Biaromatic ring inhibitor targeting c-Myc protein

Abstract

The inventor aims to develop a novel c-Myc inhibitor as well as a pharmaceutical composition and application thereof. The compound can be used for preventing and / or treating c-Myc-mediated related tumor diseases.

Description

Background Art

[0001] The transcription factor c-Myc is the main control factor of normal gene expression, regulating biological processes such as normal cell proliferation, cell cycle, differentiation, metabolism, apoptosis and angiogenesis (Nat Rev Cancer. 2008 Dec; 8 (12): 976-90.). c-Myc plays a key role in tumorigenesis, maintenance and drug resistance. Due to gene amplification, ectopic location, mRNA upregulation and abnormal protein stability, c-Myc protein expression is dysregulated in 70% of tumors (Cell. 2012 Mar 30; 149 (1): 22-35.). Myc protein itself has poor stability and only has a stable conformation after binding to Max. After forming the Myc-Max complex, it binds to DNA-Ebox to initiate downstream gene transcription (Mol Cancer. 2021 Jan 4; 20 (1): 3.). Silencing Myc expression in multiple tumor models leads to tumor growth inhibition or regression (Science. 2002 Jul 5; 297(5578): 102-4., Cancer Res. 65, 4471-4474.), therefore, targeting dysregulated Myc protein has a wide range of therapeutic effects (Cold Spring Harb Perspect Med. 2014 Oct 1; 4(10): a014266.).

[0002] However, Myc is an intrinsically disordered protein (IDP) with no stable protein conformation and lacks a clear pocket, and has always been considered a "difficult-to-druggable target." There are currently a variety of development strategies for the development of drugs to treat Myc-related diseases, such as directly targeting the Myc-Max interaction in the Myc pathway, inhibiting the interaction between the Myc-Max complex and DNA, and indirectly regulating the upstream and downstream pathways of Myc. Over the years, researchers have discovered a number of small molecules that directly bind to Myc and inhibit Myc-Max dimerization and / or the formation of Myc-Max-DNA complexes, but most compounds have weak binding ability to Myc and low inhibitory activity on c-Myc-driven tumor cell proliferation. Most molecules have poor drugability and pharmacokinetic properties, which further limits their application in vivo (J.Am.Chem.Soc.2023,145,3259-3269), and small molecule Myc inhibitors with better drugability are urgently needed. Summary of the invention

[0003] The present inventors are committed to developing a novel c-Myc inhibitor, which can be used to prevent and / or treat c-Myc-mediated related tumor diseases.

[0004] To this end, the present invention provides a compound having a structure represented by formula (I) or a deuterated product thereof, or a pharmaceutically acceptable salt thereof:

[0005]

[0006] In ring A, X, Y, and Z are independently selected from N or CR4;

[0007] Ring B is selected from a 5-11 membered heteroaromatic ring containing 1-5 ring heteroatoms independently selected from N, O, and S, and when A is a benzene ring, B is not the following ring structure:

[0008] The C ring is selected from: a benzene ring, a 5-6 membered monocyclic heteroaromatic ring containing 1-3 ring heteroatoms independently selected from N, O, and S, an 8-10 membered bicyclic fused heteroaromatic ring containing 1-5 ring heteroatoms independently selected from N, O, and S, a bicyclic ring composed of a 3-7 membered alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, and S and a 3-7 membered alicyclic ring, a bicyclic ring composed of a 3-7 membered alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, and S and a 3-7 membered alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, and S, a bicyclic ring composed of a 3-7 membered alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, and S and a 3-7 membered alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, and S and a benzene ring The invention further comprises a bicyclic ring, a bicyclic ring composed of a 3-7-membered alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, and S and a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms independently selected from N, O, and S, a bicyclic ring composed of a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms independently selected from N, O, and S and a 3-7-membered alicyclic ring, a 3-7-membered alicyclic ring (preferably a 4-6-membered alicyclic ring), a 5-10-membered bridged alicyclic ring (preferably a 5-8-membered bridged alicyclic ring), a 3-7-membered alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, and S, and a 5-8-membered bridged alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, and S;

[0009] R1 is selected from: -OR5, -N(R5)R6, -COOR5, -CHF2, -N(R5)C(O)R6, -N(R5)S(O)2R6;

[0010] R2, R3 and R4 are each independently selected from: -H, halogen, -OH, -CN, -NO2, =O, C 1-10 Straight or branched alkyl (preferably C 1-4 Straight or branched chain alkyl), C 2-4 Straight or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-10 Straight chain or branched alkoxy (preferably C 1-4 Straight chain or branched chain alkoxy), C 3-7 Cycloalkyl, C 3-7Cycloalkyloxy, 3-7 membered alicyclic group containing 1-3 ring heteroatoms independently selected from N, O, and S, 3-7 membered alicyclic group containing 1-3 ring heteroatoms independently selected from N, O, and S, 5-6 membered heteroaryl containing 1-3 ring heteroatoms independently selected from N, O, and S, phenyl, -C(O)R5, -C(O)OR5, -C(O)N(R5)R6, -S(O)2R5, -S(O)2N(R5)R6, -N(R5)R6, -N(R5)C(O)R6, -N(R5)S(O)2R6, -P(O)(R5)R6, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkyloxy, alicyclic, alicyclicoxy, heteroaryl, phenyl are optionally substituted by one or more independently selected from halogen, -OH, -CN, -OR5, -C(O)R5, -C(O)OR5, -C(O)N(R5)R6, -S(O)2R5, -S(O)2N(R5)R6, -N(R5)R6, -N(R5)C(O)R6, -N(R5)S(O)2R6, -P(O)(R5)R6, C 1-4 Straight or branched alkyl, C 2-4 Straight or branched alkenyl, C 2-4 substituted with a straight-chain or branched alkynyl group;

[0011] L is an optional group, and when present, is selected from -OC(R5)R6-, -C(R5)R6O-, -NR5C(R5)R6-, -C(R5)(R6)NR5-, -NR5C(O)-, -C(O)NR5-, -S(O)2NR5-, -NR5S(O)2-, -OC(O)NR5-, -N(R5)COO-, -CO-, 3-7 membered alicyclic ring, 3-7 membered alicyclic ring-O-, -O-3-7 membered alicyclic ring, 3-7 membered alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, S, -oxy- 3-7 membered alicyclic heterocycles, 3-7 membered alicyclic heterocyclic oxy groups containing 1-3 ring heteroatoms independently selected from N, O, and S; the alicyclic and alicyclic heterocycles are substituted or unsubstituted, and when substituted, they are independently substituted by one or more of the following groups: halogen, -OH, -CN, -OR5, -C(O)R5, -C(O)OR5, -C(O)N(R5)R6, -S(O)2R5, -S(O)2N(R5)R6, -N(R5)R6, -N(R5)C(O)R6, -N(R5)S(O)2R6, -P(O)(R5)R6, C 1-10 Straight or branched alkyl (preferably C 1-4 Straight or branched chain alkyl), C 2-4 Straight or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-10 Straight chain or branched alkoxy (preferably C1-4 Straight chain or branched chain alkoxy), C 3-7 Cycloalkyl (preferably C 3-5 Cycloalkyl), C 3-7 Cycloalkoxy (preferably C 3-5 cycloalkyloxy), 3-7 membered alicyclic radicals containing 1-3 ring heteroatoms independently selected from N, O, and S, 3-7 membered alicyclic radicals containing 1-3 ring heteroatoms independently selected from N, O, and S, and 5-11 membered heteroaryl radicals containing 1-3 ring heteroatoms independently selected from N, O, and S;

[0012] Each R5 and each R6 are independently selected from -H, -OH, -CN, -NH2, C 1-10 Straight or branched alkyl (preferably C 1-4 Straight or branched chain alkyl), C 2-4 Straight or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-10 Straight chain or branched alkoxy (preferably C 1-4 The alkyl, alkenyl, alkynyl, alkoxy, alicyclic, alicyclic oxy, alicyclic heterocyclic, alicyclic heterocyclic oxy, heteroaryl, halogen, -OH, -CN, -NH2, C 1-4 Straight or branched alkyl, C 2-4 Straight or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 or R5 and R6 in the above groups together with the atoms to which they are commonly connected form a 3-7 membered alicyclic group or a 3-7 membered alicyclic group containing 1-3 ring heteroatoms independently selected from N, O, P, and S, and the alicyclic group or alicyclic group is optionally substituted by one or more independently selected from halogen, -OH, -CN, -NH2, C 1-4 Straight or branched alkyl, C 2-4 Straight or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 Substitution with straight-chain or branched alkoxy groups;

[0013] m = 0, 1, 2, 3, or 4;

[0014] n = 0, 1, 2, 3, or 4;

[0015] The halogen is selected from: F, Cl, Br, I.

[0016] Alternatively, L is an optional group, which, when present, is selected from -OC(R5)R6-, -C(R5)R6O-, -NR5C(R5)R6-, -C(R5)(R6)NR5-, -NR5C(O)-, -C(O)NR5-, -S(O)2NR5-, -NR5S(O)2-, -OC(O)NR5-, -N(R5)COO-, -CO-, a 3-7 membered alicyclic ring, a 3-7 membered alicyclic ring-O-, -O-3-7 membered alicyclic ring, a 3-7 membered alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, S -3-7 membered alicyclic heterocycle, -oxy-3-7 membered alicyclic heterocycle, 3-7 membered alicyclic heterocycle oxy containing 1-3 ring heteroatoms independently selected from N, O, and S; the alicyclic ring and alicyclic heterocycle are independently substituted by one or more of the following groups: halogen, -OH, -CN, -OR5, -C(O)R5, -C(O)OR5, -C(O)N(R5)R6, -S(O)2R5, -S(O)2N(R5)R6, -N(R5)R6, -N(R5)C(O)R6, -N(R5)S(O)2R6, -P(O)(R5)R6, C 1-10 Straight or branched alkyl (preferably C 1-4 Straight or branched chain alkyl), C 2-4 Straight or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-10 Straight chain or branched alkoxy (preferably C 1-4 Straight chain or branched chain alkoxy), C 3-7 Cycloalkyl (preferably C 3-5 Cycloalkyl), C 3-7 Cycloalkoxy (preferably C 3-5 The invention also includes 3-7 membered alicyclic groups containing 1-3 ring heteroatoms independently selected from N, O and S, 3-7 membered alicyclic groups containing 1-3 ring heteroatoms independently selected from N, O and S, and 5-11 membered heteroaryl groups containing 1-3 ring heteroatoms independently selected from N, O and S.

[0017] Optionally, the A ring is selected from the following ring structures:

[0018] Optionally, the A ring is selected from the following groups:

[0019] Optionally, the B ring is selected from the following ring structures, or a bicyclic or tricyclic fused aromatic heterocycle formed by the following ring structures themselves or fused with each other or with a benzene ring:

[0020] And the A ring is When the B ring is not the following ring structure:

[0021] Optionally, the B ring is selected from the following groups:

[0022] And the A ring is When the B ring is not the following group:

[0023] Optionally, the C ring is selected from the following ring structures:

[0024] Or the C ring is selected from the condensed ring, bicyclic ring or tricyclic compound formed by the above aromatic ring, alicyclic ring, alicyclic heterocyclic ring or heteroaromatic ring structure (preferably selected from:

[0025] Optionally, the C ring is selected from the following groups:

[0026] Alternatively, L is an optional group, which, when present, is selected from -OCH2-, -CH2O-, -NHCH2-, -CH2NH-, -NHC(O)-, -C(O)NH-, -S(O)2NH-, -NHS(O)2-, -OC(O)NH-, -NHC(O)O-, -CO-,

[0027] Optionally, R1 is selected from: -OH, -OCH3, -NH2, -NHCH3, NHCOCH3, -COOH, -CHF2, -NHS(O)2CH3;

[0028] Optionally, R2, R3 and R4 are selected from: H, F, Cl, Br, -CF3, -CF2H, -CFH2, -CH3, isopropyl, cyclopropyl, -OCH3, -OCH2CH3, -OCF3, -OCF2H, isopropoxy, cyclopropyloxy, OH, C=O, CN, NO2, -C(O)CH3, -C(O)CF3, -SO2CH3, -PO(CH3)2, S(O)(NH)CH3, -C(O)NH2, -S(O)2NH2, phenyl, substituted phenyl, pyrrole, substituted pyrrole, imidazole, substituted imidazole, pyrazole, substituted pyrazole, furan, substituted furan, thiophene, substituted thiophene, oxazole, substituted oxazole , isoxazole, substituted isoxazole, thiazole, substituted thiazole, isothiazole, substituted isothiazole, oxadiazole, substituted oxadiazole, triazole, substituted triazole, the substituent being selected from F, Cl, Br, -CF3, -CF2H, -CFH2, -CH3, ethyl, propyl, isopropyl, cyclopropyl, -OCH3, -OCH2CH3, -OCF3, -OCF2H, isopropoxy, cyclopropyloxy, -OH, -NH2, -CN, -NO2, -C(O)CH3, -C(O)CF3, -SO2CH3, -PO(CH3)2, S(O)(NH)CH3, -C(O)NH2, -S(O)2NH2, -COOH.

[0029] R3 is: -C 1-10 Straight or branched alkylene (preferably C 1-4 Straight or branched alkylene)-NH-C 1-10 Straight or branched alkyl (preferably C 1-4 Straight or branched alkyl), or -C 1-10 Straight or branched alkylene (preferably C 1-4 Straight or branched alkylene)-OC 1-10 Straight or branched alkyl (preferably C 1-4 Straight or branched chain alkyl);

[0030] Optionally, R3 is: -methylene-NH-methyl, or -methylene-O-methyl.

[0031] Optionally, the compound represented by the above formula (I) or its deuterated product, or its pharmaceutically acceptable salt is selected from the following compounds:

[0032]

[0033]

[0034]

[0035]

[0036] Optionally, the pharmaceutically acceptable salt includes anionic salts and cationic salts of the compound represented by formula (I) or its deuterated product;

[0037] Optionally, the pharmaceutically acceptable salt includes an alkali metal salt, an alkaline earth metal salt, or an ammonium salt of the compound represented by formula (I) or its deuterated product; optionally, the alkali metal includes sodium, potassium, lithium, and cesium, and the alkaline earth metal includes magnesium, calcium, and strontium;

[0038] Optionally, the pharmaceutically acceptable salt includes a salt formed by the compound represented by formula (I) or its deuterated product and an organic base;

[0039] Optionally, the organic base includes trialkylamine, pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-alkylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5, 1,8-diazabicyclo[5.4.0]undecene-7, 1,4-diazabicyclo[2.2.2]octane; Optionally, the trialkylamine includes trimethylamine, triethylamine, N-ethyldiisopropylamine; Optionally, the N-alkylmorpholine includes N-methylmorpholine;

[0040] Optionally, the pharmaceutically acceptable salt includes a salt formed by the compound represented by formula (I) or its deuterated product and an acid;

[0041] Optionally, the acid includes an inorganic acid and an organic acid; optionally, the inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; optionally, the organic acid includes formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, glutamic acid, and pamoic acid.

[0042] Another aspect of the present invention provides a pharmaceutical composition, which comprises the compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.

[0043] Another aspect of the present invention provides the use of the compound represented by formula (I) or its deuterated product, or their pharmaceutically acceptable salts, or the above pharmaceutical composition in the preparation of c-Myc inhibitors.

[0044] Another aspect of the present invention provides use of the compound represented by formula (I), a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of a drug for treating c-Myc expression-related tumors.

[0045] Optionally, the tumor is selected from: lung cancer, breast cancer, liver cancer, pancreatic cancer, colorectal cancer, melanoma, bladder cancer, prostate cancer, gastric cancer, esophageal cancer, ovarian cancer, head and neck cancer, urothelial carcinoma, endometrial cancer, thyroid cancer, renal cancer, nasopharyngeal carcinoma, glioma, osteosarcoma, lymphoma, and hematologic malignancy.

[0046] Herein, the compound of formula (I) or a deuterated substance thereof, or a pharmaceutically acceptable salt thereof includes tautomers, mesomers, racemates, enantiomers, diastereomers, or a mixture thereof.

[0047] Beneficial effects:

[0048] The present inventors are committed to developing a novel c-Myc inhibitor, and provide a compound represented by formula (I) or a deuterated product thereof, or a pharmaceutically acceptable salt thereof, which has the ability to significantly inhibit the transcriptional activity of c-Myc, and can significantly inhibit the proliferation of various tumor cells driven by c-Myc, and is used for preventing and / or treating c-Myc-mediated related tumor diseases. DETAILED DESCRIPTION

[0049] The specific embodiments of the present invention are described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate the present invention by way of example and are not used to limit the present invention.

[0050] Compound preparation scheme:

[0051] Synthesis of common intermediates common int-1 and common int-2

[0052]

[0053] Synthesis of 4-((4-chlorobenzyl)oxy)-2-hydroxybenzaldehyde (common int-1):

[0054] Compound 2,4-dihydroxybenzaldehyde (5.0g, 36.20mmol), 4-chlorobenzyl bromide (8.1g, 39.42mmol), sodium bicarbonate (6.1g, 72.61mmol), potassium iodide (0.6g, 3.61mmol) were dissolved in acetonitrile (50.0mL). Stir the reaction at 60℃ for 16 hours. When the reaction was complete, the reaction solution was cooled, water (200.0mL) was added to quench the reaction, and extracted with ethyl acetate (200mL×3). The organic phases were combined, washed with saturated brine (300mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. A white solid (6.5g) was obtained by separation by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1). LC-MS: [M+H] + :263.2.

[0055] Synthesis of 4-((4-chlorobenzyl)oxy)-2-(methoxymethoxy)benzaldehyde (common int-2):

[0056] The compound 4-((4-chlorobenzyl)oxy)-2-hydroxybenzaldehyde (3.0g, 11.42mmol) was dissolved in N,N-dimethylformamide (40.0mL), and N,N-diisopropylethylamine (5.9g, 45.65mmol) was slowly added. After the addition was complete, chloromethyl methyl ether (3.7g, 45.96mmol) was slowly added to the system. The reaction was stirred at room temperature for 18 hours. When the reaction was complete, water (30.0mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (50mL×3), the organic phases were combined, washed with saturated brine (50.0mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Purification by silica gel column chromatography (PE:EA=10:1) gave a colorless oily liquid (3.6g).

[0057] Synthesis of common intermediate common int-3

[0058]

[0059] Synthesis of 3-((4-chlorobenzyl)oxy)phenol (2):

[0060] Resorcinol (500.0 mg, 4.54 mmol), 4-chlorobenzyl bromide (699.8 mg, 3.41 mmol) and potassium carbonate (941.3 mg, 6.81 mmol) were suspended in acetone (10 mL) and reacted at 80°C for 2 hours. The reaction solution was spin-dried and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a colorless oil (330.0 mg). LC-MS: [M+H] + :235.1.

[0061] Synthesis of 2-bromo-5-((4-chlorobenzyl)oxy)phenol (3):

[0062] Dissolve 3-((4-chlorobenzyl)oxy)phenol (330.0 mg, 1.41 mmol) in dichloromethane (50 mL), slowly add N-bromosuccinimide (275.3 mg, 1.55 mmol) in batches under ice bath. React for 2 hours under ice bath, wash the reaction solution with water (20 mL × 2), dry the organic phase, and purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain a colorless oil (280.0 mg). LC-MS: [MH] + :310.7,312.8.

[0063] Synthesis of 5-((4-chlorobenzyl)oxy)-2-boronic acid pinacol ester-phenol (common int-3):

[0064] The compound 2-bromo-5-((4-chlorobenzyl)oxy)phenol (260.0 mg, 0.83 mmol), biboronic acid pinacol ester (253.9 mg, 1.00 mmol), potassium acetate (162.8 mg, 1.66 mmol) and [1,1-bis(diphenylphosphino)ferrocene] palladium dichloride (60.7 mg, 0.084 mmol) were suspended in anhydrous 1,4-dioxane (5 mL), and reacted at 85 ° C for 6 hours under nitrogen protection. The reaction system was diluted with water (8 mL) and extracted with ethyl acetate (8 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product (299.0 mg), which was directly used in the next step. LC-MS: [M+H] + :361.1.

[0065] Example 1 Synthesis of Compound DP001

[0066]

[0067] Synthesis of 4-((4-chlorobenzyl)oxy)-1-ethynyl-2-(methoxymethoxy)benzene (1):

[0068] Dissolve the compound 4-((4-chlorobenzyl)oxy)-2-(methoxymethoxy)benzaldehyde (1.0g, 3.26mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.6g, 8.33mmol) in ethanol (5.0mL), cool the system to 0°C, and slowly add cesium carbonate (3.2g, 9.82mmol). Then warm to room temperature and continue to stir and react for 12 hours. After the reaction is complete, remove the solvent in vacuo, add water (20.0mL) to dilute, and extract with ethyl acetate (20mL×3). Combine the organic phases, wash with saturated brine (20.0mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. Purify by silica gel column chromatography (PE:EA=10:1) to obtain a white solid (500.0mg).

