Selective thyroid hormone receptor-β agonist, pharmaceutical composition comprising same, and use thereof

Abstract

Provided are a selective thyroid hormone receptor-β agonist, a pharmaceutical composition comprising same, and a use thereof. Specifically provided is a compound represented by formula (I). The compound has excellent efficacy and / or specificity, and can be used for treating metabolism-related diseases.

Description

Thyroxine beta receptor selective agonist compounds, pharmaceutical compositions thereof and uses TECHNICAL FIELD

[0001] The present invention relates to thyroxine beta receptor selective agonists. More particularly, the present invention relates to a thyroxine beta subtype receptor agonist compound according to general formula (I), pharmaceutical compositions thereof, and uses thereof in the manufacture of a medicament for the treatment of related diseases. BACKGROUND

[0002] Thyroid hormone (TH) is produced by the thyroid gland and secreted into the circulation (hypothalamic / pituitary / thyroid system) in two forms, 3,5,3',5'-tetraiodo-L-thyronine (T4) and 3,5,3'-triiodo-L-thyronine (T3), which play a pivotal role in maintaining human metabolism and cardiovascular function, etc. T4 is the major form secreted by the thyroid gland and T3 is the more physiologically active form. T4 is converted to T3 by tissue-specific deiodinases, which are present in all tissues, but predominantly in the liver and kidney. The biological activity of thyroid hormone is mediated by thyroid hormone receptors (THR). THRs are encoded by different genes expressed on human chromosomes 17 and 3 for α and β, respectively, and produce different protein isoforms by alternative splicing of the primary transcript, two isoforms for each gene, i.e. THR-αl, THR-α2, THR-βl and THR-β2. THR-βl and THR-β2 are expressed from the promoter differences, and the two isoforms differ only in the amino-terminal end. THR-αl and THR-α2 are produced by differential splicing of the pre-mRNA, and differ mainly in the carboxy-terminal end. Among them, THR-αl, THR-βl and THR-β2 can bind thyroid hormone. Current studies have confirmed that the physiological effects of different thyroid hormone receptor isoforms activated by thyroid hormone are not the same. THR-αl is mainly responsible for maintaining cardiovascular function; THR-βl plays an important role in regulating thyroid-stimulating hormone and regulating thyroid hormone; and THR-β2 plays a major role in regulating thyroid-stimulating hormone. Thyroid hormone has the effect of reducing serum low density lipoprotein (LDL). Hyperthyroidism is associated with low total serum cholesterol, which is attributed to thyroid hormone increasing the expression of LDL receptors in the liver and stimulating the metabolism of cholesterol to bile acid. Hypothyroidism is associated with hypercholesterolemia, and thyroid hormone replacement therapy is known to reduce total cholesterol. Thyroid hormone can also reduce the risk of atherosclerosis and other cardiovascular diseases. The incidence of atherosclerotic vascular disease is directly related to the level of LDL cholesterol. Thyroid hormone has beneficial effects on obese patients by increasing metabolic rate, oxygen consumption and heat release, thereby reducing body weight, improving obesity-related comorbidities, and can also have beneficial effects on blood glucose control in obese patients with type II diabetes.

[0003] Thyroid analogs that avoid the adverse effects of hyperthyroidism and hypothyroidism while retaining the beneficial effects of thyroid hormones would be a new approach to treat patients with metabolic diseases, such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, and other conditions, such as metabolic dysfunction associated steatohepatitis (MASH), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease, and related conditions and diseases.

[0004] MGL-3196 is the first THR-β agonist approved by FDA on March 14, 2024 for treating MASH, ending the 40-year plight of MASH without available drugs. The results of its clinical phase II experiment show that the health-related quality of life (HRQL) of MASH and liver fibrosis patients is significantly improved, and the NAS score is significantly reduced (NCT02912260). The results of the clinical phase III experiment show that the proportion of MASH regression and no fibrosis deterioration in the 80 mg dose experiment group and the 100 mg dose experiment group taking MGL-3196 for 52 weeks is 25.9% and 29.9%, which is significantly higher than that of the control group (9.7) (NCT03900429). Safety tests show that the side effects of MGL-3196 are only common in the early stage of taking the drug, and most of them are mild adverse reactions such as nausea and diarrhea, showing good safety and tolerability of MGL-3196 (NCT04197479).

[0005] Although MGL-3196 is the first and currently the only THR-β agonist for treating MASH on the market, its therapeutic effect is still not as expected. It is still a challenging task to develop new compounds that maximize the therapeutic effect of thyromimetic therapy, avoid side effects, and have good oral bioavailability and drug properties. Therefore, there is still a need to develop THR-β selective agonists with better specificity / pharmacodynamics / pharmacokinetics in the art, and the present application provides such compounds. SUMMARY

[0006] An object of the present application is to provide a compound represented by the general formula (I), a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, a stereoisomer, an enantiomer, a diastereomer, an atropisomer, a racemate, a polymorph, a solvate, or an isotopically labeled compound (including deuterium substitution) thereof.

[0007] Another object of the present application is to provide a pharmaceutical composition comprising the compound.

[0008] Another object of the present invention is to provide the use of the compound in pharmaceutical manufacturing.

[0009] According to one embodiment of this disclosure, a compound of formula (I), or a pharmaceutically acceptable salt thereof, a stereoisomer, an enantiomer, a diastereomer, a transisomer, a racemic mixture, or an isotopically labeled compound is provided:

[0010] Where X is selected from N and CH;

[0011] R2 and R3 are each independently selected from hydrogen, halogen, and methyl;

[0012] Part B is selected from:

[0013] When B is When A is R0;

[0014] R0 is selected from hydrogen, substituted or unsubstituted C. 1-10 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl groups, and substituted or unsubstituted 3-10 membered heterocyclic alkyl groups, wherein the substituents are selected from halogen atoms, hydroxyl groups, =O, C... 1-6 Alkoxy, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, substituted or unsubstituted C 6-1 0 aryl, and substituted or unsubstituted 5-10 heteroaryl; wherein the substituted or unsubstituted C 6-10 Among aryl, substituted or unsubstituted 5-10 membered heteroaryl groups, the substituents are selected from halogens, C 1-10 Alkyl, C 1-10 Haloalkyl, C 3-10 Cycloalkyl, hydroxyl, -NR 10 R 11 C 1-10 Alkoxy, C 1-10 Halogenated alkoxy groups, -CN, nitro groups, -C(=O)R 11 -C(=O)NR 10 R 11 -NR 10 C(=O)C 1-10 Alkyl, -SR 11 -S(=O)R 11 -S(=O)2R 11 、 and -S(=O)2NR 10 R 11 ;

[0015] R4 is selected from hydrogen, hydroxyl, halogen, cyano, -NR b R c, -C(=O)R a , -C(=O)OR b , -C(=O)NR b R c , and -P(=O)R b R c ;

[0016] Y is selected from CR 10 R 11 , NR 11 , O, S and -S=O;

[0017] L is selected from NR 11 , CR 10 R 11 , or L is absent;

[0018] when B is A is

[0019] R1is one or more each independently selected from a group consisting of nitro, cyano, hydroxy, -BR 10 R 11 , -C(=O)R 11 , -C(=O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(=O)R 11 , -PR 10 R 11 , -P(=O)R 10 R 11 , -SR 11 , -S(=O)R 11 , -S(=O)2R 11 , -S(=O)2NR 10 R 11 , substituted C 1-3 alkyl, substituted or unsubstituted C 3-10 cycloalkyl, and substituted or unsubstituted 3-10 membered heterocycloalkyl, the substituents being selected from a group consisting of halogen atom, hydroxy, nitro, CN, =O, -NR 10 R 11 , -C(=O)R 11 , -C(=O)NR 10 R 11 , and -NR 10 R 11 ;

[0020] R5is selected from hydrogen, cyano, -NR 10 R 11 , and substituted or unsubstituted C1-6 alkyl, said substituents being halogen, hydroxyl, cyano, C 1-6 alkoxy, or -NR 10 R 11 ;

[0021] each R 10 is independently selected from hydrogen, substituted or unsubstituted C 1-3 alkyl, and substituted or unsubstituted C 1-3 alkoxy, said substituents being selected from the group consisting of halogen, hydroxyl, and C 1-3 alkoxy;

[0022] each R 11 is independently selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, and substituted or unsubstituted C 1-3 alkoxy, said substituents being selected from the group consisting of halogen, hydroxyl, and C

[0023] or R 10 and R 11 together with the carbon atom to which they are attached form a 3- to 6-membered ring containing 0 to 3 heteroatoms selected from the group consisting of N, O, and S;

[0024] each R a is independently hydrogen, hydroxyl, C 1-6 alkyl, C 3-10 cycloalkyl, or 3- to 10-membered heterocycloalkyl, said alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, amino, and C 1-6 alkyl;

[0025] each R b and R c are independently hydrogen, hydroxyl, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-3 alkoxy, or 3- to 10-membered heterocycloalkyl; said alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, amino, C 2-6 alkenyl, and C 1-6 alkynyl;

[0026] or R b and R c together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl, said heterocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, amino, and C 1-6 alkyl;

[0027] wherein said compound is not

[0028] According to one embodiment of the present disclosure, wherein the compound is selected from the group consisting of compounds represented by formula (II):

[0029] R0is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 3-10 cycloalkyl, and substituted or unsubstituted 3-10 membered heterocycloalkyl, the substituents being selected from the group consisting of halogen atoms, hydroxyl, =0, C 1-6 alkoxy, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted C 6-10 aryl, and substituted or unsubstituted 5-10 membered heteroaryl; wherein the substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, the substituents being selected from the group consisting of halogen, C 1-10 alkyl, C 1-10 haloalkyl, C 3-10 cycloalkyl, hydroxyl, -NR 10 R 11 , C 1-10 alkoxy, C 1-10 haloalkoxy, -CN, nitro, -C(=O)R 11 , -C(=O)NR 10 R 11 , -NR 10 C(=O)C 1-10 alkyl, -SR 11 , -S(=O)R 11 , -S(=O)2R 11 , and -S(=O)2NR 10 R 11 ;

[0030] R2and R3are each independently selected from the group consisting of hydrogen, halogen and methyl;

[0031] Y is selected from NR 11 and O;

[0032] L is selected from NR 11 and CR 10 R 11 , or L is absent;

[0033] R4is selected from the group consisting of hydrogen, hydroxyl, cyano, -NR b R c , -C(=O)R a , -C(=O)NR b R c , -C(=O)OR b , and -P(=O)Rb R c ;

[0034] R 10 , R 11 , R a , R b , R c are the same as the definitions given above for general formula I,

[0035] wherein the compound is not

[0036] According to one embodiment of the present disclosure, wherein the compound is selected from the compounds represented by formula (III):

[0037] R1is one or more each independently selected from the group consisting of nitro, cyano, hydroxy, -BR 10 R 11 , -C(=O)R 11 , -C(=O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(=O)R 11 , -PR 10 R 11 , -P(=O)R 10 R 11 , -SR 11 , -S(=O)R 11 , -S(=O)2R 11 , -S(=O)2NR 10 R 11 , C 3-10 cycloalkyl, and 3-10 membered heterocycloalkyl;

[0038] R2and R3are each independently selected from the group consisting of hydrogen, halogen, and methyl;

[0039] R5is selected from the group consisting of hydrogen, cyano, -NR 10 R 11 , and substituted or unsubstituted C 1-6 alkyl, the substituents being selected from the group consisting of halogen, hydroxy, and -NR 10 R 11 ;

[0040] R 10 , R 11 are the same as the definitions given above for general formula I.

[0041] According to one embodiment of the present disclosure, wherein the compound is selected from the compounds represented by formula (IV):

[0042] R1is one or more each independently selected from the group consisting of nitro, cyano, hydroxy, -C(=O)R 11 , -C(=O)NR 10 R 11 , -NR 10 R 11 , -PR 10 R 11 , -P(=O)R 10 R 11 , -SR 11 , -S(=O)R 11 , -S(=O)2R 11 , -S(=O)2NR 10 R 11 , C 3-10 cycloalkyl, and 3-10 membered heterocycloalkyl;

[0043] R2and R3are each independently selected from the group consisting of hydrogen, halogen, and methyl;

[0044] R5is selected from the group consisting of hydrogen, cyano, -NR 10 R 11 , and substituted or unsubstituted C 1-6 alkyl, said substituents being selected from the group consisting of halogen, hydroxy, and -NR 10 R 11 ;

[0045] R 10 , R 11 are the same as defined above in the general formula I.

[0046] According to one embodiment of the present disclosure, wherein the compound is selected from the group consisting of compounds represented by formula (V):

[0047] R0is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 3-10 cycloalkyl, and substituted or unsubstituted 3-10 membered heterocycloalkyl, said substituents being selected from the group consisting of halogen atoms, hydroxy, =O, C 1-6 alkoxy, C 1-6 alkyl, C 3-10 cycloalkyl, and 3-10 membered heterocycloalkyl

[0048] R2and R3are each independently selected from the group consisting of halogen and methyl;

[0049] R4is selected from the group consisting of hydrogen, hydroxy, -NR b R c , and -C(=O)OR b ;

[0050] R b , R c and the definitions of the groups in general formula I are the same as described above.

[0051] According to one embodiment of the present disclosure, wherein the compound of general formula I is selected from the following compounds:

[0052] According to one embodiment of the present disclosure, it provides a pharmaceutical composition comprising one or more of the compounds, pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, stereoisomers, enantiomers, diastereomers, atropisomers, racemates, polymorphs, solvates and isotopically-labeled compounds thereof, and optionally, pharmaceutically acceptable adjuvants.

[0053] According to one embodiment of the present disclosure, it provides the use of the compounds, pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, stereoisomers, enantiomers, diastereomers, atropisomers, racemates, polymorphs, solvates or isotopically-labeled compounds thereof or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating metabolic-related diseases.

[0054] According to one embodiment of the present disclosure, it provides a method for treating metabolic-related diseases, comprising administering to a subject an effective amount of one or more of the compounds, pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, stereoisomers, enantiomers, diastereomers, atropisomers, racemates, polymorphs, solvates and isotopically-labeled compounds thereof, or the above-mentioned pharmaceutical composition.

[0055] According to one embodiment of the present disclosure, the metabolic-related diseases are selected from obesity, hyperlipidemia, hypercholesterolemia, diabetes, metabolic dysfunction-related steatohepatitis, hepatic steatosis, atherosclerosis, hypothyroidism, thyroid cancer, seborrheic dermatitis and androgenetic alopecia.

[0056] According to one embodiment of the present disclosure, the metabolic-related diseases are selected from metabolic dysfunction-related steatohepatitis, hypothyroidism and thyroid cancer.

[0057] The compounds of the present disclosure have excellent efficacy and / or specificity, and can be used for treating metabolic-related diseases. BRIEF DESCRIPTION OF DRAWINGS

[0058] Figure 1 shows the effect of compounds ZB-B-13 and ZB-A-10 on serum ALT levels in mice with non-alcoholic steatohepatitis induced by high-fat diet combined with carbon tetrachloride after oral administration for 6 weeks. *P < 0.05, **P < 0.01 compared with the model group.

[0059] Figure 2 shows the effect of compounds ZB-B-13 and ZB-A-10 on serum total cholesterol levels in mice with non-alcoholic steatohepatitis induced by high-fat diet combined with carbon tetrachloride after oral administration for 6 weeks. **P < 0.01 compared with the model group.

[0060] Figure 3 shows the effect of compounds ZB-B-13 and ZB-A-10 on serum low-density lipoprotein cholesterol levels in mice with non-alcoholic steatohepatitis induced by high-fat diet combined with carbon tetrachloride after oral administration for 6 weeks. **P < 0.01 compared with the model group.

[0061] Figure 4 shows the effect of compounds ZB-B-13 and ZB-A-10 on liver NAS score in mice with non-alcoholic steatohepatitis induced by high-fat diet combined with carbon tetrachloride after oral administration for 6 weeks. **P < 0.01 compared with the model group.

[0062] Figure 5 shows the effect of compounds ZB-B-13 and ZB-A-10 on liver fibrosis in mice with non-alcoholic steatohepatitis induced by high-fat diet combined with carbon tetrachloride after oral administration for 6 weeks. *P < 0.05, **P < 0.01 compared with the model group.

[0063] Figure 6 shows the reducing effect of compound ZB-A-10 on serum total cholesterol (A) and low-density lipoprotein cholesterol (B) levels in mice after a single oral administration for 72 hours. **P < 0.01 compared with the solvent control group.

[0064] Figure 7 shows the effect of compound ZB-A-10 on serum ALT levels in mice with non-alcoholic steatohepatitis induced by high-fat diet combined with carbon tetrachloride after oral administration (once every 3 days) for 6 weeks. *P < 0.05, **P < 0.01 compared with the model group.

[0065] Figure 8 shows the effect of compound ZB-A-10 on serum total cholesterol levels in mice with non-alcoholic steatohepatitis induced by high-fat diet combined with carbon tetrachloride after oral administration (once every 3 days) for 6 weeks. **P < 0.01 compared with the model group.

