compounds, preparation methods and applications thereof”. The entire contents of this application are hereby incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of biopharmaceutical technology, and specifically relates to a class of aromatic hydrocarbon receptor modulator compounds, their respective optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts, and their preparation methods and applications. Background Art

[0003] Aryl hydrocarbon receptor (AHR) is a member of the bHLH-PAS (bHLH-PER-ARNT-SIM) subfamily of the basic helix-loop-helix (bHLH) superfamily and is the only receptor in the bHLH-PAS family that can be activated by ligands [Murray et al., Nat. Rev. Cancer, 2014, 14(12), 801-814; Berstenetal., Nat. Rev. Cancer, 2013, 13(12), 827-841]. The AHR present in the cytoplasm can be stimulated by aromatic hydrocarbon xenobiotics, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and then migrate into the cell nucleus to form a heterodimer with the aryl hydrocarbon receptor nuclear translocator (ARNT). The AHR / ARNT complex then interacts with the xenobiotic response element (XRE) upstream of the AHR-regulated gene, thereby regulating the transcription of the corresponding gene; AHR can also activate non-XRE-dependent protein-protein interaction pathways.

[0004] The AHR pathway is one of the best-understood mechanisms for binding environmental toxins and inducing metabolism, such as regulated cytochrome CYP450 enzymes (e.g., CYP1A1, CYP1A2, and CYP1B1), which metabolize environmental toxins [(Reyes et al., Science, 1992, 256(5060), 1193-1195; Murray et al., Nat. Rev. Cancer, 2014, 14(12), 801-814]. Activation of the AHR by environmental toxins has been shown to play a role in numerous cellular processes, such as embryonic development, tumorigenesis, and inflammation. The AHR is expressed in many cells of the immune system, including dendritic cells, macrophages, T-cells, and NK cells, and plays an important role in immune regulation (Nguyen et al., 2001). al., Front. Immunol., 2014, 5, 511). Classic exogenous AHR ligands such as TCDD induce profound immunosuppression, promote cancer occurrence and induce tumor growth [Gramatzki et al., Oncogene, 2009, 28(28), 2593-2605; Buie et al., Oncogene, 2009, 28(41), 3642-3651; Esser et al., Trends. Immunol., 2009, 30(9), 447-454].

[0005] Through XRE-dependent or independent activities, AHR regulates many key innate and adaptive immune responses. Studies have found that some AHR agonists promote the differentiation of Th17 cells (T-helper cells) and the secretion of IL-17. Other AHR agonists can induce the horizontal differentiation of Th17 cells into Treg cells, enhancing the suppressive activity of Treg [Quintana et al., Nature, 2008, 453(7191), 65-71; Mezrich et al., J. Immunol., 2010, 185(6), 3190-3198;]. Studies have shown that AHR activation can inhibit the innate inflammatory response regulated by macrophages (for example, reducing the expression of IL-1b, IL-6, IL-12 and TNF-α induced by lipopolysaccharide (LPS)) and inhibit dendritic cells (reducing the activation of dendritic cells and promoting the expression of IL-10) [Kimura et al., J. Exp. Med., 2009, 206(9), 2027-2035; Wang et al., Clin. Exp. Immunol., 2014, 177(2), 521-530; Wei et al., Lab. Invest., 2014, 94(5), 528-535; Nguyen et al., Proc. Natl. Acad. Sci. USA, 2010, 107(46), 19961-19966].

[0006] Whether a compound is an aryl hydrocarbon receptor modulator can be determined by testing whether it upregulates the expression levels of downstream related genes (such as CYP1A1, CYP1B1) and related proteins (such as CYP1A1, CYP1B1) through signaling pathways. By modulating the aryl hydrocarbon receptor signaling pathway, the activity of related xenobiotic-metabolizing enzymes in downstream target genes (such as CYP1A1, CYP1A2, and CYP1B1) can be modulated. Modulating aryl hydrocarbon receptor activity also has a significant impact on the composition and activity of immune cells in the body. Therefore, regulating aryl hydrocarbon receptor activity is of great significance for the treatment of diseases related to immunity, inflammation, infection, skin diseases, osteoporosis, cancer, and neurodegenerative diseases.

[0007] Summary of the Invention

[0008] Therefore, according to the first aspect of the present invention, an object of the present invention is to provide a class of aromatic hydrocarbon receptor modulator compounds represented by the following formula I, and their respective optical isomers, deuterated substances, prodrugs or pharmaceutically acceptable salts:

[0009] wherein R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C 1-8 Alkenyl, substituted or unsubstituted C 1-8 Alkynyl, wherein the "substituted" refers to a group containing 1-6 R a Substituents, where R a Selected from hydrogen, deuterium, halogen, OR a1 、S(O)nR a2 NR a3 R a4 、CO2R a5 ;

[0010] Among them, R a1 and R a2 Each independently selected from hydrogen, hydroxy, amino, C1-C8 alkyl, C3-C8 cycloalkyl, -C(=O)C 1-8 Alkyl, -C(=O)C3-C8 cycloalkyl, -C(=O)OC1-C8 alkyl, -C(=O)OC3-C8 cycloalkyl, -C(=O)NC1-C8 alkyl, -C(=O)NC3-C8 cycloalkyl;

[0011] R a3 and R a4 Each is independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxy, C3-C6 cycloalkyl substituted by halogen or hydroxy, C1-C3 alkoxy, C3-C6 cycloalkoxy, C1-C3 alkoxy substituted by halogen or hydroxy, C3-C6 cycloalkoxy substituted by halogen or hydroxy;

[0012] R a5 Selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl;

[0013] R3 is hydrogen, deuterium, halogen, NR b3 R b4 , substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C3-C 12 Cycloalkyl, substituted or unsubstituted C 1-10 Alkenyl, substituted or unsubstituted C 1-10 Alkynyl, C6-C 14 aryl, substituted or unsubstituted 5- to 14-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted 4- to 14-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to a 5- to 14-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to a 5- to 14-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to a 5- to 14-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to a 5- to 14-membered heteroaryl ... b Substituents, where R b Selected from hydrogen, deuterium, halogen, ORb1 、S(O)nR b2 NR b3 R b4 、CO2R b5 ;

[0014] Among them, R b1 and R b2 Each independently selected from hydrogen, hydroxy, amino, C1-C8 alkyl, C3-C8 cycloalkyl, -C(=O)C 1-8 Alkyl, -C(=O)C3-C8 cycloalkyl, -C(=O)OC1-C8 alkyl, -C(=O)OC3-C8 cycloalkyl, -C(=O)NC1-C8 alkyl, -C(=O)NC3-C8 cycloalkyl;

[0015] R b3 and R b4 Each is independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxy, C3-C6 cycloalkyl substituted by halogen or hydroxy, C1-C3 alkoxy, C3-C6 cycloalkoxy, C1-C3 alkoxy substituted by halogen or hydroxy, C3-C6 cycloalkoxy substituted by halogen or hydroxy;

[0016] R b5 Selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl;

[0017] R4 and R4' are hydrogen, deuterium, halogen, hydroxyl, C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 Alkenyloxy, C3-C 10 Cycloalkyl, C 3-10 Cycloalkoxy, C 3-10 Cycloalkenyloxy, (C 1-8 Alkoxy) C 1-8 Alkoxy, (C 2-8 alkenyl)C 1-8 Alkoxy, (C 2-8 Alkynyl)C 1-8 Alkoxy, C6-C 14 Aryl, boronic acid, borate ester;

[0018] Alternatively, R4 or R4' may form a ring with R3 to form a substituted or unsubstituted C3-C8 cycloalkyl group or a 4- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S and B, wherein the "substituted" refers to a group containing 1 to 6 R a1 ;

[0019] A ring is C 6-14Aryl, 5-14 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, substituted or unsubstituted 5-14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S; wherein the "substituted" refers to a 5-14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; c Substituents, where R c is selected from hydrogen, deuterium, halogen, cyano, hydroxy, carbonyl, carboxyl, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxy, C3-C6 cycloalkyl substituted by halogen or hydroxy, C1-C3 alkoxy, C3-C6 cycloalkyloxy, C1-C3 alkoxy substituted by halogen or hydroxy, C3-C6 cycloalkyloxy substituted by halogen or hydroxy, NR c1 R c2 、CO2R c3 , where R c1 and R c2 are each independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxy, C3-C6 cycloalkyl substituted by halogen or hydroxy, C1-C3 alkoxy, C3-C6 cycloalkyloxy, C1-C3 alkoxy substituted by halogen or hydroxy, C3-C6 cycloalkyloxy substituted by halogen or hydroxy, R c3 Selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl;

[0020] R 5 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carbonyl, carboxyl, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C3-C6 cycloalkoxy, C1-C3 alkyl substituted by halogen or hydroxyl, C3-C6 cycloalkyl substituted by halogen or hydroxyl, C1-C3 alkoxy substituted by halogen or hydroxyl, C3-C6 cycloalkoxy substituted by halogen or hydroxyl, NR d1 R d2 、CO2R d3 , where R d1 and R d2 are each independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxy, C3-C6 cycloalkyl substituted by halogen or hydroxy, C1-C3 alkoxy, C3-C6 cycloalkyloxy, C1-C3 alkoxy substituted by halogen or hydroxy, C3-C6 cycloalkyloxy substituted by halogen or hydroxy, R d3 Selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl.

[0021] However, the following compounds are not included:

[0022] Preferably, R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C 1-6Alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C 1-6 Alkenyl, substituted or unsubstituted C 1-6 Alkynyl, wherein the "substituted" refers to a group containing 1-4 R a Substituents, where R a Selected from hydrogen, deuterium, halogen, OR a1 、S(O)nR a2 NR a3 R a4 、CO2R a5 ;

[0023] Among them, R a1 and R a2 Each independently selected from hydrogen, hydroxy, amino, C1-C6 alkyl, C3-C6 cycloalkyl, -C(=O)C 1-6 Alkyl, -C(=O)C3-C6 cycloalkyl, -C(=O)OC1-C6 alkyl, -C(=O)OC3-C6 cycloalkyl, -C(=O)NC1-C6 alkyl, -C(=O)NC3-C6 cycloalkyl;

[0024] R a3 and R a4 Each is independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxy, C3-C6 cycloalkyl substituted by halogen or hydroxy, C1-C3 alkoxy, C3-C6 cycloalkoxy, C1-C3 alkoxy substituted by halogen or hydroxy, C3-C6 cycloalkoxy substituted by halogen or hydroxy;

[0025] R a5 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl;

[0026] Preferably, R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0027] Preferably, R3 is hydrogen, deuterium, halogen, NR b3 R b4 , substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C 1-8 Alkenyl, substituted or unsubstituted C 1-8 Alkynyl, C6-C 10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted 4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to a 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to a 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to a 5- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to a 5- to 10-membered heteroaryl ...b Substituents, where R b Selected from hydrogen, deuterium, halogen, OR b1 、S(O)nR b2 NR b3 R b4 、CO2R b5 ;

[0028] Among them, R b1 and R b2 Each independently selected from hydrogen, hydroxy, amino, C1-C6 alkyl, C3-C6 cycloalkyl, -C(=O)C 1-6 Alkyl, -C(=O)C3-C6 cycloalkyl, -C(=O)OC1-C6 alkyl, -C(=O)OC3-C6 cycloalkyl, -C(=O)NC1-C6 alkyl, -C(=O)NC3-C6 cycloalkyl;

[0029] R b3 and R b4 Each is independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxy, C3-C6 cycloalkyl substituted by halogen or hydroxy, C1-C3 alkoxy, C3-C6 cycloalkoxy, C1-C3 alkoxy substituted by halogen or hydroxy, C3-C6 cycloalkoxy substituted by halogen or hydroxy;

[0030] R b5 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl.

[0031] Preferably, R3 is hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dimethylcyclohexyl, vinyl, propenyl, butenyl, 3-methyl-2-butenyl.

[0032] Preferably, R4 and R4' are hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Cycloalkenyloxy, (C 1-6 Alkoxy) C 1-6 Alkoxy, (C 2-6 alkenyl)C 1-6 Alkoxy, (C 2-6 Alkynyl)C 1-6 Alkoxy, C6-C 14 Aryl, boronic acid, borate ester.

[0033] Preferably, R4 and R4' are hydrogen, deuterium, halogen, hydroxyl, C1- C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, boronic acid, borate ester.

[0034] Preferably, R4 and R4' are hydrogen, deuterium, halogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, boronic acid, or borate ester.

[0035] Preferably, R4 and R4' are hydrogen or deuterium.

[0036] Preferably, R4 or R4' can form a ring with R3 to form a substituted or unsubstituted C3-C6 cycloalkyl group or a 4-8 membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S and B, wherein the "substituted" refers to a group containing 1-4 R a1 .

[0037] Preferably, R4 or R4' can form a ring with R3 to form a substituted or unsubstituted C3-C6 cycloalkyl group or a 4- to 6-membered heterocyclic group containing 1 to 2 heteroatoms selected from N, O, S and B, wherein the "substituted" refers to a group containing 1-3 R a1 .

[0038] Preferably, ring A is C 6-10 Aryl, 5-10 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, substituted or unsubstituted 5-10 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O and S; wherein the "substituted" refers to a 5-4 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S. c Substituents, where R c is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carbonyl, carboxyl, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxyl, C3-C6 cycloalkyl substituted by halogen or hydroxyl, C1-C3 alkoxy, C3-C6 cycloalkyloxy, C1-C3 alkoxy substituted by halogen or hydroxyl, C3-C6 cycloalkyloxy substituted by halogen or hydroxyl, NR c1 R c2 、CO2R c3 , where R c1 and R c2 Each is independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxy, C3-C6 cycloalkyl substituted by halogen or hydroxy, C1-C3 alkoxy, C3-C6 cycloalkoxy, C1-C3 alkoxy substituted by halogen or hydroxy, C3-C6 cycloalkoxy substituted by halogen or hydroxy, R c3 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl.

[0039] Preferably, Ring A is:

[0040] Preferably, R5 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carbonyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, -C(=O)Omethyl, -C(=O)Oethyl, -C(=O)On-propyl, -C(=O)Oisopropyl.

[0041] Preferably, the compound represented by formula I can be represented by the following formula IIa, formula IIb or formula IIc,

[0042] wherein R1 to R4, R4' are the same as those defined in the above formula I;

[0043] A1 and A4 are each independently selected from C, N, O and S atoms, and A2 and A3 are each independently selected from C or N atoms, provided that at most two of A1 to A4 are heteroatoms selected from N, O and S, and the other two are C atoms.

[0044] dotted line Indicates that there may be a double bond at that position.

[0045] R6, R7 and R8 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, carbonyl, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted by halogen or hydroxy, C3-C8 cycloalkyl substituted by halogen or hydroxy, C1-C6 alkoxy, C3-C8 cycloalkyloxy, C1-C6 alkoxy substituted by halogen or hydroxy, C3-C8 cycloalkyloxy substituted by halogen or hydroxy;

[0046] One or more R6 can form a C3-C6 cycloalkyl group with A4, a 3-7 membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S; one or more R7 can form a C3-C6 cycloalkyl group with A3, a 3-7 membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S;

[0047] R d is selected from hydrogen, halogen, hydroxy, carboxyl, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted by halogen, C1-C6 alkoxy, C3-C8 cycloalkyloxy;

[0048] n1 and n2 are each independently an integer of 0, 1 or 2;

[0049] n3 is an integer of 0, 1, 2, 3 or 4.

[0050] Preferably, R6, R7 and R8 are each independently selected from hydrogen, halogen, hydroxy, carboxyl, carbonyl, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxy, C3-C6 cycloalkyl substituted by halogen or hydroxy, C1-C3 alkoxy, C3-C6 cycloalkyloxy, C1-C3 alkoxy substituted by halogen or hydroxy, C3-C6 cycloalkyloxy substituted by halogen or hydroxy;

[0051] Preferably, R6, R7 and R8 are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, carbonyl, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

[0052] Preferably, one or more R6 can form a C3-C6 cycloalkyl group or a 3-6 membered heterocyclic group containing 1 to 2 heteroatoms selected from N, O and S with A4, and one or more R7 can form a C3-C6 cycloalkyl group or a 3-6 membered heterocyclic group containing 1 to 2 heteroatoms selected from N, O and S with A3.

[0053] Preferably, R d is selected from hydrogen, halogen, hydroxy, carboxyl, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen, C1-C3 alkoxy, C3-C6 cycloalkyloxy;

[0054] Preferably, R d Selected from hydrogen, halogen, hydroxy, carboxyl, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

[0055] Preferably, n1 and n2 are each independently an integer of 0, 1 or 2;

[0056] Preferably, n3 is an integer of 0, 1 or 2.

[0057] Preferably, the compound represented by formula I can be represented by the following formula IIIa or IIIb,

[0058] wherein R1 to R4, R4' are the same as those defined in the above formula I;

[0059] A1 to A6 are each independently selected from C, N, O and S atoms, and A2 is a C or N atom, provided that at most two of A1 to A6 are heteroatoms selected from N, O and S, and the rest are C atoms.

[0060] dotted line Indicates that there may be a double bond at that position.

[0061] R9 are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, carbonyl, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, C6-C 14 Aryl, C6-C substituted by halogen 14 Aryl, -C(=O)OC1-C8 alkyl, 5- to 10-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, 5- to 10-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O and S;

[0062] n4 is an integer of 0, 1, 2, 3 or 4.

[0063] Preferably, R8 and R9 are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, carbonyl, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C6-C substituted by halogen 10 Aryl, -C(=O)OC1-C6 alkyl, 5- to 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, 5- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O and S.

[0064] Preferably, R9 is independently selected from hydrogen, halogen, hydroxyl, carboxyl, carbonyl, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, carbomethoxy, carboethoxy, n-propyl carbomethoxy, isopropyl carbomethoxy, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl.

[0065] Preferably, n4 is an integer of 0, 1 or 2.

[0066] Preferably, the compound represented by formula I is selected from the following compounds:

[0067] According to the second aspect of the present invention, another object of the present invention is to provide a pharmaceutical composition, which comprises a therapeutically effective amount of an aromatic hydrocarbon receptor modulator compound represented by Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IIIa or Formula IIIb according to the present invention, its respective optical isomers, deuterated substances, prodrugs or pharmaceutically acceptable salts and a pharmaceutically acceptable excipient or carrier.

[0068] According to the third aspect of the present invention, another object of the present invention is to provide an aromatic hydrocarbon receptor modulator compound represented by Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IIIa or Formula IIIb according to the present invention, and a compound Use of respective optical isomers, deuterated substances, prodrugs or pharmaceutically acceptable salts thereof as AHR pathway regulators.

[0069] According to the fourth aspect of the present invention, another object of the present invention is to provide an aromatic hydrocarbon receptor modulator compound represented by Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IIIa or Formula IIIb according to the present invention, and a compound Use of respective optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts thereof in preparing drugs for treating tumors related to the AHR pathway.

[0070] According to the fifth aspect of the present invention, another object of the present invention is to provide a method for treating tumors associated with the AHR pathway, the method comprising administering to a subject in need thereof an effective amount of an aryl hydrocarbon receptor modulator compound represented by Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IIIa or Formula IIIb according to the present invention, and a compound Their respective optical isomers, deuterated substances, prodrugs or pharmaceutically acceptable salts or the pharmaceutical composition according to the present invention.

[0071] According to the sixth aspect of the present invention, another object of the present invention is to provide an aromatic hydrocarbon receptor modulator compound represented by Formula I, Formula IIa, Formula IIb, Formula IIc, Formula IIIa or Formula IIIb according to the present invention, and a compound A method for preparing respective optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts thereof, wherein the method is selected from the following synthesis methods A, B or C; the method can adopt conventional synthesis methods, for example, coupling borate esters, boric acids or alkynes with halides in the presence of a metal palladium catalyst and 1-3 equivalents of an inorganic base such as potassium phosphate or potassium carbonate or an organic base such as triethylamine to synthesize the compounds of the present invention:

[0072] Synthesis method A:

[0073] This method can be carried out with reference to the coupling reaction method disclosed in the prior art (LW Lawrence Woo et al., J. Med. Chem., 2010, 53(5), 2155-2170);

[0074] Synthesis method B:

[0075] This method can be carried out with reference to the coupling reaction method disclosed in the prior art (Florence F. Wagner et al., Org. Lett., 2006, 8(16), 3549-3552);

[0076] Synthesis method C:

[0077] This method can be carried out with reference to the coupling reaction method disclosed in the prior art (Jean-Cyrille Hierso et al., Tetrahedron, 2005, 61(41), 9759-9766);

[0078] The substituents R1 to R4, R4', Q2, X and ring A in the above-mentioned synthesis methods A, B and C are the same as those defined in formula I. DETAILED DESCRIPTION

[0079] The present invention will be described in detail below. Before describing, it should be understood that the terms used in this specification and the appended claims should not be interpreted as limited to the general meaning and dictionary meaning, but should be interpreted according to the meaning and concept corresponding to the technical aspects of the present invention on the basis of the principle that allows the inventor to appropriately define the terms for the best interpretation. Therefore, the descriptions presented here are merely preferred examples for illustrative purposes and are not intended to limit the scope of the present invention. It should be understood that other equivalents or improvements can be obtained therefrom without departing from the spirit and scope of the present invention.

[0080] Throughout this document, all features or conditions defined as numerical ranges or percentage ranges are for simplicity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered to encompass and specifically disclose all possible subranges and individual values ​​within those ranges, particularly integer values. For example, descriptions of a range "1 to 8" should be considered to specifically disclose all possible subranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, and so forth, particularly those defined by all integer values, and should be considered to specifically disclose individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, and 8. Unless otherwise indicated, the foregoing interpretation applies to all of the present disclosure, regardless of whether the ranges are comprehensive or not.

[0081] If a quantity or other value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that all ranges consisting of any upper limit or preferred value of the range and any lower limit or preferred value of the range have been specifically disclosed herein, regardless of whether these ranges are disclosed separately. In addition, when a numerical range is mentioned herein, unless otherwise specified, the range should include its endpoints and all integers and fractions within the range.

[0082] In this document, numerical values ​​should be understood to have the accuracy of the number of significant digits of the numerical value, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

[0083] In this document, where Markush groups or optional terms are used to describe features or embodiments of the present invention, those skilled in the art will appreciate that any combination of all subgroups or individual elements within the Markush group or optional list can also be used to describe the present invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," this fully describes the claim that X is X1 and the claim that X is X1 and / or X2. Furthermore, where Markush groups or optional terms are used to describe features or embodiments of the present invention, those skilled in the art will appreciate that any combination of all subgroups or individual elements within the Markush group or optional list can also be used to describe the present invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," this fully describes the claim that X is X1, X2, or X3, and Y is Y1, Y2, or Y3.

[0084] definition

[0085] "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 C 1-6Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl) and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of alkyl is independently unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., halogen, such as F). In certain embodiments, alkyl groups are unsubstituted C 1-8 In certain embodiments, the alkyl group is a substituted C 1-8 Alkyl (eg, substituted C1 alkyl, such as -CF3).

[0086] "Alkoxy" refers to a monovalent -O-alkyl group, wherein the alkyl moiety has a specified number of carbon atoms. In the present disclosure, alkoxy groups typically contain 1-8 carbon atoms ("C1 to C8 alkoxy"), 1-6 carbon atoms ("C1 to C6 alkoxy"), or 1-4 carbon atoms ("C1-C4 alkoxy"). For example, C1-C4 alkoxy includes methoxy, ethoxy, isopropoxy, tert-butyloxy, and the like. Unless otherwise indicated, each instance of alkoxy is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkoxy") or substituted ("substituted alkoxy") with one or more substituents. In certain embodiments, alkoxy is an unsubstituted C1 to C6 alkoxy. In certain embodiments, alkoxy is a substituted C1 to C6 alkoxy.

[0087] "Cycloalkyl" refers to a non-aromatic ring system having 3 to 8 ring carbon atoms ("C 3-8 A cycloalkyl group can be a single ring (a "monocyclic group") or a fused, bridged, or spiro ring system, such as a bicyclic ring system (a "bicyclic group"), and can be saturated or partially unsaturated. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a cycloalkyl group has 5 to 8 ring carbon atoms ("C 5-8 "cycloalkyl"). Exemplary C 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3-8Cycloalkyl groups include but are not limited to the above C 3-6 Cycloalkyl groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), etc. Unless otherwise specified, each instance of cycloalkyl is independently optionally substituted, i.e., unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In certain embodiments, cycloalkyl is unsubstituted C 3-8 Cycloalkyl; in certain embodiments, cycloalkyl is substituted C 3-8 Cycloalkyl.

[0088] "Heterocycloalkyl" refers to a group of a 4 to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("4-14 membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom as long as valence permits. A heterocyclic group may be a monocyclic ring ("monocyclic heterocyclic group") or a fused ring, bridged ring or spirocyclic ring system, such as a bicyclic system ("bicyclic heterocyclic radical"), and may be saturated or partially unsaturated. "Heterocyclic group" also includes a ring system in which a heterocycle as defined above is fused to one or more cycloalkyl groups (wherein the point of attachment is on the cycloalkyl group or the heterocycle), or a ring system in which a heterocycle as defined above is fused to one or more aryl or heteroaryl groups (wherein the point of attachment is on the heterocycle), and in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclic system. Unless otherwise specified, each instance of a heterocycloalkyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heterocycloalkyl") or substituted (a "substituted heterocycloalkyl") with one or more substituents. In certain embodiments, heterocycloalkyl is an unsubstituted 4-14 membered heterocycloalkyl. In certain embodiments, heterocycloalkyl is a substituted 4-14 membered heterocycloalkyl.

[0089] "Aryl" or "aromatic ring" or "aromatic ring group" refers to a group having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system, which is a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array) ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl"; for example, anthracenyl). "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more cycloalkyl or heterocyclic groups, wherein the point of attachment is on the aromatic ring, and in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system. Unless otherwise specified, each instance of aryl is independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, aryl is unsubstituted C 6-14 In certain embodiments, aryl is a substituted C 6-14 Aryl.

[0090] “Heteroaryl” is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, a heteroaryl group is an unsubstituted 5-10 membered heteroaryl group. In certain embodiments, a heteroaryl group is a substituted 5-10 membered heteroaryl group.

[0091] "Halogen" or "halo" refers to fluorine (F, -F), chlorine (Cl, -Cl), bromine (Br, -Br), or iodine (I, -I).

[0092] "Substituted" or "optionally substituted" refers to the atoms in the group, such as hydrogen atoms are replaced. In certain embodiments, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted (e.g., "substituted" alkyl, "substituted" cycloalkyl, "substituted" heterocycloalkyl, "substituted" aryl, or "substituted" heteroaryl). Typically, the term "substituted", whether or not there is the term "optionally" before, means that at least one hydrogen present on a group (e.g., carbon or nitrogen atom) is replaced by a permissible substituent, such as a substituent that forms a stable compound after replacement, such as a compound that does not spontaneously transform (e.g., by rearrangement, cyclization, elimination or other reactions). Unless otherwise indicated, a "substituted" group has a substituent on one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is the same or different at each position. It is contemplated that the term "substituted" includes replacing with all permissible substituents of an organic compound, any substituent described herein that results in the formation of a stable compound. The present disclosure contemplates any and all of these combinations to obtain stable compounds. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatoms and result in the formation of a stable moiety. In certain embodiments, the substituents are carbon atom substituents. In certain embodiments, the substituents are nitrogen atom substituents. In certain embodiments, the substituents are oxygen atom substituents. In certain embodiments, the substituents are sulfur atom substituents.

[0093] In this document, when multiple substitutions exist in a defined substituent, there may be repeated definitions in the textual description of such multiple substitutions, but such description should be understood to at least conform to the basic rules of general medicinal chemistry. For example, when a substituent has repeated definitions, those skilled in the art can determine whether such repetition is feasible or infeasible based on general medicinal chemistry knowledge and make a reasonable choice.