[0069] Synthesis of 4-((4-chlorobenzyl)oxy)-2-(methoxymethoxy)-1-(3-(trifluoromethyl)but-3-en-1-ynyl)benzene (2):

[0070] To a suspension of 4-((4-chlorobenzyl)oxy)-1-ethynyl-2-(methoxymethoxy)benzene (580.0 mg, 1.92 mmol) and 2-bromo-3,3,3-trifluoropropane-1-ene (502.1 mg, 2.87 mmol) in tetrahydrofuran (3.0 mL) were added bis(triphenylphosphine)palladium dichloride (27.0 mg, 0.038 mmol), cuprous iodide (15.2 mg, 0.079 mmol) and triethylamine (1.0 mL) in sequence. The reaction system was stirred at 50 ° C for 12 hours under nitrogen protection. After the reaction was complete, potassium fluoride aqueous solution (10.0 mL) was added to quench the reaction, and the reaction solution was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The product was purified by silica gel column chromatography (PE:EA=10:1) to give a white solid (500.0 mg). Synthesis of N-(4-(4-((4-chlorobenzyl)oxy)-2-(methoxymethoxy)phenyl)-2-(trifluoromethyl)but-3-yn-1-yl)hydroxylamine (3):

[0071] Triethylamine (254.8 mg, 2.52 mmol) was added to a suspension of compound 4-((4-chlorobenzyl)oxy)-2-(methoxymethoxy)-1-(3-(trifluoromethyl)but-3-ene-1-ynyl)benzene (400.0 mg, 1.01 mmol) and hydroxylamine hydrochloride (140.0 mg, 2.01 mmol) in dichloromethane (4.0 mL). The reaction was heated to 40°C and stirred for 3 hours. After the reaction was complete, the solvent was removed under vacuum to obtain a brown oily liquid. Purification by silica gel column chromatography (PE:EA=10:1) gave a colorless oily liquid (340.0 mg). LC-MS: [M+H] + :430.1.

[0072] Synthesis of 2-(4-((4-chlorobenzyl)oxy)-2-(methoxymethoxy)phenyl)-4-(trifluoromethyl)-1H-pyrrole (4):

[0073] The compound N-(4-(4-((4-chlorobenzyl)oxy)-2-(methoxymethoxy)phenyl)-2-(trifluoromethyl)but-3-yn-1-yl)hydroxylamine (414.0 mg, 0.96 mmol), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene][bistrifluoromethanesulfonyl imide]gold (I) (43.3 mg, 0.05 mmol), and bistrifluoromethanesulfonyl imide (108.3 mg, 0.39 mmol) were dissolved in N,N-dimethylformamide (5.0 mL). The reaction was stirred at room temperature under nitrogen protection for 18 hours. When the reaction was complete, water (20.0 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a yellow oily liquid (200.0 mg). LC-MS: [M+H] + :412.1,414.1.

[0074] Synthesis of 5-((4-chlorobenzyl)oxy)-2-(4-(trifluoromethyl)-1H-pyrrol-2-yl)phenol (DP001):

[0075] Add hydrochloric acid ethyl acetate solution (3.0 mL, 2 mol / L) to 2-(4-((4-chlorobenzyl)oxy)-2-(methoxymethoxy)phenyl)-4-(trifluoromethyl)-1H-pyrrole (200.0 mg, 0.49 mmol) and stir at room temperature for 2 hours. After the reaction is complete, concentrate directly to obtain a crude product. The crude product is separated by preparative separation to obtain a white solid (17.1 mg). 1 H NMR (400MHz, DMSO-d6) δ11.36(s,1H),10.13(s,1H),7.50-7.47(m,5H),7.21(s,1H),6.69(s,1H),6.58-6.49(m,2H),5.08(s,2H); LC-MS:[M+H] + :368.1,370.1.

[0076] Example 2 Synthesis of Compound DP002

[0077]

[0078] Synthesis of 2-(4-((4-chlorobenzyl)oxy)-2-(methoxymethoxy)phenyl)-4-(trifluoromethyl)-1H-imidazole (1):

[0079] 3,3-Dibromo-1,1,1-trifluoropropane-2-one (580.8 mg, 2.16 mmol) and sodium acetate (353.2 mg, 4.32 mmol) were dissolved in water (4 mL), and the resulting mixture was stirred at 100 ° C for 0.5 hours, and a mixture of 4-((4-chlorobenzyl)oxy)-2-(methoxymethoxy)benzaldehyde (600.0 mg, 1.96 mmol) and ammonia water (1.2 mL) in methanol (8 mL) was added. The resulting mixture was stirred at room temperature for 12 hours. When the reaction was complete, water (10 mL) was added to quench the reaction, and ethyl acetate was extracted (10 mL×3). The organic phases were combined and washed with saturated brine (10 mL×3), and finally dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. A white solid (440.0 mg) was obtained by column chromatography separation (petroleum ether: ethyl acetate = 3:1). LC-MS: [M+H] + :413.2. Synthesis of 5-((4-chlorobenzyl)oxy)-2-(4-(trifluoromethyl)-1H-imidazol-2-yl)phenol (DP002):

[0080] To a solution of 2-(4-((4-chlorobenzyl)oxy)-2-(methoxymethoxy)phenyl)-4-(trifluoromethyl)-1H-imidazole (100.0 mg, 0.24 mmol) in ethyl acetate (1 mL) was added hydrochloric acid-ethyl acetate (2 mL, 2 mol / L) under stirring, and nitrogen was replaced three times. The mixture was stirred at room temperature for 6 hours until the raw material was completely consumed. The reaction solution was concentrated to obtain a crude product. A white solid (8.0 mg) was obtained by alkaline preparation. 1 H NMR (400MHz, DMSO-d6) δ13.0(s,1H),11.67(s,1H),7.91(s,1H),7.84(d,J= 8.8Hz,1H),7.50-7.45(m,4H),6.66-6.62(m,2H),5.14(s,2H); LC-MS:[M+H] + :369.1.

[0081] Example 3 Synthesis of Compound DP003

[0082]

[0083] Synthesis of 2-(4-((4-chlorobenzyl)oxy)-2-(methoxymethoxy)phenyl)-1-methyl-4-(trifluoromethyl)-1H imidazole (2):

[0084] Dissolve 2-(4-((4-chlorobenzyl)oxy)-2-(methoxymethoxy)phenyl)-4-(trifluoromethyl)-1H-imidazole (300.0 mg, 0.73 mmol) in tetrahydrofuran (3 mL) and cool the system to 0°C. Slowly add sodium hydride (34.9 mg, 0.87 mmol, purity 60%) to the system, continue stirring and reacting at 0°C for 1 hour, then add iodomethane (103.2 mg, 0.73 mmol), then warm to room temperature and continue stirring and reacting for 1 hour. When the reaction is complete, add water (10 mL) to quench the reaction, extract with ethyl acetate (3×10 mL), combine the organic phases, wash with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. Separate by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a colorless oily liquid (130.0 mg). LC-MS: [M+H] + :427.1,429.0.

[0085] Synthesis of 5-((4-chlorobenzyl)oxy)-2-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenol (DP003):

[0086] To a solution of 2-(4-((4-chlorobenzyl)oxy)-2-(methoxymethoxy)phenyl)-1-methyl-4-(trifluoromethyl)-1H-imidazole (120.0 mg, 0.28 mmol) in ethyl acetate (1 mL) was added hydrochloric acid-ethyl acetate (2 mL, 2 mol / L), and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was concentrated to obtain a crude product. A white solid (44.0 mg) was obtained by alkaline preparation. 1 H NMR (400MHz, CDCl3) δ11.65 (s, 1H), 7.46 (d, J = 8.8Hz, 1H), 7.37 (s, 4H), 7.22 (s, 1H), 6. 70(d,J=2.4Hz,1H),6.55(dd,J=8.8,2.4Hz,1H),5.06(s,2H),3.92(s,3H); LC-MS:[M+H] + :383.1,385.1.

[0087] Example 4 Synthesis of Compound DP004

[0088]

[0089] Synthesis of 2-bromo-4-((4-chlorobenzyl)oxy)benzaldehyde (2)

[0090] The compound 2-bromo-4-hydroxybenzaldehyde (3.0g, 14.92mmol), 4-chlorobenzyl bromide (3.06g, 14.89mmol) and potassium carbonate (4.14g, 29.95mmol) were dissolved in N,N-dimethylformamide (30.0mL) and stirred at 120°C for 18 hours. After the reaction was complete, the reaction solution was cooled, water (200.0mL) was added to quench the reaction, and it was extracted with ethyl acetate (3×100mL). The organic phases were combined and washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) gave a white solid (3.1g). LC-MS: [M+H] + :325.0,327.0.

[0091] Synthesis of 2-(2-bromo-4-((4-chlorobenzyl)oxy)phenyl)-4-(trifluoromethyl)-1H-imidazole (3):

[0092] 3,3-Dibromo-1,1,1-trifluoropropane-2-one (5.0 g, 18.53 mmol) and sodium acetate (1.5 g, 18.29 mmol) were dissolved in water (30 mL), and the resulting mixture was stirred at 100 ° C for 0.5 hours. After the reaction solution was cooled to room temperature, 2-bromo-4-((4-chlorobenzyl)oxy)benzaldehyde (3.0 g, 9.21 mmol) in ammonia water (5 mL) / methanol (30 mL) was added. The resulting mixture was stirred at 80 ° C for 3 hours. After the reaction was complete, the reaction solution was concentrated to remove methanol, and then water (30 mL) was added to quench the reaction, extracted with ethyl acetate (3×100 mL), and the organic phases were combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. A light green solid (2.5 g) was obtained by column chromatography separation (petroleum ether: ethyl acetate = 3:1). LC-MS: [M+H] + :431.0,432.9.

[0093] Synthesis of 5-((4-chlorobenzyl)oxy)-2-(4-(trifluoromethyl)-1H-imidazol-2-yl)aniline (DP004):

[0094] 2-(2-bromo-4-((4-chlorobenzyl)oxy)phenyl)-4-(trifluoromethyl)-1H-imidazole (500.0 mg, 1.16 mmol), cuprous iodide (44.0 mg, 0.23 mmol), p-toluenesulfonic acid (220.3 mg, 1.28 mmol) and sodium azide (150.6 mg, 2.32 mmol) were placed in N,N-dimethylacetamide (6 mL) and stirred at 80 ° C for 18 hours under nitrogen protection. LCMS monitored the successful reaction. After cooling the reaction solution, it was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). After combining the organic phases, they were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by preparative purification to obtain a white solid (11.7 mg).

[0095] 1 H NMR(400MHz,DMSO-d6)δ12.76(s,1H),7.80(s,1H),7.60(d,J=8.7Hz,1H),7.47(s,4 H),6.79(s,2H),6.39(s,1H),6.30(dd,J=8.8,2.4Hz,1H),5.07(s,2H); LC-MS:[M+H] + :368.3,370.3.

[0096] Example 5 Synthesis of Compound DP005

[0097]

[0098] Synthesis of 4-((4-chlorobenzyl)oxy)-2-methoxybenzaldehyde (1):

[0099] Compound 4-((4-chlorobenzyl)oxy)-2-hydroxybenzaldehyde (200.0 mg, 0.76 mmol), iodomethane (113.0 mg, 0.79 mmol), potassium carbonate (315.0 mg, 2.28 mmol) were placed in N,N-dimethylformamide (2 mL), heated to 80 ° C and reacted for 2 hours. After the reaction solution was cooled, it was diluted with water (15 mL) and extracted with ethyl acetate (2×15 mL). The combined organic phases were washed with saturated sodium chloride (4×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (0-10% methanol / dichloromethane) to obtain a white solid (190.0 mg). LC-MS: [M+H] + :277.3.

[0100] Synthesis of 2-(4-((4-chlorobenzyl)oxy)-2-methoxyphenyl)-4-(trifluoromethyl)-1H imidazole (DP005):

[0101] Compound 3,3-dibromo-1,1,1-trifluoropropane-2-one (178.0 mg, 0.66 mmol) and sodium acetate (160.0 mg, 1.95 mmol) were dissolved in water (2 mL), heated to 100 ° C and reacted for 0.5 hours. After the reaction solution was cooled to room temperature, 4-((4-chlorobenzyl)oxy)-2-methoxybenzaldehyde (180.0 mg, 0.65 mmol), ammonia (227.0 mg, 6.48 mmol), methanol (2 ml) and N, N-dimethylformamide (2 mL) were added in sequence, and stirring was continued at room temperature for 2 hours. The reaction solution was diluted with water (25 mL) and extracted with ethyl acetate (2×25 mL). The organic phases were combined and washed with saturated brine (2×40 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative high performance liquid chromatography to obtain a white solid (16.4 mg). 1 H NMR(400MHz,DMSO-d6)δ12.17(s,1H),7.94(d,J=8.8Hz,1H),7.67(s,1H),7.49-7.46(m,4H) ,6.80(d,J=2.4Hz,1H),6.73(dd,J=8.8,2.4Hz,1H),5.18(s,2H),3.93(s,3H); LC-MS:[M+H] + :383.0.

[0102] Example 6 Synthesis of Compound DP006

[0103]

[0104] Synthesis of 5-((4-chlorobenzyl)oxy)-2-(1H-imidazol-2-yl)phenol (DP006):

[0105] The compound 4-((4-chlorobenzyl)oxy)-2-hydroxybenzaldehyde (150.0 mg, 0.57 mmol), glyoxal (36.5 mg, 0.63 mmol), and ammonia water (1 mL, 30%) were dissolved in N,N-dimethylformamide (1 mL) and methanol (1 mL). After reacting at 30°C for 2 hours, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with saturated brine (3×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative purification to obtain (12.1 mg). 1 H NMR (400MHz, DMSO-d6) δ13.15 (s, 1H), 12.67 (s, 1H), 7.76 (d, J = 8.4Hz, 1H), 7.5 1-7.44(m,4H),7.25-7.10(m,2H),6.59-6.57(m,2H),5.13(s,2H); LC-MS:[M+H]+ :301.0,302.8.

[0106] Example 7 Synthesis of Compound DP007

[0107]

[0108] Synthesis of 5-((4-chlorobenzyl)oxy)-2-(6-(trifluoromethyl)pyridin-3-yl)phenol (DP007):

[0109] Compound 5-((4-chlorobenzyl)oxy)-2-boronic acid pinacol ester-phenol (140.0 mg, 0.39 mmol), 5-bromo-2-trifluoromethylpyridine (131.6 mg, 0.58 mmol), potassium carbonate (160.9 mg, 1.16 mmol) and tetrakis(triphenylphosphine)palladium (48.3 mg, 0.042 mmol) were suspended in 1,4-dioxane (5 mL) and water (1 mL), and reacted at 110 ° C for 3 hours under nitrogen protection. The system was diluted with water (5 mL) and extracted with ethyl acetate (5 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was acidified to obtain a white solid (26.6 mg). 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),8.90(d,J=1.6Hz,1H),8.19(d,J=9.6Hz,1H),7.89(d,J =8.0Hz,1H),7.48(s,4H),7.36(d,J=8.4Hz,1H),6.68-6.54(m,2H),5.12(s,2H); LC-MS:[M+H] + :380.1.

[0110] Example 8 Synthesis of Compound DP008

[0111]

[0112] Synthesis of 5-((4-chlorobenzyl)oxy)-2-(4-(trifluoromethyl)pyridin-2-yl)phenol (DP008):

[0113] Compound 5-((4-chlorobenzyl)oxy)-2-boronic acid pinacol ester-phenol (140.0 mg, 0.39 mmol), 2-bromo-4-(trifluoromethyl)pyridine (131.6 mg, 0.58 mmol), potassium carbonate (160.9 mg, 1.16 mmol) and tetrakis(triphenylphosphine)palladium (48.3 mg, 0.042 mmol) were suspended in 1,4-dioxane (5 mL) and water (1 mL), and reacted at 110°C for 3 hours under nitrogen protection. The system was diluted with water (5 mL) and extracted with ethyl acetate (5 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was acidified to obtain a white solid (17.6 mg). 1 H NMR (400MHz, DMSO-d6) δ13.45(s,1H),8.83(d,J=5.2Hz,1H),8.42(s,1H),8.13(d,J=8.8Hz, 1H),7.68(d,J=5.2Hz,1H),7.54-7.43(m,4H),6.66-6.56(m,2H),5.17(s,2H); LC-MS:[M+H] + :380.1.

[0114] Example 9 Synthesis of Compound DP009

[0115]

[0116] Synthesis of 6-chloro-4-hydroxynicotinic acid methyl ester (2):

[0117] Compound 6-chloro-4-methoxynicotinic acid methyl ester (3.0 g, 14.88 mmol) and aluminum chloride (5.9 g, 44.24 mmol) were placed in toluene (50 mL) and stirred at 100 ° C for 1 hour. The reaction solution was cooled and concentrated, and 50 mL of saturated sodium carbonate solution was added and stirred for 20 minutes. The reaction solution was extracted with dichloromethane (3×40 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a white solid (1.8 g). LC-MS: [M+H] + :188.0,190.0.

[0118] Synthesis of 6-chloro-4-((4-methoxybenzyl)oxy)nicotinate (3):

[0119] Compound 6-chloro-4-hydroxynicotinic acid methyl ester (1.8 g, 9.60 mmol) and potassium carbonate (2.0 g, 14.47 mmol) were placed in N, N-dimethylformamide (20 mL), 4-methoxybenzyl chloride (2.3 g, 14.69 mmol) was slowly added, and stirred at room temperature for 3 hours. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 4:1 to 1:1) to obtain a white solid (1.2 g). 1 H NMR (400MHz, DMSO-d6) δ8.59(s,1H),7.47(s,1H),7.41(d,J=8.8Hz,2H),6.98(d,J=8.8Hz,2H),5.28(s,2H),3.80(s,3H),3.77(s,3H); LC-MS:[M+H] + :308.1,310.1.

[0120] Synthesis of (6-chloro-4-((4-methoxybenzyl)oxy)pyridin-3-yl)methanol (4):

[0121] Dissolve the compound 6-chloro-4-((4-methoxybenzyl)oxy)nicotinic acid methyl ester (1.2 g, 3.90 mmol) in anhydrous tetrahydrofuran (10 mL), cool to -10 ° C, slowly add lithium aluminum hydride (222.3 mg, 5.86 mmol), and continue stirring at this temperature for 1 hour. The reaction solution is quenched with sodium sulfate decahydrate, filtered, and the filter cake is washed with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated to obtain a white solid (750.0 mg). LC-MS: [M+H] + :280.1,282.1.

[0122] Synthesis of 6-chloro-4-((4-methoxybenzyl)oxy)nicotinaldehyde (5):

[0123] The compound (6-chloro-4-((4-methoxybenzyl)oxy)pyridin-3-yl)methanol (750.0 mg, 2.68 mmol) was dissolved in dichloromethane (10 mL), and Dess-Martin periodinane (2.3 g, 5.42 mmol) was added, and the mixture was reacted at 0°C under nitrogen protection for 2 hours. The reaction solution was diluted with water (10 mL) and extracted with dichloromethane (3×15 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 1:1) to obtain a white solid (450.0 mg). LC-MS: [M+H] + :278.1,280.1.

[0124] Synthesis of 2-chloro-4-((4-methoxybenzyl)oxy)-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)pyridine (6):

[0125] The compound 6-chloro-4-((4-methoxybenzyl)oxy)nicotinaldehyde (450.0 mg, 1.62 mmol), 2-bromo-3,3,3-trifluoropropene (567.0 mg, 3.24 mmol), p-toluenesulfonyl hydrazide (360.8 mg, 1.94 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (738.7 mg, 4.85 mmol) were dissolved in toluene (15 mL) and reacted at 60°C under nitrogen protection for 16 hours. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (petroleum ether: ethyl acetate = 5:1 to 1:1) to obtain a white solid (380.0 mg). LC-MS: [M+H] + :384.1,386.1.

[0126] Synthesis of 2-((4-chlorobenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)pyridine (7):

[0127] Compound 2-chloro-4-((4-methoxybenzyl)oxy)-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)pyridine (150.0 mg, 0.39 mmol), 4-chlorobenzyl alcohol (112.0 mg, 0.79 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (35.3 mg, 0.039 mmol) and cesium carbonate (319.5 mg, 0.98 mmol) were placed in toluene (10 mL) and reacted at 120°C under nitrogen protection for 10 hours. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (petroleum ether: ethyl acetate = 5:1 to 1:1) to obtain a white solid (80.0 mg). LC-MS: [M+H] + :490.1.

[0128] Synthesis of 2-((4-chlorobenzyl)oxy)-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)pyridin-4-ol (DP009):

[0129] The compound 2-((4-chlorobenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)pyridine (80.0 mg, 0.16 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) and triethylsilane (0.2 mL) were added in sequence, and the mixture was reacted at room temperature for 2 hours. After the reaction solution was concentrated, 10 mL of water was added and the pH value was adjusted to alkaline with aqueous ammonia, and then extracted with dichloromethane (3×10 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. A yellow solid (3.2 mg) was obtained by preparative purification. 1 H NMR (400MHz, DMSO-d6) δ8.37(s,1H),7.50-7.40(m,4H),7.02(s,1H),6.33(s,1H),5.34(s,2H); LC-MS:[M+H] + :370.1.