[0066] Figure 9 shows the effect of compound ZB-A-10 on serum low-density lipoprotein cholesterol levels in mice with non-alcoholic steatohepatitis induced by high-fat diet combined with carbon tetrachloride after oral administration (once every 3 days) for 6 weeks. **P < 0.01 compared with the model group.

[0067] Figure 10 shows the effect of compound ZB-A-10 on NAS score of liver in mice induced by high-fat diet combined with carbon tetrachloride after oral administration (once every 3 days) for 6 weeks. **P<0.01 compared with model group.

[0068] Figure 11 shows the effect of compound ZB-A-10 on liver fibrosis in mice induced by high-fat diet combined with carbon tetrachloride after oral administration (once every 3 days) for 6 weeks. *P<0.05, **P<0.01 compared with model group. Examples

[0069] In the following examples, the optimum reaction conditions and reaction times for each individual step can vary depending on the particular reactants used and the substituents present in all reactants. The solvent, temperature, and other reaction conditions can be readily selected by one skilled in the art unless otherwise specified. Specific procedures are provided in the Synthetic Examples section. The reactions can be further worked up in the conventional manner, for example by removing the solvent from the residue and further purified according to methods generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration, and chromatography. The starting materials and reagents are commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature unless otherwise stated.

[0070] Routine experimentation, including appropriate adjustment of reaction conditions, reagents and sequences of the synthetic routes, protection of any chemically sensitive functional groups, which can not be compatible with the reaction conditions, and deprotection at appropriate points in the reaction sequence of the process, are included within the scope of the present application. Appropriate protecting groups and methods of protection and deprotection of various substituents using such appropriate protecting groups are well known to those skilled in the art; examples of which are found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rded.), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the present application can be achieved by methods analogous to those described in the synthetic schemes described above and in the specific examples.

[0071] Starting materials, if not commercially available, can be prepared by steps selected from standard organic chemical techniques, techniques analogous to the synthesis of known structural analogs, or techniques analogous to the steps described in the schemes above or in the Synthetic Examples section. When optically active forms of the compounds of the present application are desired, they can be obtained either by carrying out one of the procedures described herein using an optically active starting material (e.g., prepared by asymmetric induction of the appropriate reaction step) or by resolution of a stereoisomeric mixture of a compound or intermediate by using standard procedures (e.g., chromatographic separation, recrystallization, or enzymatic resolution).

[0072] Similarly, when pure geometric isomers of the compounds of the present application are desired, they can be obtained from one of the above steps using pure geometric isomers as starting materials, or by separation of mixtures of geometric isomers of the compounds or intermediates by using standard procedures, such as chromatographic separation.

[0073] For illustrative purposes, the following examples can be used, which are only for the purpose of explaining the technical solutions of the present application, and are not intended to limit the present application to these examples.

[0074] Example 1: Preparation of intermediate 1f

[0075] First step: Preparation of compound 1b

[0076] Into a 250 mL flask was added 1a (5 g, 42.3 mmol), 3,5-dichloro-4-fluoronitrobenzene (10.66 g, 50.7 mmol), potassium carbonate (8.77 g, 63.4 mmol), N,N-dimethylformamide (50 mL), and heated to 80 °C with stirring. TLC monitoring, 2 hours reaction was completed. Added appropriate amount of ethyl acetate, washed the organic layer with saturated sodium chloride solution 3 times, extracted the water layer with ethyl acetate once, added anhydrous sodium sulfate to the organic layer to dry, filtered. The filtrate was distilled under reduced pressure, separated by column chromatography to obtain compound 1b. LC-MS [M+H] + : 308.

[0077] Second step: Preparation of compound 1c

[0078] Into a 100 mL flask was added 1b (2.445 g, 7.93 mmol), dichloromethane (40 mL). Added m-chloroperoxybenzoic acid (2.05 g, 11.9 mmol) in batches at 0 °C, then restored to room temperature and stirred. LC-MS monitoring, 2 hours reaction was completed. Extracted with ethyl acetate 3 times. Added anhydrous sodium sulfate to the organic layer to dry, filtered. The filtrate was distilled under reduced pressure to obtain compound 1c. 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.62 (s, 2H), 7.55 (d, J = 3.2 Hz, 1H), 7.49 (d, J = 9.4 Hz, 1H), 6.45 (d, J = 3.2 Hz, 1H), 6.29 (d, J = 9.4 Hz, 1H); LC-MS [M+H] + : 324.

[0079] Third step: Preparation of compound 1d

[0080] Into a 100 ml flask was added 1c (2.57 g, 7.93 mmol), N,N-dimethylformamide (15 mL). At 0 °C was added trifluoroacetic anhydride (16.65 g, 79.3 mmol) and then allowed to stir at room temperature. LC-MS monitoring, 8 hours reaction was complete. To the reaction was added toluene (10 mL) and distilled under reduced pressure until no fraction distilled. Anhydrous ethanol (5 mL) was added and distilled under reduced pressure until no fraction distilled. Water (30 mL) was added slowly dropwise and filtered to collect the filter cake to give compound 1d. 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.62 (s, 2H), 7.55 (d, J = 3.2 Hz, 1H), 7.49 (d, J = 9.4 Hz, 1H), 6.45 (d, J = 3.2 Hz, 1H), 6.29 (d, J = 9.4 Hz, 1H); LC-MS [M+H] + : 324.

[0081] Fourth Step: Preparation of Compound 1e

[0082] Into a microwave tube was added 1d (0.5 g, 1.54 mmol), isopropyl bromide (0.758 g, 6.17 mmol), potassium carbonate (0.639 g, 4.62 mmol), 1,4-dioxane (10 mL), and heated at 140 °C for 6 hours in a microwave. TLC monitoring, 6 hours reaction was complete. Column chromatography separation to give compound 1e. 1 H NMR (400 MHz, CDCl3) δ 8.38 (s, 2H), 6.97 (d, J = 3.3 Hz, 1H), 6.93 (d, J = 9.5 Hz, 1H), 6.59 (d, J = 3.3 Hz, 1H), 6.39 (d, J = 9.4 Hz, 1H), 5.69 - 5.22 (m, 1H), 1.61 (d, J = 7.1 Hz, 6H); LC-MS [M+H] + : 366.

[0083] Fifth Step: Preparation of Compound 1f

[0084] Into a 50 ml flask was added 1e (0.471 g, 1.28 mmol), stannous chloride dihydrate (1.45 g, 6.43 mmol), anhydrous ethanol (15 mL), and heated to reflux at 90 °C. TLC monitoring, 8 hours reaction was complete. A suitable amount of ethyl acetate was added and the reaction was poured into a separatory funnel. The organic layer was washed twice with 2 M sodium hydroxide solution until the aqueous layer had a pH > 9. The aqueous layer was extracted once with ethyl acetate. Anhydrous sodium sulfate was added to the organic layer and dried, and filtered. The filtrate was distilled under reduced pressure and column chromatography separation to give compound 1f. 1H NMR (400 MHz, DMSO-d6) δ 7.25 (d, J = 3.2 Hz, 1H), 7.06 (d, J = 9.4 Hz, 1H), 6.75 (s, 2H), 6.58 (d, J = 3.2 Hz, 1H), 6.16 - 5.98 (m, 3H), 5.40 - 5.02 (m, 1H), 1.49 (d, J = 7.0 Hz, 6H); LC-MS [M+H] + : 336.

[0085] Example 2: Preparation of compound ZB-A-03

[0086] Into a 50 mL flask was added 1f (50 mg, 0.148 mmol), 1,4-dioxane (3 mL), trichloromethyl chloroformate (14.7 mg, 0.0743 mmol). Stirring at 60 °C. After 2 hours, methyl carbamate (13.3 mg, 0.178 mmol) was added, 3 drops of triethylamine was added, stirring at 80 °C. TLC monitoring, 1 hour reaction was completed. Compound ZB-A-03 was isolated by column chromatography. LC-MS [M+H] + : 437.

[0087] Example 3: Preparation of compounds ZB-A-04 and ZB-A-05

[0088] First step: Preparation of compound 4a

[0089] Into a 50 mL flask was added 1d (0.1 g, 0.308 mmol), potassium carbonate (0.127 g, 0.925 mmol), 4-methoxychlorobenzene (0.193 g, 1.23 mmol), 1,4-dioxane (10 mL), stirring at 100 °C. TLC monitoring, 8 hours reaction was completed. Solvent was distilled under reduced pressure, compound 4a was isolated by column chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 8.61 (s, 2H), 7.46 (d, J = 3.2 Hz, 1H), 7.40 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 9.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 6.70 (d, J = 3.2 Hz, 1H), 6.24 (d, J = 9.4 Hz, 1H), 3.72 (s, 3H); LC-MS [M+H] + : 444.

[0090] Second step: Preparation of compound 4b

[0091] To a 50 mL flask was added 4a (0.4 g, 0.9 mmol), stannous chloride dihydrate (1.01 g, 4.5 mmol), anhydrous ethanol (10 mL), and heated to reflux with stirring at 90 °C. The reaction was poured into a separatory funnel and the organic layer was washed twice with 2 M NaOH until the aqueous layer was > pH 9. The aqueous layer was extracted once with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to give compound 4b. 1 H NMR (600 MHz, DMSO-d6) δ 7.39 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 3.1 Hz, 1H), 7.15 (d, J = 9.4 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 6.75 (s, 2H), 6.50 (d, J = 3.2 Hz, 1H), 6.17 (d, J = 9.4 Hz, 1H), 6.08 (s, 2H), 5.21 (s, 2H), 3.71 (s, 3H); LC-MS [M+H] + : 414.

[0092] Third Step: Preparation of compound 4c

[0093] To a 50 mL flask was added 4b (0.1 g, 0.241 mmol), dichloromethane (3 mL), triethylamine (48.8 mg, 0.482 mmol) at 0 °C, and methyl malonate acid chloride (39.5 mg, 0.289 mmol). TLC was monitored. Compound 4c was isolated by column chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.87 (s, 2H), 7.39 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 3.2 Hz, 1H), 7.24 (d, J = 9.4 Hz, 1H), 6.89 (d, J = 8.5 Hz, 2H), 6.59 (d, J = 3.2 Hz, 1H), 6.19 (d, J = 9.4 Hz, 1H), 5.23 (s, 2H), 3.71 (s, 3H), 3.68 (s, 3H), 3.56 (s, 2H); LC-MS [M+H] + : 514.

[0094] Second Step: Preparation of compounds ZB-A-04 and ZB-A-05

[0095] Into a 50 mL flask was added 4c (0.1 g, 0.194 mmol), dichloromethane (4 mL). The flask was cooled to -78 °C and 2 M boron tribromide in dichloromethane (3.4 mL) was added dropwise. The reaction was monitored by LC-MS and was complete after 3 h. The reaction was quenched with saturated sodium bicarbonate solution at 0 °C and ethyl acetate was added. The reaction mixture was extracted with ethyl acetate (3x) and the organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The compound was isolated by column chromatography.

[0096] Compound ZB-A-04. 1 H NMR (600 MHz, DMSO-d6) δ 10.78 (s, 1H), 7.87 (s, 2H), 7.36 (d, J = 3.2 Hz, 1H), 7.28 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 9.4 Hz, 1H), 6.70 (d, J = 8.5 Hz, 2H), 6.59 (d, J = 3.2 Hz, 1H), 6.19 (d, J = 9.4 Hz, 1H), 5.17 (s, 2H), 3.67 (s, 3H); LC-MS [M-H] - : 498; and

[0097] Compound ZB-A-05. 1 H NMR (600 MHz, DMSO-d6) δ 12.82 (s, 1H), 10.73 (s, 1H), 9.39 (s, 1H), 7.88 (s, 2H), 7.35 (s, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 9.4 Hz, 1H), 6.70 (d, J = 8.0 Hz, 2H), 6.58 (s, 1H), 6.18 (d, J = 9.3 Hz, 1H), 5.17 (s, 2H), 3.43 (s, 2H); LC-MS [M-H] - : 484.

[0098] Example 4: Preparation of compounds ZB-A-06, ZB-A-07 and ZB-A-08

[0099] First Step: Preparation of compound ZB-A-06

[0100] Into a 50 mL flask was added 4b (0.1 g, 0.241 mmol), tetrahydrofuran (5 ml), dichloromethane (5 mL), 2,2-dimethyl-1,3-dioxane-4,6-dione (0.1 g, 0.693 mmol) and the reaction mixture was heated to reflux at 80 °C. The reaction was monitored by LC-MS and was complete after 8 h. The compound ZB-A-06 was isolated by column chromatography. 1H NMR (600 MHz, DMSO-d6) δ 10.73 (s, 1H), 7.89 (s, 2H), 7.42-7.37 (m, 3H), 7.28 (d, J = 9.4 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 3.2 Hz, 1H), 6.22 (d, J = 9.4 Hz, 1H), 5.24 (s, 2H), 3.71 (s, 3H), 3.43 (s, 2H); LC-MS [M-H] - : 498.

[0101] Second Step: Preparation of compound ZB-A-07

[0102] Into a 50 mL flask was added ZB-A-06 (0.1 g, 0.199 mmol), dichloromethane (5 mL), 2M dimethylamine in tetrahydrofuran (0.12 mL) at 0 °C, N, N- diisopropylethylamine (DIPEA, 61.9 mg, 0.479 mmol), 2-(7-azobenzotriazol)-N, N, N', N'- tetramethyluronium hexafluorophosphate (HATU, 91.1 mg, 0.239 mmol), then stirred at room temperature. LC-MS monitoring, 8 hours reaction was completed. Compound ZB-A-07 was obtained by column chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 10.73 (s, 1H), 7.89 (s, 2H), 7.42-7.37 (m, 3H), 7.28 (d, J = 9.4 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 3.2 Hz, 1H), 6.22 (d, J = 9.4 Hz, 1H), 5.24 (s, 2H), 3.71 (s, 3H), 3.43 (s, 2H); LC-MS [M-H] + : 527.

[0103] Third Step: Preparation of compound ZB-A-08

[0104] Into a 50 mL flask was added ZB-A-07 (90 mg, 0.17 mmol), dichloromethane (3 mL). -78 °C replaced gas 3 times, dropwise added 2M boron tribromide dichloromethane solution (2.98 mL), raised to -10 °C stirred. LC-MS monitoring, 3 hours reaction was completed. Added saturated sodium bicarbonate solution at 0 °C, after the reaction was quenched, added ethyl acetate, added a small amount of saturated sodium chloride solution, extracted with ethyl acetate 3 times, added anhydrous sodium sulfate to the organic layer, dried, removed the solvent under reduced pressure. Compound ZB-A-08 was obtained by column chromatography.1 H NMR (600 MHz, DMSO-d6) δ 10.67 (s, 1H), 7.89 (s, 2H), 7.37 (d, J = 3.2 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 9.4 Hz, 1H), 6.70 (d, J = 8.5 Hz, 2H), 6.59 (d, J = 3.2 Hz, 1H), 6.20 (d, J = 9.4 Hz, 1H), 5.18 (s, 2H), 3.55 (s, 2H), 3.01 (s, 3H), 2.86 (s, 3H); LC-MS [M-H] - : 511.

[0105] Example 5: Preparation of compound ZB-A-09

[0106] Into a 50 mL flask was added ZB-A-01 (0.1 g, 0.229 mmol), 7 M ammonia methanol solution (5 mL), stirred at room temperature. LC-MS monitoring, 8 hours reaction was completed, separated by column chromatography to obtain compound ZB-A-09. LC-MS [M+H] + : 421.

[0107] Example 6: Preparation of compound ZB-A-10

[0108] First step: Preparation of compound 7a

[0109] Into a 50 mL flask was added 1f (0.157 g, 0.383 mmol), dichloromethane (5 mL), triethylamine (77.63 mg, 0.767 mmol) was added at 0 °C, oxalyl monomethyl chloride (62.8 mg, 0.46 mmol), then stirred at room temperature. TLC monitoring, 3 hours reaction was completed. Separated by column chromatography to obtain compound 7a. 1 H NMR (600 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.13 (s, 2H), 7.39 (d, J = 3.2 Hz, 1H), 7.15 (d, J = 9.4 Hz, 1H), 6.69 (d, J = 3.3 Hz, 1H), 6.10 (d, J = 9.4 Hz, 1H), 5.44-5.12 (m, 1H), 4.34 (q, J = 7.1 Hz, 2H), 1.50 (d, J = 7.1 Hz, 6H), 1.33 (t, J = 7.1 Hz, 3H); LC-MS [M+H] + : 436.

[0110] Second step: Preparation of compound ZB-A-10

[0111] To a 50 ml flask was added 7a (0.1 g, 0.229 mmol), ethanol (2 mL), 1 M aqueous sodium hydroxide (2 mL), stirred at room temperature. LC-MS monitoring, 2 hours reaction was completed, dropwise 1 M aqueous hydrochloric acid (2 mL). Extracted with ethyl acetate 3 times, to the organic layer was added anhydrous sodium sulfate dried, filtered. The solvent was removed by distillation under reduced pressure, separated by preparative liquid phase to obtain compound ZB-A-10 (60 mg, yield 64%). 1 H NMR (600 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.15 (s, 2H), 7.40 (d, J = 3.3 Hz, 1H), 7.17 (d, J = 9.4 Hz, 1H), 6.69 (d, J = 3.3 Hz, 1H), 6.11 (d, J = 9.4 Hz, 1H), 5.28 (br s, 1H), 1.55 (d, J = 7.0 Hz, 6H); LC-MS [M-H] - : 406.

