Small molecule compound with substituted diphenyl ether structure as well as preparation and application of small molecule compound

Abstract

The invention discloses a novel amide compound with a substituted diphenyl ether structure as well as a preparation method and application of the novel amide compound. The compound comprises a structure as shown in a general formula (I) or a general formula (II), and is characterized in that a benzo five-membered aromatic heterocycle (including but not limited to benzofuran, benzothiophene, indole and the like) is connected with a substituted diphenyl ether group through an amido bond to form a unique molecular skeleton. Diversified substituent groups R1 such as halogen, alkyl and heterocyclic rings can be introduced into a benzene ring, substituent groups R2 such as alkyl and alkoxy (n is an integer from 0 to 2) are introduced into an intermediate connecting chain, and therefore diversity optimization of the molecular structure is achieved. A biological activity test shows that the compound has remarkable proliferation inhibition activity on SK-N-AS neuroblastoma cells, and shows potential treatment value on malignant tumors such as neuroblastoma. Through systematic molecular design, a substituted diphenyl ether structure compound with a novel structure is constructed, and a brand new chemical entity is provided for developing new anti-cancer drugs.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceuticals, specifically relating to a small molecule compound with a substituted diphenyl ether structure and its preparation and application. Background Technology

[0002] Cancer, also known as malignant tumor in medical terms, is a biologically characterized by abnormal cell differentiation and proliferation, uncontrolled growth, invasiveness, and metastasis. It can occur in any tissue of any organ. When cancer cells grow and multiply rapidly and irregularly, they continuously consume large amounts of nutrients from the body and destroy the tissue structure and function of normal organs, forming a cancerous mass that invades adjacent tissues and can spread (metastasize) throughout the body. With the continuous development of science and technology and the deepening of medical research, the field of cancer treatment is ushering in exciting breakthroughs and challenges. Today, our methods for treating cancer are no longer limited to surgery, chemotherapy, and radiotherapy; innovative treatment methods for cancer have emerged. These include cancer immunotherapy represented by PD-1 inhibitors and T-cell receptors (TCRs), chimeric antigen T-cell (CAR-T) therapy, IDO inhibitor therapy, epigenetic therapy, and gene therapy, which has been extensively studied in recent years. Currently, a small molecule targeted drug, AOH1996, has been developed that can kill various solid malignant tumors. AOH1996 can not only kill more than 70 cancer cell line models in vitro, but also treat animal models derived from seven types of cells, including breast cancer, prostate cancer, brain cancer, ovarian cancer, cervical cancer, skin cancer, and lung cancer, in vivo. In addition, it has shown good inhibitory activity against SK-N-AS, SK-N-DZ, and SK-N-BE cells.

[0003] However, the molecular structure of the small molecule targeted drug AOH1996 lacks diversity, has strong lipid solubility, and slightly poor water solubility (CLogP: 4.4624). Summary of the Invention

[0004] The purpose of this invention is to discover small molecule targeted drugs with diverse molecular structures, and to further modify the structure of the existing small molecule targeted drug AOH1996 to increase the diversity of molecular structures, so as to meet the requirements of compound drugability for different cancer treatments.

[0005] This invention provides a small molecule compound having a substituted diphenyl ether structure, wherein the small molecule compound or its enantiomer or racemate or mixture thereof, or its pharmaceutically acceptable salt, hydrate or solvate, comprises the structure shown in formula (I) or formula (II):

[0006]

[0007] In formula (I) or formula (II):

[0008] X, Y, and Z are each independently selected from N, NH, O, S, or CH; the dashed lines in the structural segments containing X, Y, and Z represent single or double bonds, forming suitable benzo[c][1,2,5]oxadiazole; in addition, the intermediate chains shown in formulas (I) and (II) are connected to the benzene ring at any position;

[0009] R1 represents substitution at any position on the benzene ring, independently selected from any of the following: H, halogen, hydroxyl, amino, nitro, substituted or unsubstituted 5-12 membered heteroaromatic rings containing N, O, or S atoms, substituted or unsubstituted 5-13 membered saturated heterocycles containing N, O, or S atoms, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or Unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkylethynyl, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C1-C4 alkylcarbonylamino, substituted or unsubstituted C1-C4 alkoxycarbonylamino, substituted or unsubstituted C1-C4 sulfonyl, substituted or unsubstituted C1-C4 alkyl-S-, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C1-C4 alkylcarbonyl, substituted or unsubstituted C1-C4 alkylaminocarbonyl.

[0010] Preferably, the small molecule compound having a substituted diphenyl ether structure has any of the following structures:

[0011]

[0012]

[0013] Another aspect of the present invention provides a method for preparing the small molecule compound having the substituted diphenyl ether structure described above, wherein the preparation steps of the compounds shown in formulas (I) and (II) are as follows:

[0014]

[0015] Step 1: The compound shown in formula (I) or (II) is prepared in one step by an amidation step. The preparation route is as follows: amine S1 is mixed with the corresponding carboxylic acid S2 or S3 in a suitable solvent, phosphorus oxychloride is added, and the reaction is carried out at room temperature to obtain the compound shown in formula (I) or (II). The solvent is pyridine.

[0016] Alternatively, S2 or S3 can be first prepared into acyl chlorides, and then mixed with the corresponding amine S1 in a solvent, such as tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, or N,N-dimethylformamide; a base (triethylamine, diisopropylethylamine, pyridine, or N-methylmorpholine, etc.) is added, and the reaction is carried out at room temperature, low temperature (-10℃ to 0℃), or elevated temperature (40-50℃) to obtain the small molecule compounds shown in formula (I) and formula (II).

[0017] Another aspect of the present invention provides an inhibitor for the treatment of cancer, the inhibitor comprising the small molecule compound having the substituted diphenyl ether structure described herein, or its enantiomers, diastereomers, racemates or mixtures thereof, as well as pharmaceutically acceptable salts, hydrates and solvates thereof.

[0018] Another aspect of the present invention provides a pharmaceutical composition comprising the aforementioned small molecule compound having a substituted diphenyl ether structure, or an enantiomer, diastereomer, racemate, or mixture thereof, and one or more of its pharmaceutically acceptable salts, hydrates, and solvates, and a pharmaceutically acceptable carrier.

[0019] Preferably, the pharmaceutical composition further includes pharmaceutically acceptable excipients selected from the group consisting of: binders, fillers, diluents, disintegrants, suspending agents, suspending aids, sustained-release agents, lyophilization protectants, coating agents, enteric materials, lubricants, flow aids, anti-adhesion agents, sweeteners, flavoring agents, plasticizers, light-blocking agents, solubilizers, humectants, solvents, osmotic pressure regulators, colorants, pigments, surfactants, emulsifiers, water-soluble matrices, fat-soluble matrices, lipophilic matrices, pore-forming agents, gelling agents, preservatives, buffers, chelating agents, antioxidants, or combinations thereof.

[0020] Preferably, the pharmaceutical composition is used to prepare a medicament for treating diseases related to the activity or expression level of anticancer drugs, wherein the diseases related to the activity or expression level of anticancer drugs are selected from the group consisting of: fallopian tube cancer, prostate cancer, peritoneal cancer, breast cancer, gastric cancer, brain cancer, lung cancer, liver cancer, colorectal cancer, skin cancer, esophageal cancer, cervical cancer, ovarian cancer, bladder cancer, and pancreatic cancer.

[0021] The present invention has the following advantages over the prior art:

[0022] The present invention describes a small molecule compound with a substituted diphenyl ether structure, which is a novel amide compound. The preparation process is simple and easy, requiring only one step. It can be used to synthesize drugs for cancer prevention or treatment of diseases or symptoms mediated by DNA transcription-replication conflicts using existing compounds. The diverse molecular structures meet the drug-likeness requirements of compounds for different cancer treatments. Detailed Implementation

[0023] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While a detailed explanation of the terminology will be readily understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0024] As used herein, the terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0025] As used in this article, the term "hydrogen" refers to protium (H), deuterium (D), and tritium (T).

[0026] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. 1-12 Alkyl groups refer to those having 1 to 12, for example, 1 to 6 carbon atoms (C2, C3, C4, C5, C6, C6, C7, C8, C9 ... 1-6 Alkyl groups or 1 to 4 carbon atoms (C 1-4 Alkyl). For example, as used herein, the term "C 1-6 "Alkyl" refers to a branched or subdivided group with 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl) optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogens (in which case the group is called "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C" 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain with 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0027] As used herein, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing one or more double bonds and having 2–6 carbon atoms ("C"). 2-6The alkenyl group is, for example, vinyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present invention contain an alkenyl group, the compounds may exist in pure E (iso-side) form, pure Z (iso-side) form, or any mixture thereof in any proportion.

[0028] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group containing one or more triple bonds, such as having 2, 3, 4, 5, or 6 carbon atoms, like ethynyl or propynyl.

[0029] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused, or bridged systems (such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.)) which is optionally substituted with one or more (such as one to three) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-6 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) with 3 to 6 cyclic carbon atoms, which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0030] As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms in the ring, or one or more (e.g., one, two, three, or four) heteroatom-containing groups selected from C(=O), O, S, S(=O), S(=O)2, and NRa, where Ra represents a hydrogen atom.