[0130] Example 10 Synthesis of Compound DP010

[0131]

[0132] Synthesis of 5-bromo-2-chloro-4-(2-(trimethylsilyl)ethoxy)pyrimidine (2):

[0133] The compound 2-(trimethylsilyl)ethanol (1.8 g, 15.22 mmol) was dissolved in tetrahydrofuran (40 mL), sodium hydride (631.0 mg, 15.78 mmol, 60% w / w) was added at 0°C and stirred for 1 hour, 5-bromo-2,4-dichloropyrimidine (3.0 g, 13.17 mmol) was added to the reaction solution at 0°C, and the mixture was stirred for 4 hours after warming to room temperature. The reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate (3×40 mL), the organic phases were combined and dried with anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 4:1 to 1:1) to obtain a white solid compound (3.0 g). LC-MS: [M+H] + :309.0,311.0.

[0134] Synthesis of 5-bromo-2-((4-chlorobenzyl)oxy)-4-(2-(trimethylsilyl)ethoxy)pyrimidine (3):

[0135] The compound 4-chlorobenzyl alcohol (1.6 g, 11.22 mmol) was dissolved in tetrahydrofuran (40 mL), sodium hydride (1.5 g, 37.5 mmol, 60% w / w) was added at 0°C and stirred for 1 hour, 5-bromo-2-chloro-4-(2-(trimethylsilyl)ethoxy)pyrimidine (3.0 g, 9.69 mmol) was added to the reaction solution at 0°C and stirred at room temperature for 4 hours. The reaction solution was quenched with saturated ammonium chloride and extracted with ethyl acetate (3×40 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 4:1 to 1:1) to obtain a white solid compound (2.1 g). LC-MS: [M+H] + :415.0,417.0.

[0136] Synthesis of 2-((4-chlorobenzyl)oxy)-4-(2-(trimethylsilyl)ethoxy)pyrimidine-5-carbaldehyde (4):

[0137] The compound 5-bromo-2-((4-chlorobenzyl)oxy)-4-(2-(trimethylsilyl)ethoxy)pyrimidine (1.0 g, 2.41 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and n-butyl lithium (2.5 M, 1.0 mL, 2.5 mmol) was slowly added dropwise at -78 ° C and stirred at -78 ° C for 1 hour. N, N-dimethylformamide (350.0 mg, 4.79 mmol) was added to the reaction solution and stirred at -78 ° C for 1 hour. The reaction solution was quenched with saturated ammonium chloride and extracted with ethyl acetate (3×40 mL). The organic phases were combined and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 4:1 to 2:1) to obtain a white solid compound (400.0 mg). LC-MS: [M+H + ]:365.1,367.1.

[0138] Synthesis of 2-((4-chlorobenzyl)oxy)-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-(2-(trimethylsilyl)ethoxy)pyrimidine (5):

[0139] The compound 2-((4-chlorobenzyl)oxy)-4-(2-(trimethylsilyl)ethoxy)pyrimidine-5-carboxaldehyde (100.0 mg, 0.27 mmol), 2-bromo-3,3,3-trifluoropropene (96.0 mg, 0.55 mmol), p-toluenesulfonyl hydrazide (61.0 mg, 0.33 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (125.0 mg, 0.82 mmol) were dissolved in toluene (10 mL). The mixture was reacted at 60°C under nitrogen protection for 16 hours, 30 mL of water was added, and the mixture was extracted with ethyl acetate (3×30 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and then purified by column chromatography (petroleum ether:ethyl acetate=5:1~1:1) to obtain a white solid compound (50.0 mg). LC-MS: [M+H] + :471.1,473.1.

[0140] Synthesis of 2-((4-chlorobenzyl)oxy)-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)pyrimidin-4-ol (DP010):

[0141] The compound 2-((4-chlorobenzyl)oxy)-5-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-(2-(trimethylsilyl)ethoxy)pyrimidine (50.0 mg, 0.11 mmol) was dissolved in tetrahydrofuran (3 mL), and tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 0.2 mL, 0.2 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated and purified to obtain a white solid compound (15.5 mg). 1 H NMR (400MHz, DMSO-d6) δ13.69(s,1H),13.04(s,1H),8.38(s,1H),7.58-7.42(m,4H),7.13(s,1H),5.44(s,2H); LC-MS:[M+H] + :371.2,373.2.

[0142] Example 11 Synthesis of Compound DP011

[0143]

[0144] Synthesis of 2-chloro-5-iodo-4-((4-methoxybenzyl)oxy)pyridine (2):

[0145] Dissolve methoxybenzyl alcohol (1.1 g, 7.96 mmol) in dimethyl sulfoxide (15 mL), slowly add 60% sodium hydrogen (0.4 g, 10.0 mmol) at room temperature, and react at room temperature for 30 minutes. Add 2,4-dichloro-5-iodopyridine (1.5 g, 5.48 mmol), react at 50 ° C for 1 hour, quench with ice water (50 mL), and extract with ethyl acetate (30 mL × 3). The combined organic phases were washed with water (50 mL) and saturated brine (50 mL), dried, and spin-dried. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain a white solid (1.0 g). LC-MS: [M+H] + :376.2,378.2.

[0146] Synthesis of 2-chloro-4-((4-methoxybenzyl)oxy)-5-((trimethylsilyl)ethynyl)pyridine (3):

[0147] 2-Chloro-5-iodo-4-((4-methoxybenzyl)oxy)pyridine (1.0 g, 2.66 mmol), trimethylethynylsilane (784.5 mg, 7.99 mmol), cuprous iodide (51.4 mg, 0.27 mmol), bistriphenylphosphine palladium dichloride (186.9 mg, 0.27 mmol) and triethylamine (808.3 mg, 7.99 mmol) were suspended in acetonitrile (10 mL) and reacted at 50 ° C for 1 hour under nitrogen protection. The reaction solution was concentrated to obtain a crude product which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid (0.7 g). LC-MS: [M+H] + :346.3,348.3.

[0148] Synthesis of 2-chloro-5-ethynyl-4-((4-methoxybenzyl)oxy)pyridine (4):

[0149] Dissolve 2-chloro-4-((4-methoxybenzyl)oxy)-5-((trimethylsilyl)ethynyl)pyridine (921.0 mg, 2.66 mmol) in acetonitrile (10 mL), add 1M tetrabutylammonium fluoride (5.3 mL, 5.30 mmol) in tetrahydrofuran, and stir at room temperature for 1 hour. Dilute the reaction solution with water (10 mL) and extract with ethyl acetate (10 mL×3). Wash the organic phase with saturated sodium chloride aqueous solution (10 mL), dry, and spin dry. The crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid (225.0 mg). LC-MS: [M+H] + :274.3,276.3.

[0150] Synthesis of 2-chloro-4-((4-methoxybenzyl)oxy)-5-(3-(trifluoromethyl)but-3-en-1-yn-1-yl)pyridine (5):

[0151] 2-Chloro-5-ethynyl-4-((4-methoxybenzyl)oxy)pyridine (190.0 mg, 0.69 mmol), 2-bromo-3,3,3-trifluoropropene (145.7 mg, 0.83 mmol), bistriphenylphosphine palladium dichloride (48.7 mg, 0.069 mmol), cuprous iodide (13.3 mg, 0.070 mmol) and triethylamine (210.7 mg, 2.08 mmol) were suspended in tetrahydrofuran (6 mL) and reacted at 45°C for 18 hours under nitrogen protection. The reaction solution was dried by rotary evaporation and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a white solid (185.0 mg). LC-MS: [M+H] + :368.3,370.4.

[0152] Synthesis of N-(4-(6-chloro-4-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-(trifluoromethyl)but-3-yn-1-yl)hydroxylamine (6):

[0153] Dissolve 2-chloro-4-((4-methoxybenzyl)oxy)-5-(3-(trifluoromethyl)but-3-ene-1-yn-1-yl)pyridine (165.0 mg, 0.45 mmol) and hydroxylamine hydrochloride (62.4 mg, 0.90 mmol) in dichloromethane (10 mL), and add triethylamine (113.5 mg, 1.12 mmol) dropwise at room temperature. Heat the reaction to 40°C and stir for 2 hours. The reaction solution was dried by rotary evaporation, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a white solid (92.0 mg). LC-MS: [M+H] + :401.4,403.4.

[0154] Synthesis of 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (7):

[0155] The compound N-(4-(6-chloro-4-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-(trifluoromethyl)but-3-yn-1-yl)hydroxylamine (80.0 mg, 0.20 mmol), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene][bistrifluoromethanesulfonyl imide]gold (I) (8.6 mg, 0.01 mmol) and bistrifluoromethanesulfonyl imide (22.5 mg, 0.08 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The reaction was stirred at room temperature under nitrogen protection for 18 hours. When the reaction was complete, water (7 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (7 mL×3). The organic phases were combined, washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a white solid (45.0 mg). LC-MS: [M+H] + :383.0,385.0.

[0156] Synthesis of 2-((4-chlorobenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (8):

[0157] 2-Chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (40.0 mg, 0.10 mmol), 4-chlorobenzyl alcohol (17.9 mg, 0.13 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (9.5 mg, 0.01 mmol) and cesium carbonate (102.2 mg, 0.31 mmol) were suspended in toluene (3 mL), reacted at 80°C for 3 hours under nitrogen protection, cooled, diluted with water (5 mL), and extracted with ethyl acetate (5 mL×3). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and prepared on a silica gel plate to obtain a white solid (25.0 mg). LC-MS: [M+H] + :489.1,491.1.

[0158] Synthesis of 2-((4-chlorobenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (PR-03-079):

[0159] 2-((4-chlorobenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (15.0 mg, 0.03 mmol) was dissolved in dichloromethane (1 mL), and triethylsilane (7.0 mg, 0.06 mmol) and trifluoroacetic acid (1 mL) were added dropwise at room temperature, and reacted at room temperature for 1 hour. The reaction solution was spin-dried to obtain a crude product to obtain a white solid (2.5 mg). 1 HNMR(400MHz,MeOD)δ8.09(s,1H),7.45-7.37(m,4H),7.13(s,1H),6.67(s,1H),6.22(s,1H),5.26(s,2H); LC-MS:[M+H] + :369.0,371.0.

[0160] Synthesis of common intermediate common int-4

[0161]

[0162] Synthesis of 2-(4-((4-chlorobenzyl)oxy)-2-(methoxymethoxy)phenyl)-4-(trifluoromethyl)-1H-imidazole (1):

[0163] 3,3-Dibromo-1,1,1-trifluoropropane-2-one (580.8 mg, 2.15 mmol) and sodium acetate (353.2 mg, 4.32 mmol) were dissolved in water (4 mL), and the resulting mixture was stirred at 100 ° C for 0.5 hours, and a mixture of 4-((4-chlorobenzyl)oxy)-2-(methoxymethoxy)benzaldehyde (600.0 mg, 1.96 mmol) and ammonia water (1.2 mL) in methanol (8 mL) was added. The resulting mixture was stirred at room temperature for 12 hours. When the reaction was complete, water (10 mL) was added to quench the reaction, and ethyl acetate was extracted (10 mL×3). The organic phases were combined and washed with saturated brine (10 mL×3), and finally dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. A white solid (440.0 mg) was obtained by column chromatography separation (petroleum ether: ethyl acetate = 3:1). LC-MS: [M+H] + :413.2. Synthesis of common intermediates common int-5 and common int-6

[0164]

[0165] Synthesis of 2-chloro-5-iodo-4-((4-methoxybenzyl)oxy)pyridine (2):

[0166] Dissolve methoxybenzyl alcohol (1.1 g, 7.96 mmol) in dimethyl sulfoxide (15 mL), slowly add 60% sodium hydrogen (0.4 g, 10.0 mmol) at room temperature, and react at room temperature for 30 minutes. Add 2,4-dichloro-5-iodopyridine (1.5 g, 5.48 mmol), react at 50 ° C for 1 hour, quench with ice water (50 mL), and extract with ethyl acetate (30 mL × 3). The combined organic phases were washed with water (50 mL) and saturated brine (50 mL), dried, and spin-dried. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain a white solid (1.0 g). LC-MS: [M+H] + :376.2,378.2.

[0167] Synthesis of 2-chloro-4-((4-methoxybenzyl)oxy)-5-((trimethylsilyl)ethynyl)pyridine (commonint-5):

[0168] 2-Chloro-5-iodo-4-((4-methoxybenzyl)oxy)pyridine (1.0 g, 2.66 mmol), trimethylethynylsilane (784.5 mg, 7.99 mmol), cuprous iodide (51.4 mg, 0.27 mmol), bistriphenylphosphine palladium dichloride (186.9 mg, 0.27 mmol) and triethylamine (808.3 mg, 7.99 mmol) were suspended in acetonitrile (10 mL) and reacted at 50 ° C for 1 hour under nitrogen protection. The reaction solution was concentrated to obtain a crude product which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid (0.7 g). LC-MS: [M+H] + :346.3,348.3.

[0169] Synthesis of 2-chloro-5-ethynyl-4-((4-methoxybenzyl)oxy)pyridine (3):

[0170] Dissolve 2-chloro-4-((4-methoxybenzyl)oxy)-5-((trimethylsilyl)ethynyl)pyridine (921.0 mg, 2.66 mmol) in acetonitrile (10 mL), add 1M tetrabutylammonium fluoride (5.3 mL, 5.30 mmol) in tetrahydrofuran, and stir at room temperature for 1 hour. Dilute the reaction solution with water (10 mL) and extract with ethyl acetate (10 mL×3). Wash the organic phase with saturated sodium chloride aqueous solution (10 mL), dry, and spin dry. The crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid (225.0 mg). LC-MS: [M+H] + :274.3,276.3.

[0171] Synthesis of 2-chloro-4-((4-methoxybenzyl)oxy)-5-(3-(trifluoromethyl)but-3-en-1-yn-1-yl)pyridine (4):

[0172] 2-Chloro-5-ethynyl-4-((4-methoxybenzyl)oxy)pyridine (190.0 mg, 0.69 mmol), 2-bromo-3,3,3-trifluoropropene (145.7 mg, 0.83 mmol), bistriphenylphosphine palladium dichloride (48.7 mg, 0.069 mmol), cuprous iodide (13.3 mg, 0.070 mmol) and triethylamine (210.7 mg, 2.08 mmol) were suspended in tetrahydrofuran (6 mL) and reacted at 45°C for 18 hours under nitrogen protection. The reaction solution was dried by rotary evaporation and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a white solid (185.0 mg). LC-MS: [M+H] + :368.3,370.4.

[0173] Synthesis of N-(4-(6-chloro-4-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-(trifluoromethyl)but-3-yn-1-yl)hydroxylamine (5):

[0174] Dissolve 2-chloro-4-((4-methoxybenzyl)oxy)-5-(3-(trifluoromethyl)but-3-ene-1-yn-1-yl)pyridine (165.0 mg, 0.45 mmol) and hydroxylamine hydrochloride (62.4 mg, 0.90 mmol) in dichloromethane (10 mL), and add triethylamine (113.5 mg, 1.12 mmol) dropwise at room temperature. Heat the reaction to 40°C and stir for 2 hours. The reaction solution was dried by rotary evaporation, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a white solid (92.0 mg). LC-MS: [M+H] + :401.4,403.4.

[0175] Synthesis of 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (commonint-6):

[0176] The compound N-(4-(6-chloro-4-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-(trifluoromethyl)but-3-yn-1-yl)hydroxylamine (80.0 mg, 0.20 mmol), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene][bistrifluoromethanesulfonyl imide]gold (I) (8.6 mg, 0.01 mmol) and bistrifluoromethanesulfonyl imide (22.5 mg, 0.08 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The reaction was stirred at room temperature under nitrogen protection for 18 hours. When the reaction was complete, water (7 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (7 mL×3). The organic phases were combined, washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a white solid (45.0 mg). LC-MS: [M+H] + :383.0,385.0.

[0177] Synthesis of common intermediate common int-7

[0178]

[0179] Synthesis of 5-bromo-2-chloro-4-(2-(trimethylsilyl)ethoxy)pyrimidine (2):

[0180] The compound 2-(trimethylsilyl)ethanol (1.8 g, 15.22 mmol) was dissolved in tetrahydrofuran (40 mL), sodium hydride (631.0 mg, 15.78 mmol, 60% w / w) was added at 0°C and stirred for 1 hour, 5-bromo-2,4-dichloropyrimidine (3.0 g, 13.16 mmol) was added to the reaction solution at 0°C, and the mixture was stirred for 4 hours after warming to room temperature. The reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate (40 mL × 3), the organic phases were combined and dried with anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain a white solid compound (3.0 g). LC-MS: [M+H] + :309.0,311.0.

[0181] Synthesis of 5-bromo-2-((4-chlorobenzyl)oxy)-4-(2-(trimethylsilyl)ethoxy)pyrimidine (common int-7):

[0182] The compound 4-chlorobenzyl alcohol (1.6 g, 11.22 mmol) was dissolved in tetrahydrofuran (40 mL), sodium hydride (1.5 g, 37.5 mmol, 60% w / w) was added at 0°C and stirred for 1 hour, 5-bromo-2-chloro-4-(2-(trimethylsilyl)ethoxy)pyrimidine (3.0 g, 9.69 mmol) was added to the reaction solution at 0°C and stirred at room temperature for 4 hours. The reaction solution was quenched with saturated ammonium chloride and extracted with ethyl acetate (40×3 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 4:1 to 1:1) to obtain a white solid compound (2.1 g). LC-MS: [M+H] + :415.0,417.0.

[0183] Synthesis of common intermediate common int-8

[0184]

[0185] Synthesis of tert-butyl 2-(6-chloro-4-((4-methoxybenzyl)oxy)pyridin-3-yl)-4-(trifluoromethyl)-1H-pyrrole-1-carboxylate:

[0186] Dissolve 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (999.0 mg, 2.61 mmol) in dichloromethane (20 mL), cool in an ice bath, add di-tert-butyl dicarbonate (685.3 mg, 3.14 mmol), and then add 4-dimethylaminopyridine (68.3 mg, 0.56 mmol). The reaction solution was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The reaction solution was directly concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a light yellow solid (1.2 g). LC-MS: [M+H] + :483.1,485.1.

[0187] Synthesis of common intermediate common int-9

[0188]

[0189] Synthesis of tert-butyl 2-(4-((4-methoxybenzyl)oxy)-6-vinylpyridin-3-yl)-4-(trifluoromethyl)-1H-pyrrole-1-carboxylate (common int-9):

[0190] Dissolve tert-butyl 2-(6-chloro-4-((4-methoxybenzyl)oxy)pyridin-3-yl)-4-(trifluoromethyl)-1H-pyrrole-1-carboxylate (48.3 mg, 0.10 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL), then add potassium vinyl trifluoroborate (28.1 mg, 0.21 mmol), cesium carbonate (84.7 mg, 0.26 mmol) and [1,1-bis(diphenylphosphino)ferrocene] palladium dichloride (7.3 mg, 0.01 mmol), react in an oil bath at 95°C under nitrogen protection for 3 hours, concentrate the reaction solution, dilute with water (10 mL), extract with ethyl acetate (10 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate to dryness. Purify by thin layer preparative separation (petroleum ether: ethyl acetate = 4:1) to obtain a white solid (46.0 mg). LC-MS: [M+H] + :475.2.

[0191] Synthesis of common intermediate common int-10

[0192]

[0193] Synthesis of (Z)-3-chloro-N',4-dihydroxy-5-methylbenzamidine (2):

[0194] Dissolve the compound 3-chloro-4-hydroxy-5-methylbenzonitrile (300.0 mg, 1.79 mmol) and hydroxylamine hydrochloride (248.1 mg, 3.57 mmol) in ethanol (5 mL), add N,N-diisopropylethylamine (696.6 mg, 5.39 mmol), and heat the reaction solution to 80°C for 16 hours. After the reaction is completed, concentrate the reaction solution to dryness, pour into aqueous solution (30 mL), and then extract with ethyl acetate (40 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate to dryness to obtain a crude brown solid (220.7 mg). LC-MS: [M+H] + :201.1,203.1.

[0195] Synthesis of ethyl 3-(3-chloro-4-hydroxy-5-methylphenyl)-1,2,4-oxadiazole-5-carboxylate (common int-10):

[0196] Dissolve compound (Z)-3-chloro-N',4-dihydroxy-5-methylbenzamidine (220.7 mg, 1.10 mmol) in pyridine (1 mL), slowly dropwise add ethyl oxalyl chloride (166.6 mg, 1.22 mmol), and heat the reaction system to 60°C and stir for 2 hours. After the reaction is completed, concentrate the reaction solution to dryness, pour into aqueous solution (10 mL), and then extract with ethyl acetate (10 mL×3). Combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate to dryness, and purify by chromatography column (petroleum ether: ethyl acetate = 10:1) to obtain a white solid (270.0 mg). LC-MS: [M+H] + :283.3,285.3.