[0112] Example 7: Preparation of compound ZB-A-11

[0113] First step: Preparation of compound 8a

[0114] To a 50 ml flask was added 4b (0.192 g, 0.463 mmol), dichloromethane (5 mL), triethylamine (0.234 g, 2.31 mmol) was added at 0 °C, oxalyl monomethyl chloride (0.189 g, 1.39 mmol), then stirred at room temperature. TLC monitoring, 3 hours reaction was completed. Separated by column chromatography to obtain 8a. 1 H NMR (600 MHz, Chloroform-d) δ 9.53 (s, 1H), 7.91 (s, 2H), 7.34 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 9.4 Hz, 1H), 6.92 (d, J = 3.2 Hz, 1H), 6.84 (d, J = 8.6 Hz, 2H), 6.43 (d, J = 9.4 Hz, 1H), 6.33 (d, J = 3.2 Hz, 1H), 5.34 (s, 2H), 4.43 (q, J = 7.2 Hz, 2H), 3.76 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H); LC-MS [M+H] + : 514.

[0115] Second step: Preparation of compound ZB-A-11

[0116] To a 50 mL flask was added 8a (0.1 g, 0.194 mmol), ethanol (2 mL), 1 M aqueous sodium hydroxide (2 mL), stirred at room temperature. LC-MS monitoring, 2 hours reaction was completed, dropwise 1 M hydrochloric acid (2 ml). Extracted with ethyl acetate 3 times. To the organic layer was added anhydrous sodium sulfate dried, filtered. The solvent was removed by distillation under reduced pressure, separated by preparative liquid phase to obtain compound ZB-A-11. 1 H NMR (600 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.14 (s, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 3.2 Hz, 1H), 7.24 (d, J = 9.4 Hz, 1H), 6.89 (d, J = 8.3 Hz, 2H), 6.59 (d, J = 3.3 Hz, 1H), 6.20 (d, J = 9.4 Hz, 1H), 5.23 (s, 2H), 3.71 (s, 3H); LC-MS [M-H] - : 484.

[0117] Example 8: Preparation of compound ZB-A-12

[0118] First step: Preparation of compound 9a

[0119] To a 50 mL flask was added 1d (0.3 g, 0.925 mmol), 1-(bromomethyl)-4- cyclopropylbenzene (0.234 g, 1.11 mmol), potassium carbonate (0.383 g, 2.77 mmol), 1,4-dioxane (10 mL), heated to reflux at 100 °C stirred. TLC monitoring, separated by column chromatography to obtain compound 9a. 1 H NMR (600 MHz, DMSO-d6) δ 8.61 (s, 2H), 7.45 (d, J = 3.2 Hz, 1H), 7.34-7.30 (m, 3H), 7.03 (d, J = 8.1 Hz, 2H), 6.67 (d, J = 3.1 Hz, 1H), 6.24 (d, J = 9.5 Hz, 1H), 5.25 (s, 2H), 1.89-1.83 (m, 1H), 0.93-0.89 (m, 2H), 0.65-0.60 (m, 2H); LC-MS [M+H] + : 454.

[0120] Second step: Preparation of compound 9b

[0121] To a 50 ml flask was added 9a (0.3 g, 0.66 mmol), stannous chloride dihydrate (0.745 g, 3.3 mmol), ethanol (5 mL), heated to reflux with stirring at 90 °C. TLC monitoring, 8 hours reaction was completed. Added appropriate amount of ethyl acetate, the reaction was poured into a separatory funnel, the organic layer was washed with 2M sodium hydroxide solution 2 times, washed until the water layer pH > 9. The water layer was extracted with ethyl acetate 1 time. To the organic layer was added anhydrous sodium sulfate drying, filtration. The filtrate was distilled under reduced pressure, separated by column chromatography to obtain compound 9b. 1 H NMR (600 MHz, DMSO-d6) δ 7.30 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 3.2 Hz, 1H), 7.16 (d, J = 9.4 Hz, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.75 (s, 2H), 6.46 (d, J = 3.1 Hz, 1H), 6.17 (d, J = 9.4 Hz, 1H), 6.08 (s, 2H), 5.22 (s, 2H), 1.89 - 1.81 (m, 1H), 0.93 - 0.87 (m, 2H), 0.66 - 0.58 (m, 2H). LC-MS [M+H] + : 424.

[0122] Third step: preparation of compound 9c

[0123] To a 50 ml flask was added 9b (0.179 g, 0.421 mmol), dichloromethane (5 mL), triethylamine (0.213 g, 2.1 mmol) was added at 0 °C, oxalyl chloride monoethyl ester (0.172 g, 1.26 mmol), then stirred at room temperature. TLC monitoring, 3 hours reaction was completed, separated by column chromatography to obtain 9c. 1 H NMR (600 MHz, DMSO-d6) δ 7.30 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 3.2 Hz, 1H), 7.16 (d, J = 9.4 Hz, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.75 (s, 2H), 6.46 (d, J = 3.1 Hz, 1H), 6.17 (d, J = 9.4 Hz, 1H), 6.08 (s, 2H), 5.22 (s, 2H), 1.89 - 1.81 (m, 1H), 0.93 - 0.87 (m, 2H), 0.66 - 0.58 (m, 2H). LC-MS [M+H] + : 524.

[0124] Fourth step: preparation of compound ZB-A-12

[0125] To a 50 mL flask was added 9c (0.1 g, 0.19 mmol), ethanol (2 mL), 1 M sodium hydroxide solution (2 mL), stirred at room temperature. LC-MS monitoring, 2 hours reaction was completed, dropwise 1 M hydrochloric acid (2 mL). Extracted with ethyl acetate 3 times. To the organic layer was added anhydrous sodium sulfate dried, filtered. The solvent was removed by distillation under reduced pressure, separated by column chromatography to obtain compound ZB-A-12. 1 H NMR (600 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.14 (s, 2H), 7.36 (d, 1H), 7.30 (d, J = 7.8 Hz, 2H), 7.25 (d, J = 9.3 Hz, 1H), 7.02 (d, J = 7.2 Hz, 2H), 6.56 (d, 1H), 6.20 (d, J = 9.4 Hz, 1H), 5.24 (s, 2H), 1.90 - 1.82 (m, 1H), 0.92 - 0.88 (m, 2H), 0.64 - 0.60 (m, 2H); LC-MS [M-H] - : 494.

[0126] Example 9: Preparation of compound ZB-A-13

[0127] First step: Preparation of compound 10a

[0128] To a 50 mL flask was added 1d (0.3 g, 0.925 mmol), 1-(4- (bromomethyl)phenyl)ethanone (0.236 g, 1.11 mmol), potassium carbonate (0.383 g, 2.77 mmol), added 1,4-dioxane (10 mL), heated to reflux at 100 °C stirred. TLC monitoring, separated by column chromatography to obtain compound 10a. 1 H NMR (600 MHz, DMSO-d6) δ 8.61 (s, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 3.2 Hz, 1H), 7.38 (d, J = 9.5 Hz, 1H), 6.64 (d, J = 3.3 Hz, 1H), 6.27 (d, J = 9.5 Hz, 1H), 5.40 (s, 2H), 2.55 (s, 3H); LC-MS [M+H] + : 456.

[0129] Second step: Preparation of compound 10b

[0130] To a 50 ml flask was added 10a (456.28, 0.25 g, 0.547 mmol), stannous chloride dihydrate (225.65, 0.618 g, 2.73 mmol), ethanol (5 ml), heated to reflux with stirring at 90 °C. TLC monitoring, 8 hours reaction was completed. Added appropriate amount of ethyl acetate, the reaction was poured into a separatory funnel, the organic layer was washed with 2M sodium hydroxide solution 2 times, washed until the water layer pH > 9. The water layer was extracted with ethyl acetate 1 time. To the organic layer was added anhydrous sodium sulfate drying, filtration. The filtrate was distilled under reduced pressure, separated by column chromatography to obtain compound 10b. 1 H NMR (600 MHz, DMSO-d6) δ 7.92 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 3.1 Hz, 1H), 7.21 (d, J = 9.4 Hz, 1H), 6.75 (s, 2H), 6.44 (d, J = 3.1 Hz, 1H), 6.21 (d, J = 9.4 Hz, 1H), 6.09 (s, 2H), 5.37 (s, 2H), 2.54 (s, 3H); LC-MS [M+H] + : 426.

[0131] Third step: preparation of compound 10c

[0132] To a 50 ml flask was added 10b (0.217 g, 0.509 mmol), dichloromethane (5 ml), triethylamine (0.257 g, 2.54 mmol) was added at 0 °C, oxalyl chloride monoethyl ester (0.208 g, 1.52 mmol), then stirred at room temperature. TLC monitoring, 3 hours reaction was completed, separated by column chromatography to obtain 10c. 1 H NMR (600 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.13 (s, 2H), 7.93 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 3.2 Hz, 1H), 7.30 (d, J = 9.4 Hz, 1H), 6.55 (d, J = 3.2 Hz, 1H), 6.23 (d, J = 9.4 Hz, 1H), 5.39 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 2.54 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); LC-MS [M+H] + : 526.

[0133] Fourth step: preparation of compound ZB-A-13

[0134] To a 50 mL flask was added 10c (0.1 g, 0.189 mmol), ethanol (2 mL), 1 M sodium hydroxide solution (2 mL), stirred at room temperature. LC-MS monitoring, 2 hours reaction was completed, dropwise 1 M hydrochloric acid (2 mL). Extracted with ethyl acetate 3 times. To the organic layer was added anhydrous sodium sulfate drying, filtration. The solvent was removed by distillation under reduced pressure, separated by column chromatography to give compound ZB-A-13. 1 H NMR (600 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.15 (s, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 3.2 Hz, 1H), 7.30 (d, J = 9.4 Hz, 1H), 6.54 (d, J = 3.2 Hz, 1H), 6.23 (d, J = 9.4 Hz, 1H), 5.39 (s, 2H), 2.54 (s, 3H); LC-MS [M-H] - : 496.

[0135] Example 10: Preparation of compound ZB-A-14

[0136] First step: Preparation of compound 11a

[0137] To a 50 mL flask was added 1d (0.3 g, 0.925 mmol), 4-cyanobromobenzyl (0.217 g, 1.11 mmol), potassium carbonate (0.383 g, 2.77 mmol), 1,4-dioxane (10 mL), heated to reflux at 100 °C stirring. TLC monitoring, separated by column chromatography to give compound 11a. 1 H NMR (600 MHz, DMSO-d6) δ 8.62 (s, 2H), 7.83 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 3.2 Hz, 1H), 7.39 (d, J = 9.5 Hz, 1H), 6.67 (d, J = 3.3 Hz, 1H), 6.27 (d, J = 9.5 Hz, 1H), 5.41 (s, 2H); LC-MS [M+H] + : 439.

[0138] Second step: Preparation of compound 11b

[0139] To a 50 mL flask was added 11a (0.28 g, 0.637 mmol), stannous chloride dihydrate (0.719 g, 3.18 mmol), ethanol (5 mL), and heated to reflux with stirring at 90 °C. TLC monitoring, 8 h reaction was complete. Added a suitable amount of ethyl acetate, and poured the reaction into a separatory funnel, washed the organic layer with 2 M NaOH solution twice, washing until the aqueous layer was >9 pH. Extracted the aqueous layer with ethyl acetate once. Added anhydrous sodium sulfate to the organic layer and dried, filtered. The filtrate was distilled under reduced pressure, and separated by column chromatography to give compound 11b. 1 H NMR (600 MHz, DMSO-d6) δ 7.82 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 3.1 Hz, 1H), 7.22 (d, J = 9.4 Hz, 1H), 6.76 (s, 2H), 6.47 (d, J = 3.1 Hz, 1H), 6.20 (d, J = 9.4 Hz, 1H), 6.09 (s, 2H), 5.38 (s, 2H); LC-MS [M+H] + : 409.

[0140] Third Step: Preparation of compound 11c

[0141] To a 50 mL flask was added 11b (0.24 g, 0.586 mmol), dichloromethane (5 mL), triethylamine (0.296 g, 2.93 mmol) at 0 °C, oxalyl chloride monoethyl ester (0.24 g, 1.75 mmol), then stirred to room temperature. TLC monitoring, 3 h reaction was complete. Separated by column chromatography to give 11c. 1 H NMR (600 MHz, DMSO-d6) δ 7.82 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 3.1 Hz, 1H), 7.22 (d, J = 9.4 Hz, 1H), 6.76 (s, 2H), 6.47 (d, J = 3.1 Hz, 1H), 6.20 (d, J = 9.4 Hz, 1H), 6.09 (s, 2H), 5.38 (s, 2H); LC-MS [M+H] + : 509.

[0142] Fourth Step: Preparation of compound ZB-A-14

[0143] To a 50 mL flask was added 11c (0.1 g, 0.196 mmol), ethanol (2 mL), 1 M sodium hydroxide solution (2 mL), stirred at room temperature. LC-MS monitoring, 2 hours reaction was completed, dropwise 1 M hydrochloric acid (2 ml). Extracted with ethyl acetate 3 times. To the organic layer was added anhydrous sodium sulfate drying, filtration. Distilled under reduced pressure to remove the solvent, separated by column chromatography to obtain compound ZB-A-14.1H NMR (600 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.15 (s, 2H), 7.82 (d, J = 6.3 Hz, 2H), 7.54 (d, J = 7.9 Hz, 2H), 7.40 (d, 1H), 7.32 (d, J = 9.5 Hz, 1H), 6.57 (d, 1H), 6.23 (d, J = 7.2 Hz, 1H), 5.40 (s, 2H); LC-MS [M-H] - : 479.

[0144] Example 11: Preparation of compound ZB-A-15

[0145] To a 50 mL flask was added 8a (0.187 g, 0.363 mmol), anhydrous ethanol (5 ml), hydroxylamine hydrochloride (0.126 g, 1.81 mmol) was added at 0 °C, sodium hydroxide (72.7 mg, 1.81 mmol), then stirred to room temperature. LC-MS monitoring, 8 hours reaction was completed. Distilled under reduced pressure to remove the solvent, separated by preparative liquid to obtain compound ZB-A-15. 1 H NMR (600 MHz, DMSO-d6) δ 11.88 (s, 1H), 11.21 (s, 1H), 8.19 (s, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 3.1 Hz, 1H), 7.24 (d, J = 9.4 Hz, 1H), 6.89 (d, J = 8.6 Hz, 2H), 6.59 (d, J = 3.2 Hz, 1H), 6.20 (d, J = 9.4 Hz, 1H), 5.23 (s, 2H), 3.71 (s, 3H); LC-MS [M-H] - : 499.

[0146] Example 12: Preparation of compound ZB-A-16

[0147] To a 50 mL flask was added 7a (0.25 g, 0.573 mmol), absolute ethanol (5 mL), hydroxylamine hydrochloride (0.199 g, 2.86 mmol), sodium hydroxide (0.114 g, 2.86 mmol) at 0 °C, then stirred at room temperature. LC-MS monitoring, 8 h reaction was complete. The solvent was removed by distillation under reduced pressure, and the compound ZB-A-16 was obtained by preparative liquid chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 11.89 (s, 1H), 11.22 (s, 1H), 9.49 (s, 1H), 8.20 (s, 2H), 7.37 (d, J = 3.2 Hz, 1H), 7.14 (d, J = 9.3 Hz, 1H), 6.68 (d, J = 3.2 Hz, 1H), 6.10 (d, J = 9.3 Hz, 1H), 5.28 (s, 1H), 1.50 (d, J = 7.0 Hz, 6H); LC-MS [M-H] - : 421.

[0148] Example 13: Preparation of compound ZB-A-17

[0149] First step: Preparation of compound 14a

[0150] To a 50 mL flask was added 1d (1.19 g, 3.67 mmol), tert-butyl p-chloromethylbenzoate (1 g, 4.41 mmol), potassium carbonate (1.52 g, 11 mmol), 1,4-dioxane solution (20 mL), heated to reflux with stirring at 100 °C. TLC monitoring, 8 h reaction was complete. The solvent was removed by distillation under reduced pressure, and the compound 14a was separated by column chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 8.61 (s, 2H), 7.87 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 3.3 Hz, 1H), 7.37 (d, J = 9.5 Hz, 1H), 6.61 (d, J = 3.4 Hz, 1H), 6.27 (d, J = 9.4 Hz, 1H), 5.39 (s, 2H), 1.52 (s, 9H); LC-MS [M+H] + : 514.