[0031] As used herein, the term “5-12 membered heteroaryl” refers to a monocyclic aromatic group of a ring member, wherein the ring member is saturated with at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from N, O, and S, such as “5-6 membered heteroaryl”, 5-membered heteroaryl, 6-membered heteroaryl, etc. Specific examples include, but are not limited to, furanyl, thiophene, pyrrole, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, imidazole, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridyl, 2-pyridoneyl, 4-pyridoneyl, pyrimidinyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetraazinyl, etc.

[0032] As used herein, the term "halogenated" or "halogenated" group is defined as including F, Cl, Br, or I.

[0033] As used herein, the term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0034] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0035] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number found in nature. Suitable isotopes to be included in the compounds of this invention (e.g., deuterium) 2 H) Tritium ( 3 H): Isotopes of carbon (e.g., H) 11 C 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); isotopes of sulfur (e.g. 35 S). Certain isotope-labeled compounds of the present invention (e.g., doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium ( 3 H) and carbon-14 ( 14 C) It is particularly suitable for this purpose because ① it is incorporated and easily detected. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13 N) Substitution can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can be prepared by methods similar to those described and accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0036] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts.

[0037] Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts, examples of which include aspartate, gluconate, lactate, palmitate, hydrochloride and other similar salts.

[0038] Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, sodium salts, calcium salts, potassium salts, choline salts, and other similar salts.

[0039] The compounds of the present invention may exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0040] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0041] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0042] Example 1: 57 small molecule compounds with substituted diphenyl ether structures

[0043] The specific structural formulas and Chinese names of 57 small molecule compounds with substituted diphenyl ether structures are shown in Table 1.

[0044] Table 1. Specific structural formulas and Chinese names of 57 small molecule compounds with substituted diphenyl ether structures.

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052] The specific preparation methods for the above 57 small molecule compounds with substituted diphenyl ether structures are as follows: Synthetic intermediate M1: 2-amino-N-(2-phenoxyphenyl)acetamide (28-195-40)

[0053]

[0054] Step 1: At room temperature, 1-fluoro-2-nitrobenzene S1 (2.0 g, 14.2 mmol), phenol (1.5 g, 15.5 mmol), and K2CO3 (2.7 g, 19.8 mmol) were added to a reaction flask containing 20 mL of N,N-dimethylformamide (DMF), and the mixture was heated to 160 °C under argon atmosphere and reacted for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and water (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (200 mL x 2). The combined organic phases were backwashed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and finally concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 15) and concentrated to give 3.0 g of the target compound 1-nitro-2-phenoxybenzene (M1-1, 28-174-37) as a pale yellow oil, with a yield of 100.0%. 1H NMR (400MHz, CDCl3): δ7.95 (dd, J=8.2, 1.6Hz, 1H), 7.50 (m, J=8.4, 7.5, 1.7Hz, 1H), 7 .41–7.36(m,2H),7.22–7.17(m,2H),7.08–7.04(m,2H),7.01(dd,J=8.4,1.1Hz,1H).

[0055] Step 2: At room temperature, M1-1 (28-174-37, 3.4 g, 15.8 mmol) was dissolved in 35 mL of methanol solution, and 10% Pd / C (wetted with ca. 55% Water) (168.3 mg, 1.58 mmol) was added. The mixture was protected with argon and bubbled for 5 minutes, then protected with hydrogen and bubbled with hydrogen for 20 minutes. The temperature was raised to 60 °C, and the reaction was carried out for 7 hours. After the reaction was complete, the mixture was filtered while hot, and the filter cake was washed with methanol. The filtrate was collected, evaporated to dryness, and concentrated. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 60 to 1 / 50) and concentrated to obtain 1.7 g of the target compound 1-amino-2-phenoxybenzene (M1-2, 28-178-41) as an orange-yellow oil, with a yield of 98.8%. 1 H NMR (400MHz, CDCl3): δ7.36–7.29(m,2H),7.10–7.06(m,1H),7.05–6.96(m,3H),6.90(dd,J=8.0, 1.4Hz, 1H), 6.85 (dd, J=7.9, 1.5Hz, 1H), 6.74 (m, J=12.8, 6.9, 3.2Hz, 1H), 3.77 (d, J=34.8Hz, 2H).

[0056] Step 3: Under 0℃ conditions, N-Boc-glycine (2.3 g, 13.0 mmol), benzotriazol-1-yl-oxytripyrrolidinephosphine hexafluorophosphate (PyBOP) (7.4 g, 14.3 mmol), and N,N-diisopropylethylamine (DIPEA) (5.9 g, 3.5 mmol) were added to a reaction flask containing 10 mL of dichloromethane and stirred for 10 minutes. Then, M1-2 (28-178-41, 2.4 g, 13.0 mmol) was added and stirred for 5 minutes. The reaction was allowed to proceed at room temperature, and the reaction was observed by TLC. After 22 hours, the reaction was complete. The reaction was quenched with 3M HCl, and a mixture of NaHCO3 was added for extraction with dichloromethane (200 mL x 2). The combined organic phases were first backwashed with saturated brine (200 mL), then dried over anhydrous sodium sulfate, and finally concentrated under vacuum. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) and concentrated to give 4.0 g of the target compound 3-oxo-3-((2-phenoxyphenyl)amino)propyl)carbamate tert-butyl ester (M1-3,28-192-40) as a white solid, with a yield of 89.9%. 1 H NMR (400MHz, CDCl3): δ8.43 (dd, J=8.1, 1.2Hz, 2H), 7.37–7.32 (m, 2H), 7.12 (m, J=8.7, 4.3Hz, 2H) ,7.04–6.98(m,3H),6.85(dd,J=8.1,1.2Hz,1H),5.12(s,1H),3.92(d,J=5.4Hz,2H),1.38(s,9H).

[0057] Step 4: At 0°C, add M1-3 (28-192-40, 4.0 g, 12.0 mmol) to dichloromethane (3.3 mL), and slowly add trifluoroacetic acid (4.9 g, 43.2 mmol). After the addition is complete, bring the temperature to room temperature and react for 3 h. After the reaction is complete, quench the reaction with water, and extract the mixture with dichloromethane (200 mL x 2). The combined organic phases are first backwashed with saturated brine (200 mL), then dried with anhydrous sodium sulfate, and finally concentrated under vacuum. The crude product is purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20) and concentrated to give 2.0 g of the target compound 2-amino-N-(2-phenoxyphenyl)acetamide (M1, 28-195-40), a yellow oily liquid, with a yield of 67.0%. 1¹H NMR (400MHz, CDCl₃): δ 9.88 (s, 1H), 8.50 (dd, J = 8.1, 1.5Hz, 1H), 7.36–7.30 (m, 2H), 7.16–7.09 (m, 2H), 7.05–6.99 (m, 3H), 6.91 (dd, J = 8.1, 1.4Hz, 1H), 3.44 (s, 2H). Synthetic intermediate M₂: 2-amino-N-(2-(2-methoxyphenoxy)phenyl)acetamide (29-57-30)

[0058]

[0059] Step 1: The preparation method is the same as that of M1-1. The target compound 1-methoxy-2-(2-nitrophenoxy)benzene (M2-1, 29-50-35) is a pale yellow oil with a yield of 96.66%. 1 H NMR (400MHz, CDCl3): δ7.98-8.01(m,1H),7.45–7.49(m,1H),7.28(s,1H),7.1 2–7.18(m,2H),7.04–7.07(m,2H),6.86–6.89(m,1H),3.84(d,J=14.4Hz,3H).

[0060] Step 2: At room temperature, weigh M2-1 (29-50-35, 500 mg, 2.04 mmol) and iron powder (558 mg, 10 mmol) and add them to a gaiwan-shaped reaction flask containing 2.1 mL of water. Slowly add 0.032 mL of concentrated hydrochloric acid to the mixture. Under argon protection, react at room temperature for 4 h. After the reaction is complete, extract the mixture with ethyl acetate, dry it with anhydrous sodium sulfate, and finally concentrate it under vacuum. Purify the crude product by silica gel column chromatography to obtain 350 mg of the target compound 2-(2-methoxyphenoxy)aniline (M2-2, 29-52-28) as an orange solid, with a yield of 79.79%. 1 H NMR (400MHz, CDCl3): δ7.04–7.09(m,1H),6.99(d,J=7.9Hz,1H),6.94(t,J=7.5Hz,1H) ,6.87–6.88(m,2H),6.79(dd,J=13.1,7.8Hz,2H),6.68(t,J=7.6Hz,1H),3.89(s,3H).

[0061] Step 3: The preparation method is the same as that of M1-3. The target compound (2-((2-(2-methoxyphenoxy)phenyl)amino)-2-oxyethyl)carbamate tert-butyl ester (M2-3, 29-54-33)) was obtained as a pure white solid, 414.3 mg, with a yield of 85.66%. 1H NMR (400MHz, CDCl3): δ8.53(s,1H),8.38(dd,J=8.1,1.2Hz,1H),7.13–7.16(m,1H),7.04–7.06(m,1H),6.98–7.02(m ,2H),6.90–6.97(m,2H),6.71(dd,J=8.1,1.4Hz,1H),5.27(s,1H),3.96(d,J=4.7Hz,2H),3.80(s,3H),1.39(s,9H).