[0094] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0095] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared by reacting a compound having a specific substituent discovered by the present invention with a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt (i.e., a pharmaceutically acceptable salt) can be obtained by contacting the neutral form of such compound with a sufficient amount of an acid in a pure solution or a suitable inert solvent. Examples include inorganic acid salts and organic acid salts. The inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, etc.; the organic acid includes, for example, benzoic acid, 2-hydroxyethanesulfonic acid, aminosulfonic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid The present invention also includes salts of amino acids (such as arginine) and organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain basic and acidic functional groups and can be converted into either base or acid addition salts. The parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

[0096] As used herein, the modifier term "about" refers to variations in values ​​that may occur, for example, through routine testing and processing; through inadvertent errors in such testing and processing; through differences in the manufacture, origin, or purity of the ingredients used in the present invention; and the like. As used herein, "about" a particular value also includes that particular value, for example, "about 10%" includes 10%. Whether or not modified by the term "about," the claims include equivalents of the recited quantities. In one embodiment, the term "about" means within 20% of the reported value.

[0097] As used herein, the term "treating" refers to eliminating, alleviating or ameliorating a disease or condition and / or symptoms associated therewith. Although not excluded, treating a disease or condition does not require the complete elimination of the disease, condition or symptoms associated therewith. As used herein, the term "treatment" and the like may include "prophylactic treatment," which refers to reducing the likelihood of re-development of a disease or condition or recurrence of a previously controlled disease or condition in a subject who is not or is at risk of developing or susceptible to a disease or condition or recurrence of a disease or condition. The term "treating" and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

[0098] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0099] The AHR pathway-related diseases according to the present invention include, but are not limited to, tumors, immune diseases, and neurodegenerative diseases related to the AHR pathway.

[0100] The following examples are merely examples of embodiments of the present invention and do not constitute any limitation thereto. Those skilled in the art will appreciate that modifications without departing from the spirit and scope of the present invention fall within the scope of protection of the present invention. Unless otherwise specified, the reagents and instruments used in the following examples are commercially available products.

[0101] Example 1

[0102] Step 1: Synthesis of compound 1-A

[0103] To a solution of 2-bromo-1,3-dimethoxybenzene (30 g, 138.2 mmol) in 1,4-dioxane (300 mL) and water (75 mL) were added sodium carbonate (43.9 g, 414.6 mmol), isopropenylboronic acid pinacol ester (30.2 g, 179.6 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (5.06 g, 6.91 mmol). The reaction was stirred at 100°C overnight. LCMS confirmed the reaction was complete. The mixture was cooled and concentrated under reduced pressure. Ethyl acetate (600 mL) and water (100 mL) were added, and the mixture was separated by extraction. The organic phase was washed three times with saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product 1,3-dimethoxy-2-isopropenyl-benzene (1-A) (2.3 g, 12.9 mmol, yield 9.34%) as a colorless oil. LCMS (ESI): [M+H] + =179.4.

[0104] Step 2: Synthesis of Compound 1-B

[0105] 1,3-Dimethoxy-2-isopropenyl-benzene (1-A) (2.3 g, 12.9 mmol) was dissolved in methanol (15 mL), and 10% palladium on carbon (180 mg, 0.17 mmol) was added. The reaction was stirred at room temperature for 2 hours under hydrogenation. LCMS confirmed the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford the product, 1,3-dimethoxy-2-isopropyl-benzene (1-B) (1.9 g, 10.54 mmol, 81.6% yield), as a colorless oil. 1 H NMR (400MHz, CDCl3): δ7.10 (t, J = 8.4Hz, 1H), 6.55 (d, J = 8.4Hz, 2H), 3.81 (s, 6H), 3.67-3.56 (m, 1H), 1.29 (d, J = 7.2Hz, 6H).

[0106] Step 3: Synthesis of Compound 1-C

[0107] To a solution of 1,3-dimethoxy-2-isopropyl-benzene (1-B) (1.9 g, 10.54 mmol) in tetrahydrofuran (40 mL) were added pinacol diboron (3.2 g, 12.65 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (0.28 g, 1.05 mmol), and methoxy(cyclooctadiene)iridium dimer (0.35 g, 0.53 mmol). The reaction mixture was heated to 80°C and stirred overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to afford 2-[3,5-dimethoxy-4-(isopropyl)-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1-C) (2.30 g, 7.51 mmol, 71.2% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ6.84 (s, 2H), 3.76 (s, 6H), 3.62-3.48 (m, 1H), 1.29 (s, 12H), 1.20 (d, J = 7.2Hz, 6H).

[0108] Step 4: Synthesis of compound 1-D

[0109] 2-[3,5-Dimethoxy-4-(isopropyl)-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1-C) (300 mg, 0.98 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL). 3-Bromo-2H-chromen-2-one (264 mg, 1.17 mmol), potassium carbonate (406 mg, 2.94 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (71.6 mg, 0.098 mmol) were added. The mixture was heated to 100°C and stirred overnight. LCMS confirmed the reaction was complete. The mixture was cooled, filtered, and concentrated under reduced pressure. Ethyl acetate (80 mL) and water (10 mL) were then added to dilute the mixture. The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product 3-[3,5-dimethoxy-4-(isopropyl)-phenyl]-2-hydrogen-chromen-2-one (1-D) (174 mg, 0.536 mmol, yield 54.7%) as a white solid. 1HNMR (400MHz, DMSO-d6): δ8.31(s,1H),7.78(dd,J=7.6,1.6Hz,1H),7.63(dd,J=4.8,3.6Hz,1H),7.45(d,J= 8.4Hz, 1H), 7.40 (dd, J = 7.6, 0.8Hz, 1H), 7.00 (s, 2H), 3.82 (s, 6H), 3.64-3.51 (m, 1H), 1.25 (d, J = 7.2Hz, 6H).

[0110] Step 5: Synthesis of compound 1

[0111] 3-[3,5-Dimethoxy-4-(isopropyl)-phenyl]-2-hydrogen-chromen-2-one (1-D) (174 mg, 0.536 mmol) was dissolved in dichloromethane (5 mL) and a 1 M boron tribromide / dichloromethane solution (3.22 mL, 3.22 mmol) was slowly added at -30°C. The reaction was slowly warmed to room temperature and stirred overnight. LCMS confirmed the reaction was complete. The reaction solution was cooled to 0°C, and water (1 mL) and dichloromethane (5 mL) were added, resulting in the appearance of a solid. The reaction solution was concentrated under reduced pressure and diluted with water (5 mL) and ethyl acetate (60 mL). The organic phase was separated and washed three times with saturated sodium chloride solution (10 mL), dried, and concentrated under reduced pressure. Dichloromethane (5 mL) was added to the residue and stirred at room temperature for 10 minutes. The filter cake was collected by filtration, washed with dichloromethane, and dried in vacuo to give 3-[3,5-dihydroxy-4-(isopropyl)-phenyl]-2-hydrogen-chromen-2-one (1) (100 mg, 0.337 mmol, yield 62.9%) as a white solid. LCMS (ESI): [M+H] + =297.2; 1 H NMR (400MHz, DMSO-d6): δ9.18 (s, 2H), 8.05 (s, 1H), 7.78 (dd, J = 7.6, 1.2Hz, 1H), 7.67- 7.54(m,1H),7.48-7.29(m,2H),6.63(s,2H),3.54-3.41(m,1H),1.26(d,J=7.2Hz,6H).

[0112] Example 2

[0113] Step 1: Synthesis of compound 2-A

[0114] 2-[3,5-Dimethoxy-4-(isopropyl)-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1-C) (300 mg, 0.98 mmol) was dissolved in 1,4-dioxane (12 mL) and water (2 mL). Potassium carbonate (406 mg, 2.94 mmol), 3-bromo-4-hydrogen-chromen-4-one (287 mg, 1.27 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (72 mg, 0.098 mmol) were added, and the mixture was stirred at 100°C overnight. LCMS confirmed the reaction was complete. The reaction system was cooled to room temperature, concentrated under reduced pressure, and diluted with ethyl acetate (80 mL) and water (10 mL). The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product 3-[3,5-dimethoxy-4-(isopropyl)-phenyl]-4-hydrogen-chromen-4-one (2-A) (191 mg, 0.589 mmol, yield 60.1%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ8.60(s,1H),8.15(d,J=1.6Hz,1H),7.84(s,1H),7.71(d,J=8.4Hz,1 H), 7.53 (s, 1H), 6.86 (s, 2H), 3.80 (d, J = 2.8Hz, 6H), 3.62-3.51 (m, 1H), 1.24 (d, J = 7.2Hz, 6H).

[0115] Step 2: Synthesis of compound 2

[0116] 3-[3,5-Dimethoxy-4-(isopropyl)-phenyl]-4-hydrogen-chromen-4-one (2-A) (174 mg, 0.536 mmol) was dissolved in dichloromethane (5 mL) and 1 M boron tribromide / dichloromethane solution (3.22 mL, 3.22 mmol) was slowly added at -30°C. The reaction was stirred at -30°C for 30 minutes and then at room temperature overnight. LCMS confirmed the reaction was complete. The reaction system was cooled to 0°C and diluted with dichloromethane (80 mL) and water (10 mL). The organic phase was washed with saturated sodium chloride solution (10 mL), dried, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product 3-[3,5-dihydroxy-4-(isopropyl)-phenyl]-4-hydrogen-chromen-4-one (2) (87 mg, 0.293 mmol, 59.5% yield) as a white solid. LCMS(ESI):[M+H] + =297.2; 1H NMR (400MHz, DMSO): δ9.11(s,2H),8.38(s,1H),8.14(dd,J=8.0,1.6Hz,1H),7.82(ddd,J=8.8,7.2,1.6Hz,1H ),7.67(d,J=8.4Hz,1H),7.58-7.45(m,1H),6.46(s,2H),3.47(dt,J=14.0,7.2Hz,1H),1.26(d,J=7.2Hz,6H).

[0117] The compounds in Table 1 below were synthesized according to the similar procedures as in Example 1 or Example 2.

[0118] Table 1

[0119] Example 3

[0120] Step 1: Synthesis of compound 3-A

[0121] 4-Bromo-3,5-dihydroxybenzoic acid (45.0 g, 193 mmol) was dissolved in methanol (500 mL) and concentrated sulfuric acid (18.5 mL, 348 mmol) was slowly added dropwise with stirring. The reaction was stirred and refluxed at 70 ° C for 16 hours. LCMS detected that the reaction was complete. The reaction solution was concentrated under reduced pressure, the residue was diluted with water (250 mL), and the aqueous phase was extracted four times with ethyl acetate (250 mL). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product 4-bromo-3,5-dihydroxybenzoic acid methyl ester (3-A) (45 g, 182 mmol, yield 94.3%) as an off-white solid. LCMS (ESI): [M+H] + =249.0; 1 H NMR (400MHz, DMSO-d6): δ10.45(s,2H),7.01(s,2H),3.80(s,3H).

[0122] Step 2: Synthesis of compound 3-B

[0123] Methyl 4-bromo-3,5-dihydroxybenzoate (3-A) (25 g, 101 mmol) was dissolved in dichloromethane (250 mL), and N,N-diisopropylethylamine (41.8 mL, 253 mmol) was added. After stirring at 0°C for 5 minutes, methoxymethyl bromide (31.6 g, 253 mmol) was slowly added dropwise. After the addition was complete, the reactants were stirred at 25°C for 3 hours. LCMS confirmed the reaction was complete. The reaction solution was slowly poured into water (250 mL) to quench the mixture, and the aqueous phase was extracted three times with ethyl acetate (500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the product, methyl 4-bromo-3,5-bis[(methoxymethyl)oxy]benzoate (3-B) (28 g, 83.5 mmol, yield 82.6%), as an off-white solid. LCMS (ESI): [M+H] + =335.3; 1 H NMR (400MHz, DMSO-d6): δ7.48(s,2H),5.30(s,4H),3.91(s,3H),3.53(s,6H).

[0124] Step 3: Synthesis of compound 3-C

[0125] The experimental method is the same as that of 1-C: From methyl 4-bromo-3,5-bis[(methoxymethyl)oxy]benzoate (3-B) (12 g, 35.8 mmol) and 2-propenylboronic acid pinacol ester (9.02 g, 53.7 mmol), methyl 3,5-bis[(methoxymethyl)oxy]-4-(2-propenyl)benzoate (3-C) (6 g, 20.2 mmol, yield 56.4%) was obtained as a colorless oil. LCMS (ESI): [M+H] + =297.2; 1 H NMR (400MHz, DMSO-d6): δ7.46(s,2H),5.36-5.31(m,1H),5.21(s,4H),4.92-4.85(m,1H),3.90(s,3H),3.47(s,6H),2.04(s,3H).

[0126] Step 4: Synthesis of compound 3-D

[0127] Same method as 1-D: From 3,5-bis[(methoxymethyl)oxy]-4-(2-propenyl)benzoic acid methyl ester (5 g, 16.8 mmol), the product 3,5-bis[(methoxymethyl)oxy]-4-isopropyl-benzoic acid methyl ester (3-D) (4.6 g, 15.4 mmol, yield 91.4%) was obtained as a colorless oil. LCMS (ESI): [M+H] + =299.2; 1H NMR (400MHz, DMSO-d6): δ7.41 (s, 2H), 5.23 (s, 4H), 3.88 (s, 3H), 3.68 (p, J = 7.2Hz, 1H), 3.50 (s, 6H), 1.32 (d, J = 7.2Hz, 6H).

[0128] Step 5: Synthesis of compound 3-E

[0129] 3,5-bis[(methoxymethyl)oxy]-4-isopropyl-benzoic acid methyl ester (3-D) (3g, 10mmol) was dissolved in tetrahydrofuran (20mL) and slowly added dropwise to a suspension of lithium aluminum tetrahydride (1.14g, 30.2mmol) in tetrahydrofuran (20mL) under ice bath. The reaction was stirred at 0°C under nitrogen protection for 2 hours. LCMS detection showed that the reaction was complete. Sodium sulfate decahydrate (2.5g) was added to the reaction to quench the reaction. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the product 3,5-bis[(methoxymethyl)oxy]-4-isopropyl-benzyl alcohol (3-E) (2.6g, 9.6mmol, yield 95.7%) as an off-white solid. LCMS (ESI): [M+H] + =271; 1 H NMR (400MHz, DMSO-d6): δ6.80-6.74(m,2H),5.20-5.14(m,4H),4.60(s,2H),3.70-3.60(m,1H),3.48(s,6H),1.31(d,J=7.2Hz,6H).

[0130] Step 6: Synthesis of compound 3-F

[0131] 3,5-Bis[(methoxymethyl)oxy]-4-isopropyl-benzyl alcohol (3-E) (2.6 g, 9.6 mmol) was dissolved in dichloromethane (25 mL), cooled to 0°C, and Dess-Martin reagent (4.90 g, 11.5 mmol) was added under nitrogen. The temperature was naturally raised to room temperature and stirred for 2 hours. LCMS confirmed the completion of the reaction. The reaction was quenched by the addition of saturated aqueous sodium thiosulfate (25 mL) and saturated aqueous sodium bicarbonate (25 mL). The reaction system was extracted three times with ethyl acetate (100 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the product 3,5-bis[(methoxymethyl)oxy]-4-isopropyl-benzaldehyde (3-F) (2.2 g, 8.2 mmol, yield 85.2%) as an off-white solid. LCMS (ESI): [M+H] + =269.0; 1H NMR (400MHz, DMSO-d6): δ9.87 (s, 1H), 7.27 (s, 2H), 5.25 (s, 4H), 3.75-3.66 (m, 1H), 3.50 (s, 6H), 1.33 (d, J = 7.2Hz, 6H).

[0132] Step 7: Synthesis of Compound 3-G

[0133] 3,5-bis[(methoxymethyl)oxy]-4-isopropyl-benzaldehyde (3-F) (800 mg, 3 mmol) was dissolved in anhydrous methanol (10 mL), and dimethyl (1-diazo-2-oxopropyl)-phosphonate (0.9 mL, 6 mmol) and potassium carbonate (825 mg, 6 mmol) were added. The mixture was stirred at 25°C for 16 hours. LCMS showed that the reaction was complete, and the reaction was quenched with saturated brine (10 mL) and filtered. The filtrate was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the product 1,3-bis[(methoxymethyl)oxy]-5-ethynyl-2-isopropyl-benzene (3-G) (720 mg, 2.7 mmol, yield 91.4%) as a light yellow solid. LCMS (ESI): [M+H] + =265; 1 H NMR (400MHz, DMSO-d6): δ6.91 (s, 2H), 5.16 (s, 4H), 3.62 (dt, J = 14.0, 6.8Hz, 1H), 3.48 (s, 6H), 2.99 (s, 1H), 1.30 (d, J = 7.2Hz, 6H).

[0134] Step 8: Synthesis of compound 3-H

[0135] Dissolve 1,3-bis((methoxymethyl)oxy)-5-ethynyl-2-isopropyl-benzene (3-G) (260 mg, 0.98 mmol) in anhydrous toluene (10 mL). Add 2-iodobenzyl alcohol (345 mg, 1.48 mmol), cuprous iodide (19 mg, 0.1 mmol), triphenylphosphine (38 mg, 0.15 mmol), bis(triphenylphosphine palladium dichloride) (12 mg, 0.02 mmol), and triethylamine (2.05 mL, 14.8 mmol). Heat at 80°C under nitrogen for 18 hours. LCMS analysis indicates the reaction is complete. The reaction solution is diluted with ethyl acetate (50 mL) and filtered. The filtrate is washed three times with saturated sodium chloride solution (10 mL). The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product. The crude product was purified by column chromatography to give 2-({3,5-bis[(methoxymethyl)oxy]-4-isopropyl-phenyl}ethynyl)benzyl alcohol (3-H) (280 mg, 0.76 mmol, 76.8% yield) as a light yellow solid. LCMS (ESI): [M+H] + =371; 1 H NMR (400MHz, DMSO-d6): δ7.86-7.77(m,2H),7.67(qd,J=6.8,2.4Hz,2H),7.62-7.56(m,2H), 5.52(s,4H),5.22(s,2H),3.97(dt,J=14.4,7.2Hz,1H),3.82(s,6H),1.64(d,J=7.2Hz,6H).

[0136] Step 9: Synthesis of compound 3-J

[0137] 2-({3,5-bis[(methoxymethyl)oxy]-4-isopropyl-phenyl}ethynyl)benzyl alcohol (3-H) (260 mg, 0.7 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and palladium acetate (32 mg, 0.14 mol) was added. The mixture was stirred at 25°C under nitrogen for 24 hours. LCMS analysis showed that the reaction was complete. The reaction system was diluted with ethyl acetate (20 mL) and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the product 3-{3,5-bis[(methoxymethyl)oxy]-4-isopropyl-phenyl}-1-hydro-2-benzopyran (3-J) (110 mg, 0.3 mmol, yield 42.3%). LCMS (ESI): [M+H] + =371; 1H NMR (400MHz, DMSO-d6): δ7.26 (td, J=7.2, 1.6Hz, 1H), 7.21-7.13 (m, 3H), 7.07 (s, 2H), 6.6 3(s,1H),5.26(s,4H),5.18(s,2H),3.65-3.55(m,1H),3.41(s,6H),1.28(d,J=7.2Hz,6H).

[0138] Step 10: Synthesis of compound 3

[0139] 3-{3,5-di[(methoxymethyl)oxy]-4-isopropyl-phenyl}-1-hydrogen-2-benzopyran (3-J) (110 mg, 0.3 mmol) was dissolved in anhydrous tetrahydrofuran (2.5 mL), cooled to 0°C in an ice bath, and 4M hydrogen chloride / dioxane solution (2.5 mL) was slowly added dropwise. Under nitrogen protection, the mixture was naturally warmed to room temperature and stirred for 2.5 hours. The reaction was monitored by TLC to be complete. Under an ice-water bath, saturated sodium bicarbonate solution (5 mL) was slowly added dropwise to neutralize the mixture. The aqueous phase was separated and extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep-HPLC (0.1% formic acid addition) to obtain the product 3-(3,5-dihydroxy-4-isopropyl-phenyl)-1-hydrogen-2-benzopyran (3) (3 mg, 0.01 mmol, yield 3.6%) as a white solid. LCMS(ESI):[M+H] + =283; 1 H NMR (400MHz, DMSO-d6): δ9.16 (s, 2H), 7.24 (td, J=6.8, 2.4Hz, 1H), 7.15 (q, J=7.6Hz, 3H), 6 .64(s,2H),6.32(s,1H),5.14(s,2H),3.44(dd,J=14.0,7.2Hz,1H),1.23(d,J=7.2Hz,6H).

[0140] Example 4

[0141] Step 1: Synthesis of compound 4-A

[0142] 4-Isopropyl-3,5-bis[(methoxymethyl)oxy]benzaldehyde (3-F) (100 mg, 0.37 mmol) was dissolved in ethanol (1.5 mL), and 2'-hydroxyacetophenone (53 mg, 0.39 mmol) was added. The mixture was cooled to 0°C and stirred for 10 minutes, followed by the dropwise addition of 40% aqueous sodium hydroxide solution (0.4 mL, 5.6 mmol). The reaction system was stirred at 25°C for 18 hours, and the reaction was complete by LCMS. The reaction system was adjusted to pH 2 with 6M hydrochloric acid and filtered. The filter cake was washed five times with 2 mL of water. The filter cake was collected and purified by column chromatography to yield the product, E-1-(2-hydroxyphenyl)-3-{4-isopropyl-3,5-bis[(methoxymethyl)oxy]}prop-2-en-1-one (4-A) (90 mg, 0.233 mmol, 62.4% yield), as a yellow solid. LCMS (ESI): [M+H] + =387; 1 H NMR (400MHz, CDCl3): δ12.9(s,1H),7.97-7.88(m,1H),7.84(d,J=15.6Hz,1H),7.55(d,J=15.6Hz,1H),7.52-7.46(m,1H),7. 09(s,2H),7.02(d,J=8.4Hz,1H),6.95(t,J=7.6Hz,1H),5.25(s,4H),3.75-3.60(m,1H),3.52(s,6H),1.34(d,J=7.2Hz,6H).

[0143] Step 2: Synthesis of compound 4

[0144] E-1-(2-hydroxyphenyl)-3-{4-isopropyl-3,5-di[(methoxymethyl)oxy]}prop-2-en-1-one (4-A) (90 mg, 0.233 mmol) was dissolved in dimethyl sulfoxide (10 mL), iodine (60 mg, 0.233 mmol) was added, and the mixture was stirred at 140°C for 3 hours. LCMS showed that the reaction was complete. The reaction solution was slowly poured into water (150 mL) to quench the mixture, and the aqueous phase was extracted three times with ethyl acetate (150 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep-HPLC (with 0.1% formic acid) to obtain the product 2-[(3,5-dihydroxy-4-isopropyl)phenyl]-4-hydro-chromen-4-one (4) (14 mg, 0.047 mmol, yield 20.3%) as an off-white solid. LCMS (ESI): [M+H] + =297,[2M+Na] + =615; 1H NMR (400MHz, DMSO-d6): δ9.56(brs,2H),8.08-8.03(m,1H),7.84(t,J=6.8Hz,1H),7.66(d,J=8.4Hz,1H ),7.51(t,J=7.6Hz,1H),6.90(d,J=1.6Hz,2H),6.56(s,1H),3.55-3.45(m,1H),1.26(d,J=7.2Hz,6H).

[0145] Example 5

[0146] Step 1: Synthesis of compound 5-A

[0147] To a solution of (2E)-3-{3,5-bis[(methoxymethyl)oxy]-4-(isopropyl)-phenyl}-1-(2-hydroxyphenyl)prop-2-en-1-one (4-A) (500 mg, 1.29 mmol) in methanol (5 mL) at 0°C was added 20% sodium hydroxide solution (1.29 mL, 6.46 mmol). 30% hydrogen peroxide (366 mg, 3.23 mmol) was then added dropwise at 0°C. The reaction mixture was stirred at 0°C for 1 hour and then at room temperature overnight. LCMS confirmed the reaction was complete. The reaction mixture was cooled to 0°C and diluted with water (10 mL) and ethyl acetate (80 mL). The organic phase was separated, washed with saturated sodium chloride solution (10 mL), dried, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product 2-{3,5-bis[(methoxymethyl)oxy]-4-(isopropyl)-phenyl}-3-hydroxy-4-hydrogen-chromen-4-one (5-A) (368 mg, 0.92 mmol, yield 71%) as a colorless oil. 1 H NMR (400MHz, DMSO-d6): δ9.54(s,1H),8.11(dd,J=8.0,1.6Hz,1H),7.83-7.76(m,1H),7.72(d,J=8.0Hz, 1H), 7.60 (s, 2H), 7.52-7.42 (m, 1H), 5.28 (s, 4H), 3.71-3.58 (m, 1H), 3.44 (s, 6H), 1.32 (d, J = 7.2Hz, 6H).

[0148] Step 2: Synthesis of compound 5

[0149] 2-{3,5-bis[(methoxymethyl)oxy]-4-(isopropyl)phenyl}-3-hydroxy-4-hydrogen-chromen-4-one (5-A) (150 mg, 0.375 mmol) was dissolved in methanol (5 mL) and concentrated hydrochloric acid (0.1 mL, 1.2 mmol) was added. The reaction was stirred at 50°C for 30 minutes. LCMS confirmed the reaction was complete. The reaction mixture was cooled and concentrated under reduced pressure. The reaction mixture was diluted with ethyl acetate (80 mL) and water (10 mL). The organic phase was separated, washed with saturated sodium chloride solution (10 mL), dried, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give 2-[3,5-dihydroxy-4-(isopropyl)-phenyl]-3-hydroxy-4-hydrogen-chromen-4-one (5) (56 mg, 0.18 mmol, 47.9% yield) as a white solid. LCMS (ESI): [M+H] + =313.2; 1 H NMR(400MHz,DMSO-d6)δ9.38(d,J=9.6Hz,3H),8.11(dd,J=8.0,1.2Hz,1H),7.84-7.76(m,1H),7 .61(d,J=8.2Hz,1H),7.52-7.42(m,1H),7.19(s,2H),3.54-3.44(m,1H),1.27(d,J=7.2Hz,6H).

[0150] Example 6

[0151] Step 1: Synthesis of compound 6-A

[0152] Concentrated H2SO4 (38 mL) was added to water (10 mL), the temperature was raised to 80°C, methyl 3,5-dimethoxybenzoate (10 g, 50.9 mmol) was added, and then isopropanol (3.95 mL, 50.9 mmol) was added dropwise at 80°C. The mixture was stirred at 80°C for 1.5 hours. The reaction was complete after LCMS detection. Water (10 mL) and ethyl acetate (80 mL) were added to the reaction system, and the organic phase was separated. The organic phase was washed with saturated sodium chloride solution (10 mL), dried and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the product 3,5-dimethoxy-4-isopropyl-benzoic acid (6-A) (9.9 g, 44.1 mmol, yield 86.6%), a colorless oil. 1 H NMR (400MHz, DMSO-d6): δ12.85 (s, 1H), 7.15 (s, 2H), 3.80 (s, 6H), 3.62-3.50 (m, 1H), 1.22 (d, J = 7.2Hz, 6H).

[0153] Step 2: Synthesis of compound 6-B

[0154] 3,5-Dimethoxy-4-isopropyl-benzoic acid (6-A) (500 mg, 2.23 mmol) and thionyl chloride (5 mL) were mixed and stirred at 80°C for 2 hours. The reaction system was concentrated under reduced pressure to obtain the crude product 3,5-dimethyl-4-isopropyl-benzoyl chloride (6-B) (520 mg, 1.7 mmol, 76.9% yield), which was used directly in the next reaction without purification.

[0155] Step 3: Synthesis of compound 6-C

[0156] 3,5-Dimethoxy-4-isopropyl-benzoyl chloride (6-B) (520 mg, 2.14 mmol) was dissolved in dichloromethane (5 mL), and 2-acetylphenol (438 mg, 3.21 mmol) and triethylamine (0.893 mL, 6.43 mmol) were added. The mixture was stirred at 0°C for 2 hours. LCMS confirmed the reaction was complete. The reaction system was cooled and concentrated under reduced pressure, then diluted with dichloromethane (80 mL) and water (10 mL). The organic phase was separated, washed with saturated sodium chloride solution (10 mL), dried, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the product, 3,5-dimethoxy-4-(isopropyl)benzoic acid 2-acetylphenol ester (6-C) (520 mg, 1.52 mmol, 70.9% yield), as a yellow oil. 1 H NMR (400MHz, DMSO-d6): δ7.96(dd,J=7.6,1.6Hz,1H),7.72-7.66(m,1H),7.50-7.42(m,1H),7.35(dd,J=8. 0,0.8Hz,1H),7.32(s,2H),3.85(s,6H),3.62(dd,J=14.0,7.2Hz,1H),2.52(s,3H),1.26(d,J=7.2Hz,6H).