[0197] Example 12 Synthesis of Compound M45

[0198]

[0199] Synthesis of 5-ethynyl-4-methoxypicolinic acid methyl ester (2):

[0200] To a solution of 5-bromo-4-methoxypicolinic acid methyl ester (2.5g, 10.16mmol) in N,N-dimethylformamide (20mL) were added cuprous iodide (1.9g, 9.98mmol), ethynyltrimethylsilane (1.0g, 10.18mmol), triethylamine (2mL) and bis(triphenylphosphine)palladium dichloride (710.0mg, 1.01mmol) in sequence. Under nitrogen protection, the mixture was heated to 80°C and stirred for 16 hours. After the reaction was complete, the reaction solution was cooled, water (200.0mL) was added to quench the reaction, and extracted with ethyl acetate (200mL×3). The organic phases were combined, washed with saturated brine (300mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. A white solid (520.0mg) was obtained by separation by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1). LC-MS: [M+H] + :192.1. Synthesis of methyl 4-methoxy-5-(3-(trifluoromethyl)but-3-ene-1-yn-1-yl)picolinate (3):

[0201] To a suspension of 5-ethynyl-4-methoxypicolinic acid methyl ester (367.0 mg, 1.92 mmol) and 2-bromo-3,3,3-trifluoroprop-1-ene (502.1 mg, 2.87 mmol) in tetrahydrofuran (3.0 mL) were added di(triphenylphosphine)palladium dichloride (27.0 mg, 0.038 mmol), cuprous iodide (15.2 mg, 0.08 mmol) and triethylamine (1.0 mL) in sequence. The reaction system was stirred at 50 ° C for 12 hours under nitrogen protection. After the reaction was complete, potassium fluoride aqueous solution (10.0 mL) was added to quench the reaction, and the reaction solution was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) gave a white solid (438.0 mg). LC-MS: [M+H] + :286.1. Synthesis of methyl 4-methoxy-5-(4,4,4-trifluoro-3-((hydroxyamino)methyl)but-1-yn-1-yl)picolinate (4):

[0202] Triethylamine (254.8 mg, 2.52 mmol) was added to a suspension of compound 4-methoxy-5-(3-(trifluoromethyl)but-3-ene-1-yn-1-yl)picolinic acid methyl ester (288.0 mg, 1.01 mmol) and hydroxylamine hydrochloride (140.0 mg, 2.01 mmol) in dichloromethane (4.0 mL). The reaction was heated to 40°C and stirred for 3 hours. After the reaction was complete, the solvent was removed under vacuum to obtain a brown oily liquid. Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) gave a colorless oily liquid (290.0 mg). LC-MS: [M+H] + :319.1.

[0203] Synthesis of methyl 4-methoxy-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)picolinate (5):

[0204] Compound 4-methoxy-5-(4,4,4-trifluoro-3-((hydroxyamino)methyl)but-1-yn-1-yl)picolinic acid methyl ester (152.6mg, 0.48mmol), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene][bistrifluoromethanesulfonyl imide]gold (I) (21.7mg, 0.025mmol), bistrifluoromethanesulfonyl imide (54.1mg, 0.19mmol) were placed in N,N-dimethylformamide (5.0mL) and stirred at room temperature under nitrogen protection for 18 hours. After the reaction was complete, water (20.0mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (20mL×3). The organic phases were combined, washed with saturated brine (20.0mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a yellow oily liquid (73.4 mg). LC-MS: [M+H] + :301.1.

[0205] Synthesis of N-(4-chlorophenyl)-4-methoxy-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)picolinamide (6):

[0206] 4-Methoxy-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)picolinic acid methyl ester (40.0 mg, 0.13 mmol) and 4-chloroaniline (50.8 mg, 0.40 mmol) were dissolved in toluene (10 mL), stirred at 80 ° C for 0.5 hours under nitrogen protection, and trimethylaluminum (0.4 mL, 0.4 mmol, 1 M) was added thereto. The mixture was stirred at 80 ° C for 16 hours until the raw material disappeared completely. The reaction mixture was cooled to room temperature and concentrated in vacuo, and the residue was purified by silica gel column (dichloromethane: methanol = 20: 1) to give a yellow solid (45.0 mg). LC-MS: [M+H] + :396.2.

[0207] Synthesis of N-(4-chlorophenyl)-4-hydroxy-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)picolinamide (M45):

[0208] Dissolve N-(4-chlorophenyl)-4-methoxy-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)picolinamide (45.0 mg, 0.11 mmol) and trimethylsilyl iodide (240.0 mg, 1.19 mmol) in anhydrous acetonitrile (5 mL), and then stir the mixture at 80 ° C for 4 hours. TLC detected that the raw material reaction was complete. Dilute the reaction solution with water (20 mL) and extract with ethyl acetate (20 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain a yellow solid (9.1 mg). 1 H NMR (400MHz, DMSO) δ11.90 (s, 2H), 10.70 (s, 1H), 8.83 (s, 1H), 7.94 (d, J = 7.6Hz, 2H), 7.71 (s, 1H), 7.43-7.41 (m, 3H), 7.08 (s, 1H); LC-MS: [M+H] + :382.0.

[0209] Example 13 Synthesis of Compound M63

[0210]

[0211] Synthesis of (2-trifluoromethyl-pyridin-4-yl)-methanol (2):

[0212] The compound 2-(trifluoromethyl)isonicotinic acid (600.0 mg, 3.14 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and 1M borane-tetrahydrofuran solution (6.28 mL, 6.28 mmol) was slowly added dropwise under nitrogen protection at 0°C, and reacted for 4 hours under nitrogen protection at 70°C. The mixture was quenched with ice water, extracted with ethyl acetate (10 mL×3), the organic phases were combined and dried with anhydrous sodium sulfate, and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain an anhydrous oily compound (390.0 mg). LC-MS: [MH] - :176.2.

[0213] Synthesis of 4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)-2-((2-(trifluoromethyl)pyridin-4-yl)methoxy)pyridine (3):

[0214] The compound 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (175.7 mg, 0.46 mmol), (2-trifluoromethyl-pyridin-4-yl)-methanol (161.9 mg, 0.91 mmol), cesium carbonate (446.6 mg, 1.37 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (41.4 mg, 0.046 mmol) was dissolved in toluene (6 mL), reacted at 90° C. under nitrogen protection for 3 hours, concentrated and purified by column chromatography (petroleum ether:ethyl acetate=25:1) to obtain a yellow solid compound (52.0 mg). LC-MS: [M+H] + :524.1.

[0215] Synthesis of 5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)-2-((2-(trifluoromethyl)pyridin-4-yl)methoxy)pyridin-4-ol (M63):

[0216] The compound 4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)-2-((2-(trifluoromethyl)pyridin-4-yl)methoxy)pyridine (50.0 mg, 0.096 mmol) was dissolved in dichloromethane (0.5 mL), and triethylsilane (0.3 mL) and trifluoroacetic acid (0.3 mL) were added in sequence. The mixture was stirred at room temperature for 3 hours, 1 mL of ammonia water and 5 mL of water were added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to obtain a white solid compound (7.6 mg). 1 H NMR (400MHz, DMSO) δ11.58(s,1H),8.75(d,J=4.8Hz,1H),8.25(s,1H),8.14(s,1H),7.92(s, 1H),7.73(d,J=4.8Hz,1H),7.30(s,1H),6.74(s,1H),6.42(s,1H),5.51(s,2H); LC-MS:[M+H] + :404.1.

[0217] Example 14 Synthesis of Compound M44

[0218]

[0219] Synthesis of 4-chloro-N-(4-((4-methoxybenzyl)oxy)-5-((trimethylsilyl)ethynyl)pyridin-2-yl)benzamide (1):

[0220] The compound 2-chloro-4-((4-methoxybenzyl)oxy)-5-((trimethylsilyl)ethynyl)pyridine (692.0 mg, 2.00 mmol), 4-chlorobenzamide (311.2 mg, 2.00 mmol), palladium acetate (44.9 mg, 0.20 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (124.5 mg, 0.20 mmol) and potassium carbonate (827.0 mg, 5.98 mmol) were suspended in dioxane (10 mL) and reacted at 100° C. for 4 hours under nitrogen protection. The reaction solution was dried by rotary evaporation, and the crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid (400.0 mg). LC-MS: [M+H] + :465.2,467.2.

[0221] Synthesis of 4-chloro-N-(5-ethynyl-4-((4-methoxybenzyl)oxy)pyridin-2-yl)benzamide (2):

[0222] The compound 4-chloro-N-(4-((4-methoxybenzyl)oxy)-5-((trimethylsilyl)ethynyl)pyridin-2-yl)benzamide (390.0 mg, 0.84 mmol) was dissolved in acetonitrile (5 mL), and 1M tetrabutylammonium fluoride tetrahydrofuran solution (1.5 mL, 1.5 mmol) was added. The mixture was reacted at room temperature for 1 hour, and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL×3). The organic phase was washed with saturated sodium chloride aqueous solution (10 mL), dried, and spin-dried. The crude product was prepared by formic acid reverse phase to obtain a white solid (160.0 mg). LC-MS: [M+H] + :393.4,395.4.

[0223] Synthesis of 4-chloro-N-(4-((4-methoxybenzyl)oxy)-5-(3-(trifluoromethyl)but-3-en-1-yn-1-yl)pyridin-2-yl)benzamide (3):

[0224] The compound 4-chloro-N-(5-ethynyl-4-((4-methoxybenzyl)oxy)pyridin-2-yl)benzamide (150.0 mg, 0.38 mmol), 2-bromo-3,3,3-trifluoropropene (80.5 mg, 0.46 mmol), bis(triphenylphosphine)palladium(II) dichloride (26.8 mg, 0.038 mmol), cuprous iodide (7.3 mg, 0.038 mmol) and triethylamine (115.9 mg, 1.15 mmol) were suspended in tetrahydrofuran (8 mL) and reacted at 45° C. for 18 hours under nitrogen protection. The reaction solution was dried by rotary evaporation, and the crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a white solid (100.0 mg). LC-MS: [M+H]+ :487.4,489.4.

[0225] Synthesis of 4-chloro-N-(4-((4-methoxybenzyl)oxy)-5-(4,4,4-trifluoro-3-((hydroxyamino)methyl)but-1-yn-1-yl)pyridin-2-yl)benzamide (4):

[0226] The compound 4-chloro-N-(4-((4-methoxybenzyl)oxy)-5-(3-(trifluoromethyl)but-3-ene-1-yn-1-yl)pyridin-2-yl)benzamide (85.0 mg, 0.17 mmol) and hydroxylamine hydrochloride (24.3 mg, 0.35 mmol) were dissolved in dichloromethane (0.5 mL), and triethylamine (44.5 mg, 0.44 mmol) was added dropwise. The mixture was reacted at 40°C for 2 hours, and the solvent was removed under vacuum to obtain a brown oily liquid. The mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a colorless oily liquid (50.0 mg). LC-MS: [M+H] + :520.5,522.4.

[0227] Synthesis of 4-chloro-N-(4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)benzamide (5):

[0228] Compound 4-chloro-N-(4-((4-methoxybenzyl)oxy)-5-(4,4,4-trifluoro-3-((hydroxyamino)methyl)but-1-yn-1-yl)pyridin-2-yl)benzamide (45.0 mg, 0.086 mmol), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene][bistrifluoromethanesulfonyl imide]gold (I) (3.7 mg, 0.0043 mmol) and trifluoromethanesulfonamide (5.2 mg, 0.035 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). The reaction was stirred at room temperature under nitrogen protection for 18 hours. When the reaction was complete, water (5 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (5 mL×3). The organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a white solid (30.0 mg). LC-MS: [M+H] + :502.2,504.1.

[0229] Synthesis of 4-chloro-N-(4-hydroxy-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)benzamide (M44):

[0230] The compound 4-chloro-N-(4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)benzamide (30.0 mg, 0.06 mmol) was dissolved in dichloromethane (0.5 mL), and triethylsilane (10.0 mg, 0.086 mmol) and TFA (1 mL) were added dropwise. The reaction was carried out at room temperature for 1 hour. The reaction solution was dried by rotary evaporation, and the crude product was subjected to reverse phase preparation (ammonium bicarbonate) to obtain a white solid (7.1 mg). 1 H NMR(400MHz,DMSO)δ11.70(s,1H),11.45(s,1H),10.81(s,1H),8.49(s,1H),8. 03-7.70(m,3H),7.59(d,J=8.4Hz,2H),7.32(s,1H),6.84(s,1H); LC-MS:[M+H] + :382.1,384.1.

[0231] Example 15 Synthesis of Compound M62

[0232]

[0233] Synthesis of 2-((3-fluoro-4-(trifluoromethyl)benzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (1):

[0234] The compounds 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (50.0 mg, 0.13 mmol), (3-fluoro-4-(trifluoromethyl)phenyl)methanol (38.8 mg, 0.20 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (11.8 mg, 0.013 mmol), and cesium carbonate (85.1 mg, 0.26 mmol) were dissolved in toluene (1 mL), the temperature was raised to 80° C. and stirred for 3 hours. LCMS monitored that the raw materials had reacted completely. Water (10 mL) was added to the reaction solution to dilute it, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 0-25%) to obtain a yellow solid (50.0 mg). LC-MS: [M+H] + :541.1.

[0235] Synthesis of 2-((3-fluoro-4-(trifluoromethyl)benzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (M62):

[0236] Compound 2-((3-fluoro-4-(trifluoromethyl)benzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (40.0 mg, 0.074 mmol) and triethylsilane (31.5 mg, 0.27 mmol) were dissolved in dichloromethane (1 mL), 4M hydrochloric acid dioxane solution (0.2 mL, 0.80 mmol) was added dropwise to the reaction solution, and stirred at room temperature for 4 hours. LCMS monitored that the raw material had basically reacted, saturated sodium bicarbonate (5 mL) was added to the reaction solution to quench, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (20 mL×3), the combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the crude product was spin-dried to obtain a yellow solid (3.1 mg). 1 H NMR (400MHz, DMSO) δ11.68(s,1H),8.24(s,1H),7.79(t,J=8.0Hz,1H),7.55(d,J=11.6Hz,1 H),7.46(d,J=8.0Hz,1H),7.29(s,1H),6.72(s,1H),6.34(s,1H),5.43(s,2H); LC-MS:[M+H] + :421.3.

[0237] Example 16 Synthesis of Compound M35

[0238]

[0239] Synthesis of 2-((4-chlorobenzyl)oxy)-4-(2-(trimethylsilyl)ethoxy)-5-((trimethylsilyl)ethynyl)pyrimidine (1):

[0240] The compound 5-bromo-2-((4-chlorobenzyl)oxy)-4-(2-(trimethylsilyl)ethoxy)pyrimidine (500.0 mg, 1.20 mmol), ethynyltrimethylsilane (141.4 mg, 1.44 mmol), triethylamine (486.7 mg, 4.81 mmol), cuprous iodide (22.9 mg, 0.12 mmol) and bis(triphenylphosphine)palladium dichloride (84.4 mg, 0.12 mmol) were dissolved in acetonitrile (8 mL), and the temperature was raised to 80°C for 4 hours. Water (40 mL) was added to the reaction solution for dilution, and ethyl acetate was used for extraction (40 mL×3). The organic phases were combined and washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain a red oil (480.0 mg). LC-MS: [M+H] + :433.1,435.1.

[0241] Synthesis of 2-((4-chlorobenzyl)oxy)-5-ethynyl-4-(2-(trimethylsilyl)ethoxy)pyrimidine (2):

[0242] The compound 2-((4-chlorobenzyl)oxy)-4-(2-(trimethylsilyl)ethoxy)-5-((trimethylsilyl)ethynyl)pyrimidine (459.0 mg, 1.06 mmol) and potassium carbonate (176.9 mg, 1.28 mmol) were dissolved in methanol (7 mL) and tetrahydrofuran (7 mL). After stirring at room temperature for 1 hour, the reaction solution was filtered to remove potassium carbonate. The filtrate was dried by oil pump at room temperature, and water (20 mL) was added to dilute it. The aqueous phase was extracted with ethyl acetate (30 mL×3), and the organic phases were combined and washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and dried to obtain a crude product. A red oil (298.0 mg) was obtained by silica gel column (petroleum ether: ethyl acetate = 20:1). LC-MS: [M+H] + :361.0,363.0.

[0243] Synthesis of 2-((4-chlorobenzyl)oxy)-5-(3-(trifluoromethyl)but-3-en-1-yn-1-yl)-4-(2-(trimethylsilyl)ethoxy)pyrimidine (3):

[0244] The compound 2-((4-chlorobenzyl)oxy)-5-ethynyl-4-(2-(trimethylsilyl)ethoxy)pyrimidine (270.0 mg, 0.75 mmol), 2-bromo-3,3,3-trifluoropropene (169.7 mg, 0.97 mmol), triethylamine (302.5 mg, 2.99 mmol), cuprous iodide (15.2 mg, 0.08 mmol) and bis(triphenylphosphine)palladium dichloride (52.6 mg, 0.075 mmol) were dissolved in acetonitrile (4 mL), heated to 80°C for 2 hours, and then diluted with water (40 mL), extracted with ethyl acetate (40 mL×3), and the combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain a colorless oil (131.0 mg). LC-MS: [M+H] + :455.1,457.1.

[0245] Synthesis of N-(4-(2-((4-chlorobenzyl)oxy)-4-(2-(trimethylsilyl)ethoxy)pyrimidin-5-yl)-2-(trifluoromethyl)but-3-yn-1-yl)hydroxylamine (4):

[0246] The compound 2-((4-chlorobenzyl)oxy)-5-(3-(trifluoromethyl)but-3-ene-1-yn-1-yl)-4-(2-(trimethylsilyl)ethoxy)pyrimidine (118.3 mg, 0.26 mmol), hydroxylamine hydrochloride (36.8 mg, 0.53 mmol) and triethylamine (66.7 mg, 0.66 mmol) were dissolved in dichloromethane (3 mL). After stirring at 40°C for 4 hours, the reaction solution was diluted with water (10 mL), extracted with dichloromethane (10 mL×3), and the combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain a colorless oil (92.0 mg). LC-MS: [M+H] + :488.2,490.2.

[0247] Synthesis of 2-((4-chlorobenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)-4-(2-(trimethylsilyl)ethoxy)pyrimidine (5):

[0248] The compound N-(4-(2-((4-chlorobenzyl)oxy)-4-(2-(trimethylsilyl)ethoxy)pyrimidin-5-yl)-2-(trifluoromethyl)but-3-yn-1-yl)hydroxylamine (83.0 mg, 0.17 mmol), trifluoromethanesulfonamide (28.3 mg, 0.19 mmol) and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene][bistrifluoromethanesulfonyl imide]gold (I) (7.4 mg, 0.0085 mmol) were dissolved in N,N-dimethylformamide (3 mL). After stirring at room temperature for 8 hours, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 20:1) to obtain a colorless oil (68.0 mg). LC-MS: [M+H] + :470.1,472.1.

[0249] Synthesis of 2-((4-chlorobenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyrimidin-4-ol (M35):

[0250] The compound 2-((4-chlorobenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)-4-(2-(trimethylsilyl)ethoxy)pyrimidine (51.7 mg, 0.11 mmol) and tetrabutylammonium fluoride (138.5 mg, 0.53 mmol) were dissolved in tetrahydrofuran (2 mL) and heated to 50°C for 5 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL×3), and the combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product, which was purified by silica gel column (ethyl acetate: petroleum ether = 20:1) to obtain a white solid (22.6 mg). 1 H NMR (400MHz, DMSO) δ12.84(s,1H),11.69(s,1H),8.23(s,1H),7.52-7.45(m,4H),7.28(s,1H),6.89(s,1H),5.39(s,2H); LC-MS:[M+H] + :370.1,372.0.

[0251] Example 17 Synthesis of Compound DP017

[0252]

[0253] Synthesis of 2-((4-chlorobenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (1):

[0254] Compound (4-chlorophenyl)methanol (200.0 mg, 1.40 mmol) was dissolved in toluene (20 mL), and 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (500.0 mg, 1.31 mmol), cesium carbonate (1143.6 mg, 3.51 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6 '-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (127.2 mg, 0.14 mmol), heated at 100°C under nitrogen protection for 10 hours, concentrated the reaction solution, added water (30 mL), extracted with ethyl acetate (30 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain a yellow solid (363.0 mg). LC-MS: [M+H] + :489.1,491.1.

[0255] Synthesis of 5-(5-chloro-4-(trifluoromethyl)-1H-pyrrol-2-yl)-2-((4-chlorobenzyl)oxy)-4-((4-methoxybenzyl)oxy)pyridine (2):

[0256] 2-((4-chlorobenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (100.0 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (1 mL), and N-chlorosuccinimide (41.4 mg, 0.31 mmol) was added at -78°C. After stirring for 5 minutes, the mixture was gradually warmed to room temperature and stirred for 10 hours. The reaction solution was concentrated, and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL×3). The organic phase was washed with sodium chloride aqueous solution (10 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and separated by thin layer preparation (petroleum ether: ethyl acetate = 4:1) to obtain a transparent oily liquid (100.0 mg). LC-MS: [M+H] + :523.0,525.0.

[0257] Synthesis of 5-(5-chloro-4-(trifluoromethyl)-1H-pyrrol-2-yl)-2-((4-chlorobenzyl)oxy)pyridin-4-ol (DP017):

[0258] The compound 5-(5-chloro-4-(trifluoromethyl)-1H-pyrrol-2-yl)-2-((4-chlorobenzyl)oxy)-4-((4-methoxybenzyl)oxy)pyridine (100.0 mg, 0.19 mmol) was dissolved in dichloromethane (1 mL), and triethylsilane (0.2 mL) was added. Trifluoroacetic acid (1 mL) was added at 0°C and reacted at room temperature for 1 hour. The reaction solution was concentrated and quenched with aqueous sodium bicarbonate solution. The pH was adjusted to neutral, and water (10 mL) and dichloromethane (10 mL×3) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and prepared by separation to obtain a white solid (2.7 mg). 1 H NMR (400MHz, Methanol-d4) δ8.21 (s, 1H), 7.45 (d, J = 8.4Hz, 2H), 7.39 (d, J = 8.4Hz, 2H), 7.18 (d, J = 1.2Hz, 1H), 6.22 (s, 1H), 5.28 (s, 2H); LC-MS: [M+H] + :402.8,404.8.