[0062] Step 4: The preparation method is the same as that of M1-3. The target compound 2-amino-N-(2-(2-methoxyphenoxy)phenyl)acetamide (M2,29-57-30) is a pure white solid with a yield of 100%. 1 ¹H NMR (400MHz, CDCl₃): δ 9.88 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.91–7.00 (m, 4H), 6.71 (d, J = 8.1 Hz, 1H), 3.80 (s, 3H), 3.46 (s, 2H). Synthetic intermediate M3: 2-amino-N-(2-(3-methoxyphenoxy)phenyl)acetamide (29-75-36)

[0063]

[0064] Step 1: The preparation method is the same as that of M1-1, yielding 1-(3-methoxyphenoxy)-2-nitrobenzene (M3-1,28-172-30) as a pale yellow oil with a yield of 98.5%. 1 H NMR (400MHz, CDCl3): δ7.97 (dd, J=8.2, 1.6Hz, 1H), 7.50-7.55 (m, 1H), 7.27–7.30 (m, 1H), 7.20 -7.24(m,1H),7.07(dd,J=8.4,1.2Hz,1H),6.73-6.76(m,1H),6.61–6.64(m,2H),3.81(s,3H).

[0065] Step 2: The preparation method is the same as that of M2-2, yielding 2-(3-methoxyphenoxy)aniline (M3-2, 29-68-35) blood orange oil droplets with a yield of 78.44%. 1H NMR (400MHz, CDCl3): δ7.20(t,J=8.3Hz,1H),6.97–7.01(m,1H),6.90(dd,J=8.0,1.2Hz,1H),6.83(d d,J=7.8,1.4Hz,1H),6.71–6.75(m,1H),6.60–6.63(m,1H),6.55(dd,J=8.5,1.4Hz,2H),3.77(s,3H).

[0066] Step 3: The preparation method is the same as that of M1-3, yielding (2-((2-(3-methoxyphenoxy)phenyl)amino)-2-oxyethyl)carbamate tert-butyl ester (M3-3, 29-69-35) white solid with a yield of 64.4%. 1 H NMR (400MHz, CDCl3): δ8.42(d,J=8.1Hz,2H),7.23(dd,J=15.6,6.9Hz,1H),7.11(t,J=7.7Hz,1H),7.02(t,J=7.6Hz,1 H),6.89(d,J=7.9Hz,1H),6.67–6.69(m,1H),6.56(t,J=6.4Hz,2H),3.91(d,J=5.4Hz,2H),3.77(s,3H),1.39(s,9H).

[0067] Step 4: The preparation method is the same as that of M1-4. The target compound 2-amino-N-(2-(3-methoxyphenoxy)phenyl)acetamide (M3,28-181-40) is a pure white solid with a yield of 90.8%. 1 H NMR (400MHz, CDCl3): δ9.81(s,1H),8.48(dd,J=8.1,1.4Hz,1H),7.20–7.24(m,1H),7.12–7.16(m,1H),7.03(td, J=7.8,1.6Hz,1H),6.93(dd,J=8.1,1.4Hz,1H),6.64–6.67(m,1H),6.56–6.58(m,2H),3.77(s,3H),3.47(s,2H).

[0068] Synthetic intermediate M4: 2-amino-N-(2-(4-methoxyphenoxy)phenyl)acetamide (29-56-30)

[0069]

[0070] Step 1: The preparation method is the same as that of M1-1, yielding 1-(4-methoxyphenoxy)-2-nitrobenzene (M4-1,29-51-34) white solid with a yield of 38.97%.1 H NMR (400MHz, CDCl3): δ7.92(dd,J=8.1,1.6Hz,1H),7.42–7.47(m,1H),7.10–7.14(m,1H),7.00–7.04(m,2H),6.92(dd,J=9.7,2.8Hz,3H),3.82(s,3H).

[0071] Step 2: The preparation method is the same as that of M2-2, yielding 2-(4-methoxyphenoxy)aniline (M4-2,29-53-30) as an orange-yellow oil with a yield of 76.3%. 1 H NMR (400MHz, CDCl3): δ6.91 (dd, J=34.2, 8.4Hz, 5H), 6.80 (dd, J=13.8, 7.8Hz, 2H), 6.70 (d, J=7.0Hz, 1H), 3.79 (s, 3H).

[0072] Step 3: The preparation method is the same as that of M1-3, yielding (2-((2-(4-methoxyphenoxy)phenyl)amino)-2-oxyethyl)carbamate tert-butyl ester (M4-3, 29-55-32) as a pure white solid with a yield of 63.34%. 1 H NMR (400MHz, CDCl3): δ8.52(s,1H),8.40(dd,J=8.1,1.3Hz,1H),7.04(td,J=8.0,1.1Hz,1H),6.94–6.99(m,3H) ,6.87–6.90(m,2H),6.73(dd,J=8.1,1.2Hz,1H),5.24(s,1H),3.94(d,J=5.4Hz,2H),3.80(s,3H),1.39(s,9H).

[0073] Step 4: The preparation method is the same as that of M1-4. The target compound 2-amino-N-(2-(4-methoxyphenoxy)phenyl)acetamide (M4,29-56-30) is a pure white solid with a yield of 52.96%. 1 H NMR (400MHz, CDCl3): δ9.91 (s, 1H), 8.48 (dd, J=8.1, 1.5Hz, 1H), 7.08 (td, J=8.0, 1.3Hz, 1H), 6.96–7.00(m,3H),6.86–6.90(m,2H),6.79(dd,J=8.1,1.4Hz,1H),3.80(s,3H),3.47(s,2H).

[0074] Synthetic intermediate M5: 2-amino-N-(2-(o-tolyloxy)phenyl)acetamide (29-70-35)

[0075]

[0076] Step 1: The preparation method is the same as that of M1-1, yielding a pale yellow oily substance of 1-methyl-2-(2-nitrophenoxy)benzene (M5-1,29-58-32) with a yield of 100.0%. 1 H NMR (400MHz, CDCl3): δ7.95 (dd, J=8.1, 1.6Hz, 1H), 7.42–7.46 (m, 1H), 7.29 (d, J=7.4Hz, 1H), 7. 19–7.23(m,1H),,7.11–7.16(m,2H),6.94(d,J=7.9Hz,1H),6.81(d,J=8.4Hz,1H),2.24(s,3H).

[0077] Step 2: The preparation method is the same as that of M2-2, yielding 500 mg of 2-(o-tolyloxy)aniline (M5-2,29-61-30) blood orange oil, with a yield of 95.6%. 1 H NMR (400MHz, CDCl3): δ7.25(d,J=7.0Hz,1H),7.11–7.16(m,1H),7.03(t,J=7.4Hz,1H ),6.92–6.96(m,1H),6.81–6.84(m,2H),6.66–6.71(m,2H),3.72(s,2H),2.32(s,3H).

[0078] Step 3: The preparation method is the same as that of M1-3, yielding a transparent solid of (2-oxo-2-((2-(o-tolyloxy)phenyl)amino)ethyl)carbamate (M5-3, 29-66-34), with a yield of 85.66%. 1 H NMR (400MHz, CDCl3): δ8.63(s,1H),8.42(d,J=7.9Hz,1H),7.25(d,J=8.0Hz,1H),7.13–7.18(m,1H),7.09(d,J=7.3Hz,1H),7.04(dd,J=14.1,6.6 Hz,1H),6.94(t,J=7.3Hz,1H),6.86(d,J=7.9Hz,1H),6.63(dd,J=8.1,0.8Hz,1H),5.38(s,1H),3.93(d,J=5.3Hz,2H),2.23(s,3H),1.37(s,9H).

[0079] Step 4: The preparation method is the same as that of M1-4, to obtain the target compound 2-amino-N-(2-(o-tolyloxy)phenyl)acetamide (M5, 29-70-35) as a white solid with a yield of 83.97%. 1 H NMR (400MHz, CDCl3): δ9.98(s,1H),8.52(dd,J=8.1,1.5Hz,1H),7.25–7.27(m,1H),7.14–7.18(m,1H),7.05–7.11 (m,1H),6.98(td,J=8.0,1.6Hz,1H),6.86(d,J=8.0Hz,1H),6.73(dd,J=8.1,1.3Hz,1H),3.48(s,2H),2.28(s,3H).

[0080] Synthetic intermediate M6: 2-amino-N-(2-(m-tolyloxy)phenyl)acetamide (29-77-35)

[0081]

[0082] Step 1: The preparation method is the same as that of M1-1, yielding pale yellow oily droplets of 1-nitro-2-(m-tolyloxy)benzene (M6-1, 29-71-31) with a yield of 96.8%. 1 H NMR (400MHz, CDCl3): δ8.00–8.02(m,1H),7.57(dd,J=9.8,3.6Hz,1H),7.24–7.35(m,2H),7.08–7.10(m,2H),6.92–6.96(m,2H),2.43(s,3H).

[0083] Step 2: The preparation method is the same as that of M2-2, yielding blood-red droplets of 2-(m-tolyloxy)aniline (M6-2, 29-73-30) with a yield of 90.57%. 1 H NMR (400MHz, CDCl3): δ7.20(t,J=7.7Hz,1H),7.00(t,J=7.6Hz,1H),6.89(d,J=7.9Hz,2H),6. 84(d,J=7.9Hz,1H),6.80(d,J=11.7Hz,2H),6.74(t,J=7.7Hz,1H),3.60(s,2H),2.33(s,3H).