[0157] Step 4: Synthesis of compound 6-D

[0158] 2-Acetylphenol 3,5-dimethoxy-4-(isopropyl)benzoate (6-C) (420 mg, 1.23 mmol) was dissolved in pyridine (4 mL), sodium hydroxide (73.6 mg, 1.84 mmol) was added, and the mixture was stirred at 50°C for 3 hours. The reaction was complete by LCMS. The pH was adjusted to <7 with 1N hydrochloric acid. The reaction was diluted with ethyl acetate (80 mL) and water (10 mL), and the organic phase was separated, washed with saturated sodium chloride solution (10 mL), dried, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product 1-[3,5-dimethoxy-4-(isopropyl)-phenyl]-3-(2-hydroxyphenyl)propane-1,3-dione (6-D) (257 mg, 0.75 mmol, yield 61%) as a colorless oil. LCMS (ESI): [MH] - =341.1.

[0159] Step 5: Synthesis of compound 6-E

[0160] 1-[3,5-dimethoxy-4-(isopropyl)-phenyl]-3-(2-hydroxyphenyl)propane-1,3-dione (6-D) (297 mg, 0.867 mmol) was dissolved in acetonitrile (10 mL), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (369 mg, 1.04 mmol) was added, and the mixture was stirred at room temperature overnight. Sulfuric acid (0.083 mL, 1.56 mmol) was then added to the reaction mixture, and stirring was continued at room temperature for 1 hour. LCMS detection showed that the reaction was complete. The reaction mixture was diluted with ethyl acetate (80 mL) and water (10 mL), and the organic phase was separated. The organic phase was washed with saturated sodium chloride solution (10 mL), dried, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product 2-(2-fluoro-4-isopropyl-3,5-dimethoxyphenyl)-4-hydrogen-chromen-4-one (6-E) (72 mg, 0.21 mmol, yield 24.2%) as a colorless oil. LCMS (ESI): [M+H] + =343.1.

[0161] Step 6: Synthesis of compound 6

[0162] To a solution of 2-(2-fluoro-4-isopropyl-3,5-dimethoxyphenyl)-4-hydrogen-chromen-4-one (6-E) (72 mg, 0.21 mmol) in dichloromethane (2 mL) was slowly added 1 M boron tribromide / dichloromethane solution (0.84 mL, 0.84 mmol) at -30°C. The reaction system was stirred at -30°C for 30 minutes and then at room temperature for 3 hours. LCMS confirmed the reaction was complete. The mixture was cooled to 0°C, and dichloromethane (70 mL) and water (10 mL) were added. The organic phase was separated, washed with saturated sodium chloride solution (10 mL), dried, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product, 2-(2-fluoro-3,5-dihydroxy-4-isopropylphenyl)-4-hydrogen-chromen-4-one (6) (17.4 mg, 0.055 mmol, 26.3% yield), as a white solid. LCMS(ESI):[M+H] + =315.2; 1 H NMR (400MHz, DMSO-d6): δ9.58(d,J=19.2Hz,2H),8.06(dd,J=8.0,1.6Hz,1H),7.88-7.82(m,1H),7.65(d,J= 8.0Hz,1H),7.57-7.47(m,1H),6.81(d,J=5.6Hz,1H),6.65(s,1H),3.56-3.46(m,1H),1.28(d,J=7.2Hz,6H); 19 F NMR (400MHz, DMSO-d6): δ-145.65.

[0163] Example 7

[0164] Step 1: Synthesis of compound 7-A

[0165] 5-Bromo-1,3-dimethoxybenzene (4.8 g, 22.1 mmol) and benzofuran-2-boronic acid pinacol ester (4.5 g, 18.4 mmol) were dissolved in tetrahydrofuran (130 mL) and water (130 mL). Tetrakis(triphenylphosphine)palladium (1.06 g, 0.92 mmol) and potassium carbonate (9 g, 65.1 mmol) were added and reacted at 90°C for 18 hours. LCMS confirmed the reaction was complete. The reaction system was diluted with ethyl acetate (300 mL) and filtered. The filter cake was washed three times with 100 mL of ethyl acetate. The combined organic phases were concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 2-(3,5-dimethoxyphenyl)benzofuran (7-A) (4.3 g, 16.9 mmol, 91.7% yield). LCMS (ESI): [M+H] + =255; 1H NMR (400MHz, CDCl3): δ7.60-7.51(m,2H),7.32-7.27(m,1H),7.26-7.21(m,1H), 7.04(d,J=2.4Hz,2H), 7.02(d,J=1.2Hz,1H), 6.48(t,J=2.4Hz,1H), 3.88(s,6H).

[0166] Step 2: Synthesis of compound 7-B

[0167] 2-(3,5-Dimethoxyphenyl)benzofuran (7-A) (2.0 g, 7.87 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0°C in an ice-water bath, and 2.5 M n-butyllithium / tetrahydrofuran solution (3.78 mL, 9.44 mmol) was slowly added dropwise with stirring for 30 minutes. The reaction system was cooled to -78°C, and 0.6 M iodine / tetrahydrofuran solution (16.4 mL, 9.83 mmol) was slowly added dropwise. The temperature was naturally raised to 25°C and the reaction was allowed to proceed for 1.5 hours. TLC confirmed the reaction was complete. The reaction system was quenched by the slow addition of saturated ammonium chloride solution (25 mL), and extracted three times with 30 mL of ethyl acetate. The combined organic phases were concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain 2-(4-iodo-3,5-dimethoxyphenyl)benzofuran (7-B) (1.35 g, 4.82 mmol, 61.3% yield). LCMS(ESI):[M+H] + =281,[M+Na] + =403; 1 H NMR (400MHz, CDCl3): δ7.62-7.50 (m, 2H), 7.35-7.29 (m, 1H), 7.25-7.22 (m, 1H), 7.10 (d, J = 0.8Hz, 1H), 7.01 (s, 2H), 4.00 (s, 6H).

[0168] Step 3: Synthesis of compound 7-C

[0169] 2-(4-iodo-3,5-dimethoxyphenyl)benzofuran (7-B) (250 mg, 0.66 mmol) was dissolved in toluene (5 mL). Cyclopropylboronic acid (565 mg, 6.6 mmol), tetrakis(triphenylphosphine)palladium (76 mg, 0.066 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (48 mg, 0.066 mmol), potassium phosphate (2.09 g, 9.85 mmol), tricyclohexylphosphine (37 mg, 0.132 mmol), and water (0.25 mL) were added. The mixture was refluxed at 105°C for 18 hours. LCMS confirmed the reaction was complete. The reaction was diluted with ethyl acetate (10 mL) and filtered. The filtrate was extracted three times with 5 mL of ethyl acetate, and the combined organic phases were concentrated under reduced pressure. The above experiment was repeated for two batches, and the combined crude products were purified by column chromatography to obtain the product 2-(4-cyclopropyl-3,5-dimethoxyphenyl)benzofuran (7-C) (120 mg, 0.408 mmol, yield 20.6%). LCMS (ESI): [M+H] + =295; 1 H NMR (400MHz, CDCl3): δ7.62-7.50(m,2H),7.32-7.27(m,1H),7.26-7.21(m,1H),7.04(s,2H), 7.00(d,J=0.8Hz,1H),3.92(s,6H),2.00-1.90(m,1H),1.10-1.02(m,2H),0.92-0.84(m,2H).

[0170] Step 4: Synthesis of compound 7

[0171] Under ice-cooling, 2-(4-cyclopropyl-3,5-dimethoxyphenyl)benzofuran (7-C) (120 mg, 0.408 mmol) was dissolved in dichloromethane (6 mL), and 1 M boron tribromide / dichloromethane solution (4 mL, 4 mmol) was slowly added dropwise. The mixture was reacted at 0°C for 45 minutes, and the reaction was monitored by TLC. The reaction solution was slowly added dropwise to saturated ammonium chloride solution (30 mL), extracted three times with ethyl acetate (50 mL), and the combined organic phases were concentrated under reduced pressure. The crude product was purified by prep-RP-HPLC (adding 0.1% formic acid) to obtain the product 2-(4-cyclopropyl-3,5-dihydroxyphenyl)benzofuran (7) (4 mg, 0.015 mmol, yield 3.68%). LCMS (ESI): [M+H] + =267; 1H NMR (400MHz, DMSO): δ9.27(s,2H),7.65-7.55(m,2H),7.32-7.20(m,2H),7.06(d,J =0.8Hz,1H),6.79(s,2H),1.91-1.84(m,1H),1.10-1.05(m,2H),0.75-0.68(m,2H).

[0172] Example 8

[0173] Step 1: Synthesis of compound 8-A

[0174] At 0°C, 3-[(3,5-dimethoxy-4-isopropyl)-phenyl]-2H-methoxy-2-one (1-D) (100 mg, 0.308 mmol) was dissolved in dichloromethane (3 mL), and indium tribromide (5.32 mg, 0.03 mmol) and triethylsilane (143 mg, 1.23 mmol) were added. The reaction was stirred at 0°C for 3 hours. The reaction solution was diluted with dichloromethane (60 mL) and water (6 mL), and the liquids were separated by extraction. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the product, 3-[(3,5-dimethoxy-4-isopropyl)-phenyl]-3,4-dihydro-2H-chromene (8-A) (68 mg, 0.22 mmol, 70.6% yield), as a colorless oil. LCMS (ESI): [M+H] + =313.2.

[0175] Step 2: Synthesis of compound 8-B

[0176] At -30°C. 3-[(3,5-Dimethoxy-4-isopropyl)-phenyl]-3,4-dihydro-2H-chromene (8-A) (60 mg, 0.19 mmol) was dissolved in dichloromethane (3 mL), and 1 M boron tribromide / dichloromethane solution (1.15 mL, 1.15 mmol) was slowly added dropwise. The reaction system was stirred at -30°C for 30 minutes and then stirred at room temperature overnight. LCMS detected that the reaction was complete. The reaction solution was quenched with water (2 mL), diluted with dichloromethane (70 mL) and water (10 mL), and the organic phase was separated, extracted, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product 5-[1-bromo-3-(2-hydroxyphenyl)propyl-2-yl]-2-isopropylbenzene-1,3-diol (8-B) (50 mg, 0.137 mmol, yield 71.3%) as a colorless oil. LCMS (ESI): [M+H] + =365.2,367.2.

[0177] Step 3: Synthesis of Compound 8

[0178] 5-[1-Bromo-3-(2-hydroxyphenyl)propyl-2-yl]-2-isopropyl-benzene-1,3-diol (8-B) (50 mg, 0.137 mmol) was dissolved in acetonitrile (3 mL), potassium carbonate (57 mg, 0.41 mmol) was added, and the mixture was stirred at 40°C for 3 hours. The reaction was determined to be complete by TLC. The reaction system was cooled, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product 5-(3,4-dihydro-2-hydro-chromen-3-yl)-2-isopropyl-benzene-1,3-diol (8) (3 mg, 0.01 mmol, yield 7.6%) as a white solid. LCMS (ESI): [M+H] + =285.2; 1 H NMR (400MHz, DMSO-d6): δ8.91 (s, 2H), 7.18 (d, J = 7.2Hz, 1H), 7.07 (t, J = 7. 6z,1H),6.79(t,J=7.2z,1H),6.72(d,J=8.0,1H),6.17(s,2H),4.87(dd,J= 14.8,7.6Hz,1H),3.41(dd,J=14.4,7.2Hz,1H),3.22(dd,J=15.6,8.8Hz,1 H), 2.92-2.75 (m, 2H), 2.67 (dd, J = 13.8, 6.0Hz, 1H), 1.21 (d, J = 7.2Hz, 6H).

[0179] Example 9

[0180] Step 1: Synthesis of compound 9-A

[0181] 5-Bromo-1,3-dimethoxy-2-isopropyl-benzene (500 mg, 1.93 mmol), tert-butyl carbamate (339 mg, 2.89 mmol), tris(dibenzylideneacetone)dipalladium (177 mg, 0.193 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (223 mg, 0.386 mmol), and cesium carbonate (1.89 g, 5.79 mmol) were added to dioxane (15 mL) and stirred under nitrogen at 100°C overnight. LCMS confirmed the reaction was complete. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added, followed by extraction. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product [(1,3-dimethoxy-2-isopropyl)-phenyl-5-yl]carbamic acid tert-butyl ester (9-A) (320 mg, 1.08 mmol, yield 56.2%) as a white solid. 1H NMR (400MHz, CDCl3): δ7.80-7.70 (m, 1H), 6.59 (s, 2H), 3.78 (s, 6H), 3.56-3.45 (m, 1H), 1.51 (s, 9H), 1.24 (d, J = 7.2Hz, 6H).

[0182] Step 2: Synthesis of compound 9-B

[0183] Tert-butyl [(1,3-dimethoxy-2-isopropyl)-phenyl-5-yl]carbamate (9-A) (320 mg, 1.08 mmol) was dissolved in anhydrous dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction system was stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product, 3,5-dimethoxy-4-isopropyl-aniline (9-B) (120 mg, 0.615 mmol, 56.9% yield), as a white solid. 1 H NMR (400MHz, DMSO-d6): δ5.83 (s, 2H), 4.87 (s, 2H), 3.63 (s, 6H), 3.40-3.30 (m, 1H), 1.13 (d, J = 7.2Hz, 6H).

[0184] Step 3: Synthesis of compound 9-C

[0185] 3,5-Dimethoxy-4-isopropyl-aniline (9-B) (120 mg, 0.615 mmol) and 2-nitrobenzene-1-carbaldehyde (111 mg, 0.737 mmol) were added to isopropanol (15 mL) and stirred at 80°C overnight. Tributylphosphine (303 mg, 1.84 mmol) was added to the reaction system and stirring continued at 80°C overnight. The reaction was complete by LCMS. The reaction mixture was diluted with saturated ammonium chloride solution (30 mL) and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the product, 2-[(3,5-dimethoxy-4-isopropyl)-phenyl]indazole (9-C) (130 mg, 0.439 mmol, 71.4%), as a light yellow solid. 1 H NMR (400MHz, CDCl3): δ8.38(d,J=0.8Hz,1H),7.79(d,J=8.4Hz,1H),7.70(d,J=8.4Hz,1H),7.36-7 .30(m,1H),7.15-7.08(m,1H),7.06(s,2H),3.91(s,6H),3.68-3.58(m,1H),1.31(d,J=7.2Hz,6H).

[0186] Step 4: Synthesis of compound 9

[0187] 2-[(3,5-Dimethoxy-4-isopropyl)-phenyl]indazole (9-C) (120 mg, 0.405 mmol) was dissolved in anhydrous dichloromethane (6 mL) and 1 M boron tribromide / dichloromethane solution (2.4 mL, 2.4 mmol) was added at -30°C. The reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into saturated ammonium chloride (30 mL) and extracted twice with dichloromethane (30 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product 5-(indazol-2-yl)-2-isopropyl-benzene-1,3-diol (9) (30 mg, 0.112 mmol, 27.6%) as a white solid. LCMS (ESI): [M+H] + =269.2; 1 H NMR (400MHz, DMSO-d6): δ9.56(s,2H),8.70(s,1H),7.75(d,J=8.4Hz,1H),7.66(d,J=8.4Hz,1H ),7.32-7.26(m,1H),7.12-7.05(m,1H),6.91(s,2H),3.53-3.43(m,1H),1.27(d,J=7.2Hz,6H).

[0188] Example 10

[0189] Step 1: Synthesis of compound 10-A

[0190] 2-(3,5-Dimethoxyphenyl)benzofuran (7-A) (800 mg, 3.15 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to -78°C in a dry ice-ethanol bath, and 2.5 M n-butyllithium / tetrahydrofuran solution (1.38 mL, 3.46 mol) was slowly added dropwise. After reacting at -78°C for 30 min, cyclobutanone (330 mg, 4.72 mmol) was slowly added dropwise. After completion of the addition, the temperature was slowly raised to 25°C and allowed to react for 18 hours. LCMS confirmed the reaction was complete, and the mixture was quenched with water (5 mL) and extracted three times with ethyl acetate (10 mL). The combined organic phases were dried by spin drying. The crude product was purified by column chromatography to yield 2-[4-(1'-hydroxycyclobutyl)-3,5-dimethoxyphenyl]benzofuran (10-A) (450 mg, 1.39 mmol, 44.1% yield). LCMS(ESI):[M-H2O+H] + =307.4.

[0191] Step 2: Synthesis of compound 10-B

[0192] 2-[4-(1'-Hydroxycyclobutyl)-3,5-dimethoxy-phenyl]benzofuran (10-A) (450 mg, 1.39 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C in an ice bath, and trifluoroacetic acid (0.32 mL, 4.16 mmol) was added dropwise. After reacting for 5 minutes, triethylsilyl hydrochloride (1.1 mL, 6.94 mmol) was added dropwise. The temperature was slowly raised to 25°C and reacted for 2 hours. LCMS detected that the reaction was complete, and the mixture was quenched with water (15 mL) and extracted three times with dichloromethane (30 mL). The combined organic phases were concentrated to obtain the crude product, which was purified by prep-TLC to obtain the product 2-(4-cyclobutyl-3,5-dimethoxyphenyl)benzofuran (10-B) (150 mg, 0.486 mmol, 35% yield). LCMS (ESI): [M+H] + =309.4; 1 H NMR (400MHz, CDCl3): δ7.60-7.55(m,1H),7.53(d,J=7.6Hz,1H),7.31-7.27(m,1H),7.23(td,J=7.2,1.2Hz,1H),7.03(s, 2H), 6.99 (d, J = 0.8Hz, 1H), 4.00 (q, J = 9.2Hz, 1H), 3.92 (s, 6H), 2.67-2.54 (m, 2H), 2.28-2.18 (m, 2H), 1.98-1.85 (m, 2H).

[0193] Step 3: Synthesis of compound 10

[0194] Under ice bath, 2-(4-cyclobutyl-3,5-dimethoxyphenyl)benzofuran (150 mg, 0.486 mmol) was dissolved in dichloromethane (10 mL), and 1 M boron tribromide / dichloromethane solution (3 mL, 3 mmol) was slowly added dropwise. The temperature was naturally raised to 25°C and the reaction was allowed to react for 1 hour. TLC monitored the completion of the reaction, and the reaction solution was slowly added dropwise to saturated ammonium chloride solution (30 mL). The mixture was extracted three times with ethyl acetate (50 mL), and the combined organic phases were concentrated under reduced pressure. The crude product was purified by prep-RP-HPLC (adding 0.1% formic acid) to obtain the product 2-(4-cyclobutyl-3,5-dihydroxyphenyl)benzofuran (10) (40 mg, 0.143 mmol, yield 29.3%). LCMS (ESI): [M+H] + =281.1; 1H NMR (400MHz, DMSO-d6): δ9.39 (s, 2H), 7.69-7.50 (m, 2H),7.32-7.20(m,2H),7.06(s,1H),6.80(s,2H),3.90(p,J=9.6Hz,1H),2.74-2.63(m,2H),2.10-2.02(m,2H),1.93-1.75(m,2H).

[0195] Example 11

[0196] Step 1: Synthesis of compound 11-A

[0197] E-1-(2-Hydroxyphenyl)-3-{4-isopropyl-3,5-di[(methoxymethyl)oxy]}prop-2-en-1-one (4-A) (1.05 g, 2.72 mmol) was dissolved in acetonitrile (2 mL), and a 1 M aqueous cesium fluoride solution (26 μL, 26 μmol) was added dropwise. The mixture was sealed and reacted at 80°C for 4 hours. The reaction was monitored by TLC. After cooling to room temperature, the reaction solution was added dropwise to water (5 mL) and extracted three times with ethyl acetate (25 mL). The combined organic phases were concentrated, and the crude product was purified by column chromatography to obtain the product, 2-(3,5-dimethoxymethyl-4-isopropyl-phenyl)-benzo-2-hydro-3,4-dihydropyran-4-one (11-A) (680 mg, 1.76 mmol, 68% yield), as a colorless oil. 1 H NMR (400MHz, CDCl3): δ7.92(d,J=8.0Hz,1H),7.50(t,J=7.6Hz,1H),7.05(t,J=7.2Hz,2H),6.89(s,2H),5.39(dd,J=13.2,2.0 Hz,1H),5.23-5.17(m,4H),3.69-3.61(m,1H),3.49(s,6H),3.15-3.06(m,1H),2.87(d,J=16.8Hz,1H),1.32(d,J=7.2Hz,6H).

[0198] Step 2: Synthesis of compound 11

[0199] Under ice-cooling, 2-(3,5-dimethoxymethyl-4-isopropyl-phenyl)-benzo-2-hydro-3,4-dihydropyran-4-one (11-A) (100 mg, 0.285 mmol) was dissolved in tetrahydrofuran (1.5 mL), and a 4M hydrogen chloride / dioxane solution (1.5 mL, 6 mmol) was added. The mixture was reacted at room temperature for 3 hours under nitrogen protection. The reaction was monitored by TLC to be complete. Saturated sodium bicarbonate solution (3 mL) was added dropwise to the reaction solution, and the reaction solution was extracted three times with ethyl acetate (25 mL). The organic phases were combined and dried by spin drying. The crude product was purified by prep-RP-HPLC (0.1% formic acid addition) to obtain the product 2-(3,5-dihydroxy-4-isopropyl-phenyl)-2-hydro-benzo-3,4-dihydropyran-4-one (11) (30 mg, 0.1 mmol, yield 35.3%) as a white solid. LCMS (ESI): [M+H] + =299.2; 1 H NMR (400MHz, DMSO-d6): δ9.13(s,2H),7.77(dd,J=7.6,1.6Hz,1H),7.64-7.54(m,1H),7.16-6.98(m,2H),6.38(s,2H),5.4 4(dd,J=12.0,3.2Hz,1H),3.42(m,1H),3.05(dd,J=16.8,12.2Hz,1H),2.77(dd,J=16.8,3.2Hz,1H),1.22(d,J=7.2Hz,6H).

[0200] Example 12

[0201] Step 1: Synthesis of compound 12-A

[0202] In a rigid glass tube, 2-(3,5-dimethoxymethyl-4-isopropyl-phenyl)-benzo-2-hydro-3,4-dihydropyran-4-one (11-A) (680 mg, 1.76 mmol) was dissolved in tetrahydrofuran (5 mL). BAST (5 mL, 27.1 mmol) and ethanol (0.01 mL) were added dropwise under ice-cooling. The mixture was stirred for 10 minutes under nitrogen and then heated to 70°C for 12 hours. The reaction system was quenched by adding saturated ammonium chloride solution (20 mL) and extracted three times with ethyl acetate (50 mL). The combined organic phases were then dried by spin drying. The crude product was purified by column chromatography to yield 2-(3,5-dimethoxymethyl-4-isopropyl-phenyl)-4,4-difluorobenzo-2-hydro-3,4-dihydropyran (12-A) (150 mg, 0.367 mmol, 20.9% yield) as a colorless oil. 1H NMR (400MHz, CDCl3): δ7.66-7.60(m,1H),7.40-7.33(m,1H),7.05(t,J=7.6Hz,1H),6.97(d,J=8.4Hz,1H), 6.87(s,2H),5.24-5.17(m,5H),3.70-3.61(m,1H),3.50(s,6H),2.69-2.55(m,2H),1.32(d,J=7.2Hz,6H).

[0203] Step 2: Synthesis of compound 12

[0204] 2-(3,5-Dimethoxymethyl-4-isopropylphenyl)-4,4-difluorobenzo-2-hydro-3,4-dihydropyran (12-A) (45 mg, 0.11 mmol) was dissolved in tetrahydrofuran (1 mL), and a 4 M hydrogen chloride / dioxane solution (1 mL, 4 mmol) was added under ice-cooling. The mixture was reacted at 0°C under nitrogen for 5 hours. TLC was used to monitor the reaction until completion. The reaction solution was added dropwise to a saturated sodium bicarbonate solution (3 mL), and the reaction solution was extracted three times with ethyl acetate (25 mL). The organic phases were combined and dried by rotary evaporation. The crude product was purified by prep-RP-HPLC (0.1% formic acid addition) to obtain the product 2-(3,5-hydroxy-4-isopropylphenyl)-4,4-difluorobenzo-2-hydro-3,4-dihydropyran (12) (12 mg, 0.037 mmol, 34% yield) as a white solid. LCMS (ESI): [M+H] + =321.0; 1 H NMR (400MHz, DMSO-d6): δ9.18(s,2H),7.60(d,J=7.6Hz,1H),7.46(t,J=7.6Hz,1H),7.11(t,J=7.2Hz,1H),6.97 (d,J=8.4Hz,1H),6.39(s,2H),5.09-5.03(m,1H),3.45(m,1.6Hz,1H),2.70-2.54(m,2H),1.23(d,J=7.2Hz,6H); 19 F NMR (400MHz, DMSO-d6): δ-71.6,-97.8.

[0205] Example 13

[0206] Step 1: Synthesis of compound 13

[0207] 2-(3,5-Dihydroxy-4-isopropyl-phenyl)benzo-2-hydro-3,4-dihydropyran-4-one (130 mg, 0.436 mmol) was dissolved in methanol (2.5 mL) and sodium borohydride (33 mg, 0.872 mmol) was added under nitrogen protection. The reaction was allowed to react at room temperature for 3 hours. TLC was used to monitor the completion of the reaction. Water (5 mL) was added to quench the reaction. The reaction solution was extracted three times with ethyl acetate (25 mL). The combined organic phases were dried by spin drying. The crude product was purified by prep-RP-HPLC to obtain the product 2-(3,5-dimethoxymethyl-4-isopropyl-phenyl)-4-hydroxybenzo-2-hydro-3,4-dihydropyran (13) (40 mg, 0.133 mmol, yield 30.6%, white solid). LCMS (ESI): [M-H2O+H] + =283.2,[MH] - =299.2; 1 H NMR (400MHz, DMSO-d6): δ9.05(s,2H),7.44(d,J=7.6Hz,1H),7.17-7.06(m,1H),6.90(td,J=7.6,1.2Hz,1H),6.71(dd,J=8.0,1.0Hz,1H),6.33 (s,2H),5.45(d,J=6.8Hz,1H),5.02-4.86(m,2H),3.49-3.37(m,1H),2.29-2.14(m,1H),1.84(dd,J=23.6,12.0Hz,1H),1.23(d,J=7.2Hz,6H).

[0208] Example 14

[0209] Step 1: Synthesis of compound 14-A

[0210] 5-Bromo-1,3-dihydroxy-2-isopropylbenzene (1 g, 4.33 mmol) was dissolved in dioxane (30 mL) and water (8 mL). Benzofuran-2-boronic acid pinacol ester (1.58 g, 6.49 mmol), potassium phosphate (2.76 g, 13 mmol), and tetrakis(triphenylphosphine)palladium (0.5 g, 0.433 mmol) were added, and the mixture was heated to 100°C for 16 hours. LCMS confirmed the reaction was complete. Saturated ammonium chloride (10 mL) was added to the reaction system, and the mixture was extracted three times with ethyl acetate (40 mL). The organic phases were combined, washed three times with saturated sodium chloride solution (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified on a silica gel column to yield 5-(1-benzofuran-2-yl)-1,3-dihydroxy-2-isopropylbenzene (14-A) (0.8 g, 2.99 mmol, 69.1%) as a brown solid. LCMS(ESI):[M+H]+ =269.2; 1 H NMR (400MHz, DMSO-d6): δ9.32(s,2H),7.58(d,J=7.2Hz,1H),7.51(d,J=7.2Hz,1H),7 .33-7.20(m,2H),6.93(s,1H),6.88(s,2H),3.58-3.45(m,1H),1.42(d,J=7.2Hz,6H).