[0259] Example 18 Synthesis of Compound DP018

[0260]

[0261] Synthesis of 2-((4-chlorobenzyl)oxy)-5-(3,5-dichloro-4-(trifluoromethyl)-1H-pyrrol-2-yl)-4-((4-methoxybenzyl)oxy)pyridine (1):

[0262] 2-((4-chlorobenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (88.0 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (1 mL), N-chlorosuccinimide (73.7 mg, 0.55 mmol) was added at 0°C, the mixture was slowly heated to room temperature and stirred for 10 hours, the reaction solution was concentrated, water (10 mL) was added, ethyl acetate (10 mL × 3) was extracted, the organic phase was washed with sodium chloride aqueous solution (10 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and separated by thin layer preparation (petroleum ether: ethyl acetate = 4:1) to obtain a transparent oily liquid (65.0 mg). LC-MS: [M+H] + :557.1,559.1.

[0263] Synthesis of 2-((4-chlorobenzyl)oxy)-5-(3,5-dichloro-4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (DP018):

[0264] 2-((4-chlorobenzyl)oxy)-5-(3,5-dichloro-4-(trifluoromethyl)-1H-pyrrol-2-yl)-4-((4-methoxybenzyl)oxy)pyridine (61.3 mg, 0.11 mmol) was dissolved in dichloromethane (1Ml), and triethylsilane (1Ml) was added. Trifluoroacetic acid (1Ml) was added at 0°C and reacted at room temperature for 20 minutes. The reaction solution was concentrated and quenched with aqueous sodium bicarbonate solution. The Ph was adjusted to neutral, and water (10 ml) and dichloromethane (10Ml×3) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and prepared by separation to obtain a white solid (19.1 mg). 1 H NMR (400MHz, DMSO-d6) δ12.86(s,1H),11.23(s,1H),7.98(s,1H),7.64-7.35(m,4H),6.34(s,1H),5.34(s,2H); LC-MS:[M+H] + :437.0,439.0.

[0265] Example 19 Synthesis of Compound DP019

[0266]

[0267] Synthesis of (4-chloro-3,5-difluorophenyl)methanol (2):

[0268] The compound 4-chloro-3,5-difluorobenzaldehyde (500.0 mg, 2.83 mmol) was dissolved in methanol (5 mL), and sodium borohydride (214.1 mg, 5.66 mmol) was added to react at room temperature for 20 minutes. After the reaction was completed, the reaction solution was concentrated, extracted with water (30 mL) and ethyl acetate (30 mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white solid (328.0 mg), which was directly used in the next step.

[0269] Synthesis of 2-((4-chloro-3,5-difluorobenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (3):

[0270] Compound (4-chloro-3,5-difluorophenyl)methanol (100.0 mg, 0.56 mmol) was dissolved in toluene (10 mL) and then 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (214.4 mg, 0.56 mmol), cesium carbonate (456.2 mg, 1.40 mmol) and methanesulfonic acid (2-dicyclohexyl) were added. 1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (50.8 mg, 0.056 mmol), reacted in an oil bath at 100°C under nitrogen protection for 12 hours, concentrated the reaction solution, extracted with water (30 mL) and ethyl acetate (30 mL × 3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated. Purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain a white oily liquid (150.0 mg). LC-MS: [M+H] + :525.1,527.1.

[0271] Synthesis of 2-((4-chloro-3,5-difluorobenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (DP019):

[0272] The compound 2-((4-chloro-3,5-difluorobenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (147.0 mg, 0.28 mmol) was dissolved in dichloromethane (6 Ml), and triethylsilane (0.3 Ml) was added. Trifluoroacetic acid (1.5 Ml) was added at 0°C, and the mixture was reacted for 30 minutes at room temperature. The reaction solution was concentrated, and the pH was adjusted to neutral with sodium bicarbonate aqueous solution, and water (30 Ml) and dichloromethane (30 Ml×3) were added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. A white solid (11.0 mg) was obtained by preparative separation. 1 H NMR (400MHz, DMSO-d6) δ11.61(s,1H),11.37(s,1H),8.26(s,1H),7.40(d,J= 8.4Hz,2H),7.30(s,1H),6.73(s,1H),6.35(s,1H),5.34(s,2H); LC-MS:[M+H] + :405.1,407.1.

[0273] Example 20 Synthesis of Compound DP020

[0274]

[0275] Synthesis of (4-chloro-3-methylphenyl)methanol (2):

[0276] The compound 4-chloro-3-methylbenzaldehyde (499.0 mg, 3.23 mmol) was dissolved in methanol (5 mL), and sodium borohydride (244.8 mg, 6.47 mmol) was added to react at room temperature for 20 minutes. After the reaction was completed, the reaction solution was concentrated, and water (30 mL) and ethyl acetate (30 mL×3) were added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white oily liquid (419.0 mg), which was directly used in the next step reaction.

[0277] Synthesis of 2-((4-chloro-3-methylbenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (3):

[0278] The compound (4-chloro-3-methylphenyl)methanol (100.2 mg, 0.64 mmol) was dissolved in toluene (10 mL), and 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (245.0 mg, 0.64 mmol), cesium carbonate (521.3 mg, 1.60 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (57.9 mg, 0.064 mmol) were added. The reaction was carried out in an oil bath at 100°C under nitrogen protection for 12 hours. The reaction solution was concentrated, extracted with water (30 mL) and ethyl acetate (30 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate = 4:1) gave a white oily liquid (134.0 mg). LC-MS: [M+H] + :503.2,505.2.

[0279] Synthesis of 2-((4-chloro-3-methylbenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (DP020):

[0280] The compound 2-((4-chloro-3-methylbenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (130.8 mg, 0.26 mmol) was dissolved in dichloromethane (3 mL) and triethylsilane (0.3 mL) was added. Trifluoroacetic acid (1.5 mL) was added at 0°C and reacted at room temperature for 30 minutes. The reaction solution was concentrated, quenched with sodium bicarbonate aqueous solution, the pH was adjusted to neutral, and water (10 mL) and dichloromethane (10 mL×3) were added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. A white solid (12.5 mg) was obtained by preparative separation. 1 H NMR(400MHz,DMSO-d6)δ11.58(s,1H),8.25(s,1H),7.45-7.37(m,2H),7.32-7 .23(m,2H),6.73(s,1H),6.30(s,1H),5.27(s,2H),2.33(s,3H); LC-MS:[M+H] + :382.8,384.8.

[0281] Example 21 Synthesis of Compound DP021

[0282]

[0283] Synthesis of (4-chloro-2-methylphenyl)methanol (2):

[0284] The compound 4-chloro-2-methylbenzaldehyde (499.3 mg, 3.23 mmol) was dissolved in methanol (10 mL), and sodium borohydride (244.7 mg, 6.47 mmol) was added to react at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated, and water (30 mL) and ethyl acetate (30 mL×3) were added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a transparent oily liquid (400.0 mg), which was directly used in the next step reaction.

[0285] Synthesis of 2-((4-chloro-2-methylbenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (3):

[0286] The compound (4-chloro-2-methylphenyl)methanol (81.4 mg, 0.52 mmol) was dissolved in toluene (8 mL), and 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (199.0 mg, 0.52 mmol), cesium carbonate (423.4 mg, 1.30 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (47.1 mg, 0.052 mmol) were added. The reaction was carried out in an oil bath at 100°C under nitrogen protection for 12 hours. The reaction solution was concentrated, extracted with water (30 mL) and ethyl acetate (30 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (petroleum ether:ethyl acetate=4:1) gave a yellow solid (137.0 mg). LC-MS: [MH] - :501.1,502.9.

[0287] Synthesis of 2-((4-chloro-2-methylbenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (DP021):

[0288] The compound 2-((4-chloro-2-methylbenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (137.0 mg, 0.27 mmol) was dissolved in dichloromethane (3 mL) and triethylsilane (0.3 mL) was added. Trifluoroacetic acid (1.5 mL) was added at 0°C and reacted at room temperature for 30 minutes. The reaction solution was concentrated, quenched with sodium bicarbonate aqueous solution, adjusted to neutral pH, extracted with water (10 mL) and dichloromethane (10 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. A white solid (10.4 mg) was obtained by preparative separation. 1 H NMR (400MHz, DMSO-d6) δ11.59(s,1H),8.26(s,1H),7.40(d,J=8.4Hz,1H),7.32(d,J=2.4Hz,1H),7.29 (s,1H),7.25(dd,J=8.0,2.4Hz,1H),6.72(s,1H),6.30(s,1H),5.28(s,2H),2.33(s,3H).LC-MS:[M+H] + :382.8,384.8.

[0289] Example 22 Synthesis of Compound M61

[0290]

[0291] Synthesis of tert-butyl 2-(6-((4-chloro-3-fluorobenzyl)oxy)-4-((4-methoxybenzyl)oxy)pyridin-3-yl)-4-(trifluoromethyl)-1H-pyrrole-1-carboxylate (1):

[0292] (4-chloro-3-fluorophenyl)methanol (33.7 mg, 0.21 mmol), 2-(6-chloro-4-((4-methoxybenzyl)oxy)pyridin-3-yl)-4-(trifluoromethyl)-1H-pyrrole-1-carboxylic acid tert-butyl ester (101.4 mg, 0.21 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) Palladium (II) (19.0 mg, 0.021 mmol) and cesium carbonate (202.0 mg, 0.62 mmol) were suspended in toluene (3 mL) and reacted at 100 ° C for 18 hours under nitrogen protection. The reaction solution was cooled, water (10 mL) was added, and ethyl acetate was extracted (10 mL × 3). The organic phase was washed with saturated sodium chloride aqueous solution (20 mL), dried, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to prepare a white solid (99.0 mg). LC-MS: [M+H] + :607.1,609.1.

[0293] Synthesis of 2-((4-chloro-3-fluorobenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (M61):

[0294] 2-(6-((4-chloro-3-fluorobenzyl)oxy)-4-((4-methoxybenzyl)oxy)pyridin-3-yl)-4-(trifluoromethyl)-1H-pyrrole-1-carboxylic acid tert-butyl ester (97.0 mg, 0.16 mmol) was dissolved in dichloromethane (1 mL), and triethylsilane (37.1 mg, 0.32 mmol) and trifluoroacetic acid (1 mL) were added dropwise at room temperature, and reacted at room temperature for 1 hour. The reaction solution was spin-dried, and the crude product was prepared by formic acid inversion to obtain a white solid (26.2 mg). 1 H NMR (400MHz, DMSO) δ11.57(s,1H),11.35(s,1H),8.26(s,1H),7.59(t,J=8.0Hz,1H),7. 48-7.40(m,1H),7.30-7.22(m,2H),6.73(s,1H),6.34(s,1H),5.33(s,2H); LC-MS:[M+H] + :386.9,388.9.

[0295] Example 23 Synthesis of Compound DP023

[0296]

[0297] Synthesis of 2-((3-chloro-4-(trifluoromethyl)benzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (2):

[0298] The compound (3-chloro-4-(trifluoromethyl)phenyl)methanol (54.8 mg, 0.26 mmol) was dissolved in toluene (5 mL), and then 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (99.6 mg, 0.26 mmol), cesium carbonate (212.0 mg, 0.65 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (23.6 mg, 0.026 mmol) were added, and stirred at 100°C under nitrogen protection for 12 hours. The reaction solution was concentrated, extracted with water (10 mL) and ethyl acetate (10 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (petroleum ether: ethyl acetate = 4:1) gave a yellow oily liquid (83.0 mg). LC-MS: [M+H] + :557.0,559.0.

[0299] Synthesis of 2-((3-chloro-4-(trifluoromethyl)benzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (DP023):

[0300] The compound 2-((3-chloro-4-(trifluoromethyl)benzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (83.0 mg, 0.15 mmol) was dissolved in dichloromethane (2.5 mL), and triethylsilane (0.2 mL) was added. Trifluoroacetic acid (1 mL) was added at 0°C. After reacting at room temperature for 30 minutes, the reaction solution was concentrated, the pH was adjusted to neutral with sodium bicarbonate aqueous solution, and water (10 mL) and dichloromethane (10 mL×3) were added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. A white solid (4.4 mg) was obtained by preparative separation. 1H NMR (400MHz, DMSO-d6) δ11.60(s,1H),8.26(s,1H),7.92(s,1H),7.75-7.70(m,2H),7.30(s,1H),6.73(s,1H),6.33(s,1H),5.40(s,2H). LC-MS:[M+H] + :436.7,438.7.

[0301] Example 24 Synthesis of Compound DP024

[0302]

[0303] Synthesis of 2-chloro-5-(hydroxymethyl)benzonitrile (2):

[0304] The compound 2-chloro-5-formylbenzonitrile (200.0 mg, 1.21 mmol) was dissolved in methanol (4 mL), and sodium borohydride (91.5 mg, 2.42 mmol) was added to react at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated, and water (30 mL) and ethyl acetate (30 mL×3) were added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a white solid (92.0 mg), which was directly used in the next step reaction.

[0305] Synthesis of 2-chloro-5-(((4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)oxy)methyl)benzonitrile (3):

[0306] The compound 2-chloro-5-(hydroxymethyl)benzonitrile (87.2 mg, 0.52 mmol) was dissolved in toluene (8 mL), and then 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (199.2 mg, 0.52 mmol), cesium carbonate (423.8 mg, 1.30 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (47.2 mg, 0.052 mmol) were added, and stirred at 100°C under nitrogen protection for 12 hours. The reaction solution was concentrated, extracted with water (30 mL) and ethyl acetate (30 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=4:1) to obtain a white solid (41.0 mg). LC-MS: [M+H] + :514.0,516.0.

[0307] Synthesis of 2-chloro-5-(((4-hydroxy-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)oxy)methyl)benzonitrile (DP024):

[0308] The compound 2-chloro-5-(((4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)oxy)methyl)benzonitrile (41.0 mg, 0.08 mmol) was dissolved in dichloromethane (2 mL), and triethylsilane (0.1 mL) was added. Trifluoroacetic acid (0.5 mL) was added at 0°C and stirred at room temperature for 30 minutes. The reaction solution was concentrated, the pH was adjusted to neutral with sodium bicarbonate aqueous solution, and water (10 mL) and dichloromethane (10 mL×3) were added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. A white solid (6.5 mg) was obtained by preparative separation. 1 H NMR (400MHz, Methanol-d4) δ8.13(s,1H),7.90(d,J=2.0Hz,1H),7.74(dd,J=8.4,2.0Hz,1H ),7.64(d,J=8.4Hz,1H),7.13(s,1H),6.67(s,1H),6.27(s,1H),5.34(s,2H); LC-MS:[M+H] + :393.7,395.7.

[0309] Example 25 Synthesis of Compound DP025

[0310]

[0311] Synthesis of 2-((4-chloro-3-(trifluoromethyl)benzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (2):

[0312] The compound (4-chloro-3-(trifluoromethyl)phenyl)methanol (54.8 mg, 0.26 mmol) was dissolved in toluene (5 mL), and then 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (99.6 mg, 0.26 mmol), cesium carbonate (212.0 mg, 0.65 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (23.6 mg, 0.026 mmol) were added, and stirred at 100°C under nitrogen protection for 12 hours. The reaction solution was concentrated, and water (10 mL) and ethyl acetate (10 mL×3) were added for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography (petroleum ether:ethyl acetate=4:1) gave a yellow solid (83.0 mg). LC-MS: [M+H] + :557.0,559.0.

[0313] Synthesis of 2-((4-chloro-3-(trifluoromethyl)benzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (DP025):

[0314] The compound 2-((4-chloro-3-(trifluoromethyl)benzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (84.0 mg, 0.15 mmol) was dissolved in dichloromethane (2.5 mL), and triethylsilane (0.2 mL) was added. Trifluoroacetic acid (1 mL) was added at 0°C, and the mixture was reacted for 30 minutes at room temperature. The reaction solution was concentrated, the pH was adjusted to neutral with sodium bicarbonate aqueous solution, and water (10 mL) and dichloromethane (10 mL×3) were added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. A white solid (6.9 mg) was obtained by preparative separation. 1 H NMR (400MHz, DMSO-d6) δ11.57(s,1H),8.26(s,1H),7.87(d,J=8.0Hz,1H),7.77(s,1H), 7.59(d,J=8.0Hz,1H),7.30(s,1H),6.74(s,1H),6.38(s,1H),5.43(s,2H).LC-MS:[M+H] + :436.7,438.7.

[0315] Embodiment 26

[0316]

[0317] Synthesis of (E)-N'-(3-fluoro-4-(trifluoromethyl)benzylidene)-4-methylbenzenesulfonylhydrazide (2):

[0318] Dissolve the compound 3-fluoro-4-trifluoromethylbenzaldehyde (1.0 g, 5.20 mmol) in anhydrous methanol (12 mL), add 4-methylbenzenesulfonyl hydrazide (970.3 mg, 5.21 mmol), react at room temperature for 3 hours, cool to 0°C, precipitate a white solid, filter, wash with a small amount of methanol, and take the filter cake to obtain a white solid (1.8 g). Use it directly in the next step. LC-MS: [M+H] + :361.0.

[0319] Synthesis of tert-butyl 2-(6-(2-(3-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)-4-((4-methoxybenzyl)oxy)pyridin-3-yl)-4-(trifluoromethyl)-1H-pyrrole-1-carboxylate (3):

[0320] Compound (E)-N'-(3-fluoro-4-(trifluoromethyl)benzylidene)-4-methylbenzenesulfonylhydrazide (36.0 mg, 0.10 mmol) was dissolved in 1,4-dioxane (1 mL), and tert-butyl 2-(4-((4-methoxybenzyl)oxy)-6-vinylpyridin-3-yl)-4-(trifluoromethyl)-1H-pyrrole-1-carboxylate (39.4 mg, 0.083 mmol) and potassium carbonate (29.0 mg, 0.21 mmol) were added, and the mixture was reacted at 100°C under nitrogen protection for 1.5 hours. The reaction solution was concentrated, diluted with water (10 mL), extracted with ethyl acetate (10 mL×3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by TLC preparative (petroleum ether: ethyl acetate = 4:1) chromatography to obtain a white solid (20.0 mg). LC-MS: [M+H] + :651.2.

[0321] Synthesis of 2-(2-(3-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (4):

[0322] Dissolve tert-butyl 2-(6-(2-(3-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)-4-((4-methoxybenzyl)oxy)pyridin-3-yl)-4-(trifluoromethyl)-1H-pyrrole-1-carboxylate (78.1 mg, 0.12 mmol) in dichloromethane (1 mL), then add triethylsilane (0.3 mL), and add trifluoroacetic acid (1.5 mL) at 0°C. React at room temperature for 40 minutes. Concentrate the reaction solution, quench with aqueous sodium bicarbonate solution, adjust the pH to neutral, extract with water (10 mL) and dichloromethane (10 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate to dryness. The crude product was separated by preparative separation to give a white solid (30.0 mg). LC-MS: [M+H] + :431.1.

[0323] Racemate 4 was separated and purified by SFC (chromatographic column: ChiralPak IH, 250×30 mm ID; mobile phase: phase A: CO2; phase B: MeOH (0.1% 2 mol / L NH3 in MeOH); gradient: B%: 20.0%, 4.5 min) to obtain white solid DP026 and white solid DP027.

[0324] DP026:

[0325] Chiral analysis conditions: chromatographic column: CHIRALPAK IH 5um 4.6*100mm, mobile phase: phase A: CO2, phase B: MeOH (0.05% DEA v / v); gradient: B%: 10%, retention time 1.249 minutes, ee = 100%;

[0326] 1 H NMR (400MHz, Methanol-d4) δ8.12 (s, 1H), 7.61 (t, J = 8.0Hz, 1H), 7.35-7.04 (m, 3H), 6 .74(d,J=1.6Hz,1H),6.32(s,1H),2.64-2.16(m,2H),1.85-1.58(m,2H); LC-MS:[M+H] + :431.1.

[0327] DP027:

[0328] Chiral analysis conditions: chromatographic column: CHIRALPAK IH 5um 4.6*100mm, mobile phase: phase A: CO2, phase B: MeOH (0.05% DEA v / v); gradient: B%: 10%, retention time 1.637 minutes, ee = 96.95%;

[0329] 1H NMR (400MHz, Methanol-d4) δ8.16 (s, 1H), 7.61 (t, J = 8.0Hz, 1H), 7.26-7.13 (m, 3H), 6.81-6.7 0(m,1H),6.36(s,1H),2.60-2.42(m,1H),2.38-2.27(m,1H),1.79-1.61(m,2H); LC-MS:[M+H] + :431.1.