[0151] Second step: Preparation of compound 14b

[0152] To a 50 ml flask was added 14a (0.86 g, 1.6 mmol), 4 M hydrogen chloride in 1,4-dioxane (6 mL) and stirred at room temperature. LC-MS monitoring, the reaction was completed after 3 hours. The solvent was removed by distillation under reduced pressure to give compound 14b, which was used without further purification. LC-MS [M-H] - : 456.

[0153] Step 3: Preparation of compound 14c

[0154] To a 50 ml flask was added 14b (0.976 g, 2.13 mmol), triethylamine (0.67 g, 6.62 mmol), diphenyl phosphorazide (1.82 g, 6.62 mmol), t-butanol (10 mL) and heated at 85 °C. TLC monitoring, the reaction was completed after 8 hours. The filtrate was distilled under reduced pressure and separated by column chromatography to give 14c. LC-MS [M+H] + : 529.

[0155] Step 4: Preparation of compound 14d

[0156] To a 50 ml flask was added 14c (0.5 g, 0.944 mmol), 4 M hydrogen chloride in 1,4-dioxane (5 mL). LC-MS monitoring, the reaction was completed after 2 hours, 2 M aqueous sodium hydroxide (8 mL) was added, the organic layer was washed with saturated sodium chloride solution 3 times, the aqueous layer was extracted with ethyl acetate once, anhydrous sodium sulfate was added to the organic layer and dried, filtered. The filtrate was distilled under reduced pressure and the solvent was removed by distillation under reduced pressure to give compound 14d, which was used without further purification. LC-MS [M+H] + : 429.

[0157] Step 5: Preparation of compound 14e

[0158] To a 50 ml flask was added 14d (0.3 g, 0.698 mmol), dichloromethane (5 mL), triethylamine (0.707 g, 6.98 mmol) was added at 0 °C, acetyl chloride (0.164 g, 2.09 mmol) was added, then stirred at room temperature. TLC monitoring, the reaction was completed after 3 hours. 14e was separated by column chromatography. 1H NMR (600 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.60 (s, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 3.3 Hz, 1H), 7.36 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 9.5 Hz, 1H), 6.67 (d, J = 3.3 Hz, 1H), 6.24 (d, J = 9.5 Hz, 1H), 5.75 (s, 1H), 5.25 (s, 2H), 2.01 (s, 3H); LC-MS [M+H] + : 471.

[0159] Step 6: Preparation of compound 14f

[0160] Into a 50 mL flask was added 14e (0.2 g, 0.424 mmol), stannous chloride dihydrate (0.478 g, 2.12 mmol), absolute ethanol (15 mL), and heated to reflux at 90 °C. TLC monitoring, 8 h reaction was complete. Added appropriate amount of ethyl acetate, poured the reaction into a separatory funnel, washed the organic layer with 2 M sodium hydroxide solution twice, washed until the aqueous layer pH > 9. Extracted the aqueous layer with ethyl acetate once. Added anhydrous sodium sulfate to the organic layer, dried, filtered. The filtrate was distilled under reduced pressure, and compound 14f was obtained by column chromatography. LC-MS [M+H] + : 441

[0161] Step 7: Preparation of compound 14g

[0162] Into a 50 mL flask was added 14f (0.12 g, 0.271 mmol), N-cyanoacetylamide (51 mg, 0.326 mmol), acetonitrile (3 mL), and acetic acid (3 mL). Added tert-butyl nitrite (33.6 mg, 0.326 mmol) dropwise at 0 °C. LC-MS monitoring, 30 min reaction was complete. Added water (30 mL) dropwise to the reaction, filtered, and collected the filter cake to give 14g. LC-MS [M+H] + : 541.

[0163] Step 8: Preparation of compound ZB-A-17

[0164] Into a 50 mL flask was added 14g (0.1 g, 0.164 mmol), anhydrous sodium acetate (20 mg, 0.246 mmol), acetic acid (3 mL), and heated to reflux at 120 °C. LC-MS monitoring, 4 h reaction was complete. Distilled the solvent under reduced pressure, and compound ZB-A-17 was obtained by preparative liquid chromatography. LC-MS [M-H] + : 511.

[0165] Example 14: Preparation of compound ZB-A-18

[0166] First Step: Preparation of compound 15a

[0167] Into a 50ml flask was added 1f (50mg, 0.148mmol), 1,4-dioxane (3ml), trichloromethyl chloroformate (14.7mg, 0.0743mmol). Stirring at 60C. After 2 hours diethyl phosphite (24.6mg, 0.178mmol) was added, 3 drops of triethylamine was added, stirring at 80C. TLC monitoring, reaction was complete in 1 hour. Compound 15a was isolated by column chromatography. LC-MS [M+H] + : 500.

[0168] Second Step: Preparation of compound ZB-A-18

[0169] Into a 50ml flask was added 15a (0.14g, 0.279mmol), dichloromethane (5ml), trimethylsilyl bromide (0.64g, 4.18mmol) was added dropwise at -30C, then stirred at room temperature. LC-MS monitoring, reaction was complete in 8 hours. Compound ZB-A-18 was isolated by preparative liquid chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.18 (s, 2H), 7.41 (d, J = 3.2 Hz, 1H), 7.19 (d, J = 9.3 Hz, 1H), 6.70 (d, J = 3.3 Hz, 1H), 6.14 (d, J = 9.3 Hz, 1H), 5.31 (td, J = 5.0 Hz, 1H), 1.50 (d, J = 7.0 Hz, 6H); LC-MS [M-H] - : 442.

[0170] Example 15: Preparation of compound ZB-A-19

[0171] First Step: Preparation of compound 16a

[0172] Into a microwave tube was added 1d (0.5g, 1.54mmol), bromocyclohexane (1g, 6.17mmol), potassium carbonate (0.639g, 4.62mmol), 1,4-dioxane (10ml), microwave heating at 140C for 6 hours. TLC monitoring, reaction was complete. Compound 16a was isolated by column chromatography. 1H NMR (600 MHz, Chloroform-d) δ 8.37 (s, 2H), 6.96 (d, J = 3.3 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 6.64 (d, J = 12.1 Hz, 1H), 6.39 (d, J = 9.4 Hz, 1H), 2.36 - 2.19 (m, 1H), 1.96 - 1.46 (m, 10H); LC-MS [M+H] + : 406.

[0173] Second Step: Preparation of compound 16b

[0174] Into a 50 mL flask was added 16a (0.157 g, 0.386 mmol), stannous chloride dihydrate (0.436 g, 1.93 mmol), anhydrous ethanol (15 mL), and heated to reflux with stirring at 90 °C. TLC monitoring, 8 hours reaction was completed. Added appropriate amount of ethyl acetate, the reaction was poured into a separatory funnel, the organic layer was washed with 2M sodium hydroxide solution 2 times, washed until the water layer pH > 9. The water layer was extracted with ethyl acetate once. Added anhydrous sodium sulfate to the organic layer, dried, filtered. The filtrate was distilled under reduced pressure, separated by column chromatography to obtain compound 16b. 1 H NMR (600 MHz, Methanol-d4) δ 7.17 (d, J = 5.6 Hz, 1H), 7.16 (d, 1H), 6.78 (s, 2H), 6.68 (d, 1H), 6.31 (d, J = 9.2 Hz, 1H), 2.50 - 2.40 (m, 1H), 2.00 - 1.36 (m, 10H); LC-MS [M+H] + : 376.

[0175] Third Step: Preparation of compound 16c

[0176] Into a 50 mL flask was added 16b (0.11 g, 0.292 mmol), dichloromethane (5 mL), triethylamine (0.147 g, 1.46 mmol) was added at 0 °C, oxalyl chloride monoethyl ester (79.8 mg, 0.584 mmol), then stirred at room temperature. TLC monitoring, 3 hours reaction was completed. Separated by column chromatography to obtain 16c. 1 H NMR (600 MHz, Chloroform-d) δ 9.80 (s, 1H), 7.96 (s, 2H), 6.98 - 6.93 (m, 2H), 6.57 (d, 1H), 6.38 (d, J = 9.4 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 2.34 - 2.23 (m, 1H), 2.00 - 1.45 (m, 10H), 1.42 (t, J = 7.1 Hz, 3H); LC-MS [M+H] +: 476.

[0177] Fourth Step: Preparation of Compound ZB-A-19

[0178] Into a 50 mL flask was added 16c (0.1 g, 0.21 mmol), ethanol (2 mL), 1 M sodium hydroxide solution (2 mL), and stirred at room temperature. LC-MS monitoring, 2 hours reaction was completed, dropwise added 1 M hydrochloric acid (2 mL). Extracted with ethyl acetate 3 times. To the organic layer was added anhydrous sodium sulfate drying, filtration. The solvent was removed by distillation under reduced pressure, and compound ZB-A-19 was obtained by preparative liquid chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.14 (s, 2H), 7.38 (d, J = 3.2 Hz, 1H), 7.14 (d, J = 9.4 Hz, 1H), 6.73 (d, J = 3.1 Hz, 1H), 6.11 (d, J = 9.4 Hz, 1H), 2.39-2.27 (m, 1H), 1.91-1.19 (m, 10H); LC-MS [M-H] - : 446.

[0179] Example 16: Preparation of Compound ZB-B-01

[0180] First Step: Preparation of Compound 17a

[0181] Into a 50 mL flask was added 10b (0.17 g, 0.398 mmol), N-cyanoacetylurea (74.8 mg, 0.478 mmol), acetonitrile (3 mL), acetic acid (3 mL). At 0 °C, slowly dropwise added tert-butyl nitrite (49.3 mg, 0.478 mmol), keep stirring at 0 °C. LC-MS monitoring, 30 minutes reaction was completed. To the reaction was slowly dropwise added water (30 mL), filtration, collected the filter cake to obtain compound 17a. LC-MS [M+H] + : 593.

[0182] Second Step: Preparation of Compound ZB-B-01

[0183] Into a 50 mL flask was added 17a (0.19 g, 0.32 mmol), anhydrous sodium acetate (39.3 mg, 0.48 mmol), acetic acid (3 mL), heated to reflux stirring at 120 °C. LC-MS monitoring, 4 hours reaction was completed and compound ZB-B-01 was obtained by column chromatography. 1H NMR (600 MHz, DMSO-d6) δ 13.32 (s, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.89 (s, 2H), 7.51 (d, J = 7.8 Hz, 2H), 7.47 (d, 1H), 7.40 (d, J = 9.6 Hz, 1H), 6.60 (d, 1H), 6.24 (d, J = 9.8 Hz, 1H), 5.40 (s, 2H), 2.55 (s, 3H); LC-MS [M+H] + : 547.

[0184] Example 17: Preparation of compound ZB-B-02

[0185] First step: Preparation of compound 18b

[0186] Into a 50 mL flask was added 18a (10 g, 83.9 mmol), 3,5-dichloro-4-fluoronitrobenzene (21.15 g, 100 mmol), potassium carbonate (17.4 g, 125 mmol), N,N-dimethylformamide (50 mL), and heated to 80 °C with stirring. TLC monitoring, 2 hours reaction was completed. Added appropriate amount of ethyl acetate, washed the organic layer with saturated sodium chloride solution 3 times, extracted the water layer with ethyl acetate once, added anhydrous sodium sulfate to the organic layer and dried, filtered. The filtrate was distilled under reduced pressure, and compound 18b was obtained by column chromatography. LC-MS [M+H] + : 309.

[0187] Second step: Preparation of compound 18c

[0188] Into a 100 mL flask was added 18b (26 g, 84.1 mmol), dichloromethane (40 mL). Added m-chloroperoxybenzoic acid (21.77 g, 126 mmol) in batches at 0 °C, then restored to room temperature and stirred. LC-MS monitoring, 2 hours reaction was completed. Extracted with ethyl acetate 3 times. Added anhydrous sodium sulfate to the organic layer and dried, filtered. The filtrate was distilled under reduced pressure to obtain compound 18c. LC-MS [M+H] + : 325.

[0189] Third step: Preparation of compound 18d

[0190] Into a 100 mL flask was added 18c (27 g, 84.1 mmol), N,N-dimethylformamide (50 mL). At 0 °C, trifluoroacetic anhydride (210 g, 841 mmol) was added, and the reaction was stirred to room temperature. The reaction was monitored by LC-MS, and was complete in 8 h. Toluene (50 mL) was added to the reaction, and the mixture was distilled under reduced pressure until no distillate was obtained. Anhydrous ethanol (50 mL) was added, and the mixture was distilled under reduced pressure until no distillate was obtained. Water (300 mL) was added slowly, and the mixture was filtered to collect the filter cake to give compound 18d. LC-MS [M+H] + : 325.

[0191] Fourth Step: Preparation of compound 18e

[0192] Into a 100 mL flask was added 18d (0.5 g, 1.53 mmol), 4-methoxychlorobenzene (0.963 g, 6.15 mmol), potassium carbonate (0.63 g, 4.61 mmol), 1,4-dioxane (10 mL), and the mixture was stirred at 100 °C under reflux. The reaction was monitored by TLC, and was complete in 8 h. The solvent was distilled under reduced pressure, and the mixture was separated by column chromatography to give 18e. 1 H NMR (600 MHz, DMSO-d6) δ 8.63 (s, 2H), 8.35 (s, 1H), 7.65 (d, J = 9.6 Hz, 1H), 7.43 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 6.62 (d, J = 9.6 Hz, 1H), 5.25 (s, 2H), 3.72 (s, 3H); LC-MS [M+H] + : 445.

[0193] Fifth Step: Preparation of compound 18f

[0194] Into a 50 mL flask was added 18e (0.142 g, 0.319 mmol), stannous chloride dihydrate (0.36 g, 1.59 mmol), and anhydrous ethanol (10 mL). The mixture was stirred at 90 °C under reflux. The reaction was monitored by TLC, and was complete in 1 h. The reaction was poured into a separatory funnel, and the organic layer was washed twice with 2 M sodium hydroxide solution until the aqueous layer had a pH > 9. The aqueous layer was extracted once with ethyl acetate. Anhydrous sodium sulfate was added to the organic layer, and the mixture was dried and filtered. The filtrate was distilled under reduced pressure, and the mixture was separated by column chromatography to give compound 18f. 1H NMR (600 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.45 (d, J = 9.5 Hz, 1H), 7.41 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 6.75 (s, 2H), 6.51 (d, J = 9.5 Hz, 1H), 6.19 (s, 2H), 5.21 (s, 2H), 3.72 (s, 3H); LC-MS [M+H] + : 415.

[0195] Step 6: Preparation of compound 18g

[0196] Into a 100 mL flask was added 18f (0.111 g, 0.268 mmol), N-cyanoacetylurea (50.3 mg, 0.32 mmol), acetonitrile (1.5 mL), acetic acid (1.5 mL). At 0 °C, tert-butyl nitrite (33.1 mg, 0.32 mmol) was added dropwise slowly, keeping 0 °C stirring. LC-MS monitoring, 30 min reaction was completed. To the reaction solution was added water (30 mL) dropwise slowly, filtered, and the filter cake was collected to give compound 18g. LC-MS [M+H] + : 582.

[0197] Step 7: Preparation of compound 18h

[0198] Into a 100 mL flask was added 18g (0.1 g, 0.171 mmol), anhydrous sodium acetate (21.1 mg, 0.257 mmol), acetic acid (2 mL), heated to reflux stirring at 120 °C. LC-MS monitoring, 2 h reaction was completed. Column chromatography separation to give compound 18h. LC-MS [M+H] + : 536.

[0199] Step 8: Preparation of compound ZB-B-02

[0200] Into a 50 mL two-necked flask was added 18h (61 mg, 0.113 mmol), dichloromethane (3 mL). Replaced gas 3 times at -78 °C, dropwise added 2M boron tribromide dichloromethane solution (2 mL), raised to -10 °C stirring. LC-MS monitoring, 3 h reaction was completed. Added saturated sodium bicarbonate solution at 0 °C, after the reaction was quenched, added ethyl acetate, added a small amount of saturated sodium chloride solution, extracted with ethyl acetate 3 times, added anhydrous sodium sulfate to the organic layer, dried, removed the solvent under reduced pressure. Column chromatography separation to give compound ZB-B-02. LC-MS [M-H] - : 520; 1H NMR (600 MHz, DMSO-d6) δ 13.35 (s, 1H), 8.28 (s, 1H), 7.93 (s, 2H), 7.69 (d, J = 9.6 Hz, 1H), 7.32 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 6.57 (d, J = 9.6 Hz, 1H), 5.19 (s, 2H).

[0201] Example 18: Preparation of ZB-B-03

[0202] First Step: Preparation of compound 19a

[0203] Into a 50 mL flask was added 18h (0.1 g, 0.186 mmol), acetic acid (3 mL), concentrated hydrochloric acid (3 mL), heated to reflux with stirring. LC-MS monitoring, 3 hours reaction was completed. To the reaction solution was slowly added water (30 mL), filtered, collected the filter cake to give compound 19a. LC-MS [M-H] - : 553.

[0204] Second Step: Preparation of compound 19b

[0205] Into a 50 mL flask was added 19a (0.175 g, 0.315 mmol), triethylamine (98.8 mg, 0.976 mmol), diphenyl phosphorazide (2.68 g, 9.76 mmol), added t-butanol (10 mL), heated to reflux with stirring at 85 °C. TLC monitoring, separated by column chromatography to give compound 19b. LC-MS [M+H] + : 626.