[0211] Step 2: Synthesis of compound 14-B

[0212] 5-(1-Benzofuran-2-yl)-1,3-dihydroxy-2-isopropylbenzene (14-A) (0.8 g, 2.99 mmol) was dissolved in dichloromethane (20 mL), and pyridine (0.48 mL, 5.96 mmol) and N,N-dimethylaminopyridine (36 mg, 0.3 mmol) were added. Trifluoromethanesulfonic anhydride (840 mg, 2.98 mmol) was added dropwise at 0°C. The reaction was stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete, and saturated ammonium chloride (15 mL) was added to the reaction system. The mixture was extracted three times with dichloromethane (30 mL). The organic phases were combined, washed three times with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column to give the product 5-(1-benzofuran-2-yl)-3-hydroxy-2-isopropylphenol trifluoromethanesulfonate (14-B) (0.4 g, 1 mmol, 33.4%) as a yellow oil. LCMS (ESI): [M+H] + =401.2; 1 H NMR (400MHz, DMSO-d6): δ10.59(s,H),7.70-7.64(m,2H),7.44-7.41(m,2H),7 .38-7.36(m,1H),7.34-7.26(m,2H),3.29-3.22(m,1H),1.36(d,J=6.8Hz,6H).

[0213] Step 3: Synthesis of compound 14-C

[0214] 5-(1-Benzofuran-2-yl)-3-hydroxy-2-isopropylphenol trifluoromethanesulfonate (14-B) (180 mg, 0.45 mmol) was dissolved in a mixture of dioxane (3 mL) and toluene (10 mL). Bis(pinacol)diboron (228 mg, 0.9 mmol), potassium acetate (132 mg, 1.35 mmol), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (38 mg, 0.045 mmol) were added. The mixture was reacted at 95°C under nitrogen for 16 hours. LCMS confirmed the reaction was complete. Saturated ammonium chloride (10 mL) was added to the reaction system, and the mixture was extracted three times with ethyl acetate (40 mL). The organic phases were combined, washed three times with saturated sodium chloride solution (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column to give the product 5-(1-benzofuran-2-yl)-2-isopropyl-3-hydroxyphenylboronic acid pinacol ester (14-C) (36 mg, 0.095 mmol, 21.2%) as a yellow oil. LCMS (ESI): [M+H] + =379.2.

[0215] Step 4: Synthesis of compound 14

[0216] 5-(1-Benzofuran-2-yl)-2-isopropyl-3-hydroxyphenylboronic acid pinacol ester (14-C) (36 mg, 0.095 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL). Ammonium acetate (18 mg, 0.238 mmol) and sodium periodate (51 mg, 0.238 mmol) were added and stirred at room temperature for 16 hours. LCMS confirmed the reaction was complete. The reaction system was concentrated under reduced pressure and the residue was purified by prep-RP-HPLC to give 5-(1-Benzofuran-2-yl)-2-isopropyl-3-hydroxyphenylboronic acid (14) (12 mg, 0.041 mmol, 43.2%) as a white solid. LCMS (ESI): [M+H] - =297.2; 1 H NMR (400MHz, DMSO-d6): δ9.37 (s, 1H), 8.16 (s, 2H), 7.63-7.58 (m, 2H), 7.29-7.22 (m, 5H), 3.15-3.10 (m, 1H), 1.31 (d, J = 6.8Hz, 6H).

[0217] Example 15

[0218] Step 1: Synthesis of compound 15-A

[0219] 3-Bromofuran (1 g, 6.8 mmol), phenylboronic acid (0.92 g, 7.55 mmol), potassium phosphate (2.64 g, 12.5 mmol), and tetrakis(triphenylphosphine)palladium (0.39 g, 0.34 mmol) were added to 1,4-dioxane (15 mL) and water (3 mL). The mixture was stirred at 90°C under nitrogen for 12 hours, and the reaction was monitored by TLC. The reaction system was concentrated under reduced pressure and purified on a silica gel column to obtain the product, 3-phenylfuran (15-A) (450 mg, 3.12 mmol, 45.9% yield), as a white solid. 1 H NMR (400MHz, CDCl3) δ7.73 (dd, J = 1.6, 1.2 Hz, 1H), 7.52-7.46 (m, 3H), 7.41-7.35 (m, 2H), 7.30-7.24 (m, 1H), 6.71 (dd, J = 1.6, 0.8 Hz, 1H).

[0220] Step 2: Synthesis of compound 15-B

[0221] At -78°C, 3-phenylfuran (15-A) (300 mg, 2.08 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and 2.5 M n-butyllithium (1.25 mL, 3.12 mmol) was added dropwise. After completion of the addition, the reaction system was warmed to -40°C and stirred for 30 minutes. The reaction system was then cooled to -78°C, and 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (774 mg, 4.16 mmol) was added dropwise. The reaction system was warmed to room temperature and stirred for 2 hours. LCMS detected the formation of product. Saturated ammonium chloride (20 mL) was added to quench the reaction, and the mixture was extracted twice with ethyl acetate (20 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product 4,4,5,5-tetramethyl-2-(4-phenylfuran-2-yl)-1,3,2-dioxaborolane (15-B) (600 mg, crude product). The crude product was used directly in the next reaction. LCMS (ESI): [M+H] + =271.2.

[0222] Step 3: Synthesis of Compound 15

[0223] 4,4,5,5-Tetramethyl-2-(4-phenyl-2-furyl)-1,3,2-dioxaborolane (15-B) (300 mg, 1.11 mmol), 5-bromo-2-isopropyl-benzene-1,3-diol (256 mg, 1.11 mmol), tetrakis(triphenylphosphine)palladium (64 mg, 0.056 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (40 mg, 0.056 mmol), and potassium phosphate (707 mg, 3.33 mmol) were added to 1,4-dioxane (10 mL) and water (2 mL). The mixture was stirred at 85°C under nitrogen for 16 hours. LCMS confirmed the reaction was complete. Water and ethyl acetate were added, and the mixture was separated. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain a crude product, which was then purified by prep-HPLC (0.1% formic acid addition) to obtain 2-isopropyl-5-(4-phenylfuran-2-yl)benzene-1,3-diol (15) (100 mg, 0.34 mmol, 30.6% yield) as a yellow solid. LCMS (ESI): [M+H] + =295.2; 1 H NMR (400MHz, DMSO-d6): δ9.10 (s, 2H), 7.71 (d, J = 1.6Hz, 1H), 7.45-7.25 (m, 5H) ,6.67(d,J=1.6Hz,1H),6.45(s,2H),3.50-3.40(m,1H),1.23(d,J=7.2Hz,6H).

[0224] Example 16

[0225] Step 1: Synthesis of compound 16-A

[0226] 2-Bromofuran (1 g, 6.8 mmol), phenylboronic acid (1 g, 8.17 mmol), potassium carbonate (2.35 g, 17 mmol), and tetrakis(triphenylphosphine)palladium (0.39 g, 0.34 mmol) were added to N,N-dimethylformamide (16 mL) and water (8 mL), and the mixture was stirred at 90°C under nitrogen for 12 hours. The reaction mixture was directly dried, and the residue was purified on a silica gel column to obtain the product 2-phenylfuran (16-A) (586 mg, 4.07 mmol, 59.7% yield) as a white solid. 1 H NMR (400MHz, CDCl3): δ7.72-7.67(m,2H),7.50-7.46(m,1H),7.42-7.37(m,2H ),7.30-7.24(m,1H),6.67(dd,J=3.2,0.4Hz,1H),6.49(dd,J=3.6,2.0Hz,1H).

[0227] Step 2: Synthesis of compound 16-B

[0228] 2-Phenylfuran (16-A) (364 mg, 2.53 mmol) was dissolved in N,N-dimethylformamide (10 mL) at 0°C, and N-bromosuccinimide (494 mg, 2.78 mmol) was added. The reaction system was stirred at room temperature for 12 hours. The mixture was diluted with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the product, 2-bromo-5-phenylfuran (16-B) (135 mg, 0.605 mmol, 24.0% yield), as a yellow oil.

[0229] Step 3: Synthesis of compound 16-C

[0230] 5-Bromo-2-phenylfuran (16-B) (135 mg, 0.605 mmol), 2-[3,5-dimethoxy-4-isopropyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxolane (202 mg, 0.66 mmol), potassium phosphate (257 mg, 1.21 mmol) and tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol) were added to 1,4-dioxane (5 mL) and water (0.5 mL). The mixture was stirred at 100°C under nitrogen for 12 hours. TLC showed that the reaction was complete. The reaction system was concentrated and the residue was purified on a silica gel column to obtain 2-[3,5-dimethoxy-4-isopropyl-phenyl]-5-phenylfuran (16-C) (84 mg, 0.261 mmol, 43.0% yield) as a white solid.

[0231] Step 4: Synthesis of compound 16

[0232] At -78 ° C, 2-[3,5-dimethoxy-4-isopropyl-phenyl]-5-phenylfuran (16-C) (74 mg, 0.23 mmol) was dissolved in dichloromethane (1.5 mL), and 1 M boron tribromide / dichloromethane solution (1.5 mL, 1.5 mmol) was added. The reaction system was warmed to room temperature and stirred for 4 hours. LCMS detection showed that the reaction was complete. The reaction was quenched by adding methanol (10 mL) at 0 ° C and concentrated. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product 5-(5-phenyl-2-furyl)-2-isopropyl-benzene-1,3-diol (16) (30 mg, 0.102 mmol, yield 44.3%) as a yellow solid. LCMS (ESI): [M+H] + =295.2; 1H NMR (400MHz, DMSO-d6): δ9.21(s,2H),7.76-7.70(m,2H),7.46(t,J=7.6Hz,2H),7.30(t,J=7.6Hz,1H) ,7.02(d,J=3.6Hz,1H),6.70(d,J=3.6Hz,1H),6.69(s,2H),3.50-3.40(m,1H),1.25(d,J=7.2Hz,6H).

[0233] Example 17

[0234] Step 1: Synthesis of compound 17-A

[0235] 1,3-Bis[(methoxymethyl)oxy]-5-ethynyl-2-isopropylbenzene (Compound 3-G) (20 mg, 0.08 mmol) was dissolved in anhydrous toluene (2 mL). Methyl 2'-iodobenzoate (17 mg, 0.07 mmol), cuprous iodide (0.6 mg, 0.003 mmol), triphenylphosphine (2.48 mg, 0.01 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.78 mg, 0.001 mmol), and triethylamine (0.088 mL, 0.63 mmol) were added. The mixture was heated at 80°C under nitrogen for 18 hours. LCMS confirmed the reaction was complete. The reaction system was diluted with ethyl acetate (5 mL) and filtered. The filtrate was washed three times with saturated sodium chloride solution (5 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give methyl 2-({3,5-bis[(methoxymethyl)oxy]-4-isopropyl-phenyl}ethynyl)benzoate (17-A) (23 mg, 0.06 mmol, 91.6% yield) as a pale yellow solid. LCMS (ESI): [M+H] + =399; 1 H NMR (400MHz, DMSO-d6): δ7.96(dd,J=8.0,0.8Hz,1H),7.62(dd,J=7.6,0.8Hz,1H),7.48(td,J=7.6,1.2Hz,1H),7.37(td,J =7.6, 1.2Hz, 1H), 6.99 (s, 2H), 5.20 (s, 4H), 3.97 (s, 3H), 3.65 (dt, J = 14.0, 7.2Hz, 1H), 3.50 (s, 6H), 1.32 (d, J = 7.2Hz, 6H).

[0236] Step 2: Synthesis of compound 17

[0237] Methyl 2-({3,5-di[(methoxymethyl)oxy]-4-isopropyl-phenyl}ethynyl)benzoate (17-A) (23 mg, 0.06 mmol) and ethanol (2.5 mL) were placed in a microwave tube, 4-methylbenzenesulfonic acid (11.34 mg, 0.07 mmol) was added, and the mixture was microwaved at 130°C under nitrogen for 1 hour. The reaction was complete as determined by LCMS. The reaction solution was diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by prep-HPLC (0.1% formic acid addition) to obtain the product 3-(3,5-dihydroxy-4-isopropyl-phenyl)-1-hydro-2-benzopyran-1-one (17) (4 mg, 0.013 mmol, yield 20.6%). LCMS (ESI): [M+H] + =297; 1 H NMR (400MHz, DMSO-d6): δ9.39(s,2H),8.15(d,J=7.8Hz,1H),7.85(t,J=7.2Hz,1H),7.75(d,J=7.6Hz,1H ), 7.58 (t, J = 7.2Hz, 1H), 7.07 (s, 1H), 6.81 (s, 2H), 3.46 (dd, J = 13.6, 6.4Hz, 1H), 1.26 (d, J = 7.2Hz, 6H).

[0238] The compounds listed in Table 2 below were synthesized according to the similar procedures as in Example 17.

[0239] Table 2

[0240] Example 18

[0241] Step 1: Synthesis of compound 18-A

[0242] 5,7-Dihydroxy-2-phenyl-4-hydrogen-chromen-4-one (1 g, 3.94 mmol) was dissolved in N,N-dimethylformamide (10 mL). Triethylamine (1.65 mL, 11.82 mmol) was added at room temperature, followed by the dropwise addition of iodomethane (0.61 mL, 9.85 mmol). After the addition was complete, the mixture was stirred at room temperature for 16 hours. LCMS confirmed the reaction was complete. The reaction system was concentrated under reduced pressure and diluted with ethyl acetate (100 mL). The organic phase was washed three times with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain 5,7-dimethoxy-2-phenyl-4-hydrogen-chromen-4-one (18-A) (1.01 g, 3.58 mmol, 90.9% yield) as a white solid. LCMS (ESI): [M+H] + =283.2.

[0243] Step 2: Synthesis of compound 18-B

[0244] 5,7-Dimethoxy-2-phenyl-4-hydrogen-chromen-4-one (18-A) (1.01 g, 3.58 mmol) was dissolved in dichloromethane (20 mL). N-bromosuccinimide (634 mg, 3.58 mmol) was added at room temperature and stirred for 2 hours. The reaction was complete by LCMS. The reaction system was concentrated under reduced pressure and diluted with dichloromethane (60 mL). The organic phase was washed three times with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain the product 8-bromo-5,7-dimethoxy-2-phenyl-4-hydrogen-chromen-4-one (18-B) (1.06 g, 2.94 mmol, yield 82.1%) as a white solid. LCMS (ESI): [M+H] + =361.0,363.0.

[0245] Step 3: Synthesis of Compound 18-C

[0246] 8-Bromo-5,7-dimethoxy-2-phenyl-4-hydrogen-chromen-4-one (18-B) (1.05 g, 2.94 mmol) was mixed with toluene (45 mL) and water (9 mL). Sodium carbonate (935 mg, 8.82 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (106 mg, 0.145 mmol) were added. The mixture was stirred at 100°C for 16 hours. LCMS confirmed the reaction was complete. The reaction system was cooled, filtered, and concentrated under reduced pressure. Dichloromethane (80 mL) was added for dilution. The organic phase was washed three times with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product 5,7-dimethoxy-2-phenyl-8-(1-propen-2-yl)-4-hydrogen-chromen-4-one (18-C) (0.8 g, 2.48 mmol, yield 84.4%) as a colorless oil. LCMS (ESI): [M+H] + =323.2.

[0247] Step 4: Synthesis of compound 18-D

[0248] 5,7-Dimethoxy-2-phenyl-8-(1-propen-2-yl)-4-hydrogen-chromen-4-one (18-C) (0.8 g, 2.48 mmol) was dissolved in methanol (10 mL), and 10% palladium / carbon (250 mg, 0.24 mmol) was added. The mixture was stirred at room temperature under hydrogen for 2 hours. LCMS confirmed the reaction was complete. The reaction system was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 8-isopropyl-5,7-dimethoxy-2-phenyl-4-hydrogen-chromen-4-one (18-D) (0.55 g, 1.7 mmol, 68.5% yield) as a yellow oil. LCMS (ESI): [M+H] + =325.1; 1 H NMR (400MHz, DMSO-d6): δ8.00-7.98(m,2H),7.59-7.57(m,3H),6.73(s,1H),6. 64(s,1H),3.96(s,3H),3.89(s,3H),3.79-3.75(m,1H),1.37(d,J=7.2Hz,6H).

[0249] Step 5: Synthesis of compound 18

[0250] 8-Isopropyl-5,7-dimethoxy-2-phenyl-4-hydrogen-chromen-4-one (18-D) (0.1 g, 0.31 mmol) was dissolved in dichloromethane (3 mL) and 1 M boron tribromide / dichloromethane solution (1.24 mL, 1.24 mmol) was added at -30°C. The reaction was stirred at -30°C for 30 minutes and at room temperature for 12 hours. LCMS confirmed the reaction was complete. The reaction system was cooled, and water (3 mL) and dichloromethane (40 mL) were added. The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product, 5,7-dihydroxy-8-isopropyl-2-phenyl-4-hydrogen-chromen-4-one (18) (52 mg, 0.176 mmol, 56.7% yield), as a colorless oil. LCMS(ESI):[M+H] + =297.2; 1 H NMR (400MHz, DMSO-d6): δ12.92(s,1H),10.79(s,1H),8.07-8.04(m,2H),7.64-7 .61(m,3H),6.97(s,1H),6.31(s,1H),3.70-3.64(m,1H),1.38(d,J=7.2Hz,6H).

[0251] Example 19

[0252] Step 1: Synthesis of compound 19-A

[0253] 5,7-Dihydroxy-2-phenyl-4-hydrogen-chromen-4-one (1 g, 3.94 mmol) was dissolved in N,N-dimethylformamide (10 mL). Triethylamine (0.83 mL, 5.91 mmol) was added at room temperature, followed by the dropwise addition of methoxymethane (489 mg, 3.94 mmol). After the addition was complete, the mixture was stirred at room temperature for 16 hours. LCMS confirmed the reaction was complete. The reaction system was concentrated under reduced pressure and diluted with ethyl acetate (100 mL). The organic phase was washed three times with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain 5-hydroxy-7-[(methoxymethyl)oxy]-2-phenyl-4-hydrogen-chromen-4-one (19-A) (0.6 g, 2.01 mmol, 51% yield) as a colorless oil. LCMS (ESI): [M+H] + =299.2; 1 HNMR (400MHz, DMSO-d6): δ12.79(s,1H),8.10-8.08(m,2H),7.60-7.58(m,3H),7.04(s,1H),6.86(s,1H),6.46(s,1H),5.33(s,2H),3.40(s,3H).

[0254] Step 2: Synthesis of compound 19-B

[0255] 5-Hydroxy-7-[(methoxymethyl)oxy]-2-phenyl-4-hydrogen-chromen-4-one (19-A) (0.6 g, 2.01 mmol) was dissolved in dichloromethane (12 mL). N-bromosuccinimide (356 mg, 2.01 mmol) was added at -78°C and stirred for 2 hours. LCMS analysis revealed the formation of two isomers with a 1:1 ratio. The reaction system was concentrated under reduced pressure, diluted with dichloromethane (60 mL), and washed three times with saturated sodium chloride solution (15 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the crude product. The crude product was purified by prep-HPLC (with 0.1% formic acid added) to afford 6-bromo-5-hydroxy-7-[(methoxymethyl)oxy]-2-phenyl-4-hydrogen-chromen-4-one (19-B) (0.33 g, 0.88 mmol, 43.8% yield) as a colorless oil. LCMS(ESI):[M+H] + =377.0,379.0; 1H NMR (400MHz, DMSO-d6): δ12.89(s,1H),8.15-8.11(m,2H),7.63-7.61(m,3H),7.15(s,1H),6.73(s,1H),5.46-5.44(s,2H),3.45(s,3H).

[0256] Step 3: Synthesis of Compound 19-C

[0257] 6-Bromo-5-hydroxy-7-[(methoxymethyl)oxy]-2-phenyl-4-hydrogen-chromen-4-one (19-B) (330 mg, 0.88 mmol) was mixed with toluene (15 mL) and water (3 mL). Sodium carbonate (280 mg, 2.64 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (32 mg, 0.044 mmol) were added. The mixture was stirred at 100°C for 16 hours. LCMS confirmed the reaction was complete. The reaction system was cooled, filtered, and concentrated under reduced pressure. Dichloromethane (40 mL) was added for dilution. The organic phase was washed three times with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product 5-hydroxy-7-[(methoxymethyl)oxy]-2-phenyl-6-(1-propen-2-yl)-4-hydrogen-chromen-4-one (19-C) (216 mg, 0.64 mmol, yield 72.7%) as a colorless oil. LCMS (ESI): [M+H] + =339.2.

[0258] Step 4: Synthesis of compound 19-D

[0259] 5-Hydroxy-7-[(methoxymethyl)oxy]-2-phenyl-6-(1-propen-2-yl)-4-hydrogen-chromen-4-one (19-C) (216 mg, 0.64 mmol) was dissolved in methanol (10 mL), and 10% palladium / carbon (64 mg, 0.06 mmol) was added. The mixture was stirred at room temperature under hydrogen for 6 hours. LCMS confirmed the reaction was complete. The reaction system was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the product, 5-hydroxy-6-isopropyl-7-[(methoxymethyl)oxy]-2-phenyl-4-hydrogen-chromen-4-one (19-D) (166 mg, 0.49 mmol, 76.6% yield), as a yellow oil. LCMS (ESI): [M+H] + =341.2.

[0260] Step 5: Synthesis of compound 19

[0261] 5-Hydroxy-6-isopropyl-7-[(methoxymethyl)oxy]-2-phenyl-4-hydrogen-chromen-4-one (21-A) (166 mg, 0.49 mmol) was dissolved in tetrahydrofuran (1 mL), and 4N hydrogen chloride / dioxane (0.5 mL, 2 mmol) was added. The mixture was stirred at room temperature for 6 hours. LCMS confirmed the reaction was complete. The reaction system was diluted with ethyl acetate (60 mL) and water (10 mL). The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative purification to give the product 5,7-dihydroxy-6-isopropyl-2-phenyl-4-hydrogen-chromen-4-one (19) (23 mg, 0.078 mmol, yield 15.9%). LCMS (ESI): [M+H] + =297.2; 1 H NMR (400MHz, DMSO-d6): δ13.30(s,1H),10.91(s,1H),8.07-8.04(m,2H),7.60-7 .57(m,3H),6.95(s,1H),6.55(s,1H),3.48-3.44(m,1H),1.28(d,J=7.2Hz,6H).

[0262] Example 20

[0263] Step 1: Synthesis of compound 20-A

[0264] 8-Bromo-5,7-dimethoxy-2-phenyl-4-hydrogen-chromen-4-one (18-B) (260 mg, 0.72 mmol) was dissolved in dichloromethane (3 mL) and a 1 M boron tribromide / dichloromethane solution (0.72 mL, 0.72 mmol) was added at -30°C. The reaction was stirred at -30°C for 30 minutes and at room temperature for 12 hours. LCMS confirmed the reaction was complete. The reaction system was cooled, and water (3 mL) and dichloromethane (40 mL) were added. The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified on a silica gel column to give the product, 8-bromo-5,7-dihydroxy-2-phenyl-4-hydrogen-chromen-4-one (20-A) (200 mg, 0.6 mmol, 83.3% yield), as a light yellow solid. LCMS (ESI): [M+H] + =333,335; 1 H NMR (400MHz, DMSO-d6): δ12.85(s,1H),10.86(s,1H),8.12-8.10(m,2H),7.64-7.62(m,3H),6.99(s,1H),6.40(s,1H).

[0265] Step 2: Synthesis of compound 20

[0266] 8-Bromo-5,7-dihydroxy-2-phenyl-4-hydrogen-chromen-4-one (20-A) (200 mg, 0.6 mmol) was added to tetrahydrofuran (8 mL) and water (8 mL), and isopentenylboronic acid pinacol ester (235 mg, 1.2 mmol), tetrakis(triphenylphosphine)palladium (35 mg, 0.03 mmol) and potassium carbonate (248 mg, 1.8 mmol) were added. The mixture was reacted at 90°C for 12 hours. The reaction was complete as determined by LCMS. The reaction system was diluted with ethyl acetate (80 mL) and filtered. The filtrate was extracted three times with 300 mL of ethyl acetate. The combined organic phases were concentrated under reduced pressure. The crude product was purified by neutral prep-HPLC to give the product 5,7-dihydroxy-8-(3-methylbutyl-2-enyl-1-yl)-2-phenyl-4-hydrogen-chromen-4-one (20) (32 mg, 0.1 mmol, yield 16.7%) as a yellow oil. LCMS(ESI):[M+H] + =323.2; 1 H NMR (400MHz, DMSO-d6): δ12.77(s,1H),10.86(s,1H),8.06-8.04(m,2H),7.61-7.59(m,3H) ,6.97(s,1H),6.32(s,1H),5.23-5.17(m,1H),3.47-3.45(m,2H),1.76(s,3H),1.63(s,3H).

[0267] Example 21

[0268] Step 1: Synthesis of compound 21-A

[0269] 6-Bromo-5-hydroxy-7-[(methoxymethyl)oxy]-2-phenyl-4-hydrogen-chromen-4-one (300 mg, 0.8 mmol) was dissolved in dioxane (5 mL) and water (1 mL). Prenyl borate (235 mg, 1.2 mmol), potassium carbonate (331 mg, 2.4 mmol), and tetrakis(triphenylphosphine)palladium (46 mg, 0.04 mmol) were added. The reaction was stirred at 110°C under nitrogen for 12 hours. LCMS confirmed the reaction was complete. The reaction was diluted with ethyl acetate (80 mL), and the organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column to give the product 5-hydroxy-7-[(methoxymethyl)oxy]-6-(3-methylbutyl-2-enyl)-2-phenyl-4-hydrogen-chromen-4-one (21-A) (120 mg, 0.33 mmol, yield 41.3%) as a white solid. 1H NMR (400MHz, DMSO-d6): δ13.05(s,1H),8.10-8.08(m,2H),7.65-7.55(m,3H),6.98(s,1H),6.90( s,1H),5.40(s,2H),5.12-5.05(m,1H),3.46(s,3H),3.32-3.24(m,2H),1.74(s,3H),1.60(s,3H).

[0270] Step 2: Synthesis of compound 21

[0271] 5-Hydroxy-7-[(methoxymethyl)oxy]-6-(3-methylbutyl-2-enyl)-2-phenyl-4-hydrogen-chromen-4-one (21-A) (120 mg, 0.33 mmol) was dissolved in tetrahydrofuran (1.2 mL), and 4N hydrogen chloride / dioxane (0.6 mL, 2.4 mmol) was added. The mixture was stirred at room temperature for 6 hours. LCMS confirmed the completion of the reaction. The reaction system was diluted with ethyl acetate (60 mL) and water (10 mL). The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative purification to give the product 5,7-dihydroxy-6-(3-methylbutyl-2-enyl)-2-phenyl-4-hydrogen-chromen-4-one (21) (20 mg, 0.06 mmol, yield 18.2%). LCMS (ESI): [M+H] + =323.2; 1 H NMR (400MHz, DMSO-d6): δ13.09(s,1H),8.08-8.04(m,2H),7.60-7.57(m,3H),6.95(s,1H) ), 6.76 (s, 1H), 5.20-5.16 (m, 1H), 3.24-3.22 (d, J = 7.2Hz, 2H), 1.73 (s, 3H), 1.63 (s, 3H).

[0272] Example 22

[0273] Step 1: Synthesis of compound 22-A

[0274] 4-Bromo-3,5-dimethoxybenzoic acid (5 g, 19.2 mmol) was dissolved in dichloromethane (50 mL). 2-Acetylphenol (3.13 g, 23 mmol), 4-dimethylamino-pyridine (0.35 g, 2.87 mmol), and triethylamine (7.99 mL, 57.5 mmol) were added in sequence. After stirring for 5 minutes, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.41 g, 22.98 mmol) was added and the mixture was stirred at room temperature for 18 hours. LCMS confirmed the reaction was complete. The reaction system was diluted with dichloromethane (100 mL) and water (25 mL). The organic phase was washed three times with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column to give the product 3,5-dimethoxybenzoic acid 2-acetylphenol ester (22-A) (3.7 g, 9.56 mmol, yield 49.9%) as a colorless oil. LCMS (ESI): [M+H] + =379,381.