[0330] Example 27 Synthesis of Compound DP028

[0331]

[0332] Synthesis of 2-((3,4-dichlorobenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (2):

[0333] Compound 3,4-dichlorobenzyl alcohol (28.3 mg, 0.16 mmol) was dissolved in toluene (4 mL) and then 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (30.0 mg, 0.078 mmol), cesium carbonate (133.6 mg, 0.41 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-trifluoromethyl)-1H-pyrrol-2-yl)pyridine were added. Isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (14.5 mg, 0.016 mmol), reacted in an oil bath at 100°C under nitrogen protection for 12 hours, the reaction solution was concentrated, extracted with water (10 mL) and ethyl acetate (10 mL×2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin layer preparation (petroleum ether: ethyl acetate = 4:1) to obtain a yellow solid (26.0 mg). LC-MS: [M+H] + :522.9,525.1.

[0334] Synthesis of 2-((3,4-dichlorobenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (DP028):

[0335] The compound 2-((3,4-dichlorobenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (26.0 mg, 0.05 mmol) was dissolved in dichloromethane (1 mL), and triethylsilane (0.3 mL) was added. Trifluoroacetic acid (1.5 mL) was added at 0°C and reacted at room temperature for 1 hour. The reaction solution was concentrated, quenched with aqueous sodium bicarbonate solution, the pH was adjusted to neutral, and water (10 mL) and dichloromethane (10 mL×3) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and prepared by separation to obtain a white solid (3.2 mg). 1 H NMR (400MHz, Methanol-d4) δ8.12(s,1H),7.62(d,J=2.0Hz,1H),7.53(d,J=8.0Hz,1H),7.37(dd,J =8.0,2.0Hz,1H),7.13(t,J=1.2Hz,1H),6.73-6.59(m,1H),6.24(s,1H),5.27(s,2H); LC-MS:[M+H] + :402.7,404.7.

[0336] Example 28 Synthesis of Compound DP029

[0337]

[0338] Synthesis of 2-((3-fluoro-4-methoxybenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (1):

[0339] Compound 3-fluoro-4-methoxybenzyl alcohol (40.6 mg, 0.26 mmol), 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (99.5 mg, 0.26 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (27.2mg, 0.03mmol), cesium carbonate (169.5mg, 0.52mmol) was dissolved in toluene (1mL), reacted at 100℃ for 2 hours, cooled, diluted with 5mL of aqueous solution, extracted with ethyl acetate (5mL×2), the organic phase was washed once with saturated sodium chloride solution (10mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a white solid (82.0mg). LC-MS: [M+H] + :503.1.

[0340] Synthesis of 2-((3-fluoro-4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (DP029):

[0341] The compound 2-((3-fluoro-4-methoxybenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (30.0 mg, 0.06 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (27.2 mg, 0.12 mmol) were dissolved in acetonitrile (0.3 mL) and water (0.3 mL), reacted at room temperature for 16 h, diluted with 3 mL of aqueous solution, extracted with ethyl acetate (3 mL×2), and the organic phase was washed once with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, concentrated, and obtained by preparative separation (1.0 mg). 1 H NMR(400MHz,MeOD)δ8.08(s,1H),7.24-7.17(m,2H),7.15-7.08(m,2H),6.67(s,1H),6.21(s,1H),5.19(s,2H),3.87(s,3H); LC-MS:[M+H] + :383.0.

[0342] Example 29 Synthesis of Compound DP030

[0343]

[0344] Synthesis of 2-((2-chloro-4-(trifluoromethyl)benzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (2):

[0345] The compound (2-chloro-4-(trifluoromethyl)phenyl)methanol (33.7 mg, 0.16 mmol) was dissolved in toluene (3 mL) and then 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (61.2 mg, 0.16 mmol), cesium carbonate (127.1 mg, 0.39 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4', 6'-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (14.5mg, 0.016mmol), reacted in an oil bath at 100℃ under nitrogen protection for 12 hours, concentrated the reaction solution, added water (30mL), extracted with ethyl acetate (30mL×3), combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin layer preparation (petroleum ether: ethyl acetate = 4:1) to obtain a pink oily liquid (15.0mg). LC-MS: [M+H] + :557.1,559.1.

[0346] Synthesis of 2-((2-chloro-4-(trifluoromethyl)benzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (DP030):

[0347] The compound 2-((2-chloro-4-(trifluoromethyl)benzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (15.0 mg, 0.027 mmol) was dissolved in dichloromethane (1 mL), and triethylsilane (0.3 mL) was added. Trifluoroacetic acid (1 mL) was added at 0°C and reacted at room temperature for 1 hour. The reaction solution was concentrated, quenched with aqueous sodium bicarbonate solution, the pH was adjusted to neutral, and water (10 mL) and dichloromethane (10 mL×3) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and prepared by separation to obtain a white solid (4.6 mg). 1 H NMR (400MHz, Methanol-d4) δ8.17(s,1H),7.77(d,J=1.6Hz,1H),7.75(d,J=8.0Hz,1H),7.68- 7.63(m,1H),7.24-7.08(m,1H),6.68(d,J=1.6Hz,1H),6.34(s,1H),5.48(s,2H); LC-MS:[M+H] + :436.7,438.7.

[0348] Example 30 Synthesis of Compound DP031

[0349]

[0350] Synthesis of 3-methyl-2-(trifluoromethyl)isonicotinic acid (2):

[0351] Compound 3-chloro-2-(trifluoromethyl)isonicotinic acid (700.0 mg, 3.10 mmol), trimethylcyclotriboroxane (1.56 g, 6.21 mmol, 50% THF solution), cesium carbonate (2.02 mg, 6.21 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (55.8 mg, 0.071 mmol) were added to anhydrous dioxane (50 mL) and stirred at 110°C under nitrogen protection for 1 hour. The reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (10 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a yellow solid (325.0 mg). LC-MS: [M+H] + :206.0.

[0352] Synthesis of (3-methyl-2-(trifluoromethyl)pyridin-4-yl)methanol (3):

[0353] The compound 3-methyl-2-(trifluoromethyl)isonicotinic acid (324.1 mg, 1.58 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and 1M borane tetrahydrofuran solution (4.8 mL, 4.8 mmol) was added dropwise under nitrogen at 0°C, and stirred for 2 hours under nitrogen at 50°C. Methanol was added dropwise to quench, and the reaction liquid was directly concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a white solid compound (101.0 mg). 1 H NMR (400MHz, DMSO) δ8.52(d,J=4.8Hz,1H),7.71(d,J=4.8Hz,1H),5.59(t,J=5.2Hz,1H),4.62(d,J=5.2Hz,2H),2.30(s,3H); LC-MS:[M+H] + :192.0.

[0354] Synthesis of 4-(((4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)oxy)methyl)-3-methyl-2-(trifluoromethyl)pyridine (4):

[0355] Compound 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (50.0 mg, 0.13 mmol), (3-methyl-2-(trifluoromethyl)pyridin-4-yl)methanol (38.2 mg, 0.20 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (11.8 mg, 0.013 mmol), and cesium carbonate (127.1 mg, 0.39 mmol) were added to anhydrous toluene (1.5 mL) and stirred at 90°C under nitrogen for 6 hours. Add 10 mL of water, extract with ethyl acetate (10 mL x 3), combine the organic phases and dry with anhydrous sodium sulfate, concentrate and purify by preparative chromatography (dichloromethane: methanol = 20: 1) to obtain a white solid compound (29.0 mg). LC-MS: [M+H] + :538.1. Synthesis of 2-((3-methyl-2-(trifluoromethyl)pyridin-4-yl)methoxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (DP031):

[0356] Compound 4-(((4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)oxy)methyl)-3-methyl-2-(trifluoromethyl)pyridine (29.0 mg, 0.054 mmol) and triethylsilane (31.4 mg, 0.27 mmol) were dissolved in dichloromethane (1 mL), and then trifluoroacetic acid (0.5 mL) was added and reacted at room temperature for 1 hour. The solution was concentrated and purified by preparative separation to obtain a white solid (6.4 mg). 1 H NMR (400MHz, DMSO) δ11.58(s,1H),8.54(d,J=4.8Hz,1H),8.26(s,1H),7.67(d,J=4.8H z,1H),7.31(s,1H),6.74(s,1H),6.43(s,1H),5.50(s,2H),2.44(s,3H); LC-MS:[M+H] + :418.3.

[0357] Example 31 Synthesis of Compound M23

[0358]

[0359] Synthesis of tert-butyl 2-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrrole-1-carboxylate (2):

[0360] Compound 5-bromo-2-chloro-4-methoxypyridine (4.7 g, 21.13 mmol), 1-Boc-pyrrole-2-boronic acid (4.5 g, 21.32 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (775.6 mg, 1.07 mmol), potassium phosphate (11.2 g, 52.76 mmol) were dissolved in 1,4-dioxane (50.0 mL) and water (5.0 mL). The reaction system was stirred at 80 ° C for 5 hours under nitrogen protection. After the reaction was complete, aqueous solution (50.0 mL) was added to quench the reaction, and ethyl acetate was extracted three times (60 mL × 3). The organic phases were combined, washed with saturated brine, and finally dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a yellow solid (4.8 g). LC-MS: [M+H] + :309.1,311.1.

[0361] Synthesis of 2-chloro-4-methoxy-5-(1H-pyrrol-2-yl)pyridine (3):

[0362] Dissolve tert-butyl 2-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrrole-1-carboxylate (4.8g, 15.55mmol) and potassium carbonate (6.5g, 47.03mmol) in methanol (50mL) and stir at 70°C for 5 hours. After the reaction is completed, concentrate the reaction solution, add water (50mL), extract with ethyl acetate (60mL×3), combine the organic phases, wash with saturated brine, and finally dry with anhydrous sodium sulfate, filter, and concentrate to obtain a crude product, which is separated by column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain a white solid (2.8g). LC-MS: [M+H] + :209.1,211.1.

[0363] Synthesis of (2-chloro-4-methoxy-5-(1-(triisopropylsilyl)-1H-pyrrol-2-yl)pyridine (4):

[0364] Dissolve 2-chloro-4-methoxy-5-(1H-pyrrol-2-yl)pyridine (2.5g, 11.98mmol) in tetrahydrofuran (30mL), add 60% sodium hydride (2.3g, 57.50mmol) at 0℃, stir the reaction system at room temperature for 2 hours, add triisopropylsilyl trifluoromethanesulfonate (18.3g, 59.72mmol) and stir at room temperature for 10 hours. After the reaction is complete, add aqueous solution (40.0mL) to quench the reaction, extract with ethyl acetate three times (40mL×3), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. Separate by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a yellow solid (3.8g). LC-MS: [M+H] + :365.2,367.2.

[0365] Synthesis of 2-chloro-5-(4-iodo-1-(triisopropylsilyl)-1H-pyrrol-2-yl)-4-methoxypyridine (5):

[0366] Dissolve (2-chloro-4-methoxy-5-(1-(triisopropylsilyl)-1H-pyrrol-2-yl)pyridine (1.2 g, 3.29 mmol) in N,N-dimethylformamide (10.0 mL) and add N-iodosuccinimide (591.0 mg, 2.63 mL). The reaction system was stirred at 0°C for 5 hours. After the reaction was complete, a saturated aqueous sodium sulfite solution (20.0 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The mixture was separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a yellow solid (1.3 g). LC-MS: [M+H] + :491.2,493.2.

[0367] Synthesis of 2-chloro-4-methoxy-5-(4-(methylsulfonyl)-1H-pyrrol-2-yl)pyridine (6):

[0368] Dissolve (2-chloro-5-(4-iodo-1-(triisopropylsilyl)-1H-pyrrol-2-yl)-4-methoxypyridine (200.0 mg, 0.41 mmol), sodium methanesulfinate (124.5 mg, 1.22 mmol), cuprous iodide (15.0 mg, 0.079 mmol), sodium hydroxide (48.8 mg, 1.22 mmol), and L-proline (18.4 mg, 0.16 mmol) in dimethylformamide. The reaction system was stirred at 100°C for 10 hours under nitrogen protection. After the reaction was complete, an aqueous solution (10.0 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, and finally dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid (30.0 mg). LC-MS [M+H] + :287.1,289.1.

[0369] Synthesis of 2-((4-chlorobenzyl)oxy)-4-methoxy-5-(4-(methylsulfonyl)-1H-pyrrol-2-yl)pyridine (7):

[0370] 2-Chloro-4-methoxy-5-(4-(methylsulfonyl)-1H-pyrrol-2-yl)pyridine (30.0 mg, 0.105 mmol), 4-chlorobenzyl alcohol (14.2 mg, 0.10 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (9.1 mg, 0.01 mmol), cesium carbonate (98.1 mg, 0.30 mmol) were dissolved in toluene (5.0 mL). The reaction system was stirred at 90°C under nitrogen protection for 10 hours. After the reaction is complete, add aqueous solution (10.0 mL) to quench the reaction, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine, and finally dry with anhydrous sodium sulfate, filter, and concentrate to obtain a crude product, which is separated by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a white solid (15.0 mg). LC-MS: [M+H] + :393.1,395.1.

[0371] Synthesis of 2-((4-chlorobenzyl)oxy)-5-(4-(methylsulfonyl)-1H-pyrrol-2-yl)pyridin-4-ol (M23):

[0372] 2-((4-chlorobenzyl)oxy)-4-methoxy-5-(4-(methylsulfonyl)-1H-pyrrol-2-yl)pyridine (15.0 mg, 0.038 mmol) was dissolved in N,N-dimethylformamide (2.0 mL) and sodium ethanethiolate (17.2 mg, 0.20 mmol) was added. The reaction system was stirred at 120°C for 30 minutes. A white solid (2.3 mg) was obtained by reverse phase preparation. 1 H NMR (400MHz, MeOD) δ8.13 (s, 1H), 7.46-7.36 (m, 5H), 6.85 (d, J = 1.6Hz, 1H), 6.22 (s, 1H), 5.27 (s, 2H), 3.11 (s, 3H); LC-MS: [M+H] + :379.1,381.1.

[0373] Example 32 Synthesis of Compound DP033

[0374]

[0375] Synthesis of methyl 4-chloro-2-(prop-1-en-2-yl)benzoate (2):

[0376] The compound methyl 2-bromo-4-chlorobenzoate (1.0 g, 4.01 mmol) was dissolved in 1,4-dioxane (20 mL) and water (2 mL), and isopropenylboronic acid pinacol ester (741.1 mg, 4.41 mmol), potassium carbonate (1.7 g, 12.30 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (290.3 mg, 0.40 mmol) were added, and the mixture was reacted in an oil bath at 100°C under nitrogen protection for 3 hours, and water (30 mL) was added, and ethyl acetate (30 mL×3) was used for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a transparent oily liquid (663.0 mg). LC-MS: [M+H] + :211.0,213.0.

[0377] Synthesis of methyl 4-chloro-2-isopropylbenzoate (3):

[0378] The compound 4-chloro-2-(prop-1-en-2-yl)benzoic acid methyl ester (300.0 mg, 1.42 mmol) was dissolved in ethanol (4 mL), and platinum (IV) dioxide (50.0 mg, 0.22 mmol) was added. The mixture was reacted at room temperature for 30 minutes under a hydrogen atmosphere and then filtered. The reaction solution was concentrated, and water (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a transparent oily liquid crude product (261.0 mg), which was directly used in the next step reaction.1 H NMR (400MHz, DMSO) δ7.69 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 8.0, 2.0 Hz, 1H), 3.83 (s, 3H), 3.58 (p, J = 6.8 Hz, 1H), 1.20 (d, J = 6.8 Hz, 6H).

[0379] Synthesis of (4-chloro-2-isopropylphenyl)methanol (4):

[0380] The compound 4-chloro-2-isopropylbenzoic acid methyl ester (240.0 mg, 1.13 mmol) was dissolved in tetrahydrofuran (1 mL), and lithium aluminum hydride (85.7 mg, 2.26 mmol) was added at 0°C, and the mixture was reacted at room temperature for 30 minutes. The mixture was quenched by adding sodium sulfate decahydrate solution, filtered, and extracted with water (10 mL) and ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product (200.0 mg), which was directly used in the next step. LC-MS: [M+H-H2O] + :167.1,169.1.

[0381] Synthesis of 2-((4-chloro-2-isopropylbenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (5):

[0382] The compound (4-chloro-2-isopropylphenyl)methanol (50.0 mg, 0.27 mmol) was dissolved in toluene (2 mL), and 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (103.3 mg, 0.27 mmol), cesium carbonate (220.6 mg, 0.68 mol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4', 6'-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (24.6 mg, 0.027 mmol), reacted in an oil bath at 100°C under nitrogen protection for 12 hours, concentrated the reaction solution, added water (30 mL), extracted with ethyl acetate (30 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin layer preparation (petroleum ether: ethyl acetate = 4:1) to obtain a yellow solid (60.0 mg). LC-MS: [MH] - :529.2,531.2.

[0383] Synthesis of 2-((4-chloro-2-isopropylbenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (DP033):

[0384] At room temperature, the compound 2-((4-chloro-2-isopropylbenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (60.0 mg, 0.11 mmol) was dissolved in dichloromethane (0.5 mL), triethylsilane (1 mL) was added, trifluoroacetic acid (0.5 mL) was added at 0°C, and the reaction was carried out for 1 hour at room temperature. The reaction solution was concentrated, quenched with aqueous sodium bicarbonate solution, the pH was adjusted to neutral, and water (20 mL) and dichloromethane (10 mL×3) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and prepared by separation to obtain a white solid (3.2 mg). 1 H NMR (400MHz, Methanol-d4) δ8.09 (s, 1H), 7.42-7.33 (m, 2H), 7.19 (d, J = 8.0Hz, 1H), 7.14 (s, 1H) ,6.67(s,1H),6.22(s,1H),5.29(s,2H),3.24-3.20(m,1H),1.27(d,J=6.8Hz,6H); LC-MS:[M+H] + :410.8,412.8.

[0385] Example 33 Synthesis of Compound DP034

[0386]

[0387] Synthesis of methyl 4-chloro-2-(dimethylphosphoryl)benzoate (2):

[0388] Compound 2-bromo-4-chlorobenzoic acid methyl ester (1000.0 mg, 4.00 mmol) was dissolved in 1,4-dioxane (10 mL). The reaction was stirred for 3 hours at 100 ° C after adding dimethylphosphine oxide (472.7 mg, 6.06 mmol), potassium phosphate (1713.0 mg, 8.07 mmol), palladium acetate (89.8 mg, 0.40 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (467.5 mg, 0.81 mmol) under nitrogen protection. The reaction solution was poured into water (30 mL), and then extracted with ethyl acetate (30 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and separated by chromatography column (petroleum ether: ethyl acetate = 5:1) to obtain a yellow solid (450.0 mg). LC-MS: [M+H] + :247.0,249.0.

[0389] Synthesis of (5-chloro-2-(hydroxymethyl)phenyl)dimethylphosphine oxide (3):

[0390] Dissolve methyl 4-chloro-2-(dimethylphosphoryl)benzoate (440.0 mg, 1.78 mmol) in tetrahydrofuran (5 mL). Add lithium borohydride (59.0 mg, 2.71 mmol) at 0°C under nitrogen protection. After stirring at room temperature for 1.5 hours, add sodium sulfate decahydrate (5.0 g) to the reaction solution, then use ethyl acetate (30 mL × 3), filter, concentrate to dryness, and separate by chromatography column (petroleum ether: ethyl acetate = 2:1) to obtain a transparent oil (330.0 mg). LC-MS: 219.1, 221.1 [M+H] + .

[0391] Synthesis of (5-chloro-2-(((4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)oxy)methyl)phenyl)dimethylphosphine oxide (4):

[0392] (5-Chloro-2-(hydroxymethyl)phenyl)dimethylphosphine oxide (110.0 mg, 0.50 mmol), cesium carbonate (407.5 mg, 1.25 mmol) and 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (244.5 mg, 0.64 mmol) were dissolved in toluene (2 mL), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (58.0 mg, 0.064 mmol) was added under nitrogen protection, and the reaction was carried out at 100° C. for 16 hours. The reaction solution was spin-dried, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to obtain a white solid (47.0 mg). LC-MS: [M+H] + :565.2,567.2.

[0393] Synthesis of (5-chloro-2-(((4-hydroxy-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)oxy)methyl)phenyl)dimethylphosphine oxide (DP034):

[0394] (5-chloro-2-(((4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)oxy)methyl)phenyl)dimethylphosphine oxide (47.0 mg, 0.083 mmol) was dissolved in dichloromethane (1 mL), and triethylsilane (0.2 mL) and trifluoroacetic acid (0.1 mL) were added in sequence. The reaction was carried out at room temperature for 1 hour, and the solvent was spin-dried. The mixture was purified by preparative separation to give a white solid (3.6 mg). 1H NMR (400MHz, MeOD) δ8.14(s,1H),7.76(dd,J=13.6,2.0Hz,1H),7.67(dd,J=8.0,2.0Hz,1H),7.61(d,J =8.0Hz,1H),7.13(s,1H),6.66(s,1H),6.29(s,1H),5.65(s,2H),1.92(d,J=13.2Hz,6H); LC-MS:[M+H] + :445.2,447.2.