[0206] Third Step: Preparation of compound 19c

[0207] Into a 50 mL flask was added 19b (0.1 g, 0.16 mmol), 4 M hydrogen chloride 1,4-dioxane solution (3 mL), stirred at room temperature. LC-MS monitoring, 3 hours reaction was completed, to give compound 19c, without further purification. LC-MS [M+H] + : 526.

[0208] Fourth Step: Preparation of compound ZB-B-03

[0209] Into a 50 mL two-necked flask was placed 19c (0.123 g, 0.233 mmol), dichloromethane (5 mL), replaced with nitrogen 3 times at 0 °C, 1 M boron tribromide in dichloromethane (8 mL) was added slowly dropwise at -80 °C, then stirred at room temperature. LC-MS monitoring, 3 hours reaction was completed. Saturated sodium bicarbonate solution was added at 0 °C, after the reaction was quenched, ethyl acetate was added, a small amount of saturated sodium chloride solution was added, extracted with ethyl acetate 3 times, anhydrous sodium sulfate was added to the organic layer, dried, and the solvent was removed by reduced pressure distillation. Compound ZB-B-03 was obtained by column chromatography. LC-MS [M+H] + : 512. 1 H NMR (600 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.22 (s, 1H), 8.06 (s, 2H), 7.59 (d, J = 9.6 Hz, 1H), 7.31 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 6.55 (d, J = 9.6 Hz, 1H), 5.19 (s, 2H).

[0210] Example 19: Preparation of compounds ZB-B-04 and ZB-B-05

[0211] First step: Preparation of compound 20a

[0212] Into a 50 mL flask was placed 18h (0.1 g, 0.186 mmol), methanol (10 mL), dichlorosulfoxide (1 mL) was added slowly dropwise, then heated to reflux at 100 °C. TLC monitoring, 2 hours reaction was completed. Compound 20a was obtained by column chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.29 (s, 1H), 7.94 (s, 2H), 7.71 (d, J = 9.5 Hz, 1H), 7.43 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 8.2 Hz, 2H), 6.56 (d, J = 9.6 Hz, 1H), 5.25 (s, 2H), 3.86 (s, 3H), 3.72 (s, 3H); LC-MS [M+H] + : 569.

[0213] Second step: Preparation of compound 20b

[0214] To a 50 ml flask was added 20a (0.113 g, 0.198 mmol), tetrahydrofuran (2 mL), water (2 mL). Sodium borohydride (11.2 mg, 0.297 mmol) was added at 0 °C, then the reaction was stirred at room temperature. TLC monitoring, the reaction was completed in 3 hours. The reaction was quenched by adding appropriate amount of water, extracted with ethyl acetate for 3 times. To the organic layer, anhydrous sodium sulfate was added to dry, filtered. The filtrate was distilled under reduced pressure to remove the solvent, separated by column chromatography to obtain compound 20b. LC-MS [M+H] + : 541.

[0215] Third step: preparation of compound 20c

[0216] To a 50 ml flask was added 20b (60 mg, 0.11 mmol), dichloromethane (5 ml), diethylamine sulfide trifluoride (71.33 mg, 0.442 mmol), stirred at room temperature. TLC monitoring, the reaction was completed in 4 hours. Separated by column chromatography to obtain compound 20c. 1 H NMR (600 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.28 (s, 1H), 8.05 (s, 2H), 7.66 (d, J = 9.5 Hz, 1H), 7.43 (d, J = 8.3 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.56 (d, J = 9.6 Hz, 1H), 5.24 (s, 2H), 4.43 (d, J = 6.1 Hz, 2H), 3.72 (s, 3H); LC-MS [M+H] + : 543.

[0217] Fourth step: preparation of compounds ZB-B-04 and ZB-B-05

[0218] To a 50 ml flask was added 20c (10 mg, 1.83 x 10 -2 mmol), dichloromethane (2 mL). Replaced gas 3 times at 0 °C, drop 1M boron tribromide dichloromethane solution (0.643 mL) at -80 °C, then stirred at room temperature. LC-MS monitoring, the reaction was completed in 3 hours. Saturated sodium bicarbonate solution was added at 0 °C, after the reaction was quenched, ethyl acetate was added, a small amount of saturated sodium chloride solution was added, extracted with ethyl acetate for 3 times, anhydrous sodium sulfate was added to the organic layer to dry, distilled under reduced pressure to remove the solvent. Separated by column chromatography to obtain compound ZB-B-04, LC-MS [M-H] - : 527; 1H NMR (600 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.26 (s, 1H), 7.97 (s, 2H), 7.67 (d, J = 9.6 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 6.73 (d, J = 8.1 Hz, 2H), 6.56 (d, J = 9.6 Hz, 1H), 5.33 (d, J = 46.7 Hz, 2H), 5.19 (s, 2H); Compound ZB-B-05, LC-MS [M-H] - : 587.

[0219] Example 20: Preparation of compound ZB-B-06

[0220] First step: Preparation of compound 21a

[0221] Into a 50 ml flask was added 4b (0.359 g, 0.866 mmol), N-cyanoacetylurea (0.162 g, 1.03 mmol), acetonitrile (2 mL), acetic acid (2 mL). At 0 °C, tert-butyl nitrite (0.107 g, 1.03 mmol) was added dropwise slowly, keeping stirring at 0 °C. LC-MS monitoring, reaction was completed in 30 min. To the reaction solution was added water (30 mL) dropwise slowly, filtered, and the filter cake was collected to give compound 21a. LC-MS [M+H] + : 581.

[0222] Second step: Preparation of compound 21b

[0223] Into a 50 ml flask was added 21a (0.4 g, 0.687 mmol), anhydrous sodium acetate (84.6 mg, 1.03 mmol), acetic acid (5 mL), heated to reflux with stirring at 120 °C. LC-MS monitoring, reaction was completed in 3 h. Added appropriate amount of ethyl acetate, washed the organic layer with saturated sodium chloride solution twice. Extracted the water layer with ethyl acetate once. Added anhydrous sodium sulfate to the organic layer to dry, filtered. The filtrate was distilled under reduced pressure to give compound 21b, without further purification. 1 H NMR (600 MHz, DMSO-d6) δ 13.33 (s, 1H), 7.89 (s, 2H), 7.47 (d, J = 3.2 Hz, 1H), 7.40 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 9.5 Hz, 1H), 6.89 (d, J = 8.3 Hz, 2H), 6.66 (d, J = 3.3 Hz, 1H), 6.21 (d, J = 9.5 Hz, 1H), 5.24 (s, 2H), 3.72 (s, 3H); LC-MS [M+H] + : 535

[0224] Step 3: Preparation of compound ZB-B-06

[0225] Into a 50ml flask was added 21b (0.35g, 0.652mmol), dichloromethane (3ml), and the flask was purged with nitrogen 3 times at 0°C. 2M boron tribromide in dichloromethane (12ml) was added dropwise at -80°C, and the reaction was allowed to warm to room temperature. LC-MS monitoring showed that the reaction was complete in 3 hours. Saturated sodium bicarbonate solution was added at 0°C, and after the reaction was quenched, ethyl acetate was added, a small amount of saturated sodium chloride solution was added, and the mixture was extracted with ethyl acetate 3 times. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Compound ZB-B-06 was obtained by column chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 13.33 (s, 1H), 9.39 (s, 1H), 7.88 (s, 2H), 7.48 (d, J = 3.2 Hz, 1H), 7.34 (d, J = 9.4 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 6.71 (d, J = 8.1 Hz, 2H), 6.65 (d, J = 3.2 Hz, 1H), 6.20 (d, J = 9.5 Hz, 1H), 5.18 (s, 2H); LC-MS [M-H] - : 519.

[0226] Example 21: Preparation of compound ZB-B-07

[0227] First step: Preparation of compound 22a

[0228] Into a 50ml flask was added 1d (0.3g, 0.925mmol), 4-bromomethyl benzoic acid methyl ester (0.84g, 3.7mmol), potassium carbonate (0.383g, 2.77mmol), 1,4-dioxane solution (10ml), and the flask was heated to reflux with stirring at 80°C. TLC monitoring showed that the reaction was complete in 8 hours. Compound 22a was obtained by column chromatography. 1H NMR (600 MHz, Chloroform-d) δ 8.38 (s, 2H), 7.99 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 9.5 Hz, 1H), 6.93 (d, J = 3.3 Hz, 1H), 6.49 (d, J = 9.5 Hz, 1H), 6.29 (d, J = 3.3 Hz, 1H), 5.45 (s, 2H), 3.89 (s, 3H); LC-MS [M+H] + : 472.

[0229] Second step: Preparation of compound 22b

[0230] Into a 50 mL flask was placed 22a (0.142 g, 0.3 mmol), stannous chloride dihydrate (0.339 g, 1.50 mmol), anhydrous ethanol (15 mL), and heated to reflux with stirring at 90 °C. TLC monitoring, 8 h reaction was complete. Added appropriate amount of ethyl acetate, poured the reaction into a separatory funnel, washed the organic layer with 2 M sodium hydroxide solution twice, washed until the aqueous layer pH > 9. Extracted the aqueous layer with ethyl acetate once. Added anhydrous sodium sulfate to the organic layer, dried, filtered. The filtrate was distilled under reduced pressure, and compound 22b was isolated by column chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 7.92 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 3.1 Hz, 1H), 7.21 (d, J = 9.4 Hz, 1H), 6.75 (s, 2H), 6.44 (d, J = 3.1 Hz, 1H), 6.20 (d, J = 9.4 Hz, 1H), 5.37 (s, 2H), 3.82 (s, 3H); LC-MS [M+H] + : 442.

[0231] Third Step: Preparation of compound 22c

[0232] Into a 50 mL flask was placed 22b (46 mg, 0.104 mmol), N-cyanoacetylurea (19.5 mg, 0.124 mmol), acetonitrile (1 mL), acetic acid (1 ml). At 0 °C, slowly added tert-butyl nitrite (12.8 mg, 0.124 mmol), kept stirring at 0 °C. LC-MS monitoring, 30 min reaction was complete. Slowly added water (30 mL) to the reaction, filtered, collected the filter cake to give compound 22c. LC-MS [M+H] + : 609

[0233] Fourth Step: Preparation of compound ZB-B-07

[0234] Into a 50 mL flask was placed 22c (40 mg, 6.56 x 10 -2 mmol), anhydrous sodium acetate (8 mg, 9.8 x 10 -2 mmol), acetic acid (10 mL), heated to reflux with stirring at 120 °C. LC-MS monitoring, 2 h reaction was complete. Compound ZB-B-07 was isolated by column chromatography. 1H NMR (600 MHz, DMSO-d6) δ 7.94 (d, J = 8.0 Hz, 2H), 7.89 (s, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 3.2 Hz, 1H), 7.41 (d, J = 9.4 Hz, 1H), 6.60 (d, J = 3.2 Hz, 1H), 6.24 (d, J = 9.4 Hz, 1H), 5.40 (s, 2H), 3.83 (s, 3H); LC-MS [M+H] + : 563.

[0235] Example 22: Preparation of compound ZB-B-08

[0236] Second step: Preparation of compound 23a

[0237] Into a 50 ml flask was added 7a (1.15 g, 2.23 mmol), stannous chloride dihydrate (2.52 g, 11.1 mmol), anhydrous ethanol (20 mL), heated to reflux with stirring at 90 °C. TLC monitoring, 1 hour reaction was completed. Added a suitable amount of ethyl acetate, washed with saturated sodium chloride solution 3 times, extracted with ethyl acetate 1 time, added anhydrous sodium sulfate to the organic layer, dried, filtered. The filtrate was distilled under reduced pressure, separated by column chromatography to obtain compound 23a. 1 H NMR (600 MHz, DMSO-d6) δ 7.94 (d, J = 8.0 Hz, 2H), 7.89 (s, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 3.2 Hz, 1H), 7.41 (d, J = 9.4 Hz, 1H), 6.60 (d, J = 3.2 Hz, 1H), 6.24 (d, J = 9.4 Hz, 1H), 5.40 (s, 2H), 3.83 (s, 3H); LC-MS [M+H] - : 426.

[0238] Third step: Preparation of compound 23b

[0239] Into a 50 ml flask was added 23a (0.2 g, 0.467 mmol), N-cyanoacetylurea (87.6 mg, 0.56 mmol), acetonitrile (2 mL), acetic acid (2 mL). At 0 °C, slowly added tert-butyl nitrite (57.8 mg, 0.56 mmol) dropwise, kept stirring at 0 °C. LC-MS monitoring, 30 minutes reaction was completed. Slowly added water (30 mL) dropwise to the reaction solution, filtered, collected the filter cake to obtain compound 23b. LC-MS [M+H] + : 595.

[0240] Fourth step: Preparation of compound 23c

[0241] Into a 50 ml flask was added 23b (0.45 g, 0.755 mmol), anhydrous sodium acetate (92.9 mg, 1.13 mmol), acetic acid (2 mL), and heated to reflux with stirring. LC-MS monitoring, 4 hours reaction was completed. Compound 23c was isolated by column chromatography. LC-MS [M+H] + : 549.

[0242] Fifth Step: Preparation of compound ZB-B-08

[0243] Into a 50 ml flask was added 23c (30 mg, 5.46 x 10 -2 mmol), dichloromethane (2 mL). Methylamine hydrochloride (4.42 mg, 6.55 x 10 -2 mmol), 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (24.9 mg, 6.55 x 10 -2 mmol), N,N-diisopropylethylamine (16.9 mg, 0.131 mmol) was added, then stirred to room temperature. LC-MS monitoring, 4 hours reaction was completed. Compound ZB-B-08 was isolated by column chromatography. LC-MS [M+H] + : 562; 1 H NMR (600 MHz, DMSO-d6) δ 13.33 (s, 1H), 8.38 (q, J = 4.5 Hz, 1H), 7.89 (s, 2H), 7.78 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 3.2 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 10.1 Hz, 1H), 6.61 (d, J = 4.0 Hz, 1H), 6.24 (d, J = 9.4 Hz, 1H), 5.37 (s, 2H), 2.76 (d, J = 4.5 Hz, 3H).

[0244] Example 23: Preparation of compound ZB-B-09

[0245] Into a 50 ml flask was added 23c (30 mg, 5.46 x 10 -2 mmol), dichloromethane (2 mL). 2M dimethylamine tetrahydrofuran solution (33 μL) was added at 0 °C, 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (24.9 mg, 6.55 x 10 -2mmol), N,N-diisopropylethylamine (16.9 mg, 0.131 mmol), followed by warming to room temperature stirring. LC-MS monitoring, 4 hours reaction was completed. Compound ZB-B-09 was obtained by column chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 13.35 (s, 1H), 7.89 (s, 2H), 7.50 (d, J = 3.2 Hz, 1H), 7.44 (d, J = 7.9 Hz, 2H), 7.40 (d, J = 9.4 Hz, 1H), 7.38 (d, J = 7.9 Hz, 2H), 6.66 (d, J = 3.2 Hz, 1H), 6.24 (d, J = 9.4 Hz, 1H), 5.35 (s, 2H), 2.92 (d, J = 43.2 Hz, 6H); LC-MS [M+H] + : 576.

[0246] Example 24: Preparation of compound ZB-B-10

[0247] First step: Preparation of compound 25a

[0248] Into a 50 ml flask was added 1d (0.3 g, 0.925 mmol), 4-bromomethylphenylboronic acid pinacol ester (1.09 g, 3.7 mmol), potassium carbonate (0.383 g, 2.77 mmol), 1,4-dioxane solution (10 mL), heated to 80 °C and stirred under reflux. TLC monitoring, 8 hours reaction was completed. Compound 25a was obtained by column chromatography. 1H NMR (600 MHz, Chloroform-d) δ 8.37 (s, 2H), 7.76 (d, J = 7.7 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7.03 (d, J = 10.3 Hz, 1H), 6.89 (d, J = 3.3 Hz, 1H), 6.48 (d, J = 9.5 Hz, 1H), 6.30 (d, J = 4.0 Hz, 1H), 5.43 (s, 2H), 1.32 (s, 12H); LC-MS [M+H] + : 540.

[0249] Second step: Preparation of compound 25b

[0250] Into a 50 ml flask was added 25a (0.162 g, 0.3 mmol), stannous chloride dihydrate (0.339 g, 1.50 mmol), anhydrous ethanol (15 mL), and heated to reflux with stirring at 90 °C. TLC monitoring, 8 hours reaction was completed. Added appropriate amount of ethyl acetate, poured into the reaction liquid into a separatory funnel, with 2M sodium hydroxide solution wash organic layer 2 times, wash until the water layer pH > 9. With ethyl acetate extraction of water layer 1 times. To the organic layer was added anhydrous sodium sulfate drying, filtration. The filtrate was distilled under reduced pressure to obtain compound 25b, without further purification. LC-MS [M+H] + : 510.