[0084] Step 3: The preparation method is the same as that of M6-3, yielding (2-oxo-2-((2-(m-tolyloxy)phenyl)amino)ethyl)carbamate tert-butyl ester (M6-3, 29-76-41) white solid with a yield of 80.0%. 1H NMR (400MHz, CDCl3): δ8.41–8.46(m,2H),7.18–7.26(m,1H),7.10(t,J=7.0Hz,1H),7.01(t,J=7.1Hz ,1H),6.93(d,J=7.2Hz,1H),6.78–6.85(m,3H),5.18(s,1H),3.91(s,2H),2.32(s,3H),1.39(s,9H).

[0085] Step 4: The preparation method is the same as that of M1-4. The target compound 2-amino-N-(2-(m-tolyloxy)phenyl)acetamide (M6,29-77-35) was obtained as a pure white droplet with a yield of 82.44%. 1 H NMR (400MHz, CDCl3): δ9.90 (s, 1H), 8.50 (d, J = 7.6Hz, 1H), 7.22 (dd, J = 17.3, 10.0Hz, 2H), 7.13 (t, J = 7.2Hz, 1H),7.04(dd,J=26.1,18.7Hz,2H),6.91(t,J=8.0Hz,2H),6.82(d,J=7.4Hz,1H),3.44(s,2H),2.32(s,3H).

[0086] Synthetic intermediate M7: 2-amino-N-(2-(p-tolyloxy)phenyl)acetamide (29-72-36)

[0087]

[0088] Step 1: The preparation method is the same as that of M1-1, yielding a pale yellow oily substance of 1-nitro-2-(p-tolyloxy)benzene (M7-1, 29-59-32) with a yield of 100.0%. 1 H NMR (400MHz, CDCl3): δ7.93 (dd, J=8.2, 1.6Hz, 1H), 7.44–7.49 (m, 1H), 7.13–7.19 (m, 3H), 6.94–6.93 (m, 3H), 2.35 (s, 3H).

[0089] Step 2: The preparation method is the same as that of M2-2, yielding 2-(p-tolyloxy)aniline (M7-2, 29-63-30) as a brownish-yellow oil with a yield of 74.9%. 1H NMR (400MHz, CDCl3): δ7.12(d,J=8.2Hz,2H),6.95–6.99(m,1H),6.88–6.90(m,2H),6.8 4(ddd,J=8.0,1.6,1.6Hz,2H),6.70–6.74(m,1H),3.67(d,J=84.0Hz,2H),2.33(s,3H).

[0090] Step 3: The preparation method is the same as that of M1-3, yielding tert-butyl (2-oxo-2-((2-(p-tolyloxy)phenyl)amino)ethyl)carbamate (M7-3, 29-67-33) as a pure white transparent solid with a yield of 83.92%. 1 H NMR (400MHz, CDCl3): δ8.56(s,1H),8.40(dd,J=8.0,1.1Hz,1H),7.12(d,J=8.3Hz,2H),7.05(t,J=7.5Hz,1H),6.96(t,J=7. 3Hz,1H),6.88(d,J=8.5Hz,2H),6.79(dd,J=8.1,1.1Hz,1H),5.41(s,1H),3.90(d,J=5.3Hz,2H),2.32(s,3H),1.38(s,9H).

[0091] Step 4: Following the synthesis method described in M1-4, the target compound 2-amino-N-(2-(p-tolyloxy)phenyl)acetamide (M7,29-72-36) was obtained as a pure white solid with a yield of 88.59%. 1 H NMR (400MHz, CDCl3): δ9.90 (s, 1H), 8.49 (d, J = 7.9Hz, 1H), 7.09–7.14 (m, 3H), 7.00(t,J=7.6Hz,1H),6.88(dd,J=20.0,7.5Hz,2H),3.44(s,2H),2.33(s,3H).

[0092] Synthetic intermediate M8: 2-amino-N-(2-(2-bromophenoxy)phenyl)acetamide (29-168-38)

[0093]

[0094] Step 1: The preparation method is the same as that of M1-1, yielding a pale yellow oily substance of 1-bromo-2-(2-nitrophenoxy)benzene (M8-1,39-25-36) with a yield of 91.4%. 1H NMR (400MHz, CDCl3): δ7.99(d,J=8.1Hz,1H),7.66(d,J=8.0Hz,1H),7.49(dd,J=8.3,7.5Hz,1H),7.33(t, J=7.8Hz,1H),7.21(t,J=7.8Hz,1H),7.11(t,J=7.7Hz,1H),7.05(d,J=8.1Hz,1H),6.85(d,J=8.4Hz,1H).

[0095] Step 2: The preparation method is the same as that of M2-2, yielding 2-(2-bromophenoxy)aniline (M8-2,29-161-35) as a colorless oil with a yield of 95.27%. 1 H NMR (400MHz, CDCl3): δ7.63(dd,J=7.9,1.5Hz,1H),7.20–7.24(m,1H),6.96–7.02(m,2H),6.83–6.86(m,3H),6.71–6.76(m,1H),3.78(s,2H).

[0096] Step 3: The preparation method is the same as that of M1-3, yielding a pale yellow oily substance of (2-((2-(2-bromophenoxy)phenyl)amino)-2-oxyethyl)carbamate tert-butyl ester (M8-3, 29-163-41), with a yield of 49.05%. 1 ¹H NMR (400MHz, CDCl₃): δ 8.50 (s, 1H), 8.42 (dd, J = 8.1, 1.2Hz, 1H), 7.63 (dd, J = 8.0, 1.5Hz, 1H), 7.27–7.30 (m, 1H), 7.10–7.14 (m, 1H), 7.06 (dd, J = 7.7, 1.3Hz, 1H), 6.97–7.04 (m, 2H), 6.74 (dd, J = 8.1, 1.0Hz, 1H), 3.96 (d, J = 5.6Hz, 2H), 1.38 (s, 9H). Step 4: The preparation method was the same as that of M1-4, yielding the target compound 2-amino-N-(2-(2-bromophenoxy)phenyl)acetamide (M8, 29-168-38) as a transparent oily droplet with a yield of 83.14%. 1H NMR (400MHz, CDCl3): δ9.96 (s, 1H), 8.50 (dd, J=8.1, 1.4Hz, 1H), 7.63 (dd, J=8.0, 1.5Hz, 1H), 7.23–7.27 (m, 1H ),7.11–7.16(m,1H),6.99–7.04(m,2H)6.92(dd,J=8.2,1.4Hz,1H),6.79(dd,J=8.1,1.3Hz,1H),3.45(s,2H).

[0097] Synthetic intermediate M9: 2-amino-N-(2-(3-bromophenoxy)phenyl)acetamide (29-148-32)

[0098]

[0099] Step 1: The preparation method is the same as that of M1-1, yielding a pale yellow crude product of 1-(3-bromophenoxy)-2-nitrobenzene (M9-1,29-136-35) with a yield of 98.5%. 1 H NMR (400MHz, CDCl3): δ8.00 (dd, J=8.2, 1.6Hz, 1H), 7.59 (ddd, J=8.4, 7.6, 1.6Hz, 1H), 7.27–7.3 4(m,3H),7.20(t,J=2.0Hz,1H),7.09(dd,J=8.3,1.2Hz,1H),7.00(ddd,J=8.1,2.4,1.0Hz,1H).

[0100] Step 2: The preparation method is the same as that of M2-2, yielding a light yellow oily substance of 2-(3-bromophenoxy)aniline (M9-2,29-138-33) with a yield of 67.79%. 1 H NMR (400MHz, CDCl3): δ7.18(t,J=4.9Hz,2H),7.12(t,J=1.9Hz,1H),7.01–7.05(m,1 H),6.88–6.92(m,2H),6.84(dd,J=7.9,1.5Hz,1H),6.72–6.77(m,1H),3.65(s,2H).

[0101] Step 3: The preparation method is the same as that of M1-3. 136.8 mg of pure white solid (2-((2-(3-bromophenoxy)phenyl)amino)-2-oxyethyl)carbamate (M9-3, 29-143-35) was obtained, with a yield of 50.66%. 1H NMR (400MHz, CDCl3): δ8.50(s,1H),8.43(d,J=8.1Hz,1H),7.24(s,1H),7.20(d,J=8.1Hz,1H),7.16(dd,J=11.9,4.9Hz, 2H), 7.05 (t, J = 7.4Hz, 1H), 6.93 (dd, J = 8.1, 1.4Hz, 1H), 6.88 (dd, J = 8.1, 0.9Hz, 1H), 3.91 (d, J = 5.7Hz, 2H), 1.38 (s, 9H).

[0102] Step 4: The preparation method is the same as that of M1-4. The target compound 2-amino-N-(2-(3-bromophenoxy)phenyl)acetamide (M9,29-148-32) white solid was obtained in a yield of 66.3 mg, with a yield of 87.0%. 1 H NMR (400MHz, CDCl3): δ9.88 (s, 1H), 8.51 (d, J = 8.2Hz, 1H), 7.23 (dd, J = 15.4, 7. 3Hz,2H),7.16–7.20(m,2H),7.04–7.08(m,1H),6.91–6.95(m,2H),3.44(s,2H).