[0395] Example 34 Synthesis of Compound DP035

[0396]

[0397] Synthesis of 5-bromo-1-chloro-2-(methoxymethoxy)-3-methylbenzene (2):

[0398] The compound 4-bromo-2-chloro-6-methylphenol (1.0 g, 4.52 mmol) and N,N-diisopropylethylamine (1560.0 mg, 12.07 mmol) were dissolved in dichloromethane (10 mL), cooled to 0°C, chloromethyl methyl ether (550.0 mg, 6.83 mmol) was dissolved in dichloromethane (10 mL) and added dropwise to the above solution, returned to room temperature, and reacted for 2 hours. Water (20 mL) was added to dilute, saturated sodium bicarbonate aqueous solution, dichloromethane extraction (30 mL × 3), the organic phases were combined and washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 20:1) to obtain a colorless oil (983.0 mg). 1 H NMR (400MHz, CDCl3) δ7.37 (d, J = 2.2 Hz, 1H), 7.22 (d, J = 2.2 Hz, 1H), 5.06 (s, 2H), 3.62 (s, 3H), 2.32 (s, 3H).

[0399] Synthesis of 3-chloro-4-(methoxymethoxy)-5-methylphenylboronic acid pinacol ester (3):

[0400] The compound 5-bromo-1-chloro-2-(methoxymethoxy)-3-methylbenzene (500.0 mg, 1.88 mmol), bipyraclostrobin (573.8 mg, 2.26 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (137.8 mg, 0.19 mmol) and potassium acetate (554.4 mg, 5.65 mmol) were dissolved in 1,4-dioxane (8 mL), replaced with nitrogen three times, heated to 100 ° C, reacted for 4 hours, TLC monitoring showed that the raw material had reacted completely and new spots were generated, and it was directly used in the next reaction without further purification.

[0401] Synthesis of (2-(3-chloro-4-(methoxymethoxy)-5-methylphenyl)pyrimidin-5-yl)methanol (4):

[0402] The compound 3-chloro-4-(methoxymethoxy)-5-methylphenylboronic acid pinacol ester (500.0 mg, 1.60 mmol), (2-chloropyrimidin-5-yl)methanol (277.5 mg, 1.92 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (117.0 mg, 0.16 mmol) and potassium phosphate (736.7 mg, 3.47 mmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL), heated to 100 ° C, and reacted for 4 hours. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 1:1) to obtain a yellow oil (48.0 mg). LC-MS: [M+H] + :295.1,297.1.

[0403] Synthesis of 2-(3-chloro-4-(methoxymethoxy)-5-methylphenyl)-5-(((4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)oxy)methyl)pyrimidine (5):

[0404] The compounds 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (62.3 mg, 0.16 mmol), (2-(3-chloro-4-(methoxymethoxy)-5-methylphenyl)pyrimidin-5-yl)methanol (48.0 mg, 0.16 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (14.8 mg, 0.016 mmol) and cesium carbonate (106.1 mg, 0.33 mmol) were dissolved in toluene (1 mL), heated to 100° C. and stirred for 6 hours. Water (10 mL) was added to the reaction solution to dilute it, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product, which was separated on a silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain a yellow oil (35.0 mg). LC-MS: [M+H] + :641.2.

[0405] Synthesis of 2-((2-(3-chloro-4-hydroxy-5-methylphenyl)pyrimidin-5-yl)methoxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (DP035):

[0406] The compound 2-(3-chloro-4-(methoxymethoxy)-5-methylphenyl)-5-(((4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)oxy)methyl)pyrimidine (35.0 mg, 0.055 mmol) and m-cresol (11.8 mg, 0.11 mmol) were dissolved in dichloromethane (2 mL), cooled to 0°C, trifluoroacetic acid (1 mL) was added dropwise to the reaction solution, heated to room temperature, and reacted for 1 hour. The reaction solution was spin-dried to obtain a white solid (4.0 mg). 1 H NMR(400MHz,DMSO)δ8.90(s,2H),8.23(s,1H),8.17(s,1H),8.11(s,1H),7. 25(s,1H),6.67(s,1H),6.17(s,1H),5.35(s,2H),2.29(s,3H); LC-MS:[M+H] + :477.0,479.0.

[0407] Example 35 Synthesis of Compound DP036

[0408]

[0409] Synthesis of methyl 4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)picolinate (1):

[0410] 2-Chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (100.0 mg, 0.26 mmol)), triethylamine (76.9 mg, 0.76 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (19.1 mg, 0.026 mmol) were suspended in a methanol (1 mL) solution and a dimethyl sulfoxide (1 mL) solution, and reacted at 60°C for 18 hours under CO protection. The reaction solution was poured into a saturated aqueous ammonium chloride solution (10 mL), and then extracted with ethyl acetate (10 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and separated by a chromatography column (petroleum ether: ethyl acetate = 3:1) to obtain a yellow solid product (90.0 mg). LC-MS: [M+H] + :407.1,409.1.

[0411] Synthesis of (4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)methanol (2):

[0412] Under the protection of nitrogen and ice bath, sodium borohydride (25.3 mg, 0.67 mmol) was slowly added to a solution of methyl 4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)picolinate (90.0 mg, 0.22 mmol) in methanol (10 mL), and the reaction was stirred at room temperature for 18 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution (10 mL), and then extracted with ethyl acetate (10 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and separated by chromatography column (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid product (80.0 mg). LC-MS: [M+H] + :379.1.

[0413] Synthesis of ethyl 3-(3-chloro-4-((4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)methoxy)-5-methylphenyl)-1,2,4-oxadiazole-5-carboxylate (3):

[0414] In an ice bath and nitrogen, di-tert-butyl azodicarboxylate (54.8 mg, 0.24 mmol) was added to a tetrahydrofuran solution (2 mL) of (4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)methanol (60.0 mg, 0.16 mmol), ethyl 3-(3-chloro-4-hydroxy-5-methylphenyl)-1,2,4-oxadiazole-5-carboxylate (44.8 mg, 0.16 mmol), and triphenylphosphine (62.4 mg, 0.24 mmol), and the mixture was reacted at 60° C. for 18 hours. The reaction solution was concentrated, and the crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to obtain a brown solid (60.0 mg). LC-MS: [M+H] + :643.1,645.1.

[0415] Synthesis of 3-(3-chloro-4-((4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)methoxy)-5-methylphenyl)-1,2,4-oxadiazole-5-carboxamide (4):

[0416] The compound 3-(3-chloro-4-((4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)methoxy)-5-methylphenyl)-1,2,4-oxadiazole-5-carboxylic acid ethyl ester (60.0 mg, 0.093 mmol) was dissolved in ammonia methanol (3 mL) solution, replaced with nitrogen three times, heated to 75 ° C and stirred for 2 hours, and the reaction solution was directly concentrated and then separated by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a yellow solid product (30.0 mg). LC-MS: [M+H] + :614.1,616.1.

[0417] Synthesis of 3-(3-chloro-4-((4-hydroxy-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)methoxy)-5-methylphenyl)-1,2,4-oxadiazole-5-carboxamide (DP036):

[0418] The compound 3-(3-chloro-4-((4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)methoxy)-5-methylphenyl)-1,2,4-oxadiazole-5-carboxamide (30.0 mg, 0.049 mmol) was dissolved in dichloromethane (2 mL) solution, and m-cresol (11.9 mg, 0.10 mmol) and trifluoroacetic acid (0.5 mL) were added dropwise under ice bath, and reacted at room temperature for 1 hour. The reaction solution was spin-dried, and the crude product was prepared by reverse phase to obtain a white solid (4.0 mg).1 H NMR (400MHz, DMSO) δ12.20(s,1H),8.79(s,1H),8.48(s,1H),8.39(s,1H),7.97(d,J=2.0Hz,1H),7. 92(d,J=2.0Hz,1H),7.28(s,1H),6.96(s,1H),6.55(s,1H),4.99(s,2H),2.34(s,3H); LC-MS:[M+H] + :493.9,495.9.

[0419] Example 36 Synthesis of Compound DP037

[0420]

[0421] Synthesis of 4-(((4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)oxy)methyl)benzaldehyde (1):

[0422] The compound 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (500.0 mg, 1.31 mmol), 4-(hydroxymethyl)benzaldehyde (266.8 mg, 1.96 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (118.4 mg, 0.13 mmol), and cesium carbonate (851.2 mg, 2.61 mmol) were dissolved in toluene (10 mL), the temperature was raised to 80°C, and the mixture was stirred for 4 hours. The reaction of the raw materials was monitored by LCMS. Water (20 mL) was added to the reaction solution to dilute it, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (40 mL × 3), the combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product, which was purified by silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain a yellow solid (250.0 mg). LC-MS: [M+H] + :483.2.

[0423] Synthesis of 1-(4-(((4-(4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)oxy)methyl)phenyl)-N-methylmethanamine (2):

[0424] 4-(((4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)oxy)methyl)benzaldehyde (60.0 mg, 0.12 mmol), methylamine hydrochloride (16.9 mg, 0.25 mmol), and acetic acid (21.62 mg, 0.36 mmol) were suspended in a methanol (2 mL) solution, and the reaction was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (15.1 mg, 0.24 mmol) was added, and the reactants were stirred at room temperature for 3 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate solution (10 mL×3). The combined organic layer was dried, filtered, and concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to give a yellow solid (40.0 mg). LC-MS: [M+H] + :498.2.

[0425] Synthesis of 2-((4-((methylamino)methyl)benzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (DP037): 1-(4-(((4-(4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-2-yl)oxy)methyl)phenyl)-N-methylmethylamine (40.0 mg, 0.08 mmol) was dissolved in dichloromethane (2 mL) solution, triethylsilane (18.6 mg, 0.16 mmol) and trifluoroacetic acid (1 mL) solution were added dropwise at room temperature, and reacted at room temperature for 1 hour. The reaction solution was spin-dried to obtain a crude product. The crude product was prepared with formic acid to obtain a white solid (11.7 mg). 1 H NMR(400MHz,DMSO)δ11.63(s,1H),8.25(s,1H),7.46-7.40(m,4H),7.29(s,1H) ,6.72(s,1H),6.29(s,1H),5.32(s,2H),3.97(s,2H),2.47(s,3H); LC-MS:[M+H] + :378.0.

[0426] Example 37 Synthesis of Compound DP038

[0427]

[0428] Synthesis of 4-((4-methoxybenzyl)oxy)-2-((4-(methoxymethyl)benzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (1):

[0429] The compound 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (100.0 mg, 0.26 mmol), (4-(methoxymethyl)phenyl)methanol (198.8 mg, 1.31 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II) (47.4 mg, 0.05 mmol), and cesium carbonate (255.4 mg, 0.78 mmol) were added to anhydrous toluene (4 mL) and reacted at 90°C under nitrogen protection for 16 hours. Add 10 mL of water, extract with ethyl acetate (10 mL x 3), combine the organic phases and dry with anhydrous sodium sulfate, concentrate, and separate and purify by preparative TLC (petroleum ether: ethyl acetate = 3:1) to obtain a white solid (80.0 mg). LC-MS: [M+H] + :499.2.

[0430] Synthesis of 2-((4-(methoxymethyl)benzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (DP038): Compound 4-((4-methoxybenzyl)oxy)-2-((4-(methoxymethyl)benzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (80.0 mg, 0.16 mmol) was dissolved in dichloromethane (4 mL), and then triethylsilane (75.4 mg, 0.65 mmol) and trifluoroacetic acid (73.9 mg, 0.65 mmol) were added in sequence, and the reaction was carried out at room temperature for 1 hour. Sodium bicarbonate was added to adjust the pH value to weak alkalinity. 10 mL of water was added, and dichloromethane (10 mL×3) was used for extraction. The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and purified by preparative separation to obtain a white solid (1.8 mg). 1 H NMR (400MHz, DMSO) δ11.70 (s, 1H), 8.24 (s, 1H), 7.41 (d, J = 8.0Hz, 2H), 7.34-7.27 (m ,3H),6.72(s,1H),6.26(s,1H),5.30(s,2H),4.41(s,2H),3.29(s,3H); LC-MS:[M+H] + :379.1.

[0431] Example 38 Synthesis of Compound DP039

[0432]

[0433] Synthesis of 2-chloro-4-((4-methoxybenzyl)oxy)-5-(1-methyl-4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (1):

[0434] The compound 2-chloro-4-((4-methoxybenzyl)oxy)-5-(4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (200.0 mg, 0.52 mmol) and potassium carbonate (288.8 mg, 2.09 mmol) were dissolved in N,N-dimethylformamide (5 mL), and iodomethane (89.0, 0.63 mmol) was added at room temperature. The reaction was allowed to react at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate (15 mL), and the organic phase was washed with water (10 mL×2) and saturated brine (10 mL), dried, and spin-dried. The crude product was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 3:1) to obtain a white solid (120.0 mg). LC-MS: [M+H] + :397.0,399.0.

[0435] Synthesis of 2-((4-chlorobenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(1-methyl-4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (2):

[0436] The compound 2-chloro-4-((4-methoxybenzyl)oxy)-5-(1-methyl-4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (100.0 mg, 0.25 mmol), 4-chlorobenzyl alcohol (89.8 mg, 0.63 mmol) and potassium tert-butoxide (42.4 mg, 0.38 mmol) were suspended in dioxane (1 mL) and reacted at 100°C for 18 hours. The reaction solution was dried by spin drying, and the crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a white solid (95.0 mg). LC-MS: [M+H] + :503.1,505.1.

[0437] Synthesis of 2-((4-chlorobenzyl)oxy)-5-(1-methyl-4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridin-4-ol (DP039):

[0438] The compound 2-((4-chlorobenzyl)oxy)-4-((4-methoxybenzyl)oxy)-5-(1-methyl-4-(trifluoromethyl)-1H-pyrrol-2-yl)pyridine (90.0 mg, 0.18 mmol) was dissolved in dichloromethane (3 mL), and triethylsilane (76.3 mg, 0.66 mmol) and trifluoroacetic acid (1.5 mL) were added dropwise at room temperature. The reaction was carried out at room temperature for 0.5 hours, and the reaction solution was dried by rotary evaporation. The crude product was prepared by reverse phase (ammonium bicarbonate) to obtain a white solid (18.9 mg). 1H NMR (400MHz, MeOD) δ7.74(s,1H),7.45-7.43(m,2H),7.40-7.37(m,2H),7.16(s,1H),6.22-6.21(m,2H),5.29(s,2H),3.51(s,3H); LC-MS:[M+H] + :383.1,385.1.

[0439] Example 39 Synthesis of Compound DP040

[0440]

[0441] Synthesis of (4-((4-chlorobenzyl)oxy)-2-hydroxyphenyl)boronic acid (1):

[0442] The compound 2-bromo-5-((4-chlorobenzyl)oxy)phenol (100.0 mg, 0.32 mmol) and biboronic acid pinacol ester (121.5 mg, 0.48 mmol) were dissolved in 1,4-dioxane (10.0 mL). Potassium acetate (93.9 mg, 0.96 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (46.3 mg, 0.057 mmol) were added to the mixture at room temperature. The mixture was stirred at 90°C for 16 hours under nitrogen protection. After the reaction, the solution was directly used for the next step without any treatment. LC-MS: [MH] - :276.9.

[0443] Synthesis of 5-((4-chlorobenzyl)oxy)-2-(6-(trifluoromethyl)pyridazin-3-yl)phenol (DP040):

[0444] 3-Chloro-6-(trifluoromethyl)pyridazine (29.5 mg, 0.16 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (15.5 mg, 0.020 mmol) were added to the reaction solution of the previous step, and the resulting mixture was stirred at 90°C for 4 hours under nitrogen protection. After the reaction was completed, it was diluted with water (10.0 mL), extracted three times with ethyl acetate (30.0 mL) and washed with brine (20.0 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography (dichloromethane: methanol = 10: 1) and separated by preparative chromatography to obtain a white solid (18.6 mg). 1HNMR: (400MHz, CD3OD) δ8.11(d,J=9.2Hz,1H),7.88(d,J=9.2Hz,1H),7.66(d,J=8.9Hz,1H),7.38(s,4H),6.68-6.61(m,2H),5.09(s,2H).LC-MS:[MH] - :379.0.

[0445] Example 40 Synthesis of Compound DP041

[0446]

[0447] Synthesis of 4-(trifluoromethyl)-2-(trimethyltinyl)pyrimidine (2):

[0448] Tetrakis(triphenylphosphine)palladium (2.0 g, 1.73 mmol) was added to a toluene (40.0 mL) solution of 2-bromo-4-(trifluoromethyl)pyrimidine (4.0 g, 17.62 mmol) and hexamethyltin (11.5 g, 35.10 mmol), the gas in the bottle was replaced with nitrogen, and then the mixture was stirred at 110°C for 1 hour. After the reaction was completed, the liquid in the bottle was concentrated by vacuum distillation to obtain a crude oil. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 8:1) to obtain a colorless oil product (1.0 g). LC-MS: [M+H] + :312.8. Synthesis of 2-(4-((4-chlorobenzyl)oxy)-2-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-4-(trifluoromethyl)pyrimidine (3):

[0449] To a 1,4-dioxane solution (2.0 mL) of 4-(trifluoromethyl)-2-(trimethyltinyl)pyrimidine (117.3 mg, 0.38 mmol), 2-(2-bromo-5-((4-chlorobenzyl)oxy)phenoxy)tetrahydro-2H-pyran (100.0 mg, 0.25 mmol) and cesium fluoride (76.4 mg, 0.50 mmol) was added di(tri-tert-butylphosphine)palladium (12.9 mg, 0.025 mmol), the gas in the bottle was replaced with nitrogen, and the mixture was stirred at 100°C for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, water (10.0 mL) was added to the resulting mixture for dilution, and then extracted twice with ethyl acetate (10.0 mL), the organic phases were combined and washed with saturated brine (20.0 mL), and the organic layer was dried over anhydrous sodium sulfate. The crude oil was obtained by concentration under reduced pressure. The obtained crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a white solid (50.0 mg). LC-MS: [M+H-THP] + :380.7.

[0450] Synthesis of 5-((4-chlorobenzyl)oxy)-2-(4-(trifluoromethyl)pyrimidin-2-yl)phenol (DP041):

[0451] A mixed solution of 2-(4-((4-chlorobenzyl)oxy)-2-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-4-(trifluoromethyl)pyrimidine (50.0 mg, 0.11 mmol) in concentrated hydrochloric acid (12M) (0.5 mL) and methanol (1.0 mL) was stirred at 25° C. for 1 hour. After the reaction was completed, the solvent was concentrated under reduced pressure and the crude product was dried to obtain a white solid (35.6 mg). 1 HNMR (400MHz, DMSO-d6) δ12.68(s,1H),9.21(d,J=5.0Hz,1H),8.28(d,J=8.9Hz,1H),7.91(d,J =5.0Hz,1H),7.48-7.46(m,4H),6.70(d,J=8.8Hz,1H),6.65(s,1H),5.19(s,2H).LC-MS:[M+H] + :380.7.

[0452] Test Example 1 Activity Test: Luciferase Reporter Gene

[0453] 1. T25 cultured 293T cells (purchased from Kobo Bio) were digested with 1 ml of 0.05% trypsin until the cells fell off, and digestion was terminated with 1 ml of complete medium. The cells were centrifuged at 1000 rpm for 3 min and the supernatant was discarded.

[0454] 2. Cells were plated in 6-well plates: resuspended cells and counted, and the cell density was adjusted to 5×10 5 cells / ml, 2 ml of cell suspension containing 1×106 cells was added to each well, and the cells were cultured in a carbon dioxide incubator;

[0455] 3.6h after cell attachment, transfection: 16μl transfection reagent + 4μg Ebox-Lucifersae plasmid, mix well, let stand at room temperature for 15min, then drop into each well of the six-well plate, and continue to culture in the cell culture incubator for 18h;

[0456] 4. Prepare the compounds to be screened: Dilute the compounds to be tested (see Table 1 below) 2-fold to the 9th concentration, i.e., from 500 μM to 1.95 μM, and record it as the compound plate. Transfer 10 μl of the solution in the compound plate to the cell plate in sequence, and set up a three-well experiment. The final concentration range of the compound is 50 μM to 0.195 μM, containing 9 groups of compounds, with a total of 10 gradients;

[0457] 5. Digest with 1 ml of 0.05% trypsin until the cells fall off, terminate digestion with 1 ml of complete medium, centrifuge at 1000 rpm for 3 min, discard the supernatant; resuspend the cells and count them, and adjust the cell density to 3.3×10 5 cells / ml, add 100 μl of cell suspension to each well of a 96-well plate and culture for 24 h;

[0458] 6. Discard the culture medium, add 100 μl of lysis buffer to each well, and lyse on ice for 5 min; take 20 μl into a white 96-well ELISA plate, add 100 μl of substrate, and detect the luminescence value of luciferase; take another 20 μl of lysis buffer into a black 96-well ELISA plate, add 20 μl of CTG2.0, and detect cell viability.

[0459] 7. Use the multiple relationship of cell viability to normalize the luciferase luminescence value. The normalization process is as follows: take the average value of the cell viability data treated with the same compound, divide the original cell viability data by the average value to obtain the relative cell viability value, and then divide the luciferase luminescence value of each well by the relative cell viability value of the corresponding well. Use GraphPad Prism to analyze the data, fit the parameter equation, and obtain the concentration response curve and IC 50 IC values ​​of each compound for the inhibitory activity of c-Myc protein 50 The values ​​are shown in Table 1.