[0251] Third step: preparation of compound 25c

[0252] Into a 50 ml flask was added 25b (71.4 mg, 0.104 mmol), N-cyanoacetyl urea (19.5 mg, 0.124 mmol), acetonitrile (1 mL), acetic acid (1 mL). At 0 °C, slowly drop in tert-butyl nitrite (12.8 mg, 0.124 mmol), keep 0 °C stirring. LC-MS monitoring, 30 minutes reaction was completed. To the reaction liquid slowly drop in water (30 mL), filtration, collected filter cake to obtain compound 25c. LC-MS [M+H] + : 677.

[0253] Fourth step: preparation of compound ZB-B-10

[0254] Into a 50 mL flask was added 25c (44.4 mg, 6.56 x 10 -2 mmol), anhydrous sodium acetate (8 mg, 9.8 x 10 -2 mmol), acetic acid (10 mL), heated to reflux with stirring at 120 °C. LC-MS monitoring, 2 hours reaction was completed. Separated by column chromatography to obtain compound ZB-B-10. 1 H NMR (600 MHz, DMSO-d6) δ 13.33 (s, 1H), 7.89 (s, 2H), 7.74 (d, J = 7.9 Hz, 2H), 7.47 (d, J = 3.2 Hz, 1H), 7.38 (d, J = 9.5 Hz, 1H), 7.35 (d, J = 7.7 Hz, 2H), 6.59 (d, J = 3.2 Hz, 1H), 6.24 (d, J = 9.4 Hz, 1H), 5.33 (s, 2H); LC-MS [M+H] + : 549.

[0255] Example 25: preparation of compound ZB-B-11

[0256] First step: preparation of compound 26a

[0257] Into a 50 mL flask was placed 9b (0.2 g, 0.471 mmol), N-cyanoacetylurea (88.4 mg, 0.565 mmol), acetonitrile (3 mL), acetic acid (3 mL). At 0 °C, tert-butyl nitrite (48.5 mg, 0.565 mmol) was added dropwise slowly, keeping stirring at 0 °C. LC-MS monitoring, 30 min reaction was completed. To the reaction was added water (30 mL) dropwise slowly, filtered, and the filter cake was collected to give 26a. LC-MS [M+H] + : 591

[0258] Fourth Step: Preparation of compound ZB-B-11

[0259] Into a 50 mL flask was placed 26a (0.25 g, 0.422 mmol), anhydrous sodium acetate (52 mg, 0.634 mmol), acetic acid (3 mL), heated to reflux with stirring at 120 °C. LC-MS monitoring, 4 h reaction was completed. Column chromatography separation gave compound ZB-B-11. 1 H NMR (600 MHz, DMSO-d6) δ 13.32 (s, 1H), 7.88 (s, 2H), 7.46 (d, J = 3.2 Hz, 1H), 7.35 (d, J = 9.4 Hz, 1H), 7.31 (d, J = 7.9 Hz, 2H), 7.03 (d, J = 7.9 Hz, 2H), 6.62 (d, J = 3.2 Hz, 1H), 6.21 (d, J = 9.4 Hz, 1H), 5.25 (s, 2H), 1.91 - 1.83 (m, 1H), 0.91 (dd, 2H), 0.63 (dd, 2H); LC-MS [M+H] + : 545.

[0260] Example 26: Preparation of compound ZB-B-12

[0261] First Step: Preparation of compound 27a

[0262] Into a 50 mL flask was placed 14f (60 mg, 0.127 mmol), N-cyanoacetylurea (23.8 mg, 0.152 mmol), acetonitrile (3 mL), acetic acid (3 mL). At 0 °C, tert-butyl nitrite (15.7 mg, 0.152 mmol) was added dropwise slowly, keeping stirring at 0 °C. LC-MS monitoring, 30 min reaction was completed. To the reaction was added water (30 mL) dropwise slowly, filtered, and the filter cake was collected to give compound 27a. LC-MS [M+H] + : 638.

[0263] Fourth Step: Preparation of compound ZB-B-12

[0264] Into a 50 mL flask was added 27a (60 mg, 9.39 x 10 -2 mmol), anhydrous sodium acetate (9.25 mg, 0.112 mmol), acetic acid (3 mL), and heated to reflux with stirring at 120 °C. LC-MS monitoring, 4 h reaction was complete. Compound ZB-B-12 was isolated by column chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 13.40 (s, 1H), 9.94 (s, 1H), 7.88 (s, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 3.2 Hz, 1H), 7.40 - 7.31 (m, 3H), 6.63 (d, J = 3.2 Hz, 1H), 6.22 (d, J = 9.4 Hz, 1H), 5.25 (s, 2H), 2.01 (s, 3H); LC-MS [M+H] + : 592.

[0265] Example 27: Preparation of compound ZB-B-13

[0266] First step: Preparation of compound 28a

[0267] Into a 50 mL flask was added 11b (0.198 g, 0.483 mmol), N-cyanoacetylurea (90.7 mg, 0.58 mmol), acetonitrile (3 mL), acetic acid (3 mL). At 0 °C, tert-butyl nitrite (59.8 mg, 0.58 mmol) was added dropwise slowly, keeping the stirring at 0 °C. LC-MS monitoring, 30 min reaction was complete. To the reaction mixture was added water (30 mL) dropwise slowly, filtered, and the filter cake was collected to give compound 28a. LC-MS [M+H] + : 576.

[0268] Fourth step: Preparation of compound ZB-B-13

[0269] Into a 50 mL flask was added 28a (0.22 g, 0.38 mmol), anhydrous sodium acetate (46.9 mg, 0.572 mmol), acetic acid (3 mL), and heated to reflux at 120 °C. LC-MS monitoring, 4 h reaction was complete. Compound ZB-B-13 (150 mg, 74% yield) was isolated by column chromatography. 1H NMR (600 MHz, DMSO-d6) δ 13.34 (s, 1H), 7.90 (s, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 3.2 Hz, 1H), 7.42 (d, J = 9.5 Hz, 1H), 6.63 (d, J = 3.2 Hz, 1H), 6.24 (d, J = 9.4 Hz, 1H), 5.41 (s, 2H); LC-MS [M+H] + : 530.

[0270] Example 28: Preparation of compound ZB-B-14

[0271] First step: Preparation of compound 29a

[0272] Into a 50 mL flask was added ZB-B-01 (0.1 g, 0.182 mmol), acetic acid (3 mL), concentrated hydrochloric acid (3 mL), heated to reflux with stirring. LC-MS monitoring, 3 hours reaction was completed. To the reaction solution was slowly added water (30 mL), filtered, collected the filter cake to give compound 29a. LC-MS [M-H] - : 564.

[0273] Second step: Preparation of compound 29b

[0274] Into a 50 mL flask was added 29a (0.17 g, 0.3 mmol), triethylamine (94.1 mg, 0.93 mmol), diphenyl phosphorazide (0.826 g, 3 mmol), tert-butyl alcohol (10 mL), heated to 85 °C. TLC monitoring, 8 hours reaction was completed. Added appropriate amount of ethyl acetate, washed the organic layer with saturated sodium chloride solution 3 times, extracted the water layer with ethyl acetate once, added anhydrous sodium sulfate to the organic layer to dry, filtered. The filtrate was distilled under reduced pressure, separated by column chromatography to give 29b. LC-MS [M+H] + : 637.

[0275] Third step: Preparation of compound ZB-B-14

[0276] Into a 50 mL flask was added 29b (0.5 g, 0.944 mmol), 4M hydrogen chloride 1, 4-dioxane solution (4 mL). LC-MS monitoring, 2 hours reaction was completed, added 2M sodium hydroxide solution (8 mL), added appropriate amount of ethyl acetate, washed the organic layer with saturated sodium chloride solution 3 times, extracted the water layer with ethyl acetate once, added anhydrous sodium sulfate to the organic layer to dry, filtered. The filtrate was distilled under reduced pressure, distilled under reduced pressure to remove the solvent, separated by column chromatography to give compound ZB-B-14. 1H NMR (600 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.03 (s, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 3.2 Hz, 1H), 7.32 (d, J = 9.4 Hz, 1H), 6.64 (s, 2H), 6.57 (d, J = 3.3 Hz, 1H), 6.24 (d, J = 9.4 Hz, 1H), 5.40 (s, 2H), 2.55 (s, 3H); LC-MS [M+H] + : 537.

[0277] Example 29: Preparation of compound ZB-B-15

[0278] Into a 50 mL flask was added 29a (70 mg, 0.123 mmol), mercaptoethanol acid (4 mL), replaced with 3 times of nitrogen, heated and stirred at 80 °C. TLC monitoring, 8 hours reaction was completed. Separated by column chromatography to obtain compound ZB-B-15. 1 H NMR (600 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.03 (s, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 3.2 Hz, 1H), 7.32 (d, J = 9.4 Hz, 1H), 6.64 (s, 2H), 6.57 (d, J = 3.3 Hz, 1H), 6.24 (d, J = 9.4 Hz, 1H), 5.40 (s, 2H), 2.55 (s, 3H); LC-MS [M+H] + : 522.

[0279] Example 30: Preparation of compound ZB-B-16

[0280] First step: Preparation of compound 31a

[0281] Into a 50 mL flask was added 1a (3 g, 25.3 mmol), pyridine (20 mL). At 0 °C, p-toluenesulfonyl chloride (5.32 g, 27.9 mmol) was added in batches, and then the temperature was restored to room temperature and stirred. LC-MS monitoring, 4 hours reaction was completed. Added appropriate amount of ethyl acetate, washed the organic layer with saturated sodium chloride solution 3 times, and then extracted the water layer with ethyl acetate. Anhydrous sodium sulfate was added to the organic layer and dried, filtered. The filtrate was distilled under reduced pressure, and compound 31a was separated by column chromatography. 1H NMR (600 MHz, DMSO-d6) δ 8.51 (d, J = 4.7 Hz, 1H), 8.31 (d, J = 8.5 Hz, 1H), 8.14 (d, J = 3.8 Hz, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.40 - 7.31 (m, 3H), 6.96 (d, J = 3.8 Hz, 1H), 2.29 (s, 3H); LC-MS [M+H] + : 273.

[0282] Second Step: Preparation of compound 31b

[0283] Into a 50 mL flask was added 31a (1 g, 3.67 mmol), dichloromethane (10 mL). At 0 °C, m-chloroperoxybenzoic acid (0.95 g, 5.5 mmol) was added portionwise, then the reaction was stirred at room temperature. LC-MS monitoring, the reaction was completed in 2 hours. Extracted with ethyl acetate for 3 times. To the organic layer, anhydrous sodium sulfate was added to dry, filtered, the filtrate was distilled under reduced pressure to obtain compound 31b. LC-MS [M+H] + : 289.

[0284] Third Step: Preparation of compound 31c

[0285] Into a 50 mL flask was added 31b (1.2 g, 4.16 mmol), N,N-dimethylformamide (15 mL). At 0 °C, trifluoroacetic anhydride (0.874 g, 41.6 mmol) was added, then the reaction was stirred at room temperature. LC-MS monitoring, the reaction was completed in 8 hours. To the reaction solution, toluene (10 mL) was added, distilled under reduced pressure until no distillate was distilled out, anhydrous ethanol (5 mL) was added, distilled under reduced pressure until no distillate was distilled out. Slowly added water (30 mL), filtered, the filter cake was collected to obtain compound 31c. 1 H NMR (600 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.01 (d, J = 9.6 Hz, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 3.6 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 6.40 (d, J = 3.7 Hz, 1H), 6.28 (d, J = 9.5 Hz, 1H), 2.33 (s, 3H); LC-MS [M+H] + : 289.

[0286] Fourth Step: Preparation of compound 31d

[0287] Into a 50 mL flask was placed 31c (1.2 g, 4.16 mmol), 4-cyanobenzyl bromide (0.652 g, 3.32 mmol), potassium carbonate (1.72 g, 12.4 mmol), 1,4-dioxane solution (10 mL), heated to reflux with stirring at 80 °C. TLC monitoring, 8 h reaction was complete. Purification by column chromatography gave 31d. 1 H NMR (600 MHz, DMSO-d6) δ 8.09 (d, J = 9.7 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 3.7 Hz, 1H), 7.75 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 3.7 Hz, 1H), 6.41 (d, J = 9.7 Hz, 1H), 5.32 (s, 2H), 2.34 (s, 3H); LC-MS [M+H] + : 404.

[0288] Fifth Step: Preparation of compound 31e

[0289] Into a 50 mL flask was placed 31d (0.577 g, 1.43 mmol), 3 mL of dimethylsulfoxide, potassium tert-butoxide (0.481 g, 4.29 mmol), stirred at room temperature. LC-MS monitoring, 1 h reaction was complete, added appropriate amount of ethyl acetate, washed the organic layer with saturated sodium chloride solution 3 times, extracted the water layer with ethyl acetate once, added anhydrous sodium sulfate to the organic layer and dried, filtered. The filtrate was distilled under reduced pressure, and compound 31e was obtained by column chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 8.09 (d, J = 9.7 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 3.7 Hz, 1H), 7.75 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 3.7 Hz, 1H), 6.41 (d, J = 9.7 Hz, 1H), 5.32 (s, 2H), 2.34 (s, 3H); LC-MS [M+H] + : 250.

[0290] Sixth Step: Preparation of compound 31g

[0291] Into a 100 mL flask was added 31f (1 g, 5.55 mmol), N-cyanoacetylurea (1.04 g, 6.66 mmol), acetonitrile (10 mL), acetic acid (10 mL). At 0 °C, tert-butyl nitrite (0.687 g, 6.66 mmol) was added dropwise slowly and the stirring was maintained at 0 °C. TLC monitoring, the reaction was completed in 30 min. Appropriate amount of ethyl acetate was added, the organic layer was washed with saturated sodium chloride solution 3 times, the water layer was extracted with ethyl acetate once, anhydrous sodium sulfate was added to the organic layer and dried, filtered. The filtrate was distilled under reduced pressure, separated by column chromatography to obtain 31g. 1 H NMR (600 MHz, DMSO-d6) δ 12.14 (s, 1H), 10.90 (s, 1H), 8.00 (s, 1H), 7.99 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H); LC-MS [M+H] + : 347.

[0292] Seventh step: Preparation of compound 31h

[0293] Into a 100 mL flask was added 31g (1.3 g, 3.74 mmol), anhydrous sodium acetate (0.46 g, 5.61 mmol), acetic acid (20 mL), heated to reflux at 120 °C. TLC monitoring, the reaction was completed in 4 h, appropriate amount of ethyl acetate was added, the organic layer was washed with saturated sodium chloride solution 3 times, the water layer was extracted with ethyl acetate once, anhydrous sodium sulfate was added to the organic layer and dried, filtered. The filtrate was distilled under reduced pressure, separated by column chromatography to obtain 31h. LC-MS [M+H] + : 301.

[0294] Eighth step: Preparation of compound 31i

[0295] Into a 50 mL flask was added 31h (0.5 g, 1.66 mmol), acetic acid (5 mL), concentrated hydrochloric acid (5 mL), heated to reflux at 100 °C with stirring. LC-MS monitoring, the reaction was completed in 2 h. Water (35 mL) was added slowly dropwise, filtered, and the filter cake was collected to obtain compound 31i without further purification. LC-MS [M-H] - : 318.

[0296] Ninth step: Preparation of compound 31j

[0297] Into a 50 mL flask was placed 31i (0.1 g, 0.312 mmol), mercapto glycolic acid (4 mL), purged with nitrogen gas 3 times, heated to 80 °C with stirring. TLC monitoring, reaction was complete in 72 h. The reaction was quenched by the addition of saturated sodium bicarbonate solution, the organic layer was washed with saturated sodium chloride solution 3 times, the aqueous layer was extracted with ethyl acetate once, the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and compound 31j was isolated by column chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 12.48 (s, 1H), 7.80 (s, 1H), 7.79 (s, 1H), 7.69 (s, 1H). LC-MS [M+H] + : 276.

[0298] Tenth step: Preparation of compound ZB-B-16

[0299] Into a 50 mL flask was placed 31e (60 mg, 0.24 mmol), N,N-dimethylformamide (3 mL), sodium hydride (11.5 mg, 0.288 mmol) was added at 0 °C with stirring. After 30 min, 31j (79.5 mg, 0.288 mmol) was added and the reaction was allowed to warm to room temperature. TLC monitoring, reaction was complete in 8 h. The reaction was quenched by the addition of ethyl acetate, the organic layer was washed with saturated sodium chloride solution 3 times, the aqueous layer was extracted with ethyl acetate once, the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and compound ZB-B-16 (17 mg, 14% yield) was isolated by column chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 12.57 (s, 1H), 7.93 (s, 2H), 7.83 (d, J = 8.1 Hz, 2H), 7.77 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 3.2 Hz, 1H), 7.37 (d, J = 9.4 Hz, 1H), 6.62 (d, J = 3.2 Hz, 1H), 6.24 (d, J = 9.4 Hz, 1H), 5.41 (s, 2H); LC-MS [M+H] + : 505.