[0103] Synthetic intermediate M10: 2-amino-N-(2-(4-bromophenoxy)phenyl)acetamide (29-114-39)

[0104]

[0105] Step 1: The preparation method is the same as that of M1-1, yielding 1-(4-bromophenoxy)-2-nitrobenzene (M10-1,29-87-35) as a pale yellow oily droplet with a yield of 97.2%. 1 H NMR (400MHz, CDCl3): δ7.95 (dd, J=8.2, 1.5Hz, 1H), 7.51–7.55 (m, 1H), 7.45–7.49 (m, 2H), 7.23(dd,J=11.4,4.2Hz,1H),7.03(d,J=8.3Hz,1H),6.92–6.94(m,1H),6.90–6.91(m,1H).

[0106] Step 2: Following the synthesis method of M2-2, 2-(4-bromophenoxy)aniline (M10-2,29-93-36) was obtained as a pale yellow oil with a yield of 58.4%. 1H NMR (400MHz, CDCl3): δ7.38–7.42(m,2H),7.02(ddd,J=15.3,7.6,1.3Hz,1H),6.84–6.87(m,4H),6.71–6.75(m,1H).

[0107] Step 3: The preparation method is the same as that of M1-3, yielding (2-((2-(3-bromophenoxy)phenyl)amino)-2-oxyethyl)carbamate tert-butyl ester (M10-3, 29-108-30) as a transparent solid with a yield of 95.23%. 1 H NMR (400MHz, CDCl3): δ8.49(s,1H),8.41(t,J=8.0Hz,1H),,7.43–7.46(m,2H),7.13(t,J=7.3Hz,1H),7. 03(t,J=7.2Hz,1H),6.87–6.90(m,2H),6.84(dd,J=8.1,0.9Hz,1H),3.91(d,J=5.6Hz,2H),1.38(s,9H).

[0108] Step 4: The preparation method is the same as that of M1-4, to obtain the target compound 2-amino-N-(2-(4-bromophenoxy)phenyl)acetamide (M10,29-114-39) as a pale yellow solid with a yield of 100%. 1 ¹H NMR (400MHz, CDCl₃): δ 9.86 (s, 1H), 8.49 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.7 Hz, 2H), 7.17 (t, J = 7.7 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.89 (dd, J = 12.0, 8.7 Hz, 3H), 3.44 (s, 2H). Synthetic intermediate M11: 2-amino-N-(2-(2-(1-isopropyl-1H-pyrazol-3-yl)phenoxy)phenyl)acetamide (39-52-30)

[0109]

[0110] Step 1: At room temperature, M8-1 (336 mg, 1.1 mmol), a substituted pyrazole borate derivative (296.4 mg, 1.3 mmol), Na2CO3 (246.2 mg, 2.3 mmol), and xphos-Pd-G2 (43.4 mg, 0.1 mmol) were added to a reaction flask containing dioxane (3 mL) and water (0.6 mL). The mixture was heated to 100 °C under argon atmosphere and reacted for 46 h. After the reaction was complete, the mixture was cooled to room temperature, the organic solvent was evaporated, water was added to the system, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and then concentrated under vacuum. The crude product was purified by silica gel column chromatography to give 334.8 mg of a yellow oily substance of 1-isopropyl-3-(2-(2-nitrophenoxy)phenyl)-1H-pyrazole (M11-1, 39-30-30), with a yield of 90.87%. 1 H NMR (400MHz, CDCl3): δ8.06(s,1H),7.91(dd,J=8.1,1.5Hz,1H),7.82(s,1H),7.65(dd,J=7.3,2.1Hz,1H),7.35(dd,J=1 1.5,4.4Hz,1H),7.20–7.28(m,2H),7.02–7.09(m,2H),6.74(d,J=8.1Hz,1H),4.40–4.50(m,1H),1.45(d,J=6.7Hz,6H).

[0111] Step 2: The preparation method is the same as that of M2-2, yielding 2-(2-(1-isopropyl-1H-pyrazol-3-yl)phenoxy)aniline (M11-2,39-33-30) brownish-yellow solid with a yield of 64.3%. 1 H NMR (400MHz, CDCl3): δ8.06(s,1H),7.90(dd,J=8.1,1.5Hz,1H),7.81(s,1H),7.65(dd,J=7.3,2.1Hz,1H),7.33–7.37(m,1H), 7.20–7.28(m,2H),7.01–7.08(m,2H),6.73(d,J=8.1Hz,1H),4.39–4.49(m,1H),1.44(d,J=6.7Hz,6H),1.44(d,J=6.7Hz,6H).

[0112] Step 3: The preparation method is the same as that of M1-3, yielding (2-(2-(1-isopropyl-1H-pyrazol-3-yl)phenoxy)phenyl)amino)-2-oxoethyl)carbamate tert-butyl ester (M11-3, 39-49-30) a light yellow oil with a yield of 55.5%. 1HNMR (400MHz, CDCl3): δ8.55(s,1H),8.36–8.40(m,1H),7.82(s,1H),7.77(s,1H),7.61(dd,J=5.9,3.4Hz,1H),7.17–7.20(m,1H),7.06( t,J=7.7Hz,1H),6.91–6.98(m,2H),6.69(d,J=8.0Hz,1H),4.42–4.52(m,1H),3.91(d,J=5.5Hz,2H),1.47(d,J=6.7Hz,6H),1.29(s,9H).

[0113] Step 4: The preparation method is the same as that of M1-4. The target compound 2-amino-N-(2-(2-(1-isopropyl-1H-pyrazol-3-yl)phenoxy)phenyl)acetamide (M11,39-52-30) is a white oily solid with a yield of 89.2%. 1 H NMR (400MHz, CDCl3): δ10.00(d,J=32.7Hz,1H),8.47(dd,J=12.8,8.5Hz,1H),7.89(s,1H),7.78(t, J=26.8Hz,1H),7.61(dd,J=5.5,3.7Hz,1H),7.21(dd,J=5.8,3.6Hz,1H),7.14–7.16(m,1H),7.11(dd ,J=14.6,6.6Hz,1H),7.00–7.05(m,1H),6.96(dd,J=10.9,7.2Hz,1H),6.88–6.90(m,1H),6.81(d,J= 8.1Hz,1H),6.71(d,J=2.0Hz,1H),4.43–4.50(m,1H),3.45(d,J=11.2Hz,2H),1.47(d,J=6.7Hz,6H).

[0114] Synthetic intermediate M12: 2-amino-N-(2-(3-(1-isopropyl-1H-pyrazol-3-yl)phenoxy)phenyl)acetamide (39-41-30)

[0115]

[0116] Step 1: The preparation method is the same as that of M11-1 type synthesis, to obtain 1-isopropyl-3-(3-(2-nitrophenoxy)phenyl)-1H-pyrazole (M12-1,39-32-30) pale yellow oil, with a yield of 95.0%. 1H NMR (400MHz, CDCl3): δ7.96(dd,J=8.2,1.6Hz,1H),7.75(s,1H),7.66(s,1H),7.47–7.52(m,1H),7.30–7.38( m,2H),7.17–7.21(m,2H),7.03(d,J=7.9Hz,1H),6.65–6.87(m,1H),4.47–4.57(m,1H),1.54(d,J=6.7Hz,6H).

[0117] Step 2: The preparation method is the same as that of M2-2, yielding 2-(3-(1-isopropyl-1H-pyrazol-3-yl)phenoxy)aniline (M12-2, 39-34-30) as a pale yellow oil with a yield of 77.8%. 1 H NMR (400MHz, CDCl3): δ7.75(d,J=4.5Hz,1H),7.64(d,J=6.5Hz,1H),7.28–7.33(m,1H),7.19(d,J=7.7Hz,1H),7.13(s,1H),6.99(t,J=7.6Hz,1 H), 6.90 (d, J = 8.0Hz, 1H), 6.84 (d, J = 7.8Hz, 1H), 6.81 (d, J = 8.0Hz, 1H), 6.74 (dt, J = 11.4, 5.2Hz, 1H), 4.48–4.54 (m, 1H), 1.54 (d, J = 6.7Hz, 6H).

[0118] Step 3: The preparation method is the same as that of M1-3. A colorless oily substance of pyrazol-3-yl)phenoxy)phenyl)amino)-2-oxoethyl)carbamate tert-butyl ester (M12-3, 39-37-30) is obtained with a yield of 74.1%. 1 H NMR (400MHz, CDCl3): δ8.51(s,1H),8.44(d,J=7.9Hz,1H),7.75(s,1H),7.65(s,1H),7.33(t,J=7.8Hz,1H),7.27(t,J=3.8Hz,1H),7.13(dd ,J=9.4,5.1Hz,2H),7.03(t,J=7.5Hz,1H),6.83–6.90(m,2H),4.48–4.58(m,1H),3.94(d,J=5.3Hz,2H),1.54(d,J=6.8Hz,6H),1.38(s,9H).

[0119] Step 4: The preparation method is the same as that of M1-4. The target compound 2-amino-N-(2-(3-(1-isopropyl-1H-pyrazol-3-yl)phenoxy)phenyl)acetamide (M12,39-41-30) is a white oily solid with a yield of 65.1%. 1 H NMR (400MHz, CDCl3): δ9.90(s,1H),8.50(dd,J=8.1,1.4Hz,1H),7.74(s,1H),7.63(s,1H),7.31(t,J=7.9Hz,1H),7.24(d,J=7.7Hz,1H),7. 12–7.16(m,2H),7.01–7.05(m,2H),6.93(dd,J=8.1,1.3Hz,1H),6.81–6.84(m,1H),4.46–4.56(m,1H),3.45(s,2H),1.53(d,J=6.7Hz,6H).