[0275] Step 2: Synthesis of compound 22-B

[0276] 2-Acetylphenol 3,5-dimethoxybenzoate (22-A) (2.7 g, 7.12 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), 1 M potassium tert-butoxide (9.97 mL, 9.97 mmol) was added, and the mixture was stirred at room temperature for 18 hours. LCMS detected that the reaction was complete. The reaction system was diluted with ethyl acetate (150 mL) and saturated brine (30 mL), and the organic phase was washed three times with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column to obtain the product 3-(4-bromo-3,5-dimethoxyphenyl)-1-(2-hydroxyphenyl)propane-1,3-dione (22-B) (1.9 g, 4.71 mmol, yield 66.2%), a colorless oil. LCMS (ESI): [M+H] + =379,381.

[0277] Step 3: Synthesis of compound 22-C

[0278] 3-(4-Bromo-3,5-dimethoxyphenyl)-1-(2-hydroxyphenyl)propane-1,3-dione (22-B) (1.9 g, 4.71 mmol) was dissolved in acetic acid (20 mL), concentrated sulfuric acid (0.534 mL, 10 mmol) was added, and the mixture was heated to 110°C and stirred for 3 hours. LCMS showed that the reaction was complete. After the reactants were concentrated under reduced pressure, water (20 mL) was added to the residue and stirred for 0.5 hours. The mixture was filtered, washed three times with water (10 mL), and the filter cake was collected and dried to obtain the product 2-(4-bromo-3,5-dimethoxyphenyl)-4-hydrogen-chromen-4-one (22-C) (1.55 g, 3.95 mmol, yield 78.8%) as a white solid. LCMS (ESI): [M+H] + =361,363; 1 H NMR (400MHz, DMSO-d6): δ8.08-8.06(m,1H),7.90-7.84(m,2H),7.55-7.51(m,1H),7.42(s,2H),7.30(s,1H),4.00(s,6H).

[0279] Step 4: Synthesis of compound 22-D

[0280] 2-(4-Bromo-3,5-dimethoxyphenyl)-4-hydrogen-chromen-4-one (22-C) (0.5 g, 1.38 mmol) was added to toluene (15 mL) and water (1.5 mL). Cyclopropylboronic acid (357 mg, 4.15 mmol), tetrakis(triphenylphosphine)palladium (162 mg, 0.14 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (101 mg, 0.14 mmol), potassium phosphate (882 mg, 4.15 mmol), and tricyclohexylphosphine (78 mg, 0.28 mmol) were added. The mixture was heated to 95°C with stirring for 18 hours. LCMS confirmed the reaction was complete. The reaction was diluted with ethyl acetate (75 mL), and the organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column to give 2-(4-cyclopropyl-3,5-dimethoxyphenyl)-4-hydrogen-chromen-4-one (22-D) (180 mg, 0.558 mmol, 40.4% yield) as a white solid. LCMS (ESI): [M+H] + =323.2.

[0281] Step 5: Synthesis of compound 22

[0282] 2-(4-Cyclopropyl-3,5-dimethoxyphenyl)-4-hydrogen-chromen-4-one (22-D) (180 mg, 0.558 mmol) was dissolved in dichloromethane (5 mL). 1 M boron tribromide / dichloromethane solution (5 mL, 5 mmol) was added at 0°C and the reaction was stirred at room temperature for 3 hours. LCMS confirmed the completion of the reaction. The reaction system was quenched with water (5 mL) and diluted with ethyl acetate (80 mL). The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product 2-(4-cyclopropyl-3,5-dihydroxyphenyl)-4-hydrogen-chromen-4-one (22) (25 mg, 0.085 mmol, yield 15.2%) as a white solid. LCMS (ESI): [M+H] + =295.2; 1 H NMR (400MHz, DMSO-d6): δ9.54(s,2H),8.06-8.03(m,1H),7.86-7.81(m,1H),7.67-7.65(m,1H),7.5 2-7.48(m,1H),6.90(s,2H),6.59(s,1H),1.96-1.91(m,1H),1.16-1.12(m,2H),0.78-0.73(m,2H).

[0283] Example 23

[0284] Step 1: Synthesis of compound 23-A

[0285] 2-(4-Bromo-3,5-dimethoxyphenyl)-4-hydrogen-chromen-4-one (22-C) (0.4 g, 1.11 mmol) was added to toluene (15 mL) and water (1.5 mL). Cyclobutylboronic acid (333 mg, 3.33 mmol), tetrakis(triphenylphosphine)palladium (127 mg, 0.11 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (101 mg, 0.14 mmol), potassium phosphate (706 mg, 3.33 mmol), and tricyclohexylphosphine (62 mg, 0.22 mmol) were added. The mixture was heated to 100°C and stirred for 18 hours. LCMS confirmed the reaction was complete. The reaction system was diluted with ethyl acetate (75 mL), and the organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column to give 2-(4-cyclobutyl-3,5-dimethoxyphenyl)-4-hydrogen-chromen-4-one (23-A) (35 mg, 0.104 mmol, yield 9.4%) as a white solid. LCMS (ESI): [M+H] + =337.

[0286] Step 2: Synthesis of compound 23

[0287] 2-(4-Cyclobutyl-3,5-dimethoxyphenyl)-4-hydrogen-chromen-4-one (23-A) (35 mg, 0.104 mmol) was dissolved in dichloromethane (5 mL). 1 M boron tribromide / dichloromethane solution (1 mL, 1 mmol) was added at 0°C and the reaction was stirred at room temperature for 3 hours. LCMS confirmed the completion of the reaction. The reaction system was quenched with water (3 mL) and diluted with ethyl acetate (60 mL). The organic phase was washed three times with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product 2-(4-cyclobutyl-3,5-dihydroxyphenyl)-4-hydrogen-chromen-4-one (23) (6 mg, 0.02 mmol, yield 19.2%) as a white solid. LCMS (ESI): [M+H] + =309.2; 1 H NMR (400MHz, DMSO-d6): δ9.62(s,2H),8.07-8.04(m,1H),7.86-7.82(m,1H),7.67-7.65(m,1H),7.53-7.49(m ,1H),6.90(s,2H),6.57(s,1H),3.97-3.87(m,1H),2.71-2.66(m,2H),2.12-2.05(m,2H),1.93-1.81(m,2H).

[0288] The compounds listed in Table 3 below were synthesized according to the similar procedures as in Example 23.

[0289] Table 3

[0290] Example 24

[0291] Step 1: Synthesis of compound 24-A

[0292] 2-(4-Bromo-3,5-dimethoxyphenyl)-4-hydrogen-chromen-4-one (22-C) (0.5 g, 1.39 mmol) was added to toluene (20 mL) and water (2 mL). Isopropenylboronic acid pinacol ester (0.7 g, 4.17 mmol), tetrakis(triphenylphosphine)palladium (162 mg, 0.14 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (128 mg, 0.14 mmol), and potassium phosphate (884 mg, 4.17 mmol) were added. The mixture was heated to 100°C and stirred for 18 hours. LCMS confirmed the reaction was complete. The reaction system was diluted with ethyl acetate (120 mL), and the organic phase was washed three times with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column to give 2-(4-isopropenyl-3,5-dimethoxyphenyl)-4-hydrogen-chromen-4-one (24-A) (0.2 g, 0.62 mmol, yield 44.6%) as a white solid. LCMS (ESI): [M+H] + =323.2.

[0293] Step 2: Synthesis of compound 24

[0294] 2-(4-Isopropenyl-3,5-dimethoxyphenyl)-4-hydrogen-chromen-4-one (24-A) (0.18 g, 0.56 mmol) was dissolved in dichloromethane (5 mL). 1 M boron tribromide / dichloromethane solution (5.6 mL, 5.6 mmol) was added at 0°C and the reaction was stirred at room temperature for 3 hours. LCMS confirmed the completion of the reaction. The reaction system was quenched with water (3 mL) and diluted with ethyl acetate (80 mL). The organic phase was washed three times with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product 2-(4-isopropenyl-3,5-dihydroxyphenyl)-4-hydrogen-chromen-4-one (24) (70 mg, 0.24 mmol, 42.9% yield) as a white solid. LCMS (ESI): [M+H] + =295.2; 1 H NMR(400MHz, DMSO-d6):8.07-8.04(m,1H),7.87-7.82(m,1H),7.68(d,J=8.4Hz,1H),7.53 -7.49(m,1H),6.95(s,2H),6.64(s,1H),5.23(s,1H),4.82(d,J=1.2Hz,1H),1.96(s,3H).

[0295] Example 25

[0296] Step 1: Synthesis of compound 25-A

[0297] 2-[(3,5-dimethoxy)phenyl]-4-hydrogen-chromen-4-one (1 g, 3.54 mmol) was dissolved in dichloromethane (20 mL), cooled to -78°C, and N-bromosuccinimide (0.69 g, 3.9 mmol) was added. After stirring at -78°C for 3 hours, the mixture was stirred at room temperature overnight. LCMS confirmed the reaction was complete. The reaction system was filtered and concentrated. The residue was purified on a silica gel column to give the product, 2-[(2-bromo-3,5-dimethoxy)phenyl]-4-hydrogen-chromen-4-one (25-A) (1.1 g, 3.05 mmol, 86% yield), as a white solid. LCMS (ESI): [M+H] + =361,363; 1 H NMR (400MHz, DMSO-d6): δ8.10(dd,J=8.0,1.6Hz,1H),7.85(ddd,J=8.8,7.2,1.6Hz,1H),7.68(d,J=8.4Hz,1H ),7.54(t,J=7.6Hz,1H),6.94(d,J=2.8Hz,1H),6.89(d,J=2.8Hz,1H),6.54(s,1H),3.91(s,3H),3.84(s,3H).

[0298] Step 2: Synthesis of compound 25-B

[0299] 2-[(2-Bromo-3,5-dimethoxy)phenyl]-4-hydrogen-chromen-4-one (25-A) (1.1 g, 3.05 mmol) was dissolved in dichloromethane (10 mL), cooled to -30°C, and a 1 M boron tribromide / dichloromethane solution (9.15 mL, 9.15 mmol) was added. The mixture was stirred at -30°C for 30 minutes and then at room temperature overnight. LCMS confirmed the reaction was complete. The reaction system was quenched with water (5 mL) and diluted with dichloromethane (100 mL). The organic phase was washed three times with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified on a silica gel column to yield 2-[(2-Bromo-3,5-dihydroxy)phenyl]-4-hydrogen-chromen-4-one (25-B) (0.65 g, 1.96 mmol, 64.3% yield) as a colorless oil. LCMS(ESI):[M+H] + =333,335.

[0300] Step 3: Synthesis of compound 25

[0301] 2-[(2-Bromo-3,5-dihydroxy)phenyl]-4-hydrochromen-4-one (25-B) (0.2 g, 0.6 mmol) was dissolved in a mixture of tetrahydrofuran (8 mL) and water (4 mL). Prenylboronic acid pinacol ester (176 mg, 0.9 mmol), potassium carbonate (248 mg, 1.8 mmol), and tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) were added. The mixture was heated to 80°C and stirred for 16 hours. LCMS confirmed the reaction was complete. The reaction system was cooled and diluted with dichloromethane (100 mL). The organic phase was washed three times with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product 2-{[3,5-dihydroxy-2-(3-methyl-2-buten-1-yl)]phenyl}-4-hydrogen-chromen-4-one (25) (27 mg, 0.084 mmol, yield 14%) as a colorless oil. LCMS (ESI): [M+H] + =323.2; 1 H NMR (400MHz, DMSO-d6): δ9.65(s,1H),9.48(br,1H),8.08-8.05(m,1H),7.85-7.80(m,1H),7.63-7.61(m,1H),7.53-7.49(m,1 H), 6.50 (d, J = 2.4Hz, 1H), 6.39 (d, J = 2.4Hz, 1H), 6.33 (s, 1H), 5.09-5.05 (m, 1H), 3.24-3.22 (m, 2H), 1.52 (s, 3H), 1.39 (s, 3H).

[0302] Example 26

[0303] Step 1: Synthesis of compound 26-A

[0304] 5-Bromo-1,3-difluoro-2-iodobenzene (10 g, 31.36 mmol) was dissolved in anhydrous methanol (100 mL). 30% sodium methoxide (3 g, 55.5 mmol) was added at room temperature and the mixture was heated to 60°C with stirring for 15 hours. The reaction system was concentrated under reduced pressure, and the residue was diluted with water (100 mL) and filtered. The filter cake was dissolved in dichloromethane (100 mL), and the organic phase was washed three times with saturated sodium chloride solution (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified on a silica gel column to obtain the product, 5-bromo-1-fluoro-2-iodo-3-methoxybenzene (26-A) (6.5 g, 19.6 mmol, 62.5% yield), as a white solid. 1H NMR (400MHz, CDCl3): δ6.90 (dd, J=7.2, 1.6Hz, 1H), 6.75 (m, 1H), 3.90 (s, 3H).

[0305] Step 2: Synthesis of compound 26-B

[0306] 5-Bromo-1-fluoro-2-iodo-3-methoxybenzene (26-A) (1 g, 3.02 mmol) was added to dioxane (20 mL) and water (2 mL). Diboronic acid pinacol ester (760 mg, 4.53 mmol), potassium carbonate (0.84 g, 6.04 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.22 g, 0.302 mmol) were then added. The reaction system was stirred at 100°C under nitrogen for 16 hours. The reaction mixture was poured into saturated ammonium chloride solution (20 mL) and extracted twice with ethyl acetate (50 mL). The combined organic phases were washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column to give the product 5-bromo-1-fluoro-3-methoxy-2-isopropenylbenzene (26-B) (600 mg, 2.45 mmol, yield 81.1%) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ6.89 (dd, J=8.4, 1.6Hz, 1H), 6.81 (m, 1H), 5.35 (m, 1H), 4.96 (s, 1H), 3.82 (s, 3H), 2.01 (s, 3H).

[0307] Step 3: Synthesis of compound 26-C

[0308] 5-Bromo-1-fluoro-3-methoxy-2-isopropenylbenzene (26-B) (300 mg, 1.22 mmol) was added to dioxane (10 mL) and water (1 mL). Benzofuran-2-boronic acid pinacol ester (299 mg, 1.22 mmol), potassium phosphate (0.78 g, 3.67 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (45 mg, 0.06 mmol), and tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) were then added. The reaction system was stirred at 100°C under nitrogen for 16 hours. The reaction mixture was poured into saturated ammonium chloride solution (20 mL) and extracted twice with ethyl acetate (50 mL). The combined organic phases were washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column to give the product 2-[5-fluoro-3-methoxy-4-isopropenylphenyl]-1-benzofuran (26-C) (310 mg, 1.098 mmol, yield 89.7%) as a colorless oil. 1H NMR (400MHz, CDCl3): δ7.59(m,1H),7.52(m,1H),7.30(m,1H),7.24(m,1H),7 .22(m,2H),7.03(m,1H),5.40(m,1H),5.04(s,1H),3.95(s,3H),2.08(s,3H).

[0309] Step 4: Synthesis of compound 26-D

[0310] 2-[5-Fluoro-3-methoxy-4-isopropenylphenyl]-1-benzofuran (26-C) (150 mg, 0.53 mmol) was dissolved in tetrahydrofuran (10 mL) and 10% palladium on carbon (56 mg, 0.53 mmol) was added. The reaction system was stirred under hydrogen at room temperature for 16 hours. LCMS confirmed the reaction was complete. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified on a silica gel column to give the product, 2-[5-fluoro-3-methoxy-4-isopropylphenyl]-1-benzofuran (26-D) (130 mg, 0.457 mmol, 86.1% yield), as a light yellow oil. 1 H NMR (400MHz, CDCl3): δ7.60(m,1H),7.53(m,1H),7.29(m,1H),7.23(m,1H), 7.21(m,2H),7.02(m,1H),3.95(s,3H),3.42(m,1H),1.29(d,J=7.2Hz,6H).

[0311] Step 5: Synthesis of compound 26

[0312] 2-[5-Fluoro-3-methoxy-4-isopropylphenyl]-1-benzofuran (26-D) (130 mg, 0.457 mmol) was dissolved in anhydrous dichloromethane (5 mL) and 1 M boron tribromide / dichloromethane solution (1.37 mL, 1.37 mmol) was slowly added dropwise at -30°C. The reaction system was warmed to room temperature and stirred for 16 hours. LCMS confirmed the completion of the reaction. The reactants were cooled to 0°C, quenched by the addition of water (2 mL), and extracted twice with dichloromethane (50 mL). The organic phases were combined, washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product 2-[5-fluoro-3-hydroxy-4-isopropylphenyl]-1-benzofuran (26) (42 mg, 0.156 mmol, yield 86.1%) as a light yellow oil. LCMS(ESI):[M+H] + =271.2; 1H NMR (400MHz, DMSO-d6): δ10.08 (s, 1H), 7.66-7.60 (m, 2H), 7.34-7.24 (m, 3H), 7.18-7.13 (m, 2H), 3.44-3.33 (m, 1H), 1.28 (d, J = 7.2Hz, 6H).

[0313] Example 27

[0314] Step 1: Synthesis of compound 27-A

[0315] 4-Isopropyl-3,5-dimethoxybenzoic acid (6-A) (5 g, 19.2 mmol) was dissolved in dichloromethane (50 mL), and 2-acetyl-4-cyanophenol (3.13 g, 23 mmol), 4-dimethylamino-pyridine (0.35 g, 2.87 mmol), and triethylamine (7.99 mL, 57.5 mmol) were added in sequence. After stirring for 5 minutes, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.41 g, 23 mmol) was added and the mixture was stirred at room temperature for 18 hours. LCMS confirmed the reaction was complete. The reaction system was diluted with dichloromethane (100 mL) and water (25 mL). The organic phase was washed three times with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column to give the product 3,5-dimethoxy-4-isopropylbenzoic acid 2-acetyl-4-cyanophenol ester (27-A) (3.7 g, 9.56 mmol, yield 49.9%) as a colorless oil. LCMS (ESI): [M+H] + =368.

[0316] Step 2: Synthesis of compound 27-B

[0317] 2-Acetyl-4-cyanophenol 3,5-dimethoxy-4-isopropylbenzoate (27-A) (2.7 g, 7.12 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), 1 M potassium tert-butoxide (9.97 mL, 9.97 mmol) was added, and the mixture was stirred at room temperature for 18 hours. LCMS detection showed that the reaction was complete. The reaction system was diluted with ethyl acetate (150 mL) and saturated brine (30 mL), and the organic phase was washed three times with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column to obtain the product 3-(4-isopropyl-3,5-dimethoxyphenyl)-1-(2-hydroxy-4-cyanophenyl)propane-1,3-dione (27-B) (1.9 g, 4.71 mmol, yield 66.2%), a colorless oil. LCMS (ESI): [M+H] + =368.

[0318] Step 3: Synthesis of Compound 27-C

[0319] 3-(4-Isopropyl-3,5-dimethoxyphenyl)-1-(2-hydroxy-4-cyanophenyl)propane-1,3-dione (27-B) (1.9 g, 4.71 mmol) was dissolved in acetic acid (20 mL), concentrated sulfuric acid (0.534 mL, 10 mmol) was added, and the mixture was heated to 110°C and stirred for 3 hours. LCMS showed that the reaction was complete. After the reactants were concentrated under reduced pressure, water (20 mL) was added to the residue and stirred for 0.5 hours. The mixture was filtered, washed three times with water (10 mL), and the filter cake was collected and dried to obtain the product 2-(4-isopropyl-3,5-dimethoxyphenyl)-6-cyano-4-hydrogen-chromen-4-one (27-C) (1.55 g, 3.95 mmol, yield 78.8%) as a white solid. LCMS (ESI): [M+H] + =350.

[0320] Step 4: Synthesis of compound 27

[0321] 2-(4-Isopropyl-3,5-dimethoxyphenyl)-6-cyano-4-hydrogen-chromen-4-one (27-C) (180 mg, 0.558 mmol) was dissolved in dichloromethane (5 mL). 1 M boron tribromide / dichloromethane solution (5 mL, 5 mmol) was added at 0°C and the reaction was stirred at room temperature for 3 hours. LCMS confirmed the completion of the reaction. The reaction system was quenched with water (5 mL) and diluted with ethyl acetate (80 mL). The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product 2-(4-isopropyl-3,5-dihydroxyphenyl)-6-cyano-4-hydrogen-chromen-4-one (27) (25 mg, 0.085 mmol, 15.2% yield) as a white solid. LCMS (ESI): [M+H] + =322.2; 1 HNMR (400MHz, DMSO-d6): δ9.62(s,2H),8.45(d,J=2.0Hz,1H),8.23(d,J=4.0,2.0Hz,1H), 7.85(d,J=8.8Hz,1H),6.91(s,2H),6.66(s,1H),3.54-3.46(m,1H),1.27(d,J=7.2Hz,6H).

[0322] The compounds listed in Table 4 below were synthesized according to the similar procedures as in Example 27.

[0323] Table 4

[0324] Example 28

[0325] Step 1: Synthesis of compound 28-A

[0326] 4-Isopropyl-3,5-bis[(methoxymethyl)oxy]benzaldehyde (3-F) (300 mg, 1.12 mmol) was dissolved in ethanol (5 mL), and 2-acetyl-4-methoxyphenol (204 mg, 1.23 mmol) was added. The mixture was cooled to 0°C and stirred for 10 minutes, followed by the dropwise addition of 40% aqueous sodium hydroxide solution (0.4 mL, 5.6 mmol). The reaction was stirred at 25°C for 18 hours, and the reaction was complete as determined by LCMS. The reaction was adjusted to pH 2 with 6M hydrochloric acid and filtered. The filter cake was washed five times with 2 mL of water. The filter cake was collected and purified by column chromatography to yield the product, E-1-(2-hydroxy-4-methoxy)phenyl-3-{4-isopropyl-3,5-bis[(methoxymethyl)oxy]}prop-2-en-1-one (4-A) (150 mg, 0.36 mmol, 32.1% yield), as a yellow solid. LCMS(ESI):[M+H] + =417; 1 H NMR (400MHz, CDCl3): δ12.29(s,1H),7.78-7.74(m,1H),7.45-7.39(m,1H),7.30(m,1H),7.09-7.06(m,1H), 7.00(s,2H),6.92(m,1H),5.17(s,4H),3.77(s,3H),3.62-3.58(m,1H),3.45(s,6H),1.27(d,J=7.2Hz,6H).

[0327] Step 2: Synthesis of compound 28

[0328] E-1-(2-Hydroxy-4-methoxy)phenyl-3-{4-isopropyl-3,5-di[(methoxymethyl)oxy]}prop-2-en-1-one (4-A) (150 mg, 0.36 mmol) was dissolved in dimethyl sulfoxide (2 mL), and iodine (91 mg, 0.36 mmol) was added. The mixture was heated to 120°C in a microwave oven under nitrogen for 1 hour. The reaction system was diluted with ethyl acetate (60 mL) and water (5 mL). The organic phase was washed once with saturated sodium sulfite (10 mL), three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product 2-(4-isopropyl-3,5-dihydroxyphenyl)-6-methoxy-4-hydrogen-chromen-4-one (28) (23 mg, 0.07 mmol, 19.4% yield) as a white solid. LCMS(ESI):[M+H]+ =327.2; 1 H NMR (400MHz, DMSO-d6): δ9.54(s,2H),7.63-7.60(m,1H),7.43-7.40(m,2H),6. 88(s,2H),6.54(s,1H),3.87(s,3H),3.53-3.46(m,1H),1.27(d,J=7.2Hz,6H).

[0329] Example 29

[0330] Step 1: Synthesis of compound 29-A

[0331] 2-{3,5-Bis[(methoxymethyl)oxy]-4-(isopropyl)-phenyl}-3-hydroxy-4-hydrogen-chromen-4-one (5-A) (50 mg, 0.125 mmol) was dissolved in N,N-dimethylformamide (2 mL). Potassium carbonate (35 mg, 0.25 mmol) and iodomethane (27 mg, 0.19 mmol) were added at 0°C. The reaction system was stirred at room temperature for 12 hours. LCMS confirmed the reaction was complete. The reaction system was diluted with ethyl acetate (60 mL) and water (5 mL). The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product 2-{3,5-bis[(methoxymethyl)oxy]-4-(isopropyl)-phenyl}-3-methoxy-4-hydrogen-chromen-4-one (29-A) (51 mg, 0.123 mmol, yield 98.6%) as a colorless oil. LCMS (ESI): [M+H] + =415.2.

[0332] Step 2: Synthesis of compound 29

[0333] 2-{3,5-Bis[(methoxymethyl)oxy]-4-(isopropyl)-phenyl}-3-methoxy-4-hydrogen-chromen-4-one (29-A) (51 mg, 0.123 mmol) was dissolved in tetrahydrofuran (1 mL) and a 4N hydrogen chloride / dioxane solution (1 mL) was added at 0°C. The mixture was stirred at 0°C for 30 minutes and then at room temperature for 3 hours. LCMS confirmed the reaction was complete. The reaction system was diluted with ethyl acetate (60 mL) and water (5 mL). The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product, 2-(3,5-dihydroxy-4-isopropylphenyl)-3-methoxy-4-hydrogen-chromen-4-one (29) (7 mg, 0.021 mmol, 17.1% yield), as a white solid. LCMS(ESI):[M+H]+ =327.2. 1 H NMR (400MHz, DMSO-d6): δ9.44(s,2H),8.10-8.07(m,1H),7.82-7.80(m,1H),7.63-7.61(m, 1H),7.51-7.49(m,1H),7.05(s,2H),3.81(s,3H),3.54-3.51(m,1H),1.27(d,J=6.8Hz,6H).

[0334] Example 30

[0335] Step 1: Synthesis of compound 30-A

[0336] 2-{3,5-Bis[(methoxymethyl)oxy]-4-(isopropyl)-phenyl}-3-hydroxy-4-hydrogen-chromen-4-one (5-A) (80 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide (2 mL). Potassium carbonate (55 mg, 0.4 mmol) and 2-bromoacetamide (41 mg, 0.3 mmol) were added at 0°C, and the reaction system was stirred at room temperature for 12 hours. LCMS confirmed the reaction was complete. The reaction system was diluted with ethyl acetate (60 mL) and water (5 mL). The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product 2-({2-[4-isopropyl-3,5-bis(methoxymethyl)oxyphenyl]-4-oxo-4-hydrogen-chromen-3-yl}oxy)acetamide (30-A) (65 mg, 0.14 mmol, yield 71%) as a colorless oil. LCMS (ESI): [M+H] + =458.2.

[0337] Step 2: Synthesis of compound 30

[0338] 2-({2-[4-Isopropyl-3,5-bis(methoxymethyl)oxyphenyl]-4-oxo-4-hydrogen-chromen-3-yl}oxy)acetamide (30-A) (65 mg, 0.14 mmol) was dissolved in tetrahydrofuran (1 mL) and a 4N hydrogen chloride / dioxane solution (1 mL) was added at 0°C. After stirring at 0°C for 30 minutes, the mixture was stirred at room temperature for 3 hours. LCMS analysis indicated that the reaction was complete. The reaction system was diluted with ethyl acetate (60 mL) and water (5 mL), and the organic phase was washed three times with a saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product 2-{[2-(3,5-dihydroxy-4-isopropylphenyl)-4-oxo-4-hydrogen-chromen-3-yl]oxy}acetamide (30) (6 mg, 0.016 mmol, yield 11.4%) as a white solid. LCMS (ESI): [M+H] + =370.2. 1 H NMR (400MHz, DMSO-d6): δ9.49(s,2H),8.12-8.09(m,1H),7.85-7.83(m,1H),7.66-7.64(m, 2H),7.54-7.50(m,2H),7.00(s,2H),4.33(s,2H),3.54-3.47(m,1H),1.27(d,J=7.2Hz,6H).

[0339] Example 31

[0340] Step 1: Synthesis of compound 31-A

[0341] 5-Bromo-1-fluoro-3-methoxy-2-isopropenylbenzene (26-B) (1.4 g, 5.7 mmol) was dissolved in ethyl acetate (70 mL), and platinum dioxide (0.3 g, 1.32 mmol) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 15 hours. LCMS confirmed the reaction was complete. The reaction system was filtered and concentrated under reduced pressure to afford the crude product, 5-bromo-1-fluoro-3-methoxy-2-isopropylbenzene (31-A) (1.4 g, 5.665 mmol, 99.2% yield), as a pale yellow oil, which was used directly in the next step. 1 H NMR (400MHz, DMSO-d6): δ6.84-6.80(m,1H),6.76-6.75(m,1H),3.81(s,3H),3.45-3.38(m,1H),1.27-1.25(m,6H).