[0300] Example 31: Preparation of compound ZB-B-17

[0301] First step: Preparation of compound 32a

[0302] To a 50 ml flask was added 1d (0.3 g, 0.925 mmol), 4-bromomethylbenzaldehyde (0.221 g, 1.11 mmol), potassium carbonate (0.383 g, 2.77 mmol), 1,4-dioxane (10 mL), heated to 100 °C and stirred at reflux. TLC monitoring, isolated by column chromatography to give compound 32a. 1 H NMR (600 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.62 (s, 2H), 7.89 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 3.2 Hz, 1H), 7.39 (d, J = 9.4 Hz, 1H), 6.66 (d, J = 3.3 Hz, 1H), 6.28 (d, J = 9.5 Hz, 1H), 5.43 (s, 2H); LC-MS [M+H] + : 442.

[0303] Second Step: Preparation of compound 32b

[0304] To a 50 ml flask was added 32a (0.25 g, 0.565 mmol), stannous chloride dihydrate (0.637 g, 2.82 mmol), ethanol (5 mL), heated to 90 °C and stirred at reflux. TLC monitoring, 8 hours reaction was completed. Added appropriate amount of ethyl acetate, poured the reaction into a separatory funnel, washed the organic layer with 2M sodium hydroxide solution 2 times, washed until the aqueous layer pH > 9. Extracted the aqueous layer with ethyl acetate once. Added anhydrous sodium sulfate to the organic layer, dried, filtered. The filtrate was distilled under reduced pressure, isolated by column chromatography to give compound 32b. LC-MS [M+H] + : 412.

[0305] Third Step: Preparation of compound 32c

[0306] To a 50 ml flask was added 32b (80 mg, 0.194 mmol), N-cyanoacetylurea (36.4 mg, 0.232 mmol), acetonitrile (3 mL), acetic acid (3 mL). At 0 °C, slowly added tert-butyl nitrite (24 mg, 0.232 mmol) dropwise, kept stirring at 0 °C. LC-MS monitoring, 30 minutes reaction was completed. Slowly added water (30 mL) dropwise to the reaction, filtered, collected the filter cake to give compound 32c. 1H NMR (600 MHz, DMSO-d6) δ 12.24 (s, 1H), 11.00 (s, 1H), 9.97 (s, 1H), 8.11 (s, 2H), 7.89 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 3.2 Hz, 1H), 7.30 (d, J = 9.4 Hz, 1H), 6.56 (d, J = 3.2 Hz, 1H), 6.25 (d, J = 9.4 Hz, 1H), 5.42 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). LC-MS [M+H] + : 579.

[0307] Fourth Step: Preparation of compound ZB-B-17

[0308] Into a 50 mL flask was added 32c (80 mg, 0.138 mmol), anhydrous sodium acetate (13.6 mg, 0.165 mmol), acetic acid (3 mL), heated to reflux at 120 °C. LC-MS monitoring, 4 hours reaction was completed. Compound ZB-B-17 was isolated by column chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 13.32 (s, 1H), 9.97 (s, 1H), 7.92-7.87 (m, 4H), 7.58 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 3.2 Hz, 1H), 7.42 (d, J = 9.5 Hz, 1H), 6.61 (d, J = 3.2 Hz, 1H), 6.25 (d, J = 9.5 Hz, 1H), 5.43 (s, 2H); LC-MS [M+H] + : 533.

[0309] Example 32: Preparation of compound ZB-B-18

[0310] First Step: Preparation of compound 33a

[0311] Into a 50 mL flask was added 1d (0.3 g, 0.925 mmol), 4-methylsulfonylbenzyl bromide (0.276 g, 1.11 mmol), potassium carbonate (0.383 g, 2.77 mmol), 1,4-dioxane (10 mL), heated to reflux at 100 °C with stirring. TLC monitoring, compound 33a was isolated by column chromatography. LC-MS [M+H]+: 492.

[0312] Second Step: Preparation of compound 33b

[0313] Into a 50 mL flask was placed 33a (0.4 g, 0.812 mmol), stannous chloride dihydrate (0.916 g, 4.06 mmol), ethanol (5 mL), and heated to reflux with stirring at 90 °C. TLC monitoring, 8 h reaction was complete. Added appropriate amount of ethyl acetate, poured the reaction into a separatory funnel, washed the organic layer with 2 M NaOH solution twice until the aqueous layer pH > 9. Extracted the aqueous layer with ethyl acetate once. Added anhydrous sodium sulfate to the organic layer, dried, and filtered. The filtrate was distilled under reduced pressure, and compound 33b was isolated by column chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 7.90 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 3.2 Hz, 1H), 7.22 (d, J = 9.4 Hz, 1H), 6.76 (s, 2H), 6.49 (d, J = 3.2 Hz, 1H), 6.21 (d, J = 9.4 Hz, 1H), 6.09 (s, 2H), 5.40 (s, 2H), 3.19 (s, 3H); LC-MS [M+H] + : 462.

[0314] Third Step: Preparation of compound 33c

[0315] Into a 50 mL flask was placed 33b (0.18 g, 0.389 mmol), N-cyanoacetylurea (73 mg, 0.467 mmol), acetonitrile (3 mL), and acetic acid (3 mL). At 0 °C, added tert-butyl nitrite (48.1 mg, 0.467 mmol) dropwise slowly, and maintained stirring at 0 °C. LC-MS monitoring, 30 min reaction was complete. Added water (30 mL) to the reaction dropwise slowly, filtered, and the filter cake was collected to give compound 33c. LC-MS [M+H] + : 629.

[0316] Fourth Step: Preparation of compound ZB-B-18

[0317] Into a 50 mL flask was placed 33c (0.2 g, 0.137 mmol), anhydrous sodium acetate (31.2 mg, 0.381 mmol), acetic acid (3 mL), and heated to reflux at 120 °C. LC-MS monitoring, 4 h reaction was complete. Compound ZB-B-18 was isolated by column chromatography. 1H NMR (600 MHz, DMSO-d6) δ 13.43 (s, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.89 (s, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 3.2 Hz, 1H), 7.42 (d, J = 9.5 Hz, 1H), 6.65 (d, J = 3.2 Hz, 1H), 6.25 (d, J = 9.4 Hz, 1H), 5.43 (s, 2H), 3.19 (s, 3H); LC-MS [M+H] + : 583.

[0318] Example 33: Preparation of compound ZB-B-19

[0319] First step: Preparation of compound 34a

[0320] Into a 50 mL flask was added 31c (0.85 g, 2.94 mmol), 4-nitrobenzyl bromide (0.7 g, 3.24 mmol), potassium carbonate (1.22 g, 8.84 mmol), 1,4-dioxane solution (10 mL), heated to reflux with stirring at 80 °C. TLC monitoring, 8 hours reaction was completed. Separated by column chromatography to get 34a. 1 H NMR (600 MHz, DMSO-d6) δ 8.14 (d, J = 8.4 Hz, 2H), 8.10 (d, J = 9.7 Hz, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 3.7 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 6.76 (d, J = 3.7 Hz, 1H), 6.42 (d, J = 9.7 Hz, 1H), 5.37 (s, 2H), 2.34 (s, 3H); LC-MS [M+H] + : 424.

[0321] Second step: Preparation of compound 34b

[0322] Into a 50 mL flask was added 34a (0.404 g, 0.95 mmol), 3 mL of dimethyl sulfoxide, potassium tert-butoxide (0.321 g, 2.86 mmol), stirred at room temperature. LC-MS monitoring, 1 hour reaction was completed, added appropriate amount of ethyl acetate, washed with saturated sodium chloride solution 3 times, extracted with ethyl acetate 1 time, added anhydrous sodium sulfate to the organic layer, dried, filtered. The filtrate was distilled under reduced pressure to obtain compound 34b without further purification. 1H NMR (600 MHz, DMSO-d6) δ 11.43 (s, 1H), 8.17 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 9.3 Hz, 1H), 7.51 (d, J = 8.7 Hz, 2H), 7.24 - 7.20 (m, 1H), 6.23 - 6.13 (m, 2H), 5.39 (s, 2H); LC-MS [M+H] + : 270.

[0323] Third Step: Preparation of compound ZB-B-19

[0324] Into a 50 ml flask was added 34b (70 mg, 0.259 mmol), N, N- dimethylformamide (3 mL), sodium hydride (12.4 mg, 0.311 mmol) was added at 0 °C, keep stirring at 0 °C. After 30 min, 31j (86.1 mg, 0.311 mmol) was added, then recover to room temperature and stir. TLC monitoring, 8 hours reaction was completed. Added appropriate amount of ethyl acetate, the organic layer was washed with saturated sodium chloride solution 3 times, the water layer was extracted with ethyl acetate once, anhydrous sodium sulfate was added to the organic layer and dried, filtered. The filtrate was distilled under reduced pressure, and compound ZB-B-19 was separated by column chromatography. 1 H NMR (600 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.23 (d, J = 8.7 Hz, 2H), 7.93 (s, 2H), 7.77 (s, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 3.2 Hz, 1H), 7.38 (d, J = 9.5 Hz, 1H), 6.62 (d, J = 3.2 Hz, 1H), 6.25 (d, J = 9.4 Hz, 1H), 5.46 (s, 2H); LC-MS [M+H] + : 525.

[0325] Example 34: Preparation of compound ZB-B-20

[0326] First Step: Preparation of compound 35a

[0327] Into a 50 ml flask was added 19a (0.5 g, 0.9 mmol), mercaptoethanol acid (4 mL), replaced gas 3 times, heated and stirred at 80 °C. TLC monitoring, 8 hours reaction was completed. Compound 35a was separated by column chromatography. 1H NMR (600 MHz, DMSO-d6) δ 12.57 (s, 1H), 8.29 (s, 1H), 7.95 (s, 2H), 7.78 (s, 1H), 7.67 (d, J = 9.6 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.57 (d, J = 9.6 Hz, 1H), 5.24 (s, 2H), 3.72 (s, 3H); LC-MS [M+H] - : 511.

[0328] Second Step: Preparation of compound ZB-B-20

[0329] Into a 50ml flask was added 35a (67mg, 0.131mmol), dichloromethane (3mL), replaced with nitrogen 3 times at 0°C. Added 2M boron tribromide in dichloromethane (2.3mL) dropwise at -80°C, and raised to room temperature. Monitored by LC-MS, reaction was completed in 3 hours. Added saturated sodium bicarbonate solution at 0°C, after the reaction was quenched, added ethyl acetate, added a small amount of saturated sodium chloride solution, extracted with ethyl acetate 3 times, added anhydrous sodium sulfate to the organic layer, dried, and removed the solvent under reduced pressure. Separated by column chromatography to obtain compound ZB-B-20. 1 H NMR (600 MHz, DMSO-d6) δ 12.57 (s, 1H), 8.29 (s, 1H), 7.95 (s, 2H), 7.78 (s, 1H), 7.67 (d, J = 9.6 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.57 (d, J = 9.6 Hz, 1H), 5.24 (s, 2H), 3.72 (s, 3H); LC-MS [M+H] - : 495.

[0330] Example 35: Preparation of compound ZB-A-20

[0331] The first step used the synthetic route of Example 1, and the raw material isopropyl bromide in the preparation of Example 1 fourth step was replaced with iodomethane. The second to fourth steps used the synthetic route of Example 7 to prepare compound ZB-A-20. 1 H NMR (600 MHz, DMSO-d6) δ 12.57 (s, 1H), 8.29 (s, 1H), 7.95 (s, 2H), 7.78 (s, 1H), 7.67 (d, J = 9.6 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.57 (d, J = 9.6 Hz, 1H), 5.24 (s, 2H), 3.72 (s, 3H); LC-MS [M+H] - : 378.

[0332] Example 36: Preparation of compound ZB-A-21

[0333] The first step was performed using the synthetic route of Example 1, replacing the starting material isopropyl bromide in the preparation of Example 1, fourth step with isobutyl bromide. The second to fourth steps were performed using the synthetic route of Example 7 to produce compound ZB-A-21. 1 H NMR (600 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.15 (s, 2H), 7.38 (d, J = 3.2 Hz, 1H), 7.21 (d, J = 9.4 Hz, 1H), 6.55 (d, J = 3.2 Hz, 1H), 6.13 (d, J = 9.4 Hz, 1H), 3.90 (d, J = 7.4 Hz, 2H), 2.25-2.14 (m, 1H), 0.91 (d, J = 6.7 Hz, 6H); LC-MS [M-H] - : 420.

[0334] Example 37: Preparation of compound ZB-A-22

[0335] The first step was performed using the synthetic route of Example 1, replacing the starting material isopropyl bromide in the preparation of Example 1, fourth step with cyclopropyl bromide. The second to fourth steps were performed using the synthetic route of Example 7 to produce compound ZB-A-22. LC-MS [M-H] - : 404.

[0336] Example 38: Preparation of compound ZB-A-24

[0337] The first to fifth steps were performed using the synthetic route of Example 1, replacing the starting material 3,5-dichloro-4-fluoronitrobenzene in the preparation of Example 1, first step with 2-fluoro-l,3 dimethyl-5-nitrobenzene. The sixth to seventh steps were performed using the synthetic route of Example 7 to produce compound ZB-A-24. LC-MS [M-H] - : 366.

[0338] Example 39: Preparation of compound ZB-A-25

[0339] The first step was performed using the synthetic route of Example 7, replacing the starting material oxalyl chloride monoethyl ester with oxalyl chloride monomethyl ester to produce compound ZB-A-25. 1H NMR (600 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.13 (s, 2H), 7.40 (d, J = 3.3 Hz, 1H), 7.18 (d, J = 9.4 Hz, 1H), 6.70 (d, J = 3.2 Hz, 1H), 6.12 (d, J = 9.4 Hz, 1H), 5.40 - 5.13 (m, 1H), 3.89 (s, 3H), 1.51 (d, J = 7.0 Hz, 6H); LC-MS [M+H] + : 422.

[0340] Example 40: Preparation of compound ZB-A-28

[0341] The first to second steps used the synthetic route of Example 1, and the raw material isopropyl bromide in the preparation of Example 1 fourth step was replaced by 2-bromopropane-d7. The third to fourth steps used the synthetic route of Example 7, and compound ZB-A-28 was prepared. 1 H NMR (600 MHz, DMSO-d6) δ 11.25 (s, 1H), 8.15 (s, 2H), 7.41 (d, J = 3.3 Hz, 1H), 7.19 (d, J = 9.3 Hz, 1H), 6.70 (d, J = 3.4 Hz, 1H), 6.14 (d, J = 9.3 Hz, 1H); LC-MS [M-H] - : 413

[0342] Example 41: Detection of agonistic activity of compounds on THRα and THRβ by THR reporter gene method

[0343] Huh7 cells were cultured in DMEM medium containing 10% FBS. Cells were seeded into 10cm cell culture dishes and allowed to proliferate to approximately 90% confluence. They were then co-transfected with human THRα eukaryotic expression plasmid or human THRβ eukaryotic expression plasmid and the reporter gene plasmid PGL4.26-DR4-Luc containing a THR response sequence driven by liposome Lipofectamine 2000. The procedure was performed according to the Lipofectamine 2000 manufacturer's instructions. The day after transfection, cells were seeded into 96-well cell culture plates with phenol red-free DMEM medium (containing 5% carbon-adsorbed fetal bovine serum) at a density of 20,000 cells per well and a volume of 135 μL per well. Six hours after seeding, cells adhered. A compound dissolved in dimethyl sulfoxide was diluted 20-fold to 10-fold with phenol red-free DMEM medium (containing 5% carbon-adsorbed fetal bovine serum) and added to each well at a final concentration of 15 μL, thus achieving a final concentration by further dilution 10-fold. The positive control was set as triiodothyronine T3 (100 nM), and the blank control was 0.5% dimethyl sulfoxide. After drug administration, the cells were cultured overnight (16 h) at 37°C in a 5% CO2 incubator. After incubation, the culture medium was discarded, and 35 μL of serum-free and phenol red-free DMEM culture medium and 35 μL of Steady-Glo were added to each well. After shaking at room temperature in the dark for 10 min, the chemiluminescence value of the samples was detected.

[0344] The agonistic activity of a compound is calculated as follows: Effect % = (Compound - Blank Control) / (Positive Control - Blank Control) × 100%. The EC50 of the compound... 50 EC was obtained by fitting the agonistic activity of the compound to the logarithm of the compound concentration using GraphPad Prism. 50 The lower the value, the better the activity.

[0345] EC50 of the compound’s agonistic activity against THRα and THRβ 50 The values ​​were first calculated using the EC50 values ​​of T3 on the agonistic activity of THRα and THRβ in the same experiment. 50 After value correction, the fold increase, i.e., receptor selectivity, is calculated based on the obtained value. The specific calculation method is as follows: Selectivity = (compound THRαEC) / (receptor selectivity) * (receptor selectivity ... 50 / T3 THRαEC 50 ) / (compound THRβEC 50 / T3 THRβEC 50 The higher the value, the higher the selectivity of the compound for the THRβ receptor.

[0346] The positive control drugs are Resmetirom (MGL-3196), ZB-H-74 and ZB-H-76. They are reported as highly active and selective THR-β agonists. (Reference: J Med Chem. 2014, 57(10): 3912-3923; CN114634486B).