[0120] Synthetic intermediate M13: 2-amino-N-(2-(4-(1-isopropyl-1H-pyrazol-3-yl)phenoxy)phenyl)acetamide (29-124-40)

[0121]

[0122] Step 1: The preparation method is the same as that of M11-1, yielding 1-isopropyl-3-(4-(2-nitrophenoxy)phenyl)-1H-pyrazole (M13-1,29-115-33) as a pale yellow oil droplet with a yield of 91.07%. 1 H NMR (400MHz, CDCl3): δ7.93(dd,J=8.1,1.0Hz,1H),7.74(s,1H),7.65(s,1H),7.49(dd,J=11.3,4 .9Hz,3H),7.17(t,J=7.8Hz,1H),7.02(t,J=8.8Hz,3H),4.47–4.57(m,1H),1.54(d,J=6.7Hz,6H).

[0123] Step 2: The preparation method is the same as that of M2-2, yielding 2-(4-(1-isopropyl-1H-pyrazol-3-yl)phenoxy)aniline (M13-2,29-117-31) as a pale yellow solid with a yield of 100.0%. 1H NMR (400MHz, CDCl3): δ7.72(s,1H),7.60(s,1H),7.41(d,J=7.6Hz,2H), 6.97(d,J=8.6Hz,2H), 6.86(dd,J=16.1,7.9Hz,2H),6.72(t,J=7.7Hz,1H),4.47–4.57(m,1H),1.54(d,J=6.8Hz,6H).

[0124] Step 3: The preparation method is the same as that of M1-3, yielding (2-(2-(4-(1-isopropyl-1H-pyrazol-3-yl)phenoxy)phenyl)amino)-2-oxoethyl)tert-butyl carbamate (M13-3,29-118-30) transparent solid with a yield of 95.4%. 1 HNMR (400MHz, CDCl3): δ8.51(s,1H),8.41(d,J=7.3Hz,1H),7.74(s,1H),7.64(s,1H),7.44(d,J=8.6Hz,2H),7.10(t,J=7.8Hz,1H) ,7.00(dd,J=12.4,5.7Hz,3H),6.85(d,J=7.2Hz,1H),4.48–4.58(m,1H),3.93(d,J=5.4Hz,2H),1.55(d,J=6.7Hz,6H),1.38(s,9H).

[0125] Step 4: The preparation method is the same as that of M1-4. The target compound 2-amino-N-(2-(4-(1-isopropyl-1H-pyrazol-3-yl)phenoxy)phenyl)acetamide (M13,29-124-40) was obtained as a transparent oily droplet with a yield of 58.06%. 1 H NMR (400MHz, CDCl3): δ9.90(s,1H),8.48–8.51(m,1H),7.74(d,J=7.1Hz,1H),7.63(d,J=8.9Hz,1H),7.43–7.49(m,2H),7.13(dd,J =11.3,4.3Hz,1H),6.99–7.05(m,3H),6.92(dd,J=8.1,1.2Hz,1H),4.47–4.55(m,1H),3.46(d,J=6.4Hz,2H),1.54(d,J=6.7Hz,6H).

[0126] Synthetic intermediate M14: 2-amino-N-(2-(2-(1-cyclopropyl-1H-pyrazol-4-yl)phenoxy)phenyl)acetamide (46-58-33)

[0127]

[0128] Step 1: The preparation method is the same as that of M11-1, yielding 1-cyclopropyl-4-(2-(2-nitrophenoxy)phenyl)-1H-pyrazole (M14-1,46-41-31) as a pale yellow oil with a yield of 76.14%. 1 H NMR (400MHz, CDCl3): δ8.05(s,1H),7.92(dd,J=8.1,1.6Hz,1H),7.81(s,1H),7.61–7.64(m,1H),7.35–7.39(m,1H),7.20–7.26 (m,2H),7.07–7.12(m,1H),6.99–7.01(m,1H),6.76(d,J=8.5Hz,1H),3.54–3.60(m,1H),1.04–1.10(m,2H),0.96–1.03(m,2H).

[0129] Step 2: The preparation method is the same as that of M2-2, yielding 2-(2-(1-cyclopropyl-1H-pyrazole-4-yl)phenoxy)aniline (M14-2, 46-47-30) as a pale yellow oil with a yield of 90.23%. 1 H NMR (400MHz, CDCl3): δ7.17(s,1H),7.13(s,1H),6.89–6.91(m,1H),6.55(s,1H),6.38–6.48(m,2H),6. 10–6.22(m,2H),6.03(dd,J=10.0,5.4Hz,2H),2.86–2.91(m,2H),0.40–0.44(m,2H),0.27–0.32(m,2H).

[0130] Step 3: The preparation method is the same as that of M1-3, to obtain (2-(2-(1-cyclopropyl-1H-pyrazole-4-yl)phenoxy)phenyl)amino)-2-oxoethyl)tert-butyl carbamate (M14-3, 46-52-35) as a colorless oil with a yield of 100.0%. 1HNMR (400MHz, CDCl3): δ8.61 (d, J = 39.5Hz, 1H), 8.37 (dd, J = 16.3, 8.4Hz, 1H), 7.77 (t, J = 9. 8Hz,2H),7.58(t,J=9.2Hz,1H),,7.20–7.23(m,1H),7.15–7.18(m,1H),7.07(t,J=7.7Hz,1H ),6.91–7.02(m,1H),6.86–6.89(m,1H),6.61–6.72(m,1H),5.25–5.31(m,1H),3.90(d,J=5 .3Hz,2H),3.56(dt,J=10.6,3.6Hz,1H),1.28(s,9H),1.07–1.28(m,2H),0.96–1.00(m,2H).

[0131] Step 4: The preparation method is the same as that of M1-4. The target compound 2-amino-N-(2-(2-(1-cyclopropyl-1H-pyrazol-4-yl)phenoxy)phenyl)acetamide (M14,46-58-33) is a colorless and transparent oil with a yield of 54.68%. 1 HNMR (400MHz, CDCl3): δ10.01 (d, J=31.2Hz, 1H), 8.47 (dd, J=12.9, 8.5Hz, 1H), 7.84 (d,J=4.6Hz,1H),7.79(d,J=19.7Hz,1H),7.58(dd,J=5.9,3.2Hz,1H),7.19–7.21(m, 1H),7.09–7.15(m,2H),6.97–7.06(m,2H),6.81–6.88(m,1H),6.72(d,J=1.8Hz,1H), 3.55–3.58(m,1H),3.45(d,J=11.4Hz,2H),1.08(d,J=1.3Hz,2H),0.96–1.08(m,2H).

[0132] Synthetic intermediate M15: 2-amino-N-(2-(2-(1-propyl-1H-pyrazol-4-yl)phenoxy)phenyl)acetamide (46-112-35)

[0133]

[0134] Step 1: The preparation method is the same as that of M11-1, yielding 4-(2-(2-nitrophenoxy)phenyl)-1-propyl-1H-pyrazole (M15-1,46-42-34) as a yellow oil with a yield of 100.0%. 1H NMR (400MHz, CDCl3): δ7.98(s,1H),7.89(dd,J=8.2,1.7Hz,1H),7.81(s,1H),7.62–7.64(m,1H),7.32–7.34(m,1H),7.19–7.25(m,2H),7. 03–7.08(m,1H),7.00(dd,J=7.7,1.7Hz,1H),6.72(dd,J=8.5,1.0Hz,1H),4.01(t,J=7.0Hz,2H),1.76–1.85(m,2H),0.77(t,J=7.4Hz,3H).

[0135] Step 2: The preparation method is the same as that of M1-2, yielding 2-(2-(1-propyl-1H-pyrazol-4-yl)phenoxy)aniline (M15-2,46-99-29) as a colorless oil with a yield of 89.8%. 1 H NMR (400MHz, CDCl3): δ7.92(s,2H),7.63–7.65(m,1H),7.10–7.12(m,2H),6.96–6.98(m,1H),6.84(ddd,J=7.9,5. 0,1.4Hz,3H),6.71(ddd,J=8.9,7.7,1.5Hz,1H),4.08(t,J=7.1Hz,2H),1.85–1.94(m,2H),0.90(t,J=7.4Hz,3H).

[0136] Step 3: The preparation method is the same as that of M1-3, yielding a colorless oily substance of (2-oxo-2-((2-(1-propyl-1H-pyrazol-4-yl)phenoxy)phenyl)amino)ethyl)carbamate (M15-3, 46-59-35), with a yield of 71.33%. 1HNMR (400MHz, CDCl3): δ8.58(d,J=36.1Hz,1H),8.37(dd,J=15.2,8.4Hz,1H),7.75–7.84(m,1H),7.62– 7.69(m,1H),7.18–7.26(m,2H),7.07(t,J=7.4Hz,1H),6.91–7.02(m,2H),6.60–6.71(m,1H),4.11(dd,J =19.7,12.6Hz,2H),3.91(s,1H),1.85(d,J=5.4Hz,2H),1.28(d,J=9.0Hz,9H),0.85(s,3H). Step 4: The preparation method is the same as that of M1-4. The target compound 2-amino-N-(2-(2-(1-propyl-1H-pyrazol-4-yl)phenoxy)phenyl)acetamide (M15,46-66-31) was obtained as a pure white solid, 31 mg, with a yield of 99.64%. 1 H NMR (400MHz, CDCl3): δ10.00 (s, 1H), 8.42 (d, J = 8.8Hz, 1H), 7.85 (s, 1H), 7. 68(s,1H),7.60–7.68(m,1H),7.21(dd,J=5.7,3.5Hz,2H),7.03(d,J=8.6Hz, 1H),6.93(dd,J=5.6,3.7Hz,1H),6.71(s,1H),4.12(q,J=7.1Hz,1H),4.05( dd,J=16.7,9.7Hz,2H),1.85(dt,J=14.4,7.0Hz,2H),0.85(t,J=7.4Hz,3H).