[0342] Step 2: Synthesis of compound 31-B

[0343] 5-Bromo-1-fluoro-3-methoxy-2-isopropylbenzene (31-A) (1.3 g, 5.26 mmol) was dissolved in anhydrous tetrahydrofuran (13 mL). 2.5 M n-butyllithium solution (2.53 mL, 6.33 mmol) was slowly added dropwise at -78°C. After the addition was complete, the mixture was stirred at -78°C for 30 minutes, and N,N-dimethylformamide (0.81 mL, 10.52 mmol) was added. After stirring at room temperature for 2 hours, LCMS indicated the reaction was complete. The reaction was quenched by pouring into saturated ammonium chloride solution (30 mL). The mixture was extracted three times with ethyl acetate (40 mL). The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product 3-fluoro-5-methoxy-4-isopropylbenzaldehyde (31-B) (380 mg, 1.94 mmol, yield 36.8%) as a light yellow solid. 1 H NMR (400MHz, DMSO-d6): δ9.87(m,1H),7.17-7.12(m,2H),3.89(s,3H),3.57-3.50(m,1H),1.32-1.30(m,6H).

[0344] Step 3: Synthesis of compound 31-C

[0345] 3-Fluoro-5-methoxy-4-isopropylbenzaldehyde (31-B) (0.38 g, 1.94 mmol) and 2-acetylphenol were dissolved in ethanol (10 mL) and 40% sodium hydroxide solution (2.05 mL, 29 mmol) was added dropwise at 0°C. After the addition was complete, the reaction system was stirred at room temperature for 12 hours. LCMS indicated the reaction was complete. The reaction mixture was poured into water (30 mL), the pH was adjusted to 6-7 with 1N hydrochloric acid, and the mixture was extracted three times with ethyl acetate (30 mL). The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield (2E)-3-(5-fluoro-3-methoxy-4-isopropylphenyl)-1-(2-hydroxyphenyl)propyl-2-enyl-1-one (31-C) (105 mg, 0.334 mmol, 17.3% yield) as a yellow oil. LCMS(ESI):[M+H] + =315.2.

[0346] Step 4: Synthesis of compound 31-D

[0347] (2E)-3-(5-Fluoro-3-methoxy-4-isopropylphenyl)-1-(2-hydroxyphenyl)propyl-2-enyl-1-one (31-C) (90 mg, 0.286 mmol) was dissolved in dimethyl sulfoxide (5 mL), iodine (36 mg, 0.143 mmol) was added, and the mixture was stirred at 140°C for 2 hours. LCMS showed that the reaction was complete. The reaction was poured into saturated sodium sulfite (20 mL) and extracted three times with ethyl acetate (30 mL). The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product, 2-(5-fluoro-3-methoxy-4-isopropylphenyl)-4-hydrogen-chromen-4-one (31-D) (60 mg, 0.192 mmol, yield 67.1%), as a light yellow solid. LCMS (ESI): [M+H] + =313.2.

[0348] Step 5: Synthesis of compound 31

[0349] 2-(5-Fluoro-3-methoxy-4-isopropylphenyl)-4-hydrogen-chromen-4-one (31-D) (50 mg, 0.16 mmol) was dissolved in anhydrous dichloromethane (2 mL). 1 M boron tribromide / dichloromethane solution (0.48 mL, 0.48 mmol) was added at -30°C and the reaction was stirred at room temperature for 2 hours. LCMS confirmed the completion of the reaction. The reaction system was quenched with water (5 mL) and diluted with dichloromethane (80 mL). The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product 2-(4-isopropyl-3,5-dihydroxyphenyl)-6-cyano-4-hydrogen-chromen-4-one (27) (12 mg, 0.04 mmol, yield 25.1%) as a white solid. LCMS (ESI): [M+H] + =299.2; 1 H NMR (400MHz, DMSO-d6): δ10.29(s,1H),8.07-8.04(m,1H),7.85-7.83(m,1H),7.74-7.72(m,1H),7.54-7 .51(m,1H),7.38-7.35(m,1H),7.3-7.30(m,1H),6.89(s,1H),3.47-3.40(m,1H),1.29(d,J=6.8Hz,6H).

[0350] The compounds listed in Table 5 below were synthesized according to the similar procedures as in Example 31.

[0351] Table 5

[0352] Example 32

[0353] Step 1: Synthesis of compound 32-A

[0354] 3,5-Dimethoxy-4-isopropylbenzoic acid (6-A) (17.92 g, 80 mmol) was dissolved in methanol (300 mL), and thionyl chloride (7 mL, 100 mmol) was slowly added dropwise. After the addition was complete, the reaction system was heated to 70 ° C and stirred for 3 hours. LCMS detection showed that the reaction was complete. The reaction system was concentrated under reduced pressure, the residue was diluted with ethyl acetate (300 mL), the organic phase was washed three times with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column to obtain the product 3,5-dimethoxy-4-isopropylbenzoic acid methyl ester (32-A) (15 g, 63 mmol, yield 78.8%), a colorless oil. LCMS (ESI): [M+H] + =239.2.

[0355] Step 2: Synthesis of compound 32-B

[0356] Methyl 3,5-dimethoxy-4-isopropylbenzoate (32-A) (15 g, 63 mmol) was dissolved in tetrahydrofuran (200 mL) and lithium aluminum tetrahydride (3.58 g, 94.4 mmol) was added at 0°C. The reaction system was stirred at room temperature for 2 hours and then quenched by the addition of sodium sulfate decahydrate (8 g). The reaction mixture was filtered and the filtrate was concentrated to give the crude product 3,5-dimethoxy-4-isopropyl-1-benzyl alcohol (32-B) (12 g, 45.7 mmol, 72.5% yield), a yellow oil, which was used directly in the next reaction. LCMS (ESI): [M+H] + =211.2.

[0357] Step 3: Synthesis of compound 32-C

[0358] 3,5-Dimethoxy-4-isopropyl-1-benzyl alcohol (32-B) (12 g, 45.7 mmol) was dissolved in dichloromethane (150 mL), and Dess-Martin reagent (38.7 g, 91.3 mmol) was added and stirred at room temperature for 3 hours. LCMS detected that the reaction was complete. The reaction system was quenched by adding saturated ammonium chloride solution (50 mL), diluted with dichloromethane (150 mL), and the organic phase was washed three times with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column to obtain

[0359] The product 3,5-dimethoxy-4-isopropylbenzaldehyde (32-C) (9 g, 43.2 mmol, yield 94.5%) was obtained as a yellow solid. LCMS (ESI): [M+H] + =209.2.

[0360] Step 4: Synthesis of compound 32-D

[0361] 3,5-Dimethoxy-4-isopropylbenzaldehyde (32-C) (9 g, 43.2 mmol) was dissolved in methanol (100 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (16.6 g, 86.4 mmol) and potassium carbonate (11.9 g, 86.4 mmol) were added. The reaction was stirred at room temperature for 16 hours. LCMS confirmed the reaction was complete. The reaction system was quenched by the addition of saturated ammonium chloride solution (50 mL), diluted with ethyl acetate (300 mL), and the organic phase was washed three times with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified on a silica gel column to yield the product, 3,5-dimethoxy-4-isopropylphenylacetylene (32-D) (7.9 g, 38.7 mmol, 89.6% yield), as a white solid. 1 H NMR (400MHz, DMSO-d6): δ6.70 (s, 2H), 4.72 (s, 1H), 3.75 (s, 6H), 3.57-3.48 (m, 1H), 1.19 (d, J = 7.2Hz, 6H).

[0362] Step 5: Synthesis of compound 32-E

[0363] 3,5-Dimethoxy-4-isopropylphenylacetylene (32-D) (100 mg, 0.49 mmol) was dissolved in N,N-dimethylformamide (3 mL). Triethylamine (2 mL), 3-fluoro-2-methoxyiodobenzene (123.5 mg, 0.49 mmol), cuprous iodide (9 mg, 0.049 mmol), and bistriphenylphosphine palladium dichloride (76 mg, 0.1 mmol) were added. The mixture was heated to 100°C for 18 hours. LCMS confirmed the reaction was complete. The reaction system was diluted with ethyl acetate (60 mL) and water (10 mL). The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column to give the product 5-[(3-fluoro-2-methoxyphenyl)ethynyl]-1,3-dimethoxy-2-isopropylbenzene (32-E) (70 mg, 0.21 mmol, yield 34.8%) as a yellow solid. LCMS (ESI): [M+H] + =329.2.

[0364] Step 6: Synthesis of compound 32

[0365] 5-[(3-Fluoro-2-methoxyphenyl)ethynyl]-1,3-dimethoxy-2-isopropylbenzene (32-E) (60 mg, 0.18 mmol) was dissolved in anhydrous dichloromethane (2 mL). 1 M boron tribromide / dichloromethane solution (1.1 mL, 1.1 mmol) was added at 0°C and the reaction was stirred at room temperature for 18 hours. LCMS confirmed the completion of the reaction. The reaction system was quenched with methanol (1 mL), diluted with dichloromethane (80 mL), and the organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product 5-(7-fluoro-1-benzofuran-2-yl)-2-isopropyl-1,3-benzenediol (32) (11 mg, 0.038 mmol, yield 21.1%) as a white solid. LCMS(ESI):[M+H] + =287.2; 1 H NMR (400MHz, DMSO-d6): δ9.39(s,2H),7.47-7.45(m,1H),7.26-7.20(m,2H) ,7.18-7.16(m,1H),6.83(s,2H),3.51-3.44(m,1H),1.26(d,J=7.2Hz,6H).

[0366] The compounds listed in Table 6 below were synthesized according to the similar procedures as in Example 32.

[0367] Table 6

[0368] Example 33

[0369] Step 1: Synthesis of compound 33-A

[0370] 5-Bromo-1,3-dimethoxy-2-isopropylbenzene (1 g, 3.86 mmol) was dissolved in dioxane (10 mL) and water (2 mL). Benzofuran-2-boronic acid pinacol ester (1.04 g, 4.25 mmol), potassium carbonate (1.6 g, 11.58 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.14 g, 0.19 mmol) were added. The mixture was heated to 100°C and stirred for 15 hours. The reaction was complete by LCMS. After the reaction system was filtered, the filtrate was diluted with ethyl acetate (120 mL) and water (10 mL), and the organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column to give the product 2-(3,5-dimethoxy-4-isopropylphenyl)-1-benzofuran (33-A) (0.89 g, 3 mmol, yield 77.7%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ7.65-7.62(m,2H),7.49(s,1H),7.34-7.24(m,2H),7.14(s,2H),3.87(s,6H),3.61-3.53(m,1H),1.24(d,J=6.8Hz,6H).

[0371] Step 2: Synthesis of compound 33-B

[0372] 2-(3,5-Dimethoxy-4-isopropylphenyl)-1-benzofuran (33-A) (0.3 g, 1 mmol) was dissolved in acetonitrile (16 mL) and water (0.8 mL). 1-Chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (394 mg, 1.11 mmol) was added at 0°C and stirred at 0°C for 20 minutes and at room temperature for 1 hour. LCMS confirmed the reaction was complete. The reaction system was diluted with dichloromethane (70 mL) and water (5 mL). The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified on a silica gel column to obtain the product, 2-(2-fluoro-4-isopropyl-3,5-dimethoxyphenyl)benzofuran (33-B) (64 mg, 0.2 mmol, 20% yield), as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ7.55-7.52(m,1H),7.47-7.45(m,1H),7.25-7.15(m,2H),7.12(s, 1H), 6.97 (s, 1H), 7.14 (s, 2H), 3.84-3.83 (m, 6H), 3.49-3.46 (m, 1H), 1.26 (d, J = 7.2Hz, 6H).

[0373] Step 3: Synthesis of compound 33

[0374] 2-(2-Fluoro-4-isopropyl-3,5-dimethoxyphenyl)benzofuran (33-B) (64 mg, 0.2 mmol) was dissolved in anhydrous dichloromethane (2 mL), and 1 M boron tribromide / dichloromethane solution (1 mL, 1 mmol) was added at 0°C. The reaction was stirred at room temperature for 18 hours. LCMS showed that the reaction was complete. The reaction system was quenched with methanol (1 mL), diluted with dichloromethane (80 mL), and the organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product 5-(benzofuran-2-yl)-4-fluoro-2-isopropyl-1,3-benzenediol (33) (20 mg, 0.07 mmol, yield 35%). LCMS (ESI): [M+H] + =287.2; 1 H NMR (400MHz, DMSO-d6): δ9.42 (d, J = 2.4Hz, 1H), 9.34 (s, 1H), 7.68-7.67 (m, 1H), 7.63-7.60 (m, 1H), 7.35-7.24(m,2H),7.27-7.26(m,1H),6.89-6.87(m,1H),3.52-3.45(m,1H),1.28(d,J=6.8Hz,6H); 19 FNMR (400MHz, DMSO-d6): δ-146.15.

[0375] Example 34

[0376] Step 1: Synthesis of compound 34

[0377] 3-Methyl-benzofuran-2-carboxylic acid (151 mg, 0.86 mmol) was dissolved in N,N-dimethylformamide (2 mL). 5-Bromo-2-isopropyl-1,3-benzenediol (100 mg, 0.43 mmol), bis(tri-tert-butylphosphine)palladium (22 mg, 0.043 mmol), tetrabutylammonium chloride (120 mg, 0.43 mmol), and cesium carbonate (423 mg, 1.3 mmol) were added. The mixture was heated to 170°C in a microwave oven for 1 hour. LCMS confirmed the formation of the desired product. The reaction mixture was diluted with saturated ammonium chloride (10 mL) and ethyl acetate (80 mL). The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid added) to give the product 5-(3-methyl-1-benzofuran-2-yl)-2-isopropyl-1,3-benzenediol (34) (20 mg, 0.07 mmol, yield 8.1%). LCMS (ESI): [M+H] + =283.2; 1 H NMR (400MHz, DMSO-d6): δ9.27(s,2H),7.62-7.60(m,1H),7.54-7.52(m,1H),7.32 -7.23(m,2H),6.79(s,2H),3.51-3.44(m,1H),2.42(s,3H),1.27(d,J=7.2Hz,6H).

[0378] Example 35

[0379] Step 1: Synthesis of compound 35-A

[0380] 4-Methanesulfonylphenol (2 g, 11.6 mmol) and methanesulfonic acid (1.74 g, 11.6 mmol) were dissolved in acetonitrile (20 mL), cooled to -20 ° C, added N-bromosuccinimide (2.27 g, 12.8 mmol), and slowly heated to room temperature for 3 hours. LCMS detection showed that the reaction was complete. Saturated ammonium chloride (10 mL) and ethyl acetate (100 mL) were added to the reaction mixture and diluted. The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column to obtain the product 2-bromo-4-methylsulfonylphenol (35-A) (1.12 g, 4.5 mmol, yield 38.8%) as a white solid. LCMS (ESI): [MH] - =248.9,250.9; 1H NMR (400MHz, DMSO-d6): δ11.55(s,1H),7.98(m,1H),7.75-7.72(m,1H),7.15(m,1H),3.39(s,3H).

[0381] Step 2: Synthesis of compound 35-B

[0382] 2-Bromo-4-methylsulfonylphenol (35-A) (615 mg, 2.45 mmol) and 5-ethynyl-1,3-dimethoxy-2-isopropylbenzene (500 mg, 2.45 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). Triethylamine (1.5 mL), cuprous iodide (47 mg, 0.245 mmol), and bis(triphenylphosphine)palladium dichloride (190 mg, 0.245 mmol) were added. The mixture was heated to 150°C in a microwave oven for 2 hours. LCMS confirmed the reaction was complete. Saturated ammonium chloride (10 mL) and ethyl acetate (100 mL) were added to the reaction mixture and diluted. The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column to give the product 2-(3,5-dimethoxy-4-isopropyl-phenyl)-5-methylsulfonylbenzofuran (35-B) (70 mg, 0.19 mmol, yield 7.6%) as a yellow oil. LCMS (ESI): [M+H] + =375.2; 1 H NMR (400MHz, DMSO-d6): δ8.25(s,1H),7.92-7.87(m,2H),7.67(s,1H),7.19 (s,2H),3.89(s,6H),3.60-3.54(m,1H),3.26(s,3H),1.24(d,J=6.8Hz,6H).

[0383] Step 3: Synthesis of compound 35

[0384] 2-(3,5-Dimethoxy-4-isopropyl-phenyl)-5-methylsulfonylbenzofuran (35-B) (70 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL), cooled to -30°C, and 1 M boron tribromide / dichloromethane solution (1.1 mL, 1.1 mmol) was added. The reaction was stirred at room temperature for 16 hours. LCMS confirmed the completion of the reaction. Saturated ammonium chloride solution (5 mL) and dichloromethane (70 mL) were added to the reaction system. The organic phase was washed three times with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% formic acid addition) to give the product 2-(3,5-dihydroxy-4-isopropyl-phenyl)-5-methylsulfonylbenzofuran (35) (32 mg, 0.09 mmol, yield 47.4%) as a white solid. LCMS (ESI): [M+H] + =347.2; 1 H NMR (400MHz, DMSO-d6): δ9.42(s,2H),8.25(s,1H),7.87-7.85(m,2H),7.25(s,1H) ,6.84(s,2H),3.89(s,6H),3.50-3.44(m,1H),3.23(s,3H),1.26(d,J=6.8Hz,6H).

[0385] Example 36

[0386] Step 1: Synthesis of compound 36-A

[0387] Methyl 4-bromo-1,3-dimethoxybenzoate (5 g, 18.2 mmol) was dissolved in 1,4-dioxane (40 mL). Diboronic acid pinacol ester (6.92 g, 27.3 mmol), potassium acetate (3.57 g, 36.4 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.33 g, 1.82 mmol) were added sequentially. The reaction mixture was stirred at 110°C for 18 hours. LCMS confirmed the reaction was complete. The reaction mixture was cooled and concentrated under reduced pressure. Ethyl acetate (150 mL) and water (30 mL) were added, and the mixture was separated by extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to yield methyl 3,5-dimethoxy-4-pinacol boronate benzoate (36-A) (3.4 g, 10.6 mmol, 58.1% yield) as a yellow oil. LCMS(ESI):[M+H] + =323.2.

[0388] Step 2: Synthesis of compound 36-B

[0389] Methyl 3,5-dimethoxy-4-pinacol boronate benzoate (36-A) (1.50 g, 4.66 mmol) was dissolved in a mixture of 1,4-dioxane (20 mL) and water (2 mL). 2-Penten-3-hydroxy trifluoromethanesulfonate (1.52 g, 7 mmol), potassium phosphate (1.98 g, 9.3 mmol), and tetrakis(triphenylphosphine)palladium (0.54 g, 0.47 mmol) were added. The reaction system was heated to 80°C and stirred for 18 hours. The reaction mixture was cooled and concentrated under reduced pressure. Ethyl acetate (100 mL) and water (20 mL) were added, and the mixture was separated by extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford methyl 3,5-dimethoxy-4-(2-penten-3-yl)benzoate (36-B) (1.1 g, 4.16 mmol, 89.3% yield) as a white solid. LCMS(ESI):[M+H] + =265.2.

[0390] Step 3: Synthesis of compound 36-C

[0391] Methyl 3,5-dimethoxy-4-(2-penten-3-yl)benzoate (36-B) (1.1 g, 4.16 mmol) was dissolved in methanol (10 mL), 10% palladium / carbon (0.44 g, 4.16 mmol) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 48 hours. The reaction system was filtered and concentrated, and the crude product was dissolved in ethanol (10 mL), 4M sodium hydroxide solution (10 mL, 40 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, 6Nd hydrochloric acid (10 mL) was added, and ethyl acetate (80 mL) was added for extraction. The organic phase was concentrated under reduced pressure to give 3,5-dimethoxy-4-(2-penten-3-yl)benzoic acid (36-C) (1 g, 3.96 mmol, yield 95.2%) as a white solid. LCMS (ESI): [M+H] + =253.2.

[0392] Step 4: Synthesis of compound 36-D

[0393] 3,5-Dimethoxy-4-(2-penten-3-yl)benzoic acid (36-C) (1 g, 3.96 mmol) was mixed with thionyl chloride (7 mL), reacted at 80°C for 3 hours, and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL) and added dropwise to a solution of 2-acetylphenol (1.05 g, 7.7 mmol) dissolved in pyridine (8 mL). The reaction system was stirred at room temperature for 2 hours. Saturated ammonium chloride solution (15 mL) was added and extracted with dichloromethane (100 mL). The organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain 2-acetylphenol 3,5-dimethoxy-4-(3-pentyl)benzoate (36-D) (1.03 g, 2.78 mmol, yield 70.2%) as a yellow solid. LCMS (ESI): [M+H] + =371.2.

[0394] Step 4: Synthesis of compound 36-E

[0395] 2-Acetylphenol 3,5-dimethoxy-4-(3-pentyl)benzoate (36-D) (1.03 g, 2.78 mmol) was dissolved in anhydrous pyridine (5 mL), and sodium hydroxide (0.5 g, 12.5 mmol) was added. The mixture was stirred at 50°C for 3 hours. The reaction system was quenched with water and the pH was adjusted to 6 with 3M hydrochloric acid. The solution was extracted with ethyl acetate (80 mL) and dried, and concentrated under reduced pressure to give 1-[3,5-dimethoxy-4-(3-pentyl)phenyl]-3-(2-hydroxyphenyl)-1,3-propanedione (36-E) (1.33 g, 2.7 mmol, 96.8% yield) as a light brown solid. LCMS (ESI): [M+H] + =371.2.

[0396] Step 5: Synthesis of compound 36-F

[0397] 1-[3,5-Dimethoxy-4-(3-pentyl)phenyl]-3-(2-hydroxyphenyl)-1,3-propanedione (36-E) (1.33 g, 2.7 mmol) was dissolved in acetic acid (12 mL), sulfuric acid (0.67 mL, 12.5 mmol) was added, and the mixture was heated to 100°C with stirring for 3 hours. The reaction system was quenched with water (20 mL) and extracted with ethyl acetate (80 mL). The organic phase was dried and concentrated under reduced pressure, and the residue was purified by column chromatography to give 2-[3,5-dimethoxy-4-(3-pentyl)phenyl]-4-hydrogen-chromen-4-one (36-F) (0.8 g, 2.27 mmol, yield 84.1%) as a light brown solid. LCMS (ESI): [M+H] + =353.2; 1H NMR (400MHz, DMSO-d6): δ8.07-8.05(m,1H),7.86-7.83(m,2H),7.55-7.48(m,1H),7.32(s,2H),7.18(s ,1H),3.88(s,6H),3.2-3.15(m,1H),1.78-1.74(m,2H),1.68-1.63(m,2H),0.72-0.68(t,J=7.2Hz,6H).

[0398] Step 5: Synthesis of compound 36

[0399] 2-[3,5-Dimethoxy-4-(3-pentyl)phenyl]-4-hydrogen-chromen-4-one (36-F) (0.8 g, 2.27 mmol) was dissolved in dichloromethane (5 mL), cooled to -20°C, and a 1 M boron tribromide solution in dichloromethane (12 mL, 12 mmol) was added. The mixture was stirred at 0°C for 8 hours. The reaction system was quenched with ice water and extracted with ethyl acetate (80 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography and recrystallized from acetonitrile to give 2-[3,5-dihydroxy-4-(3-pentyl)phenyl]-4-hydrogen-chromen-4-one (36) (0.54 g, 1.67 mmol, yield 73.6%) as an off-white solid. LCMS (ESI): [M+H] + =325.2; 1 HNMR (400MHz, DMSO-d6): δ9.45(s,2H),8.06-8.04(m,1H),7.86-7.84(m,1H),7.68-7.63(m,1H),7.54-7.48(m,1H ), 6.90 (s, 2H), 6.58 (s, 1H), 3.13-3.02 (m, 1H), 1.92-1.79 (m, 2H), 1.69-1.56 (m, 2H), 0.77-0.69 (t, J = 7.2Hz, 6H).

[0400] The compounds listed in Table 7 below were synthesized according to the similar procedures as in Example 36.

[0401] Table 7

[0402] Example 37

[0403] Step 1: Synthesis of compound 37-A

[0404] 1,2,3,4,5-Pentadeutero-6-deuterohydroxybenzene (800 mg, 8 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (2.64 mL, 16 mmol) was added. Acetyl chloride (0.85 mL, 12 mmol) was then added dropwise at 0°C. The reaction was stirred at 0°C for 30 minutes and then at room temperature overnight. Upon completion, the mixture was diluted with dichloromethane (60 mL) and water (10 mL). The organic phase was dried and concentrated under reduced pressure. The residue was purified by column chromatography to afford 2,3,4,5,6-pentadeutero-1-acetoxybenzene (37-A) (760 mg, 5.38 mmol, 67.3% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ2.30 (s, 3H).

[0405] Step 2: Synthesis of compound 37-B

[0406] 2,3,4,5,6-pentadeuterated-1-acetoxybenzene (37-A) (760 mg, 5.38 mmol) was dissolved in dichloromethane (10 mL), and aluminum chloride (790 mg, 5.9 mmol) was added. The mixture was reacted at 90°C overnight. The reaction system was cooled, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 2-acetyl-3,4,5,6-tetradeuterated phenol (37-B) (190 mg, 1.36 mol, 25.2% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ12.25 (s, 1H), 2.64 (s, 3H).

[0407] Step 3: Synthesis of compound 37-C

[0408] 2-Acetyl-3,4,5,6-tetradeuterophenol (37-B) (190 mg, 1.36 mol) was dissolved in dichloromethane (3 mL). Triethylamine (0.93 mL, 6.7 mmol) was added dropwise to the solution at 0°C. A solution of 3,5-dimethoxy-4-isopropylbenzoyl chloride (540 mg, 2.2 mmol) in dichloromethane (3 mL) was then added dropwise. The mixture was allowed to react at 0°C for 2 hours. The reaction system was concentrated under reduced pressure, and the residue was diluted with dichloromethane (60 mL) and water (10 mL). The organic phase was dried and concentrated, and the residue was purified by column chromatography to afford 2-acetyl-3,4,5,6-tetradeuterophenol 3,5-dimethoxy-4-isopropylbenzoate (37-C) (120 mg, 0.35 mmol, 25.6% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6): δ7.32 (s, 2H), 3.85 (s, 6H), 3.67-3.59 (m, 1H), 2.50 (s, 3H), 1.26 (d, J = 7.2Hz, 6H).

[0409] Step 4: Synthesis of compound 37-D

[0410] 3,5-Dimethoxy-4-isopropylbenzoic acid-2-acetyl-3,4,5,6-tetradeuterophenol ester (37-C) (120 mg, 0.35 mmol) was dissolved in pyridine (1 mL), sodium hydroxide (21 mg, 0.52 mmol) was added, and the mixture was heated to 50°C and stirred for 3 hours. The reaction system was adjusted to pH = 5 with 1N hydrochloric acid, and ethyl acetate (60 mL) and water (5 mL) were added to dilute it. The organic phase was dried and concentrated to give the product 1-(3,5-dimethoxy-4-isopropylphenyl)-3-(3,4,5,6-tetradeutero-2-hydroxyphenylpropane-1,3-dione (37-D) (78 mg, 0.225 mmol, yield 64.2%) as a colorless oil. LCMS (ESI): [M+H] + =347.2

[0411] Step 5: Synthesis of compound 37-E

[0412] 1-(3,5-Dimethoxy-4-isopropylphenyl)-3-(3,4,5,6-tetradeutero-2-hydroxyphenylpropane-1,3-dione (37-D) (78 mg, 0.225 mmol) was dissolved in acetic acid (2 mL), sulfuric acid (1 mL) was added, and the mixture was heated to 100°C and stirred for 3 hours. The reaction system was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (60 mL) and water (5 mL). The organic phase was dried and concentrated, and the residue was purified by column chromatography to give 5,6,7,8-tetradeutero-2-(1,3-dimethoxy-2-isopropylphenyl-5-yl)-4-hydrogen-chromen-4-one (50 mg, 0.152 mmol, yield 67.6%) as a white solid. LCMS (ESI): [M+H] + =329.2; 1 H NMR (400 MHz, DMSO-d6): δ7.30 (s, 2H), 7.16 (s, 1H), 3.90 (s, 6H), 3.63-3.56 (m, 1H), 1.25 (d, J = 7.2Hz, 6H).