[0460] Table 1

[0461] Compound No. <![CDATA[IC 50 (μM)]]> DP001 8.3 DP002 11.4 DP006 13.7 DP007 17.6 DP009 5.2 DP011 2.9 M63 3.5 M62 1.3 DP017 2.1 DP018 0.96 DP019 2.5 DP020 5.9 DP021 1.8 M61 4.2 DP023 1.2 DP024 4.1 DP025 1.5 DP026 2.0 DP027 9.6 DP028 3.1 DP030 1.6 DP031 2.5 DP033 1.9 DP035 7.2 DP037 10 DP039 7.2

[0462] The test results show that the compounds of the present invention can significantly inhibit c-Myc transcription activity at the cellular level.

[0463] Test Example 2 Test on HL-60 cell proliferation inhibitory activity:

[0464] Complete medium (RPMI-1640 + 10% FBS + 1% P / S) was prepared to resuscitate HL60 cells (Hefei Puruisheng), and cell lines with good growth status were selected after about two generations. Cells in the logarithmic growth phase were collected and counted, and the cells were adjusted to an appropriate concentration. The cell suspension was inoculated in a 96-well plate, and 135 μL of cell suspension was added to each well. The plate density was 2500 cells / well. The test compound (Cpd) was prepared into a storage solution with DMSO, and 15mM was used as the highest concentration. The test compound (see Table 2 below) was diluted 30 times with culture medium, and 15μL was added to a 96-well cell plate containing 135μL of cells. The culture medium without cells (containing 0.33% DMSO) was added to the Min control well, and 15μL DMSO-cell culture medium mixture (DMSO final concentration was 0.33%) was added to the Max control. Incubate for 6 days at 37°C, 5% CO2, and a relative humidity of more than 90% in an incubator. Add 50μL / well CellTiter Glo to end the reaction, incubate at room temperature in the dark for 30min, shake gently, and detect on Paradigm, and read the luminescence value of each well. The cell proliferation inhibition rate (Inhibition Rate) data is processed using the following formula:

[0465] Inhibition Rate (Inh%) = 100-(RLUCpd-RLUMin) / (RLUMax-RLUMin)*100%, wherein RLUCpd is the RLU value of the test compound well, RLUMin is the RLU value of the Min well, and RLUMax is the RLU value of the Max well.

[0466] The inhibition rate corresponding to different concentrations of compounds was calculated in EXCEL, and then the inhibition rate curve was plotted and the IC was calculated using GraphPad Prism software. 50 Table 2 shows the inhibitory activity of the compounds of the present invention on the proliferation of c-Myc driven tumor cells HL-60.

[0467] Table 2

[0468]

[0469] The test results show that the compounds of the present invention can significantly inhibit the proliferation of c-Myc-driven HL-60 cells.

[0470] Experimental Example 3. MDA-MB-231 Cell Proliferation Inhibitory Activity Test

[0471] Prepare complete medium (L-15 + 10% FBS + 1% P / S) to resuscitate MDA-MB-231 cells (Hefei Puruisheng), select cell lines with good growth status after two generations, digest and centrifuge to collect cells in logarithmic growth phase and count them, resuspend cells to appropriate concentration, inoculate cell suspension in 96-well plates, add 100 μL cell suspension to each well, and the plate density is 2000 cells / well. Place the culture plate in a 5% CO2 incubator overnight, 37°C, relative humidity 100%, and incubate for 24 hours. The next day, add 35 μL fresh culture medium to each well of the cell plate. The test compound (Cpd) (see Table 3 below) was prepared into a storage solution with DMSO, and 10mM was used as the highest concentration and then diluted 3 times with DMSO to obtain 9 concentration gradients; the test compound was diluted 10 times with culture medium, and 15μL was added to a 96-well cell plate containing 135μL of cells, and culture medium without cells (containing 1% DMSO) was added to the Min control well, and 15μL DMSO-cell culture medium mixture (DMSO final concentration was 1%) was added to the Max control, and incubated for 6 days at 37°C, 5% CO2, and a relative humidity of more than 90% in an incubator. 50μL / well CellTiter Glo was added to terminate the reaction, incubated at room temperature in the dark for 30min, and detected on Paradigm after gentle shaking, and the luminescence value RLU of each well was read. The cell proliferation inhibition rate (Inhibition Rate) data were processed using the following formula: Inhibition Rate (Inh%) = 100-(RLUCpd-RLUMin) / (RLUMax-RLUMin)*100%, where RLUCpd is the RLU value of the test compound well, RLUMin is the RLU value of the Min well, and RLUMax is the RLU value of the Max well.

[0472] The inhibition rate corresponding to different concentrations of compounds was calculated in EXCEL, and then the inhibition rate curve was plotted and the IC was calculated using GraphPad Prism software. 50 Table 3 shows the inhibitory activity of the compounds of the present invention on the proliferation of c-Myc-driven tumor cells MDA-MB-231.

[0473] Table 3

[0474]

[0475] The test results show that the compounds of the present invention can significantly inhibit the proliferation of c-Myc-driven MDA-MB-231 cells.

[0476] Experimental Example 4. HCT116 Cell Proliferation Inhibitory Activity Test

[0477] Prepare complete medium (McCoy's 5a + 10% FBS + 1% P / S) to resuscitate HCT116 cells (Zhongke Pu Ruisheng), select cell lines with good growth status after two generations, digest and centrifuge to collect cells in logarithmic growth phase and count them, resuspend cells to appropriate concentration, inoculate cell suspension in 96-well plate, add 100 μL cell suspension to each well, seed plate density is 500 cells / well, place culture plate in 5% CO2 incubator overnight, 37°C, relative humidity 100%, incubate for 24 hours. The next day, add 35 μL fresh culture medium to each well of cell plate. The test compound (Cpd) (see Table 4 below) was prepared into a storage solution with DMSO, and 20mM was used as the highest concentration, and then the solution was gradually diluted 3 times with DMSO to obtain 9 concentration gradients; the test compound was diluted 20 times with culture medium to obtain a 10X compound, and 15μL of the 10X compound was added to a 96-well cell plate containing 135μL of cells, and a culture medium without cells (containing 0.5% DMSO) was added to the Min control well, and 15μL of a DMSO-cell culture medium mixture (DMSO final concentration was 0.5%) was added to the Max control well, and incubated for 6 days at 37°C, 5% CO2, and a relative humidity of more than 90% in an incubator. 50μL / well CellTiter Glo was added to terminate the reaction, and the reaction was incubated at room temperature in the dark for 30min, and then gently shaken and detected on Paradigm, and the luminescence value RLU of each well was read. The cell proliferation inhibition rate (Inhibition Rate) data were processed using the following formula: Inhibition Rate (Inh%) = 100-(RLUCpd-RLUMin) / (RLUMax-RLUMin)*100%, where RLUCpd is the RLU value of the test compound well, RLUMin is the RLU value of the Min well, and RLUMax is the RLU value of the Max well. The inhibition rate corresponding to different concentrations of the compound was calculated in EXCEL, and then the inhibition rate curve was plotted using GraphPad Prism software and the IC was calculated. 50 value.

[0478] The inhibitory activity of the compounds of the present invention on HCT116 cell proliferation is shown in Table 4.

[0479] Table 4

[0480]

[0481] The test results show that the compounds of the present invention can significantly inhibit the proliferation of HCT116 cells.

Claims

1. A compound represented by formula (I) or a deuterated substance thereof, or a pharmaceutically acceptable salt thereof: In ring A, X, Y, and Z are independently selected from N or CR4; Ring B is selected from a 5-11 membered heteroaromatic ring containing 1-5 ring heteroatoms independently selected from N, O, and S, and when A is a benzene ring, B is not the following ring structure: The C ring is selected from: a benzene ring, a 5-6 membered monocyclic heteroaromatic ring containing 1-3 ring heteroatoms independently selected from N, O, and S, an 8-10 membered bicyclic fused heteroaromatic ring containing 1-5 ring heteroatoms independently selected from N, O, and S, a bicyclic ring composed of a 3-7 membered alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, and S and a 3-7 membered alicyclic ring, a bicyclic ring composed of a 3-7 membered alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, and S and a 3-7 membered alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, and S, a bicyclic ring composed of a 3-7 membered alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, and S and a 3-7 membered alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, and S and a benzene ring The invention further comprises a bicyclic ring, a bicyclic ring composed of a 3-7-membered alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, and S and a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms independently selected from N, O, and S, a bicyclic ring composed of a 5-7-membered heteroaromatic ring containing 1-3 ring heteroatoms independently selected from N, O, and S and a 3-7-membered alicyclic ring, a 3-7-membered alicyclic ring (preferably a 4-6-membered alicyclic ring), a 5-10-membered bridged alicyclic ring (preferably a 5-8-membered bridged alicyclic ring), a 3-7-membered alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, and S, and a 5-8-membered bridged alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, and S; R1 is selected from: -OR5, -N(R5)R6, -COOR5, -CHF2, -N(R5)C(O)R6, -N(R5)S(O)2R6; R2, R3 and R4 are each independently selected from: -H, halogen, -OH, -CN, -NO2, =O, C 1-10 Straight or branched alkyl (preferably C 1-4 Straight or branched alkyl), C 2-4 Straight or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-10 Straight chain or branched alkoxy (preferably C 1-4 Straight chain or branched chain alkoxy), C 3-7 Cycloalkyl, C 3-7 Cycloalkyloxy, 3-7 membered alicyclic group containing 1-3 ring heteroatoms independently selected from N, O, and S, 3-7 membered alicyclic group containing 1-3 ring heteroatoms independently selected from N, O, and S, 5-6 membered heteroaryl containing 1-3 ring heteroatoms independently selected from N, O, and S, phenyl, -C(O)R5, -C(O)OR5, -C(O)N(R5)R6, -S(O)2R5, -S(O)2N(R5)R6, -N(R5)R6, -N(R5)C(O)R6, -N(R5)S(O)2R6, -P(O)(R5)R6, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkyloxy, alicyclic, alicyclicoxy, heteroaryl, phenyl are optionally substituted by one or more independently selected from halogen, -OH, -CN, -OR5, -C(O)R5, -C(O)OR5, -C(O)N(R5)R6, -S(O)2R5, -S(O)2N(R5)R6, -N(R5)R6, -N(R5)C(O)R6, -N(R5)S(O)2R6, -P(O)(R5)R6, C 1-4 Straight or branched alkyl, C 2-4 Straight or branched alkenyl, C 2-4 substituted with a straight-chain or branched alkynyl group; L is an optional group, and when present, is selected from -OC(R5)R6-, -C(R5)R6O-, -NR5C(R5)R6-, -C(R5)(R6)NR5-, -NR5C(O)-, -C(O)NR5-, -S(O)2NR5-, -NR5S(O)2-, -OC(O)NR5-, -N(R5)COO-, -CO-, 3-7 membered alicyclic ring, 3-7 membered alicyclic ring-O-, -O-3-7 membered alicyclic ring, 3-7 membered alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, S, -oxy- 3-7 membered alicyclic heterocycles, 3-7 membered alicyclic heterocyclic oxy groups containing 1-3 ring heteroatoms independently selected from N, O, and S; the alicyclic and alicyclic heterocycles are substituted or unsubstituted, and when substituted, they are independently substituted by one or more of the following groups: halogen, -OH, -CN, -OR5, -C(O)R5, -C(O)OR5, -C(O)N(R5)R6, -S(O)2R5, -S(O)2N(R5)R6, -N(R5)R6, -N(R5)C(O)R6, -N(R5)S(O)2R6, -P(O)(R5)R6, C 1-10 Straight or branched alkyl (preferably C 1-4 Straight or branched chain alkyl), C 2-4 Straight or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-10 Straight chain or branched alkoxy (preferably C 1-4 Straight chain or branched chain alkoxy), C 3-7 Cycloalkyl (preferably C 3-5 Cycloalkyl), C 3-7 Cycloalkoxy (preferably C 3-5 cycloalkyloxy), 3-7 membered alicyclic radicals containing 1-3 ring heteroatoms independently selected from N, O, and S, 3-7 membered alicyclic radicals containing 1-3 ring heteroatoms independently selected from N, O, and S, and 5-11 membered heteroaryl radicals containing 1-3 ring heteroatoms independently selected from N, O, and S; Each R5 and each R6 are independently selected from -H, -OH, -CN, -NH2, C 1-10 Straight or branched alkyl (preferably C 1-4 Straight or branched chain alkyl), C 2-4 Straight or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-10 Straight chain or branched alkoxy (preferably C 1-4 The alkyl, alkenyl, alkynyl, alkoxy, alicyclic, alicyclic oxy, alicyclic heterocyclic, alicyclic heterocyclic oxy, heteroaryl, halogen, -OH, -CN, -NH2, C 1-4 Straight or branched alkyl, C 2-4 Straight or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 or R5 and R6 in the above groups together with the atoms to which they are commonly connected form a 3-7 membered alicyclic group or a 3-7 membered alicyclic group containing 1-3 ring heteroatoms independently selected from N, O, P, and S, and the alicyclic group or alicyclic group is optionally substituted by one or more independently selected from halogen, -OH, -CN, -NH2, C 1-4 Straight or branched alkyl, C 2-4 Straight or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-4 Substitution with straight-chain or branched alkoxy groups; m = 0, 1, 2, 3, or 4; n = 0, 1, 2, 3, or 4; The halogen is selected from: F, Cl, Br, I.

2. The compound of formula (I) according to claim 1, or a deuterated substance thereof, or a pharmaceutically acceptable salt thereof, characterized in that: L is an optional group, and when present, is selected from -OC(R5)R6-, -C(R5)R6O-, -NR5C(R5)R6-, -C(R5)(R6)NR5-, -NR5C(O)-, -C(O)NR5-, -S(O)2NR5-, -NR5S(O)2-, -OC(O)NR5-, -N(R5)COO-, -CO-, a 3-7 membered alicyclic ring, a 3-7 membered alicyclic ring-O-, -O-3-7 membered alicyclic ring, a 3-7 membered alicyclic ring containing 1-3 ring heteroatoms independently selected from N, O, S heterocyclic ring, -oxy-3-7 membered alicyclic heterocyclic ring, 3-7 membered alicyclic heterocyclic ring oxy containing 1-3 ring heteroatoms independently selected from N, O, and S; the alicyclic ring and alicyclic heterocyclic ring are independently substituted by one or more of the following groups: halogen, -OH, -CN, -OR5, -C(O)R5, -C(O)OR5, -C(O)N(R5)R6, -S(O)2R5, -S(O)2N(R5)R6, -N(R5)R6, -N(R5)C(O)R6, -N(R5)S(O)2R6, -P(O)(R5)R6, C 1-10 Straight or branched alkyl (preferably C 1-4 Straight or branched alkyl), C 2-4 Straight or branched alkenyl, C 2-4 Straight-chain or branched alkynyl, C 1-10 Straight chain or branched alkoxy (preferably C 1-4 Straight chain or branched chain alkoxy), C 3-7 Cycloalkyl (preferably C 3-5 Cycloalkyl), C 3-7 Cycloalkoxy (preferably C 3-5 The invention also includes 3-7 membered alicyclic groups containing 1-3 ring heteroatoms independently selected from N, O and S, 3-7 membered alicyclic groups containing 1-3 ring heteroatoms independently selected from N, O and S, and 5-11 membered heteroaryl groups containing 1-3 ring heteroatoms independently selected from N, O and S.

3. The compound of formula (I) according to claim 1 or 2, or a deuterated substance thereof, or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from the following ring structures: Optionally, the A ring is selected from the following groups: Optionally, the B ring is selected from the following ring structures, or a bicyclic or tricyclic fused aromatic heterocycle formed by the following ring structures themselves or fused with each other or with a benzene ring: And the A ring is When the B ring is not the following ring structure: Optionally, the B ring is selected from the following groups: And the A ring is When the B ring is not the following group: Optionally, the C ring is selected from the following ring structures: Or the C ring is selected from the condensed ring, bicyclic ring or tricyclic compound formed by the above aromatic ring, alicyclic ring, alicyclic heterocyclic ring or heteroaromatic ring structure (preferably selected from: ); Optionally, the C ring is selected from the following groups: Alternatively, L is an optional group, which, when present, is selected from -OCH2-, -CH2O-, -NHCH2-, -CH2NH-, -NHC(O)-, -C(O)NH-, -S(O)2NH-, -NHS(O)2-, -OC(O)NH-, -NHC(O)O-, -CO-, Optionally, R1 is selected from: -OH, -OCH3, -NH2, -NHCH3, NHCOCH3, -COOH, -CHF2, -NHS(O)2CH3; Optionally, R2, R3 and R4 are selected from: H, F, Cl, Br, -CF3, -CF2H, -CFH2, -CH3, isopropyl, cyclopropyl, -OCH3, -OCH2CH3, -OCF3, -OCF2H, isopropoxy, cyclopropyloxy, -OH, =O, -CN, -NO2, -C(O)CH3, -C(O)CF3, -SO2CH3, -PO(CH3)2, S(O)(NH)CH3, -C(O)NH2, -S(O)2NH2.

4. The compound of formula (I) according to any one of claims 1 to 3, or a deuterated substance thereof, or a pharmaceutically acceptable salt thereof, characterized in that: R3 is selected from the group consisting of: H, F, Cl, Br, -CF3, -CF2H, -CFH2, -CH3, ethyl, propyl, isopropyl, cyclopropyl, -OCH3, -OCH2CH3, -OCF3, -OCF2H, isopropoxy, cyclopropyloxy, -OH, =O, -CN, -NO2, -C(O)CH3, -C(O)CF3, -SO2CH3, -PO(CH3)2, S(O)(NH)CH3, -C(O)NH2, -S(O)2NH2, phenyl, substituted phenyl, pyrrole, substituted pyrrole, imidazole, substituted imidazole, pyrazole, substituted pyrazole, furan, substituted furan, thiophene, substituted thiophene, oxazole, substituted oxazole, Isoxazole, substituted isoxazole, thiazole, substituted thiazole, isothiazole, substituted isothiazole, oxadiazole, substituted oxadiazole, triazole, substituted triazole, the substituent being selected from F, Cl, Br, -CF3, -CF2H, -CFH2, -CH3, ethyl, propyl, isopropyl, cyclopropyl, -OCH3, -OCH2CH3, -OCF3, -OCF2H, isopropoxy, cyclopropyloxy, -OH, -NH2, -CN, -NO2, -C(O)CH3, -C(O)CF3, -SO2CH3, -PO(CH3)2, S(O)(NH)CH3, -C(O)NH2, -S(O)2NH2, -COOH.

5. The compound of formula (I) according to any one of claims 1 to 3, or a deuterated substance thereof, or a pharmaceutically acceptable salt thereof, characterized in that: R3 is: -C 1-10 Straight or branched alkylene (preferably C 1-4 Straight or branched alkylene)-NH-C 1-10 Straight or branched alkyl (preferably C 1-4 Straight or branched alkyl), or -C 1-10 Straight or branched alkylene (preferably C 1-4 Straight or branched alkylene)-OC 1-10 Straight or branched alkyl (preferably C 1-4 Straight or branched chain alkyl); Optionally, R3 is: -methylene-NH-methyl, or -methylene-O-methyl.

6. The compound of formula (I) according to any one of claims 1 to 5, or a deuterated substance thereof, or a pharmaceutically acceptable salt thereof, characterized in that: Selected from the following compounds:

7. The compound of formula (I) according to any one of claims 1 to 6, or a deuterated substance thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The pharmaceutically acceptable salts include anionic salts and cationic salts of the compound represented by formula (I) or its deuterated product; Optionally, the pharmaceutically acceptable salt includes an alkali metal salt, an alkaline earth metal salt, or an ammonium salt of the compound represented by formula (I) or its deuterated product; optionally, the alkali metal includes sodium, potassium, lithium, and cesium, and the alkaline earth metal includes magnesium, calcium, and strontium; Optionally, the pharmaceutically acceptable salt includes a salt formed by the compound represented by formula (I) or its deuterated product and an organic base; Optionally, the organic base includes trialkylamine, pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-alkylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5, 1,8-diazabicyclo[5.4.0]undecene-7, 1,4-diazabicyclo[2.2.2]octane; Optionally, the trialkylamine includes trimethylamine, triethylamine, N-ethyldiisopropylamine; Optionally, the N-alkylmorpholine includes N-methylmorpholine; Optionally, the pharmaceutically acceptable salt includes a salt formed by the compound represented by formula (I) or its deuterated product and an acid; Optionally, the acid includes an inorganic acid and an organic acid; optionally, the inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; optionally, the organic acid includes formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, glutamic acid, and pamoic acid.

8. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient.

9. Use of the compound of formula (I) according to any one of claims 1 to 7 or its deuterated product, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of a c-Myc inhibitor.

10. Use of the compound of formula (I) according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of a drug for treating tumors associated with c-Myc expression; Optionally, the tumor is selected from: lung cancer, breast cancer, liver cancer, pancreatic cancer, colorectal cancer, melanoma, bladder cancer, prostate cancer, gastric cancer, esophageal cancer, ovarian cancer, head and neck cancer, urothelial carcinoma, endometrial cancer, thyroid cancer, renal cancer, nasopharyngeal carcinoma, glioma, osteosarcoma, lymphoma, and hematologic malignancy.

Images