[0137] Synthetic intermediate M16: 2-amino-N-(2-(2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)phenoxy)phenyl)acetamide (46-109-35)

[0138]

[0139] Step 1: The preparation method is the same as that of M11-1, yielding 4-(2-(2-nitrophenoxy)phenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (M16-1,46-44-34) as a pale yellow oil with a yield of 91.2%. 1H NMR (400MHz, CDCl3): δ8.15(s,1H),7.92–7.94(m,2H),7.63–7.67(m,1H),7.36–7.41(m,1H),7.25–7 .29(m,2H),7.09–7.13(m,1H),7.00–7.04(m,1H),6.77(dd,J=8.4,0.7Hz,1H),4.67(q,J=8.4Hz,2H).

[0140] Step 2: The preparation method is the same as that of M1-2, yielding 2-(2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)phenoxy)aniline (M16-2,46-95-39) as a colorless oil with a yield of 43.8%. 1 H NMR (400MHz, CDCl3): δ8.03(d,J=16.1Hz,1H),7.97(d,J=5.0Hz,1H),7.63(dd,J=7.5,1.4Hz,1H),7.10–7.24(m,2 H),7.00(dd,J=11.2,4.0Hz,1H),6.90–6.95(m,1H),6.82–6.86(m,2H),6.70–6.76(m,1H),4.71(q,J=8.4Hz,2H).

[0141] Step 3: The preparation method is the same as that of M1-3, yielding a colorless oily substance of (2-oxo-2-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)phenoxy)phenyl)amino)ethyl)carbamate (M16-3,46-57-36), with a yield of 84.0%. 1 H NMR (400MHz, CDCl3): δ8.52(s,1H),8.37(d,J=8.0Hz,1H),7.91(d,J=8.6Hz,2H),7.61–7.63(m,1H),7.19–7.24(m,2H),7.09(t,J=7.7 Hz,1H),6.98(t,J=7.6Hz,1H),6.93(d,J=8.6Hz,1H),6.72(d,J=7.7Hz,1H),4.71(q,J=8.4Hz,2H),3.89(d,J=5.7Hz,2H),1.29(s,9H).

[0142] Step 4: The preparation method is the same as that of M1-4. The target compound 2-amino-N-(2-(2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)phenoxy)phenyl)acetamide (M16,46-109-35) is a colorless and transparent oil with a yield of 97.9%.1 ¹H NMR (400MHz, CDCl₃): δ 9.98 (s, 1H), 8.50 (dd, J = 8.1, 1.5Hz, 1H), 7.96 (d, J = 20.0Hz, 2H), 7.63 (dd, J = 7.3, 2.1Hz, 1H), 7.18 (ddd, J = 13.9, 7.1, 1.7Hz, 4H), 7.00–7.05 (m, 2H), 6.86–7.04 (m, 2H), 4.71 (q, J = 8.4Hz, 2H). Synthetic intermediate M17: (2-(2-(1-(oxecyclobutan-3-yl)-1H-pyrazol-4-yl)phenoxy)phenyl)amino)-2-oxoethyl)tert-butyl carbamate (46-67-35)

[0143]

[0144] Step 1: The preparation method is the same as that of M11-1, yielding 4-(2-(2-nitrophenoxy)phenyl)-1-(oxecyclobutane-3-yl)-1H-pyrazole (M17-1, 46-46-35) as a pale yellow oil with a yield of 87.24%. 1 H NMR (400MHz, CDCl3): δ8.21(s,1H),7.93(d,J=8.9Hz,2H),7.67(d,J=6.4Hz,1H),7.41(t,J=7.9Hz,1H),7.27(dd,J=5.9 ,1.1Hz,2H),7.13(t,J=7.7Hz,1H),7.02(d,J=7.2Hz,1H),6.81(d,J=8.5Hz,1H),5.40–5.47(m,1H),5.00–5.07(m,1H).

[0145] Step 2: The preparation method is the same as that of M1-2, yielding 2-(2-(1-(oxecyclobutane-3-yl)-1H-pyrazol-4-yl)phenoxy)aniline (M17-2, 46-69-35) as a colorless oil with a yield of 92.43%. 1 H NMR (400MHz, CDCl3): δ8.10(s,1H),8.02(s,1H),7.65(dd,J=7.2,2.1Hz,1H),7.10–7.18(m,1H),6.96–7.00(m,1H) ,6.79–6.83(m,3H),6.68–6.72(m,1H),5.41–5.48(m,1H),5.09(t,J=6.6Hz,2H),5.02(t,J=7.3Hz,2H),3.73(s,2H)

[0146] Step 3: The preparation method is the same as that of M1-3, yielding (2-(2-(1-(oxecyclobutane-3-yl)-1H-pyrazol-4-yl)phenoxy)phenyl)amino)-2-oxoethyl)tert-butyl carbamate (M17-3,46-85-33) as a colorless, transparent oil with a yield of 82.4%. 1 H NMR (400MHz, CDCl3): δ8.62(s,1H),8.37(dd,J=8.1,1.3Hz,1H),8.03(s,1H),7.89(s,1H),7.62(dt,J=7. 5,3.4Hz,1H),7.19–7.24(m,2H),7.05(t,J=7.6Hz,1H),6.95(dd,J=12.1,5.8Hz,2H),6.66(d,J=7.9Hz,1 5.40–5.46 (m, 1H), 5.03 (dt, J = 13.3, 7.0 Hz, 4H), 3.92 (d, J = 5.9 Hz, 2H), 1.27 (s, 9H). Step 4: The preparation method is the same as that of M1-4, yielding the target compound 2-amino-N-(2-(2-(1-(oxecyclobutan-3-yl)-1H-pyrazol-4-yl)phenoxy)phenyl)acetamide (M17,46-67-35) as a colorless oil with a yield of 100.0%. 1 H NMR (400MHz, CDCl3): δ9.98(s,1H),8.46(d,J=8.1Hz,1H),8.06(s,1H),7.96(s,1H),7.61–7.63(m,1H),715–7.21(m,2H),7.09(t,J=7.8H z,1H),6.98(t,J=7.8Hz,1H),6.91(dd,J=5.7,1.9Hz,1H),6.78(d,J=8.1Hz,1H),5.39–5.46(m,4H),4.99–5.06(m,4H),3.48–3.50(m,2H).

[0147] Synthetic intermediate M18: 2-amino-N-(2-(2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenoxy)phenyl)acetamide (46-108-33)

[0148]

[0149] Step 1: The preparation method is the same as that of M11-1, yielding 1-(difluoromethyl)-4-(2-(2-nitrophenoxy)phenyl)-1H-pyrazole (M18-1,46-80-30) as a colorless oil with a yield of 88.89%. 1H NMR (400MHz, CDCl3): δ8.39(s,1H),8.06(s,1H),7.97(d,J=8.1Hz,1H),7.65–7.66(m,1H),7.44(t,J=7.9H z,1H),7.28(ddd,J=7.9,7.3,4.2Hz,3H),7.17(t,J=7.7Hz,1H),6.98–7.02(m,1H),6.85(d,J=8.4Hz,1H).

[0150] Step 2: The preparation method is the same as described in the synthesis of M1-2, yielding 2-(2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenoxy)aniline (M18-2,46-81-32) as a colorless and transparent substance with a yield of 99.88%. 1 H NMR (400MHz, CDCl3): δ8.40(s,1H),8.16(s,1H),7.69(d,J=7.6Hz,1H),7.42(s,0.5H),7.32(s,0.5H),7.24–7.27 (m,1H),7.19(t,J=7.5Hz,1H),7.09(dd,J=15.2,7.7Hz,1H),6.92(dd,J=12.2,8.0Hz,3H),6.81(t,J=7.6Hz,1H).