[0413] Step 6: Synthesis of compound 37

[0414] 5,6,7,8-tetradeutero-2-(1,3-dimethoxy-2-isopropylphenyl-5-yl)-4-hydrogen-chromen-4-one (50 mg, 0.14 mmol) was dissolved in dichloromethane (0.3 mL) and cooled to -30°C. A 1 M boron tribromide dichloromethane solution (0.76 mL, 0.76 mmol) was added dropwise. The reaction was stirred at -30°C for 30 minutes and then allowed to stand at room temperature overnight. The reaction was cooled to 0°C and dichloromethane (40 mL) and water (2 mL) were added. The organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative purification to give 5,6,7,8-tetradeutero-2-(1,3-dihydroxy-2-isopropylphenyl-5-yl)-4-hydrogen-chromen-4-one (37) (31 mg, 0.1 mmol, 71.4% yield) as a white solid. LCMS (ESI): [M+H] + =301.2; 1 H NMR (400MHz, DMSO-d6): δ9.57 (s, 2H), 6.90 (s, 2H), 6.56 (s, 1H), 3.52-3.48 (m, 1H), 1.27 (d, J = 7.2Hz, 6H).

[0415] Example 38

[0416] Step 1: Synthesis of compound 38-A

[0417] 2-(4-Bromo-3,5-dimethoxyphenyl)-4-hydrogen-chromen-4-one (22-C) (1.5 g, 4.17 mmol) was dissolved in N,N-dimethylformamide (15 mL). 1-Tributyltin ethoxylate (3 g, 8.3 mmol) and tetrakis(triphenylphosphine)palladium were added sequentially. The mixture was heated to 110°C and stirred for 18 hours. The reaction mixture was poured into 1M hydrochloric acid (20 mL) and stirred for 1 hour before extraction with ethyl acetate (100 mL). The organic phase was dried and concentrated, and the residue was purified by column chromatography to afford 2-(4-acetyl-3,5-dimethoxyphenyl)-4-hydrogen-chromen-4-one (38-A) (0.8 g, 2.35 mmol, 56.4% yield) as a yellow solid. LCMS (ESI): [M+H] + =325.2.

[0418] Step 2: Synthesis of compound 38-B

[0419] 2-(4-Acetyl-3,5-dimethoxyphenyl)-4-hydrogen-chromen-4-one (38-A) (0.8 g, 2.35 mmol) was dissolved in dichloromethane (12 mL). 1N boron tribromide in dichloromethane (20 mL, 20 mmol) was added dropwise at -30°C. After stirring at room temperature for 18 hours, the reaction was quenched by adding ice water (5 mL). The mixture was diluted with ethyl acetate (80 mL). The organic phase was dried and concentrated. The residue was purified by column chromatography to give 2-(4-acetyl-3,5-dihydroxyphenyl)-4-hydrogen-chromen-4-one (38-B) (0.5 g, 1.69 mmol, 71.9% yield) as a light brown solid. LCMS (ESI): [M+H] + =297.2; 1 H NMR (400MHz, DMSO-d6): δ11.87(br,2H),8.08-8.05(m,1H),7.89-7.84(m,1H) ,7.76-7.73(m1H),7.55-7.51(m,1H),7.05(s,2H),6.90(s,1H),2.66(s,3H).

[0420] Step 3: Synthesis of compound 38-C

[0421] 2-(4-Acetyl-3,5-dihydroxyphenyl)-4-hydrogen-chromen-4-one (38-B) (0.5 g, 1.69 mmol) was dissolved in methanol (10 mL). Sodium borohydride (192 mg, 5.06 mmol) was added at 0°C and stirred at 0°C for 2 hours. Ice water (5 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (50 mL). The organic phase was dried and concentrated, and the residue was purified by column chromatography to give 2-[3,5-dihydroxy-4-(1-hydroxyethyl)phenyl]-4-hydrogen-chromen-4-one (38-C) (420 mg, 1.41 mmol, 83.4% yield) as a white solid. LCMS (ESI): [M+H] + =299.2; 1 H NMR (400MHz, DMSO-d6): δ8.06-8.02(m,1H),7.87-7.79(m,1H),7.74-7.69(m1H),7.53-7.46(m,1 H), 6.93 (s, 2H), 6.75 (s, 1H), 5.31-5.22 (m, 1H), 2.07 (s, 1H), 2.66 (s, 3H), 1.39 (d, J = 6.4Hz, 3H).

[0422] Step 4: Synthesis of compound 38-D

[0423] 2-[3,5-Dihydroxy-4-(1-hydroxyethyl)phenyl]-4-hydrochromen-4-one (38-C) (420 mg, 1.41 mmol) was dissolved in chloroform (10 mL), and 4-methylbenzenesulfonic acid pyridinium salt (35 mg, 0.14 mmol) and 2-methoxypropylene (122 mg, 1.69 mmol) were added. The mixture was stirred at room temperature for 8 hours. The reaction system was diluted with water (10 mL) and ethyl acetate (80 mL). The organic phase was dried and concentrated, and the residue was purified by column chromatography to give 2-(5-hydroxy-2,2,4-trimethyl-4-hydro-benzo[1,3]dioxane-7-yl)-4-hydrochromen-4-one (38-D) (350 mg, 1.03 mmol, 73.5% yield) as a light yellow oil. LCMS (ESI): [M+H] + =339.2; 1 H NMR (400MHz, DMSO-d6): δ10.25(s,1H),8.06-8.03(m,1H),7.86-7.82(m,1H),7.74-7.72(m1H),7.53-7 .49(m,1H),7.05(s,1H),7.01(s,1H),6.80(s,1H),5.02-4.97(m,1H),1.56-1.53(m,3H),1.35(s,6H).

[0424] Step 5: Synthesis of compound 38-E

[0425] 2-(5-Hydroxy-2,2,4-trimethyl-4-hydro-benzo[1,3]dioxane-7-yl)-4-hydro-chromen-4-one (38-D) (350 mg, 1.03 mmol) was dissolved in dichloromethane (2 mL) and tetrahydrofuran (2 mL). Triethylamine (0.58 mL, 4.14 mmol) was added at 0°C, and trifluoromethanesulfonic anhydride (438 mg, 1.55 mmol) was slowly added dropwise. The mixture was stirred at 0°C for 2 hours and at room temperature for 2 hours. The reaction system was diluted with water (2 mL) and ethyl acetate (50 mL). The organic phase was dried and concentrated, and the residue was purified by column chromatography to give 2,2,4-trimethyl-7-(4-oxochromen-2-yl)-4-hydro-[1,3]dioxane[5,4-b]phenyl-5-yl trifluoromethanesulfonate (38-E) (150 mg, 0.32 mmol, 30.8% yield) as a yellow solid. LCMS (ESI): [M+H] + =471.2.

[0426] Step 6: Synthesis of compound 38-F

[0427] 2,2,4-Trimethyl-7-(4-oxochromen-2-yl)-4-hydro-[1,3]dioxane[5,4-b]phenyl-5-yl trifluoromethanesulfonate (38-E) (120 mg, 0.26 mmol) was dissolved in 1,4-dioxane (5 mL), and diboron pinacol (259 mg, 1.02 mmol), potassium acetate (200 mg, 2.04 mmol), and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (19 mg, 0.026 mmol) were added in sequence. The mixture was heated to 90°C under nitrogen protection and reacted for 12 hours. The reaction system was diluted with water (10 mL) and ethyl acetate (80 mL). The organic phase was dried and concentrated, and the residue was purified by column chromatography to afford 2-(2,2,4-trimethyl-5-pinacol boronate-4-hydro-benzo[d][1,3]dioxan-7-yl)-4-hydro-chromen-4-one (38-F) (100 mg, 0.223 mmol, 87.4% yield) as a yellow solid. LCMS (ESI): [M+H] + =449.2.

[0428] Step 7: Synthesis of compound 38

[0429] 2-(2,2,4-Trimethyl-5-pinacol boronate-4-hydrobenzo[d][1,3]dioxane-7-yl)-4-hydrochromen-4-one (38-F) (100 mg, 0.22 mmol) was dissolved in methanol (5 mL) and 4 M hydrochloric acid (4 mL, 16 mmol) was added at 0°C. The mixture was stirred at 0°C for 3 hours. The reaction system was diluted with water (10 mL) and dichloromethane (80 mL). The organic phase was dried and concentrated. The residue was purified by preparative method to give 2-(1,4-dihydroxy-3-methyl-1,3-dihydrobenzo[c][1,2]oxaborolan-6-yl)-4-hydrochromen-4-one (38) (15 mg, 0.05 mmol, 22.7%). LCMS (ESI): [M+H] + =309.4; 1 H NMR (400MHz, DMSO-d6): δ10.16(s,1H),9.23(s,1H),8.10-8.04(m,1H),7.89-7.83(m,1H),7.82(s,1H), 7.75-7.70(m1H),7.55-7.49(m,1H),7.47(s,1H),6.77(s,1H),5.31-5.26(m,1H),1.47(d,J=6.4Hz,3H).

[0430] Example 39

[0431] Step 1: Synthesis of compound 39-A

[0432] 2-(4-Acetyl-3,5-dihydroxyphenyl)-4-hydrochromen-4-one (38-B) (0.4 g, 1.35 mmol) was dissolved in tetrahydrofuran (2 mL). N,N-diisopropylethylamine (1.12 mL, 6.75 mmol) and N,N-dimethylaminopyridine (16.5 mg, 0.14 mmol) were added, and methoxymethyl bromide (0.33 mL, 4.05 mmol) was added dropwise at 0°C. The reaction system was stirred at room temperature for 8 hours, poured into saturated ammonium chloride, and extracted with ethyl acetate (80 mL). The organic phase was dried and concentrated, and the residue was purified by column chromatography to give 2-[4-acetyl-3,5-bis(methoxymethyleneoxy)phenyl]-4-hydrochromen-4-one (39-A) (0.43 g, 1.12 mmol, 83% yield) as a yellow solid. LCMS (ESI): [M+H] + =385.2.

[0433] Step 2: Synthesis of compound 39-B

[0434] 2-[4-Acetyl-3,5-bis(methoxymethyleneoxy)phenyl]-4-hydrogen-chromen-4-one (39-A) (0.43 g, 1.12 mmol) was dissolved in a mixed solvent of methanol (2 mL) and tetrahydrofuran (1 mL). Sodium borohydride (42 mg, 1.12 mmol) was added at 0°C and stirred at room temperature for 2 hours. The reaction was quenched by the addition of saturated ammonium chloride solution (4 mL) and extracted with ethyl acetate (50 mL). The organic phase was dried and concentrated, and the residue was purified by column chromatography to give 2-[4-(1-hydroxyethyl)-3,5-bis(methoxymethyleneoxy)phenyl]-4-hydrogen-chromen-4-one (39-B) (0.42 g, 1.09 mmol, 97.3% yield) as a white solid. LCMS (ESI): [M+H] + =387.2.

[0435] Step 3: Synthesis of compound 39-C

[0436] 2-[4-(1-Hydroxyethyl)-3,5-bis(methoxymethyleneoxy)phenyl]-4-hydrogen-chromen-4-one (39-B) (0.15 g, 0.39 mmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL). 60% sodium hydride (31 mg, 0.78 mol) was added at 0°C and stirred at 0°C for 30 minutes. Iodomethane (0.3 mL, 4.8 mmol) was added and stirred at room temperature for 2 hours. The reaction was quenched by the addition of saturated ammonium chloride solution (2 mL) and extracted with ethyl acetate (60 mL). The organic phase was dried and concentrated, and the residue was purified by column chromatography to afford 2-[4-(1-methoxyethyl)-3,5-bis(methoxymethyleneoxy)phenyl]-4-hydrogen-chromen-4-one (39-C) (0.15 g, 0.375 mmol, 96.2% yield) as a white solid. LCMS (ESI): [M+H] + =401.2.

[0437] Step 4: Synthesis of compound 39

[0438] 2-[4-(1-methoxyethyl)-3,5-bis(methoxymethyleneoxy)phenyl]-4-hydrogen-chromen-4-one (39-C) (0.15 g, 0.375 mmol) was dissolved in methanol (3 mL) and water (3 mL). 2M sulfuric acid solution (3 mL, 6 mmol) was added at 0°C and the mixture was stirred at room temperature overnight. The reaction was extracted with ethyl acetate (60 mL), and the organic phase was dried and concentrated. The residue was purified by preparative purification to give 2-[4-(1-methoxyethyl)-3,5-dihydroxyphenyl]-4-hydrogen-chromen-4-one (39) (26 mg, 0.083 mmol, 22.1% yield) as a white solid. LCMS (ESI): [M+H] + =313.2; 1 H NMR (400MHz, DMSO-d6): δ9.52(s,2H),8.07-8.04(m,1H),7.87-7.82(m,1H),7.72-7.69(m1H),7. 53-7.49(m,1H),6.96(s,2H),6.73(s,1H),4.96-4.91(m,1H),3.25(s,3H),1.43(d,J=6.4Hz,3H).

[0439] Example 40

[0440] Step 1: Synthesis of compound 40-A

[0441] 4-Isopropyl-3-methoxy-benzoic acid (2.1 g, 10.8 mmol) was mixed with thionyl chloride (15 mL), reacted at 80°C for 3 hours, and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL) and added dropwise to a solution of 2-acetylphenol (2.02 g, 14.8 mmol) in pyridine (20 mL). The reaction system was stirred at room temperature for 2 hours. Saturated ammonium chloride solution (25 mL) was added, and the mixture was extracted with dichloromethane (150 mL). The organic phase was dried and concentrated, and the residue was purified by column chromatography to yield 2-acetylphenol 3-methoxy-4-isopropylbenzoate (40-A) (1.5 g, 4.8 mmol, 44.4% yield) as a yellow solid. 1 HNMR (400MHz, DMSO-d6): δ7.96-7.94(m,1H),7.74-7.68(m,2H),7.58-7.57(m,1H),7.48-7.42(m 2H),7.36-7.34(m,1H),3.89(s,3H),3.37-3.23(m,1H),2.50(s,3H),1.21(d,J=6.8Hz,6H).

[0442] Step 2: Synthesis of compound 40-B

[0443] 2-Acetylphenol 3-methoxy-4-isopropylbenzoate (40-A) (1.5 g, 4.8 mmol) was dissolved in anhydrous pyridine (10 mL), and sodium hydroxide (0.29 g, 7.25 mmol) was added. The mixture was stirred at 50°C for 3 hours. The reaction system was quenched with water and the pH was adjusted to 6 with 3M hydrochloric acid. The solution was extracted with ethyl acetate (80 mL) and dried, and concentrated under reduced pressure to give 1-(3-methoxy-4-isopropylphenyl)-3-(2-hydroxyphenyl)-1,3-propanedione (40-B) (1.3 g, 4.17 mmol, 86.9% yield) as a light brown solid. LCMS (ESI): [M+H] + =313.2.

[0444] Step 3: Synthesis of Compound 40-C

[0445] 1-(3-Methoxy-4-isopropylphenyl)-3-(2-hydroxyphenyl)-1,3-propanedione (40-B) (0.15 g, 0.48 mmol) was dissolved in ethanol (4 mL), hydrazine hydrate (0.12 mL, 2.4 mmol) was added, and the mixture was heated to 90°C with stirring for 6 hours. The reaction system was extracted with saturated ammonium chloride solution (5 mL) and ethyl acetate (80 mL). The organic phase was dried and concentrated under reduced pressure, and the residue was purified by column chromatography to give 2-[5-(3-methoxy-4-isopropylphenyl)-2-hydro-pyrazol-3-yl]phenol (40-C) (0.14 g, 0.45 mmol, yield 93.8%) as a yellow solid. LCMS (ESI): [M+H] + =309.4.

[0446] Step 4: Synthesis of compound 40

[0447] 2-[5-(3-Methoxy-4-isopropylphenyl)-2-hydro-pyrazol-3-yl]phenol (40-C) (0.14 g, 0.45 mmol) was dissolved in dichloromethane (5 mL) and cooled to -78°C. A 1 M solution of boron tribromide in dichloromethane (1.8 mL, 1.8 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was cooled to 0°C and dichloromethane (60 mL) and water (3 mL) were added. The organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative purification (0.1% trifluoroacetic acid) to give the trifluoroacetic acid salt of 2-[5-(3-hydroxy-4-isopropylphenyl)-2-hydro-pyrazol-3-yl]phenol (40) (78 mg, 0.19 mmol, 42.2% yield) as a white solid. LCMS (ESI): [M+H] + =295.2; 1 H NMR (400MHz, DMSO-d6): δ9.50(brs,1H),7.76-7.74(m,1H),7.24-7.12(m,4H ),7.07(s,1H),6.96-6.86(m,2H),3.28-3.17(m,1H),1.18(d,J=7.2Hz,6H).

[0448] The compounds listed in Table 8 below were synthesized according to the similar procedures as in Example 40.

[0449] Table 8

[0450] Example 41

[0451] Step 1: Synthesis of compound 41-A

[0452] 3,5-Dimethoxy-4-isopropylbenzoic acid (100 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (3 mL). Benzohydrazide (67 mg, 0.49 mmol) was added, followed by triethylamine (0.19 mL, 1.34 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (203 mg, 0.54 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (70 mL) and water (10 mL). The organic phase was washed with saturated brine, dried, and concentrated under reduced pressure. The residue was purified by column chromatography to give N'-benzoyl-3,5-dimethoxy-4-isopropylbenzohydrazide (41-A) (130 mg, 0.38 mmol, 85.1% yield) as a white solid. LCMS (ESI): [M+H] + =343.4.

[0453] Step 2: Synthesis of compound 41-B

[0454] N'-Benzoyl-3,5-dimethoxy-4-isopropylbenzohydrazide (41-A) (130 mg, 0.38 mmol) was dissolved in tetrahydrofuran (10 mL), and Burgess reagent (181 mg, 0.76 mmol) was added. The mixture was heated to 70°C and reacted for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography to give 5-(3,5-dimethoxy-4-isopropylphenyl)-2-phenyl-1,3,4-oxadiazole (41-B) (100 mg, 0.31 mmol, 81.2% yield) as a white solid. LCMS (ESI): [M+H] + =325.4; 1 H NMR (400MHz, CDCl3): δ8.16-8.13(m,2H),7.60-7.51(m,3H),7.29(s,2H),3.92(s,6H),3.72-3.62(m,1H),1.31(d,J=7.2Hz,6H).

[0455] Step 3: Synthesis of Compound 41

[0456] 5-(3,5-Dimethoxy-4-isopropylphenyl)-2-phenyl-1,3,4-oxadiazole (41-B) (90 mg, 0.28) was dissolved in dichloromethane (3 mL). 1 M boron tribromide dichloromethane solution (1.11 mL, 1.11 mmol) was added dropwise at -78°C. The mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled to -78°C, poured into ice water for quenching, and extracted with ethyl acetate (60 mL). The organic phase was dried and concentrated, and the residue was purified by preparative purification to give 5-(3,5-dihydroxy-4-isopropylphenyl)-2-phenyl-1,3,4-oxadiazole (41) (50 mg, 0.17 mmol, yield 60.8%) as a white solid. LCMS (ESI): [M+H] + =297.4; 1 H NMR (400MHz, DMSO-d6): δ9.63 (s, 2H), 8.05-8.01 (m, 2H), 7.66-7.61 (m, 3H), 7.04 (s, 2H), 3.53-3.49 (m, 1H), 1.27 (d, J = 6.8Hz, 6H).

[0457] Example 42

[0458] Step 1: Synthesis of compound 42-A

[0459] Methyl 3,5-dimethoxy-4-isopropylbenzoate (1 g, 4.2 mmol) was dissolved in ethanol (10 mL), hydrazine monohydrate (3 mL, 52 mmol) was added, and the mixture was heated to 90°C and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (100 mL) and water (10 mL), and the organic phase was dried and concentrated under reduced pressure. The residue was purified by column chromatography to give 3,5-dimethoxy-4-isopropylbenzohydrazide (42-A) (1 g, 4.2 mmol, 100% yield) as a yellow solid. LCMS (ESI): [M+H] + =239.2.

[0460] Step 2: Synthesis of compound 42-B

[0461] 3,5-Dimethoxy-4-isopropylbenzohydrazide (42-A) (0.3 g, 1.26 mmol) was dissolved in n-butanol (15 mL), and benzonitrile (0.51 mL, 5 mmol) and potassium carbonate (690 mg, 5 mmol) were added. The mixture was heated to 150°C and stirred for 6 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (80 mL) and water (8 mL), and the organic phase was dried and concentrated under reduced pressure. The residue was purified by column chromatography to give 3-(3,5-dimethoxy-4-isopropylphenyl)-5-phenyl-4-hydro-1,2,4-triazole (42-B) (0.3 g, 0.93 mmol, 73.7% yield) as a white solid. LCMS (ESI): [M+H] + =324.2; 1 H NMR (400MHz, DMSO-d6): δ8.11-8.07(m,2H),7.54-7.44(m,3H),7.32(s,2H),3.86(s,6H),3.62-3.54(m,1H),1.24(d,J=7.2Hz,6H).

[0462] Step 3: Synthesis of Compound 42

[0463] 3-(3,5-Dimethoxy-4-isopropylphenyl)-5-phenyl-4-hydro-1,2,4-triazole (42-B) (0.12 g, 0.37 mmol) was dissolved in dichloromethane (1.5 mL). 1 M boron tribromide dichloromethane solution (1.5 mL, 1.5 mmol) was added dropwise at -30°C. The mixture was slowly warmed to room temperature and stirred for 18 hours. The reaction mixture was cooled to -30°C, quenched by pouring into ice water, and extracted with ethyl acetate (60 mL). The organic phase was dried and concentrated, and the residue was purified by preparative purification to give 5-(5-phenyl-4-hydro-1,2,4-triazol-3-yl)-2-isopropylbenzene-1,3-diol (42) (68 mg, 0.23 mmol, yield 62.2%) as a white solid. LCMS (ESI): [M+H] + =296.2; 1 H NMR (400MHz, DMSO-d6): δ14.3(brs,1H),9.28(s,2H),8.05-8.01(m,2H),7.53-7.48(m,3H),7.01(s,2H),3.52-3.44(m,1H),1.26(d,J=7.2Hz,6H).

[0464] Example 43

[0465] Step 1: Synthesis of compound 43-A

[0466] Ethyl 3,5-dimethoxy-4-isopropylbenzoate (173 mg, 0.77 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N,N'-carbonyldiimidazole (131 mg, 0.81 mmol) was added. After stirring at room temperature for 1 hour, N-hydroxybenzamidine (100 mg, 0.73 mmol) was added, and the mixture was heated to 110°C and stirred for 15 hours. The reaction was concentrated, and the residue was purified by column chromatography to give 5-(3,5-dimethoxy-4-isopropylphenyl)-3-phenyl-1,2,4-oxadiazole (43-A) (200 mg, 0.62 mmol, 84% yield) as a white solid. LCMS (ESI): [M+H] + =325.4; 1 H NMR (400MHz, DMSO-d6): δ8.13-8.08(m,2H),7.67-7.57(m,3H),7.37(s,2H),3.90(s,6H),3.68-3.57(m,1H),1.26(d,J=6.8Hz,6H).

[0467] Step 2: Synthesis of compound 43

[0468] 5-(3,5-Dimethoxy-4-isopropylphenyl)-3-phenyl-1,2,4-oxadiazole (43-A) (100 mg, 0.31 mmol) was dissolved in dichloromethane (5 mL). 1 M boron tribromide dichloromethane solution (1.85 mL, 1.85 mmol) was added dropwise at -78°C. The mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled to -78°C, poured into ice water to quench, and extracted with ethyl acetate (60 mL). The organic phase was dried and concentrated, and the residue was purified by column chromatography to give 5-(3,5-dihydroxy-4-isopropylphenyl)-2-phenyl-1,2,4-oxadiazole (43) (60 mg, 0.2 mmol, yield 64.5%) as a white solid. LCMS (ESI): [M+H] + =297.4; 1 H NMR (400MHz, DMSO-d6): δ9.74 (s, 2H), 8.09-8.03 (m, 2H), 7.66-7.56 (m, 3H), 7.13 (s, 2H), 3.58-3.47 (m, 1H), 1.28 (d, J = 6.8Hz, 6H).

[0469] Example 44

[0470] Step 1: Synthesis of compound 44-A

[0471] 3,5-Dimethoxy-4-isopropylbenzonitrile (70 mg, 0.34 mmol) was dissolved in ethanol (10 mL), potassium carbonate (94 mg, 0.68 mmol) and hydroxylamine hydrochloride (60 mg, 0.85 mmol) were added, and the mixture was heated to 90°C and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (100 mL) and water (10 mL), and the organic phase was dried and concentrated under reduced pressure to obtain the crude product 3,5-dimethoxy-4-isopropyl-N-hydroxybenzimidamide (44-A) (75 mg, 0.315 mmol, 96.9% yield) as a yellow solid, which was used directly in the next step. LCMS (ESI): [M+H] + =239.2; 1 H NMR (400MHz, DMSO-d6): δ9.49 (brs, 1H), 6.91 (s, 2H), 5.80 (s, 2H), 3.76 (s, 6H), 3.55-3.48 (m, 1H), 1.20 (d, J = 6.8Hz, 6H).

[0472] Step 2: Synthesis of compound 44-B

[0473] 3,5-Dimethoxy-4-isopropyl-N-hydroxybenzimidamide (44-A) (75 mg, 0.315 mmol) was dissolved in dimethyl sulfoxide (0.3 mL), and methyl benzoate (64 mg, 0.47 mmol) and sodium hydroxide (25 mg, 0.63 mmol) were added. The mixture was stirred at room temperature for 18 hours. Ethyl acetate (100 mL) and water (10 mL) were added to dilute the mixture. The organic phase was dried and concentrated under reduced pressure. The residue was purified by column chromatography to give 3-(3,5-dimethoxy-4-isopropylphenyl)-5-phenyl-1,2,4-oxadiazole (44-B) (100 mg, 0.31 mmol, 98.4% yield) as a white solid. LCMS (ESI): [M+H] + =325.2; 1 H NMR (400MHz, DMSO-d6): δ8.24-8.19(m,2H),7.76-7.73(m,1H),7.70-7.67( m, 2H), 7.30 (s, 2H), 3.88 (s, 6H), 3.63-3.56 (m, 1H), 1.26 (d, J = 6.8Hz, 6H).

[0474] Step 3: Synthesis of Compound 44

[0475] 3-(3,5-Dimethoxy-4-isopropylphenyl)-5-phenyl-1,2,4-oxadiazole (44-B) (100 mg, 0.31 mmol) was dissolved in dichloromethane (0.6 mL). 1 M boron tribromide dichloromethane solution (0.6 mL, 0.6 mmol) was added dropwise at -30°C. The mixture was slowly warmed to room temperature and stirred for 18 hours. The reaction mixture was cooled to -30°C, quenched by pouring into ice water, and extracted with ethyl acetate (60 mL). The organic phase was dried and concentrated, and the residue was purified by preparative purification to give 5-(5-phenyl-1,2,4-oxadiazole-3-yl)-2-isopropylbenzene-1,3-diol (44) (15 mg, 0.05 mmol, yield 16.1%) as a white solid. LCMS (ESI): [M+H] + =297.2; 1 H NMR (400MHz, DMSO-d6): δ9.51(s,2H),8.18-8.10(m,2H),7.77-7.70(m,1H) ,7.69-7.63(m,2H),7.06(s,2H),3.55-3.45(m,1H),1.27(d,J=6.8Hz,6H).