[0347] The experimental results show that the activity or selectivity of some of the test compounds of the structure of the present disclosure is significantly higher than that of the three positive compounds, and the activity or selectivity of most of the other compounds is comparable.

[0348] Example 42: The reducing effect of a single dose of the compound on the serum total cholesterol and low-density lipoprotein cholesterol levels of mice after 24 hours

[0349] ICR mice were used as test animals to test the changes in serum total cholesterol and low-density lipoprotein cholesterol levels after oral administration of the compound to mice. ICR mice (male, 7-8 weeks old) were randomly divided according to body weight. The solvent control group was given 0.25% CMC-Na by gavage, and the compound group was given the corresponding test compound by gavage, respectively, for a single dose. On the day of administration, the mice were fasted overnight, and 24 hours after administration, blood was collected and serum was collected. The automatic biochemical analyzer was used to determine the serum total cholesterol and low-density lipoprotein cholesterol levels of mice. The percentage reduction in serum total cholesterol and low-density lipoprotein cholesterol levels of mice in each group was calculated based on the solvent control group as 100%.

[0350] The experimental results after 24 hours of administration show that the test compound has better single animal in vivo efficacy compared with the positive compound MGL-3196.

[0351] Example 43: Pharmacodynamic evaluation of the compound on a mouse model of non-alcoholic steatohepatitis induced by high-fat diet combined with carbon tetrachloride

[0352] The experiment selected male C57 mice, 5-6 weeks old, were given high-fat diet and control feed respectively, and were induced for 14 weeks. Then, the mice were injected with CCl4 (0.05 μl / g) intraperitoneally, twice a week, and the carbon tetrachloride injection was performed for 6 weeks as the endpoint of the experiment. At the same week when the CCl4 injection was started, the mice were given ZB-B-13 (3 mg / kg), ZB-A-10 (1 mg / kg) and MGL-3196 (3 mg / kg) by gavage, once a day, and the administration was continuously performed until the end of the experiment. After the end of the experiment, the blood samples of the mice were collected, and the serum was separated for detecting the biochemical indexes such as serum alanine aminotransferase (ALT), serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C); the liver was separated, fixed and embedded, and the section was cut, stained with hematoxylin-eosin (H&E) and scored for pathology; the Sirius red staining was used to evaluate the liver fibrosis level, and the therapeutic effect of the compounds on non-alcoholic steatohepatitis was comprehensively evaluated.

[0353] The experimental results are shown in FIGS. 1-5. Compared with the model control group, after 6 weeks of oral administration, ZB-B-13 (3 mg / kg), ZB-A-10 (1 mg / kg) and MGL-3196 (3 mg / kg) significantly reduced the serum ALT, total cholesterol and LDL-C levels of the mice, and ZB-A-10 (1 mg / kg) was more effective than MGL-3196 (3 mg / kg); the results of HE staining of liver sections showed that, compared with the model control group, ZB-B-13 (3 mg / kg), ZB-A-10 (1 mg / kg) and MGL-3196 (3 mg / kg) significantly improved the liver steatosis, hepatocyte ballooning and lobular inflammation of the mice, and significantly reduced the NAS score, and ZB-B-13 (3 mg / kg) and ZB-A-10 (1 mg / kg) were more effective than MGL-3196 (3 mg / kg); the results of Sirius red staining of liver tissue sections showed that, after treatment with ZB-B-13 (3 mg / kg), ZB-A-10 (1 mg / kg) and MGL-3196 (3 mg / kg), the liver fibrosis level of the NASH mice was significantly reduced, and ZB-B-13 (3 mg / kg) and ZB-A-10 (1 mg / kg) were more effective than MGL-3196 (3 mg / kg). The above results suggest that ZB-B-13 and ZB-A-10 have a significant therapeutic effect on non-alcoholic steatohepatitis mice induced by high-fat diet combined with carbon tetrachloride after long-term administration, and the drug efficacy is higher than that of MGL-3196.

[0354] Example 44: Reducing effect of a single administration of compound ZB-A-10 on serum total cholesterol and low density lipoprotein cholesterol levels of mice for 72 hours

[0355] The ICR mice were used as the test animals to test the changes of serum total cholesterol and low density lipoprotein cholesterol levels of the mice after a single gavage administration of compound ZB-A-1072 for 72 hours. The ICR mice (male, 7-8 weeks old) were randomly divided according to the body weight. The solvent control group was gavaged with 0.25% CMC-Na, and the compound group was respectively given the corresponding test compound, single administration. On the 3rd day of administration, the mice were fasted overnight, and 72 hours after administration, blood was collected and serum was collected. The automatic biochemical analyzer was used to determine the serum total cholesterol and low density lipoprotein cholesterol levels of the mice. The percentage reduction of serum total cholesterol and low density lipoprotein cholesterol levels of each group of mice was calculated based on the solvent control group as 100%.

[0356] The results showed (Figure 6) that after a single gavage administration of 3 mg / kg MGL-3196 to mice, the serum total cholesterol and low density lipoprotein cholesterol did not significantly decrease after 72 hours. However, after a single gavage administration of 1 mg / kg or 3 mg / kg ZB-A-10 to mice, the serum total cholesterol significantly decreased by 40.4% and 45.1%, and the serum low density lipoprotein cholesterol also significantly decreased by 54.3% and 55.0%, indicating that ZB-A-10 has long-term application potential for reducing serum total cholesterol and low density lipoprotein cholesterol.

[0357] Example 45: Pharmacodynamic evaluation of compound ZB-A-10 (once every 3 days orally administered) on a mouse model of non-alcoholic steatohepatitis induced by high-fat diet combined with carbon tetrachloride (HFD+CCl4)

[0358] In this experiment, male C57 mice, 5-6 weeks old, were given high-fat diet and control feed respectively, and after 14 weeks of induction, CCl4 (0.05 μl / g) was injected intraperitoneally, twice a week, and carbon tetrachloride injection was performed for 6 weeks as the endpoint of the experiment; at the same week when CCl4 injection began, ZB-A-10 (1 mg / kg, once every 3 days) and MGL-3196 (3 mg / kg, once a day) were administered by gavage, and the administration was continued until the end of the experiment. After the end of the experiment, the blood samples of the mice were collected, and the serum was separated for the detection of biochemical indicators such as serum alanine aminotransferase (ALT), serum total cholesterol (TC), and low density lipoprotein cholesterol (LDL-C); the liver was separated, fixed and embedded, and the main lobe was sectioned, stained with hematoxylin-eosin (H&E) and scored pathologically; Sirius red staining was used to evaluate the level of liver fibrosis, and the therapeutic effect of the compound on non-alcoholic steatohepatitis was comprehensively evaluated.

[0359] The experimental results are shown in Figures 7-11. Compared with the model control group (HFD+CCl4), both ZB-A-10 (1 mg / kg, once every 3 days) and MGL-3196 (3 mg / kg, once a day) significantly reduced the serum ALT, total cholesterol and LDL-C levels of mice after 6 weeks of oral administration; the results of liver section HE staining showed that, compared with the model control group, both ZB-A-10 (1 mg / kg, once every 3 days) and MGL-3196 (3 mg / kg, once a day) significantly improved the liver steatosis, hepatocyte ballooning and lobular inflammation of mice, and significantly reduced the NAS score, and the effect of ZB-A-10 (1 mg / kg, once every 3 days) was stronger than that of MGL-3196 (3 mg / kg, once a day); the results of Sirius red staining of liver tissue sections showed that, after treatment of ZB-A-10 (1 mg / kg, once every 3 days) and MGL-3196 (3 mg / kg, once a day), the liver fibrosis level of NASH mice was significantly reduced, and the effect of ZB-A-10 (1 mg / kg, once every 3 days) was stronger than that of MGL-3196 (3 mg / kg, once a day). The above results suggest that long-term administration of ZB-A-10 (once every 3 days orally) has a significant therapeutic effect on non-alcoholic steatohepatitis mice induced by high-fat diet combined with carbon tetrachloride, suggesting that it has significant long-term application potential, and the drug efficacy is better than that of MGL-3196.

[0360] Example 46: ZB-A-29 to ZB-A-33

[0361] Using the deuterium substitution technology known to those skilled in the art, various deuterated intermediates 1f were obtained, and compounds ZB-A-29, ZB-A-30, ZB-A-31, ZB-A-32, ZB-A-33 were prepared according to the preparation method of compound ZB-A-10 in Example 6.

Claims

A compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, or isotopically-labeled compound thereof: wherein X is selected from N and CH; R2and R3are each independently selected from hydrogen, halogen and methyl; B is selected from the group consisting of: When B is A is R0when X is CH; R0is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 3-10 cycloalkyl, and substituted or unsubstituted 3-10 membered heterocycloalkyl, the substituents being selected from the group consisting of halogen atoms, hydroxyl, =0, C 1-6 alkoxy, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted C 6-10 aryl, and substituted or unsubstituted 5-10 membered heteroaryl; wherein the substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, the substituents being selected from the group consisting of halogen, C 1-10 alkyl, C 1-10 haloalkyl, C 3-10 cycloalkyl, hydroxyl, -NR 10 R 11 , C 1-10 alkoxy, C 1-10 haloalkoxy, -CN, nitro, -C(=0)R 11 , -C(=0)NR 10 R 11 , -NR 10 C(=0)C 1-10 alkyl, -SR 11 , -S(=0)R 11 , -S(=0)2R 11 , and -S(=0)2NR 10 R 11 ; R4is selected from hydrogen, hydroxyl, halogen, cyano, -NR b R c , -C(=O)R a , -C(=O)OR b , -C(=O)NR b R c , and -P(=O)R b R c ; Y is selected from CR 10 R 11 , NR 11 , O, S and -S=O; L is selected from NR 11 and CR 10 R 11 or L is absent; When B is A is R1is one or more each independently selected from the group consisting of a nitro group, a cyano group, a hydroxyl group, -BR 10 R 11 , -C(=O)R 11 , -C(=O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(=O)R 11 , -PR 10 R 11 , -P(=O)R 10 R 11 , -SR 11 , -S(=O)R 11 , -S(=O)2R 11 , -S(=O)2NR 10 R 11 , a substituted C 1-3 alkyl group, a substituted or unsubstituted C 3-10 cycloalkyl group, and a substituted or unsubstituted 3- to 10-membered heterocycloalkyl group, the substituents of which are selected from the group consisting of a halogen atom, a hydroxyl group, a nitro group, CN, =O, -NR 11 R 11 , -C(=O)R 10 , -C(=O)NR 11 R 10 , and -NR 11 R 10 ; R5is selected from hydrogen, cyano, -NR 10 R 11 , and substituted or unsubstituted C 1-6 alkyl, said substituent being halogen, hydroxy, cyano, C 1-6 alkoxy, or -NR 10 R 11 ; each R is independently selected from hydrogen, substituted or unsubstituted C 10 independently selected from hydrogen, substituted or unsubstituted C 1-3 alkyl, and substituted or unsubstituted C 1-3 alkoxy, the substituents being selected from the group consisting of halogen, hydroxy and C 1-3 alkoxy; each R is independently selected from hydrogen, substituted or unsubstituted C 11 hydrogen, substituted or unsubstituted C 1-6 alkyl, and substituted or unsubstituted C 1-3 alkyl, and substituted or unsubstituted C 1-3 alkoxy; or R 10 and R 11 together with the carbon atom to which they are attached form a 3- to 6-membered ring containing 0 to 3 heteroatoms selected from N, O, and S; each R is independently hydrogen, hydroxyl, C a is independently hydrogen, hydroxyl, C 1-6 alkyl, C 3-10 cycloalkyl, or 3-10 membered heterocycloalkyl, said alkyl, cycloalkyl, and heterocycloalkyl are independently optionally substituted with one or more substituents selected from halogen, hydroxyl, amino, and C 1-6 alkyl; Each R b and R c Independently hydrogen, hydroxyl, C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-3 Alkoxy or 3-10 membered heterocyclic alkyl; the alkyl, cycloalkyl, and heterocyclic alkyl groups are independently optionally selected from halogen, hydroxyl, amino, C 2-6 alkynyl group and C 1-6 One or more substituents of the alkyl group are used for substitution; or R b and R c with the nitrogen atom to which they are attached form a 3-10 membered heterocycloalkyl group, which is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino and C 1-6 alkyl, wherein the compound is not A compound according to claim 1, pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, or isotopically labeled compound thereof: wherein, The compound is selected from the group consisting of compounds of formula (II): R0is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 3-10 cycloalkyl, and substituted or unsubstituted 3-10 membered heterocycloalkyl, the substituents being selected from the group consisting of halogen atoms, hydroxyl, =0, C 1-6 alkoxy, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, substituted or unsubstituted C 6-10 aryl, and substituted or unsubstituted 5-10 membered heteroaryl; wherein the substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, the substituents being selected from the group consisting of halogen, C 1-10 alkyl, C 1-10 haloalkyl, C 3-10 cycloalkyl, hydroxyl, -NR 10 R 11 , C 1-10 alkoxy, C 1-10 haloalkoxy, -CN, nitro, -C(=0)R 11 , -C(=0)NR 10 R 11 , -NR 10 C(=0)C 1-10 alkyl, -SR 11 , -S(=0)R 11 , -S(=0)2R 11 , and -S(=0)2NR 10 R 11 ; R2and R3are each independently selected from hydrogen, halogen and methyl; Y is selected from NR 11 and O; L is selected from NR 11 and CR 10 R 11 or L is absent; R4is selected from hydrogen, hydroxy, cyano, -NR b R c , -C(=O)R a , -C(=O)NR b R c , -C(=O)OR b , and -P(=O)R b R c ; R 10 , R 11 , R a , R b , R c are the same as defined in the general formula I in claim 1. A compound according to claim 1, pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, or isotopically labeled compound thereof: wherein, The compound is selected from the group consisting of compounds of formula (III): R1is one or more each independently selected from the group consisting of nitro, cyano, hydroxyl, -BR 10 R 11 , -C(=O)R 11 , -C(=O)NR 10 R 11 , -NR 10 R 11 , -NR 10 C(=O)R 11 , -PR 10 R 11 , -P(=O)R 10 R 11 , -SR 11 , -S(=O)R 11 , -S(=O)2R 11 , -S(=O)2NR 10 R 11 , C 3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl; R2and R3are each independently selected from hydrogen, halogen and methyl; R5is selected from hydrogen, cyano, -NR 10 R 11 , and substituted or unsubstituted C 1-6 alkyl, the substituents being selected from the group consisting of halogen, hydroxy and -NR 10 R 11 ; R 10 , R 11 are the same as defined in the general formula I in claim 1. A compound according to claim 1, pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, or isotopically labeled compound thereof: wherein, The compound is selected from the group consisting of compounds of formula (IV): R1is one or more each independently selected from the group consisting of nitro, cyano, hydroxy, -C(=O)R 11 , -C(=O)NR 10 R 11 , -NR 10 R 11 , -PR 10 R 11 , -P(=O)R 10 R 11 , -SR 11 , -S(=O)R 11 , -S(=O)2R 11 , -S(=O)2NR 10 R 11 , C 3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl; R2and R3are each independently selected from hydrogen, halogen and methyl; R5is selected from hydrogen, cyano, -NR 10 R 11 , and substituted or unsubstituted C 1-6 alkyl, the substituents being selected from the group consisting of halogen, hydroxy and -NR 10 R 11 ; R 10 , R 11 are the same as defined in the general formula I in claim 1. A compound according to claim 1, pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, or isotopically labeled compound thereof: wherein, The compound is selected from the group consisting of compounds of formula (V): R0is selected from hydrogen, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 3-10 cycloalkyl, and substituted or unsubstituted 3-10 membered heterocycloalkyl, the substituents being selected from the group consisting of halogen atoms, hydroxyl, =0, C 1-6 alkoxy, C 1-6 alkyl, C 3-10 cycloalkyl, and 3-10 membered heterocycloalkyl; R2and R3are each independently selected from hydrogen, halogen and methyl; R4is selected from hydrogen, hydroxyl, -NR b R c and -C(=O)OR b ; R b , R c are the same as defined in the general formula I in claim 1. The compound, pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, or isotopically labeled compound according to claim 1, wherein, The compounds of the general formula I are selected from the following compounds: A pharmaceutical composition comprising one or more of a compound, pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, polymorph, solvate, and isotopically-labeled compound thereof as described in any one of claims 1 to 6, and optionally, a pharmaceutically acceptable excipient. Use of a compound, pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, polymorph, solvate, or isotopically-labeled compound thereof according to any one of claims 1 to 6, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the treatment of a metabolic-related disease. The use according to claim 8, wherein the metabolic-related disease is selected from the group consisting of obesity, hyperlipidemia, hypercholesterolemia, diabetes, metabolic dysfunction-associated fatty liver disease, hepatic steatosis, atherosclerosis, hypothyroidism, thyroid cancer, seborrheic dermatitis, and androgenetic alopecia, in particular, the metabolic-related disease is selected from the group consisting of metabolic dysfunction-associated fatty liver disease, hypothyroidism, and thyroid cancer.

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