[0476] Example 45

[0477] Step 1: Synthesis of compounds 45-A and 45-A-BP

[0478] 5-(4-Fluoro-1-benzofuran-2-yl)-2-isopropylbenzene-1,3-diol (100 mg, 0.35 mmol) was dissolved in chloroform (3 mL), and [(2R,3R,4S,5R)-3,4,5-triacetoxy-6-hydroxy-3,4,5,6-tetrahydro-2-hydro-pyran-2-yl]methanol acetate (182 mg, 0.52 mmol) was added dropwise. A 3.6 M solution of boron trifluoride in ether (0.29 mL, 1.05 mmol) was added dropwise at 0°C, and the mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was diluted with dichloromethane (70 mL) and water (10 mL). The organic phase was washed with saturated brine, dried, and concentrated under reduced pressure. The residue was purified by column chromatography to afford a mixture of (45-A) and (45-A-BP) (110 mg, 0.18 mmol, 60% yield) as a brown oil. LCMS(ESI):[M+H] + =617.2.

[0479] Step 2: Synthesis of compound 45

[0480] The product mixture (45-A) and (45-A-BP) (110 mg, 0.18 mmol) from the previous step was dissolved in methanol (1 mL). 1.6 M sodium methoxide in methanol (0.13 mL, 0.21 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was quenched by the addition of saturated ammonium chloride solution (0.5 mL). The reaction system was concentrated under reduced pressure, and the residue was purified by preparative purification and SFC to give (3R,4S,5S,6R)-2-{[5-(4-fluoro-1-benzofuran-2-yl)-3-hydroxy-2-isopropylphenyl]oxy}-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol (45) (3.3 mg, 0.007 mmol, yield 4.12%) and (3R,4R,5S,6R)-2-[6-(4-fluoro-1-benzofuran-2-yl)-2,4-dihydroxy-3-isopropylphenyl]-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol (45-BP) (8.3 mg, 0.019 mmol, 10.37%).

[0481] Compound 45: LCMS (ESI): [M+H] + =449.2, [M+Na] + =471.2; 1 H NMR (400MHz, DMSO-d6): δ9.57(s,1H),7.51-7.47(m,1H),7.35-7.27(m,2H),7.20-7 .16(m,1H),7.13-7.06(m,1H),7.06-7.02(m,1H),5.24-5.18(m,1H),5.09-5.05(m, 1H),5.05-5.00(m,1H),4.91-4.83(m,1H),4.72-4.64(m,1H),3.82-3.72(m,1H),3. 65-3.53(m,1H),3.50-3.39(m,2H),3.21-3.09(m,1H),1.32-1.22(t,J=2.4Hz,6H).

[0482] Compound 45-BP: LCMS (ESI): [M+H] + =449.2; 1H NMR (400MHz, DMSO-d6): δ9.45(s,1H),8.43(s,1H),7.51-7.44(m,1H),7.37-7 .27(m,2H),7.14-7.06(m,1H),6.68(s,1H),5.48-5.35(m,1H),5.12-5.06(m,1 H),5.00-4.93(m,1H),4.83-4.75(m,1H),4.72-4.62(m,1H),3.70-3.62(m,1H ),3.62-3.49(m,3H),3.30-3.18(m,1H),3.21-3.09(m,1H),1.34-1.24(m,6H).

[0483] Example 46

[0484] Step 1: Synthesis of compound 46

[0485] 5-(Benzofuran-2-yl)-2-isopropylbenzene-1,3-diol (268 mg, 1 mmol) was dissolved in tetrahydrofuran (10 mL), and N,N-diisopropylethylamine (0.28 mL, 2 mmol) and N,N-dimethylaminopyridine (12 mg, 0.1 mmol) were added. 4-Methylpiperazine-1-carbonyl chloride (170 mg, 1.05 mmol) was added at 0°C, and the temperature was slowly raised to 40°C and stirred for 10 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain (46) (214 mg, 0.54 mmol, yield 54.3%) as a white solid. LCMS (ESI): [M+H] + =395.2; 1 H NMR (400MHz, DMSO-d6): δ9.57(s,1H),7609-7.57(m,1H),7.53-7.50(m,1H),7.31-7.20(m,2H),7.09(s,1H),7.03 (s,1H),6.94(s,1H),3.40-3.28(m,1H),3.20-3.12(m,4H),2.45(s,3H),2.24-2.20(m,4H),1.26(d,J=7.2Hz,6H).

[0486] Test Example 1: Human Aryl Hydrocarbon Receptor (AHR) Agonist Luciferase Assay

[0487] Cytochrome P450 family 1 member A1 (CYP1A1) is one of the hallmark genes regulated by the AHR signaling pathway. The upstream promoter of the CYP1A1 gene contains a specific sequence called the dioxin responsive element (DRE), which can bind to the activated AHR to initiate CYP1A1 expression. To detect AHR activation, the gene sequence from -1200bp to 0bp upstream of CYP1A1 was placed in front of the Nano-luc luciferase reporter gene to construct a reporter gene plasmid. The reporter gene plasmid was introduced into human hepatocellular carcinoma cells HepG2 by lipofectamine transfection, and stably expressing cells were selected using puromycin. The screened cells were further screened for single clones, and a single clone with normal morphology, normal growth, and the highest induction signal was selected for the human AHR agonist luciferase assay.

[0488] The HepG2 monoclonal cell line stably expressing the reporter gene was counted on the first day and the cells were counted according to the ratio of 1 to 8*10 4 The cells were seeded into a white opaque 96-well plate at a density of 100 μl / well in a complete culture medium without tryptophan and phenol red (basal culture medium MEM without tryptophan and phenol red, 10% fetal bovine serum, 1X non-essential amino acids, 1X sodium pyruvate and 1X GlutaMax) and cultured in an incubator maintained at 37°C and 5% carbon dioxide for 24 hours.

[0489] After synthesis, the test compounds were prepared into 10 mM stock solutions with dimethyl sulfoxide (DMSO) and stored at 4°C in the dark. Before treatment, the compound stock solution and the positive control compounds (such as dioxin, ITE, kynurenine, etc.) and negative control (DMSO) were diluted with complete culture medium without tryptophan and phenol red for an initial dilution (determined according to preliminary experiments) and then serially diluted 3-20 times to obtain 11 concentration points to obtain a 2X dilution solution. When treating cells, first aspirate 50 μl of culture medium from the 96-well plate inoculated with cells, and then add 50 μl of the serially diluted 2X dilution solution. Two replicate experiments were set for each compound, and each replicate experiment was set to a concentration of 0 in one well (i.e., only culture medium) to determine the base number. After treatment, the reporter cells were returned to the incubator and incubated for 4-24 hours.

[0490] After treatment, add 100 μL / well of Nano-Glo luciferase assay reagent to the 96-well plate and measure the RLU (relative fluorescence intensity) of each well. The baseline Ave RLU is calculated by taking the average of the RLU with a concentration of 0 in each 96-well plate. Vehicle The RLU of the test compound at different concentrations in the experimental group Test Cmpd and baseline Ave RLU Vehicle The activity of AhR under the action of different concentrations of test compounds was calculated according to formula (1) to determine the activation multiple.

[0491] Formula (1)

[0492] The activation fold and the corresponding compound concentration were fitted using Graphpad Prism9 [Agonist] vs. response-variable slope (four parameters) to calculate the EC of the compound to activate AHR. 50 The EC values ​​of each compound 50 The values ​​are shown in Table 2, where A represents EC 50 ≤100nM, B means 100nM<EC 50 ≤2.0μM, C means 2.0μM<EC 50 ≤100μM.

[0493] Test Example 2: Mouse-derived Aryl Hydrocarbon Receptor (AHR) Agonist Luciferase Assay

[0494] To detect AHR activation, six tandem xenobiotic responsive elements (XREs, see Buckley, SMK et al., Sci. Rep. 2015; 5:11842.) were placed in front of the Nano-luc luciferase reporter gene to construct a reporter gene plasmid. The reporter gene plasmid was introduced into mouse hepatocellular carcinoma cells Hepa1-6 by lipofectamine transfection, and the stably expressing cells were selected by puromycin for mouse AHR agonist luciferase assay.

[0495] The Hepa1-6 cell line stably expressing the reporter gene was counted on the first day and the cells were counted according to the ratio of 1 to 8*10 4 The cells were seeded into a white opaque 96-well plate at a density of 100 μl of DMEM medium without phenol red (DMEM without phenol red, 10% fetal bovine serum) per well and cultured in an incubator maintained at 37° C. and 5% carbon dioxide for 24 hours.

[0496] After synthesis, the test compounds were prepared into 10 mM stock solutions with dimethyl sulfoxide (DMSO) and stored at 4°C in the dark. Before treatment, the compound stock solution and the positive control compounds (such as dioxin, ITE, kynurenine, etc.) and negative control (DMSO) were diluted with complete culture medium without tryptophan and phenol red for an initial dilution (determined according to preliminary experiments) and then serially diluted 3-20 times to 11 concentration points to obtain a 10X dilution solution. When treating cells, first aspirate 10 μl of culture medium from the 96-well plate inoculated with cells, and then add 10 μl of the serially diluted 10X dilution solution. Two replicate experiments were set for each compound, and each replicate experiment was set to a concentration of 0 in one well (i.e., only culture medium) to determine the base number. After treatment, the reporter cells were returned to the incubator and incubated for 4-24 hours.

[0497] After treatment, add 100 μL / well of Nano-Glo luciferase assay reagent to the 96-well plate and measure the RLU (relative fluorescence intensity) of each well. The baseline Ave RLU is calculated by taking the average of the RLU with a concentration of 0 in each 96-well plate. Vehicle The RLU of the test compound at different concentrations in the experimental group Test Cmpd and baseline Ave RLU Vehicle The activity of AhR under the action of different concentrations of test compounds was calculated according to formula (1) to determine the activation multiple.

[0498] The activation fold and the corresponding compound concentration were fitted using Graphpad Prism 9 [Agonist] vs. response-variable slope (four parameters) to calculate the EC50 of the compound for AHR activation. 50 The EC values ​​of each compound 50 The values ​​are shown in Table 2, where A represents EC 50 ≤100nM, B means 100nM<EC 50 ≤2.0μM, C means 2.0μM<EC 50 ≤100μM.

[0499] Test Example 3: Rat-derived Aryl Hydrocarbon Receptor (AHR) Agonist Luciferase Assay

[0500] To detect AhR activation, a Nano-luc luciferase reporter gene associated with six tandem xenobiotic response elements (XRE, see Buckley, SMK et al., Sci. Rep. 2015; 5: 11842.) was synthesized and cloned into the lentiviral transfer plasmid pGWLV11-new via the KpnI and Xbal restriction sites. The transfer plasmid and packaging plasmid were co-transfected into 293T cells and purified to obtain a lentivirus containing the reporter gene. The reporter gene was introduced into the rat hepatoma cell line H-4-II-E by lentiviral infection, and the cells were stably expressed in the reporter gene by puromycin selection for rat AhR agonist luciferase experiments.

[0501] On the first day, the H-4-II-E cell line stably expressing the reporter gene was counted and the cells were 1-8×10 4 The cells were seeded at a density of 100 μL / well in a white opaque 96-well plate using a complete culture medium without tryptophan and phenol red (basal culture medium MEM without tryptophan and phenol red, 10% fetal bovine serum, 1× non-essential amino acids, 1× sodium pyruvate and 1× GlutaMax) and cultured in an incubator maintained at 37°C and 5% carbon dioxide for 24 hours.

[0502] The test compounds were prepared into 10 mM stock solutions with dimethyl sulfoxide (DMSO) and stored at 4°C in the dark. Before treatment, the compound stock solution and the positive control compound (such as dioxin, ITE, kynurenine, etc.) and the negative control (DMSO) were diluted with complete culture medium without tryptophan and phenol red for an initial dilution (determined according to preliminary experiments) and then serially diluted 3-20 times for 11 concentration points to obtain a 2× dilution solution. When treating cells, first aspirate 50 μL of culture medium from the 96-well plate inoculated with cells, and then add 50 μL of the serially diluted 2× dilution solution. Two replicate experiments were set for each compound, and each replicate experiment was set to a concentration of 0 in one well (i.e., only culture medium) to determine the base number. After treatment, the reporter cells were returned to the incubator and incubated for 4-24 hours.

[0503] After treatment, add 100 μL / well of Nano-Glo luciferase assay reagent to the 96-well plate and measure the RLU (relative fluorescence intensity) of each well. The baseline Ave RLU is calculated by taking the average of the RLU with a concentration of 0 in each 96-well plate. Vehicle The RLU of the test compound at different concentrations in the experimental group Test Cmpd and baseline Ave RLU Vehicle The activity of AhR under the action of different concentrations of test compounds was calculated according to formula (1) to determine the activation multiple.

[0504] Formula (1)

[0505] The activation fold and the corresponding compound concentration were fitted using Graphpad Prism 9 [Agonist] vs. response-variable slope (four parameters) to calculate the EC50 of the compound for AHR activation. 50 The EC50 values ​​of each compound are shown in Table xxxxx, where A represents EC 50 ≤100nM, B means 100nM<EC 50 ≤2.0μM, C means 2.0μM<EC 50 ≤100μM.

[0506] Table 9: EC values ​​of each compound 50 value

[0507] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any modifications or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. A class of aromatic hydrocarbon receptor modulator compounds represented by the following formula I, their respective optical isomers, deuterated substances, prodrugs or pharmaceutically acceptable salts: in, R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C 1-8 Alkenyl, substituted or unsubstituted C 1-8 Alkynyl, wherein the "substituted" refers to a group containing 1 to 6 R a Substituents, where R a Selected from hydrogen, deuterium, halogen, OR a1 、S(O)nR a2 NR a3 R a4 、CO2R a5 ; Among them, R a1 and R a2 Each is independently selected from hydrogen, hydroxyl, amino, C1-C8 alkyl, C3-C8 cycloalkyl, -C(=O)C 1-8 Alkyl, -C(=O)C3-C8 cycloalkyl, -C(=O)OC1-C8 alkyl, -C(=O)OC3-C8 cycloalkyl, -C(=O)NC1-C8 alkyl, -C(=O)NC3-C8 cycloalkyl; R a3 and R a4 Each is independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxy, C3-C6 cycloalkyl substituted by halogen or hydroxy, C1-C3 alkoxy, C3-C6 cycloalkyloxy, C1-C3 alkoxy substituted by halogen or hydroxy, C3-C6 cycloalkyloxy substituted by halogen or hydroxy; R a5 Selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl; R3 is hydrogen, deuterium, halogen, NR b3 R b4 , substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C3-C 12 Cycloalkyl, substituted or unsubstituted C 1-10 Alkenyl, substituted or unsubstituted C 1-10 Alkynyl, C6-C 14 aryl, substituted or unsubstituted 5- to 14-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted 4- to 14-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to a substituted or unsubstituted 5- to 14-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S. b Substituents, where R b Selected from hydrogen, deuterium, halogen, OR b1 、S(O)nR b2 NR b3 R b4 、CO2R b5 ; Among them, R b1 and R b2 Each is independently selected from hydrogen, hydroxyl, amino, C1-C8 alkyl, C3-C8 cycloalkyl, -C(=O)C 1-8 Alkyl, -C(=O)C3-C8 cycloalkyl, -C(=O)OC1-C8 alkyl, -C(=O)OC3-C8 cycloalkyl, -C(=O)NC1-C8 alkyl, -C(=O)NC3-C8 cycloalkyl; R b3 and R b4 Each is independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxy, C3-C6 cycloalkyl substituted by halogen or hydroxy, C1-C3 alkoxy, C3-C6 cycloalkyloxy, C1-C3 alkoxy substituted by halogen or hydroxy, C3-C6 cycloalkyloxy substituted by halogen or hydroxy; R b5 Selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl; R4 and R4' are hydrogen, deuterium, halogen, hydroxyl, C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 Alkenyloxy, C3-C 10 Cycloalkyl, C 3-10 Cycloalkoxy, C 3-10 Cycloalkenyloxy, (C 1-8 Alkoxy)C 1-8 Alkoxy, (C 2-8 (Alkenyl)C 1-8 Alkoxy, (C 2-8 Alkynyl)C 1-8 Alkoxy, C6-C 14 Aryl, boronic acid, boric ester; Alternatively, R4 or R4' may form a ring with R3 to form a substituted or unsubstituted C3-C8 cycloalkyl group or a 4-10 membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S and B, wherein the "substituted" refers to a group containing 1 to 6 R a1 ; A ring is C 6-14 aryl, 5-14 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, substituted or unsubstituted 5-14 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S; wherein the "substituted" refers to a 5-14 membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S; c Substituents, where R c is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carbonyl, carboxyl, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxyl, C3-C6 cycloalkyl substituted by halogen or hydroxyl, C1-C3 alkoxy, C3-C6 cycloalkyloxy, C1-C3 alkoxy substituted by halogen or hydroxyl, C3-C6 cycloalkyloxy substituted by halogen or hydroxyl, NR c1 R c2 、CO2R c3 , where R c1 and R c2 are each independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxy, C3-C6 cycloalkyl substituted by halogen or hydroxy, C1-C3 alkoxy, C3-C6 cycloalkyloxy, C1-C3 alkoxy substituted by halogen or hydroxy, C3-C6 cycloalkyloxy substituted by halogen or hydroxy, R c3 Selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl; R 5 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carbonyl, carboxyl, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyloxy, C1-C3 alkyl substituted by halogen or hydroxyl, C3-C6 cycloalkyl substituted by halogen or hydroxyl, C1-C3 alkoxy substituted by halogen or hydroxyl, C3-C6 cycloalkyloxy substituted by halogen or hydroxyl, NR d1 R d2 、CO2R d3 , where R d1 and R d2 Each is independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxy, C3-C6 cycloalkyl substituted by halogen or hydroxy, C1-C3 alkoxy, C3-C6 cycloalkyloxy, C1-C3 alkoxy substituted by halogen or hydroxy, C3-C6 cycloalkyloxy substituted by halogen or hydroxy, R d3 Selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl; The following compounds are not included:

2. The aromatic hydrocarbon receptor modulator compound represented by formula I according to claim 1, its respective optical isomers, deuterated substances, prodrugs or pharmaceutically acceptable salts, characterized in that: Preferably, R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C 1-6 Alkenyl, substituted or unsubstituted C 1-6 Alkynyl, wherein the "substituted" refers to a group containing 1-4 R a Substituents, where R a Selected from hydrogen, deuterium, halogen, OR a1 、S(O)nR a2 NR a3 R a4 、CO2R a5 ; Among them, R a1 and R a2 Each is independently selected from hydrogen, hydroxyl, amino, C1-C6 alkyl, C3-C6 cycloalkyl, -C(=O)C 1-6 Alkyl, -C(=O)C3-C6 cycloalkyl, -C(=O)OC1-C6 alkyl, -C(=O)OC3-C6 cycloalkyl, -C(=O)NC1-C6 alkyl, -C(=O)NC3-C6 cycloalkyl; R a3 and R a4 Each is independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxy, C3-C6 cycloalkyl substituted by halogen or hydroxy, C1-C3 alkoxy, C3-C6 cycloalkyloxy, C1-C3 alkoxy substituted by halogen or hydroxy, C3-C6 cycloalkyloxy substituted by halogen or hydroxy; R a5 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; More preferably, R1 and R2 are each independently hydrogen, deuterium, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; Preferably, R3 is hydrogen, deuterium, halogen, NR b3 R b4 , substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C 1-8 Alkenyl, substituted or unsubstituted C 1-8 Alkynyl, C6-C 10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted 4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to a substituted or unsubstituted 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S. b Substituents, where R b Selected from hydrogen, deuterium, halogen, OR b1 、S(O)nR b2 NR b3 R b4 、CO2R b5 ; Among them, R b1 and R b2 Each is independently selected from hydrogen, hydroxy, amino, C1-C6 alkyl, C3-C6 cycloalkyl, -C(=O)C 1-6 Alkyl, -C(=O)C3-C6 cycloalkyl, -C(=O)OC1-C6 alkyl, -C(=O)OC3-C6 cycloalkyl, -C(=O)NC1-C6 alkyl, -C(=O)NC3-C6 cycloalkyl; R b3 and R b4 Each is independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxy, C3-C6 cycloalkyl substituted by halogen or hydroxy, C1-C3 alkoxy, C3-C6 cycloalkyloxy, C1-C3 alkoxy substituted by halogen or hydroxy, C3-C6 cycloalkyloxy substituted by halogen or hydroxy; R b5 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; More preferably, R3 is hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dimethylcyclohexyl, vinyl, propenyl, butenyl, 3-methyl-2-butenyl; Preferably, R4 and R4' are hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, C 3-6 Cycloalkenyloxy, (C 1-6 Alkoxy)C 1-6 Alkoxy, (C 2-6 (Alkenyl)C 1-6 Alkoxy, (C 2-6 Alkynyl)C 1-6 Alkoxy, C6-C 14 Aryl, boronic acid, boric ester; More preferably, R4 and R4' are hydrogen, deuterium, halogen, hydroxyl, C 1- C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, boronic acid, boric ester; Preferably, R4 and R4' are hydrogen, deuterium, halogen, hydroxyl, methyl, ethyl, n-propyl, isopropyl, boric acid, borate; Preferably, R4 and R4' are hydrogen or deuterium Preferably, R4 or R4' can form a ring with R3 to form a substituted or unsubstituted C3-C6 cycloalkyl or a 4-8 membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, S and B, wherein the "substituted" refers to a 1-4 R a1 ; Preferably, R4 or R4' can form a ring with R3 to form a substituted or unsubstituted C3-C6 cycloalkyl or a 4-6 membered heterocyclic group containing 1 to 2 heteroatoms selected from N, O, S and B, wherein the "substituted" refers to a 1-3 R a1 ; Preferably, ring A is C 6-10 Aryl, 5-10 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, substituted or unsubstituted 5-10 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O and S; wherein the "substituted" refers to a 5-4 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S. c Substituents, where R c is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carbonyl, carboxyl, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxyl, C3-C6 cycloalkyl substituted by halogen or hydroxyl, C1-C3 alkoxy, C3-C6 cycloalkyloxy, C1-C3 alkoxy substituted by halogen or hydroxyl, C3-C6 cycloalkyloxy substituted by halogen or hydroxyl, NR c1 R c2 、CO2R c3 , where R c1 and R c2 Each is independently selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxy, C3-C6 cycloalkyl substituted by halogen or hydroxy, C1-C3 alkoxy, C3-C6 cycloalkyloxy, C1-C3 alkoxy substituted by halogen or hydroxy, C3-C6 cycloalkyloxy substituted by halogen or hydroxy, R c3 Selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl; More preferably, Ring A is: Preferably, R 5 Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, carbonyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, -C(=O)Omethyl, -C(=O)Oethyl, -C(=O)On-propyl, -C(=O)Oisopropyl.

3. The aromatic hydrocarbon receptor modulator compound represented by formula I according to claim 1, its respective optical isomers, deuterated substances, prodrugs or pharmaceutically acceptable salts, characterized in that: Preferably, the compound represented by formula I is represented by the following formula IIa, formula IIb or formula IIc, wherein R1 to R4, R4' are the same as those defined in Formula I in claim 1; A1 and A4 are each independently selected from C, N, O and S atoms, and A2 and A3 are each independently selected from C or N atoms, provided that at most two of A1 to A4 are heteroatoms selected from N, O and S, and the other two are C atoms; dotted line Indicates that the position can be a double bond; R6, R7 and R8 are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, carbonyl, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted by halogen or hydroxyl, C3-C8 cycloalkyl substituted by halogen or hydroxyl, C1-C6 alkoxy, C3-C8 cycloalkyloxy, C1-C6 alkoxy substituted by halogen or hydroxyl, C3-C8 cycloalkyloxy substituted by halogen or hydroxyl; One or more R6 can form a C3-C6 cycloalkyl group or a 3-7 membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S with A4, and one or more R7 can form a C3-C6 cycloalkyl group or a 3-7 membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S with A3; R d is selected from hydrogen, halogen, hydroxy, carboxyl, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted by halogen, C1-C6 alkoxy, C3-C8 cycloalkyloxy; n1 and n2 are each independently an integer of 0, 1 or 2; n3 is an integer of 0, 1, 2, 3 or 4; Preferably, R6, R7 and R8 are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, carbonyl, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen or hydroxyl, C3-C6 cycloalkyl substituted by halogen or hydroxyl, C1-C3 alkoxy, C3-C6 cycloalkyloxy, C1-C3 alkoxy substituted by halogen or hydroxyl, C3-C6 cycloalkyloxy substituted by halogen or hydroxyl; More preferably, R6, R7 and R8 are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, carbonyl, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy; Preferably, one or more R6 can form a C3-C6 cycloalkyl group or a 3-6 membered heterocyclic group containing 1 to 2 heteroatoms selected from N, O and S with A4, and one or more R7 can form a C3-C6 cycloalkyl group or a 3-6 membered heterocyclic group containing 1 to 2 heteroatoms selected from N, O and S with A3; Preferably, R d is selected from hydrogen, halogen, hydroxy, carboxyl, cyano, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkyl substituted by halogen, C1-C3 alkoxy, C3-C6 cycloalkyloxy; More preferably, R d is selected from hydrogen, halogen, hydroxy, carboxyl, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy; Preferably, n1 and n2 are each independently an integer of 0, 1 or 2; Preferably, n3 is an integer of 0, 1 or 2.

4. The aromatic hydrocarbon receptor modulator compound represented by formula I according to claim 1, its respective optical isomers, deuterated substances, prodrugs or pharmaceutically acceptable salts, characterized in that: Preferably, the compound represented by formula I is represented by the following formula IIIa or IIIb, wherein R1 to R4, R4' are the same as those defined in Formula I in claim 1; A1 to A6 are each independently selected from C, N, O and S atoms, A2 is a C or N atom, provided that at most two of A1 to A6 are heteroatoms selected from N, O and S, and the rest are C atoms; dotted line Indicates that the position can be a double bond; R9 are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, carbonyl, cyano, C1-C8 alkyl, C3-C8 cycloalkyl, C6-C 14 Aryl, C6-C substituted by halogen 14 Aryl, -C(=O)OC1-C8 alkyl, containing 1 or 2 optional 5- to 10-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, 5- to 10-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O and S; n4 is an integer of 0, 1, 2, 3 or 4; Preferably, R8 and R9 are each independently selected from hydrogen, halogen, hydroxyl, carboxyl, carbonyl, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C6-C substituted by halogen 10 Aryl, -C(=O)OC1-C6 alkyl, 5- to 6-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, 5- to 6-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O and S; Preferably, R9 is each independently selected from hydrogen, halogen, hydroxyl, carboxyl, carbonyl, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, carbomethoxy, carboethoxy, n-propylcarbomethoxy, isopropylcarbomethoxy, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl; Preferably, n4 is an integer of 0, 1 or 2.

5. The aromatic hydrocarbon receptor modulator compound represented by formula I according to claim 1, its respective optical isomers, deuterated substances, prodrugs or pharmaceutically acceptable salts, characterized in that: The compound represented by formula I is selected from the following compounds:

6. A pharmaceutical composition comprising a therapeutically effective amount of an aromatic hydrocarbon receptor modulator compound represented by formula I, formula IIa, formula IIb, formula IIc, formula IIIa or formula IIIb according to any one of claims 1 to 5, its respective optical isomers, deuterated substances, prodrugs or pharmaceutically acceptable salts and a pharmaceutically acceptable excipient or carrier.

7. The aromatic hydrocarbon receptor modulator compound represented by formula I, formula IIa, formula IIb, formula IIc, formula IIIa or formula IIIb according to any one of claims 1 to 5, and the compound Use of their respective optical isomers, deuterated substances, prodrugs or pharmaceutically acceptable salts as AHR pathway regulators.

8. The aromatic hydrocarbon receptor modulator compound represented by formula I, formula IIa, formula IIb, formula IIc, formula IIIa or formula IIIb according to any one of claims 1 to 5, and the compound Use of their respective optical isomers, deuterated products, prodrugs or pharmaceutically acceptable salts in preparing drugs for treating tumors related to the AHR pathway.

9. A method for treating tumors associated with the AHR pathway, the method comprising administering to a subject in need thereof an effective amount of an aromatic hydrocarbon receptor modulator compound represented by formula I, formula IIa, formula IIb, formula IIc, formula IIIa or formula IIIb according to any one of claims 1 to 5, and a compound Their respective optical isomers, deuterated substances, prodrugs or pharmaceutically acceptable salts or the pharmaceutical composition according to the present invention.

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