[0151] Step 3: The preparation method is the same as that of M1-3, yielding a colorless oily substance of (2-(2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenoxy)phenyl)amino)-2-oxoethyl)carbamate tert-butyl ester (M18-3, 46-94-37), with a yield of 67.61%. 1 H NMR (400MHz, CDCl3): δ8.48(s,1H),8.32(d,J=8.0Hz,1H),8.12(s,1H),7.92(s,1H),7.53(dd,J=7.4,1.6Hz,1H),7.15(d,J=1.6Hz,1H),7.09–7.15 (m,2H),7.02(dd,J=15.9,8.3Hz,1H),6.88–6.97(m,2H),6.80(d,J=7.8Hz ,1H),6.68(d,J=7.9Hz,1H),3.80(d,J=4.9Hz,2H),1.18(d,J=10.4Hz,1H)

[0152] Step 4: The preparation method is the same as that of M1-4. The target compound 2-amino-N-(2-(2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenoxy)phenyl)acetamide (M18,46-108-33) is obtained as a colorless oil with a yield of 76.36%. 1 ¹H NMR (400 MHz, CDCl₃): δ 9.90 (s, 1H), 8.44 (dd, J = 8.1, 1.3 Hz, 1H), 8.19 (s, 1H), 7.96 (s, 1H), 7.53 (dd, J = 7.5, 1.8 Hz, 1H), 7.13–7.16 (m, 1H), 7.05–7.12 (m, 3H), 6.94 (td, J = 7.8, 2.0 Hz, 1H), 6.81 (d, J = 8.1 Hz, 2H), 3.34 (s, 2H). Synthetic intermediate M19: 2-amino-N-(3-(4-fluorophenoxy)phenyl)acetamide (46-54-37)

[0153]

[0154] Step 1: The preparation method is the same as that of M1-1, yielding 1-(4-fluorophenoxy)-2-nitrobenzene (M19-1,46-39-29) as a pale yellow oil with a yield of 100.0%. 1 H NMR (400MHz, CDCl3): δ7.94(dd,J=8.2,1.6Hz,1H),7.50(td,J=8.3,1.4Hz,1H),7.17–7.22(m,1H),7.01–7.10(m,4H),6.96(d,J=8.4Hz,1H).

[0155] Step 2: The preparation method is the same as that of M2-2, yielding 2-(4-fluorophenoxy)aniline (M19-2,46-43-34) as a pale yellow oil with a yield of 82.87%. 1 H NMR (400MHz, CDCl3): δ6.98–7.04(m,3H),6.93–6.97(m,2H),6.84(dd,J=7.7,1.0Hz,2H),6.73(td,J=8.0,1.1Hz,1H),3.72(s,2H).

[0156] Step 3: The preparation method is the same as that of M1-3, yielding (2-((3-(4-fluorophenoxy)phenyl)amino)-2-oxyethyl)carbamate tert-butyl ester (M19-3, 46-53-35) white solid with a yield of 91.58%. 1H NMR (400MHz, CDCl3): δ8.54 (s, 1H), 8.40 (dd, J = 8.1, 1.1Hz, 1H), 6.95 -7.10(m,6H),6.77(dd,J=8.1,1.1Hz,1H),5.27(s,1H),3.92(d,J=5.7Hz,2H),1.38(s,9H).

[0157] Step 4: The preparation method is the same as that of M1-4. The target compound 2-amino-N-(3-(4-fluorophenoxy)phenyl)acetamide (M19,46-54-37) is a white solid powder with a yield of 75.75%. 1 H NMR (400MHz, CDCl3): δ9.90 (s, 1H), 8.48 (dd, J = 8.1, 1.4Hz, 1H), 7.09 -7.13 (m, 1H), 6.94 -7.05 (m, 5H), 6.83 (dd, J = 8.1, 1.3Hz, 1H), 3.44 (s, 2H).

[0158] Synthetic intermediate M20: 2-amino-N-(3-(4-chlorophenoxy)phenyl)acetamide (46-60-30)

[0159]

[0160] Step 1: The preparation method is the same as that of M1-1, yielding 1-(4-chlorophenoxy)-2-nitrobenzene (M20-1,46-40-29) as a pale yellow oil with a yield of 99.62%. 1 H NMR (400MHz, CDCl3): δ7.95 (dd, J=8.2, 1.6Hz, 1H), 7.53 (ddd, J=8.5, 7.6, 1.7Hz, 1H), 7.30–7.34(m,2H),7.21–7.26(m,1H),7.02(dd,J=8.4,1.1Hz,1H),6.95-7.03(m,2H).

[0161] Step 2: The preparation method is the same as that of M2-2, yielding 2-(4-chlorophenoxy)aniline (M20-2, 46-45-30) as an orange-yellow oil with a yield of 72.2%. 1 H NMR (400MHz, CDCl3): δ7.24–7.25(m,1H),7.27–7.28(m,1H),7.01(td,J=7.8,1.4Hz,1H) ,6.88–6.92(m,2H),6.85(ddd,J=10.9,8.0,1.4Hz,2H),6.71–6.76(m,1H),3.59(s,2H).

[0162] Step 3: The preparation method is the same as that of M1-3, yielding 2-((3-(4-chlorophenoxy)phenyl)amino)-2-oxoethyl)carbamate tert-butyl ester (M20-3, 46-55-32) as a pale yellow oil with a yield of 96.8%. 1 H NMR (400MHz, CDCl3): δ8.52(s,1H),8.40(d,J=7.3Hz,1H),7.27–7.31(m,2H),7.11(t,J=7.4Hz,1H),7.02(t,J =7.3Hz,1H),6.92–6.95(m,2H),6.83(dd,J=8.1,0.9Hz,1H),5.26(s,1H),3.90(d,J=5.6Hz,2H),1.37(s,9H).

[0163] Step 4: The preparation method is the same as that of M1-4. The target 2-amino-N-(3-(4-chlorophenoxy)phenyl)acetamide (M20,46-60-30) is obtained as a milky white droplet with a yield of 94.5%. 1 H NMR(400MHz, CDCl3): δ9.86(s,1H),8.49–8.51(m,1H),7.27–7.30(m,2H),7.17 (t,J=7.5Hz,1H),7.04(td,J=8.0,1.4Hz,1H),6.90–6.96(m,3H),3.45(s,2H).

[0164] Synthetic intermediate M21: 2-amino-N-(3-(4-(trifluoromethyl)phenoxy)phenyl)acetamide (46-79-29)

[0165]

[0166] Step 1: The preparation method is the same as that of M1-1, yielding a pale yellow oily substance of 1-nitro-2-(4-(trifluoromethyl)phenoxy)benzene (M21-1,46-70-36) with a yield of 99.072%. 1 H NMR (400MHz, CDCl3): δ8.01(dd,J=8.2,1.6Hz,1H),7.59–7.63(m,3H),7.31–7.35(m,1H),7.13(dd,J=8.3,1.0Hz,1H),7.08(d,J=8.5Hz,2H).

[0167] Step 2: The preparation method is the same as that of M1-2, yielding 2-(4-(trifluoromethyl)phenoxy)aniline (M21-2, 46-74-30) as a colorless, transparent oil with a yield of 92.52%.1 H NMR (400MHz, CDCl3): δ7.58 (d, J=8.8Hz, 2H), 7.03–7.10 (m, 3H), 6.95 (dd, J=8.0, 1.3Hz, 1H), 6.87 (dd, J=7.9, 1.4Hz, 1H), 6.79 (td, J=7.6, 1.6Hz, 1H), 3.77 (s, 2H).

[0168] Step 3: The preparation method is the same as that of M1-3, yielding tert-butyl (2-oxo-2-((3-(4-(trifluoromethyl)phenoxy)phenyl)amino)ethyl)carbamate (M21-3, 46-78-32) as a pure white solid with a yield of 79.4%. 1 H NMR (400MHz, CDCl3): δ8.59(s,1H),8.39(t,J=23.2Hz,1H),7.53(dd,J=39.4,8.1Hz,2H),7.17(t,J=7.7 Hz,1H),7.03(t,J=19.5Hz,3H),6.92(d,J=8.0Hz,1H),5.29(s,1H),3.84(t,J=21.9Hz,2H),1.34(s,9H).

[0169] Step 4: The preparation method is the same as that of M1-4, to obtain the target compound 2-amino-N-(3-(4-(trifluoromethyl)phenoxy)phenyl)acetamide (M21,46-79-29) as a white solid with a yield of 83.0%. 1 ¹H NMR (400MHz, CDCl₃): δ 9.89 (s, 1H), 8.52 (d, J = 8.0Hz, 1H), 7.57 (d, J = 8.6Hz, 2H), 7.22 (t, J = 7.7Hz, 1H), 7.07 (dd, J = 16.5, 8.1Hz, 3H), 6.99 (d, J = 8.0Hz, 1H), 3.42 (s, 2H). Synthetic intermediate M22: 2-amino-N-(3-(4-ethylphenoxy)phenyl)acetamide (46-103-31)

[0170]

[0171] Step 1: The preparation method is the same as that of M1-4, yielding 1-(4-ethylphenoxy)-2-nitrobenzene (M22-1,46-84-40) as a pale yellow oil with a yield of 98.1%. 1H NMR (400MHz, CDCl3): δ7.92 (dd, J=8.2, 1.7Hz, 1H), 7.47 (ddd, J=8.6, 7.5, 1.7Hz, 1H), 7.21 (d, J=8.6Hz,2H),7.13–7.17(m,1H),6.96–6.99(m,3H),2.65(q,J=7.6Hz,2H),1.22–1.28(m,3H).

[0172] Step 2: The preparation method is the same as that of M1-2, yielding 2-(4-ethylphenoxy)aniline (M22-2, 46-90-31) as a colorless oil with a yield of 91.9%. 1 H NMR (400MHz, CDCl3): δ7.15(d,J=8.4Hz,1H),6.98(td,J=7.6,1.4Hz,1H),6.90–6.94(m,1H),6.86(ddd,J=12.2 ,7.9,1.5Hz,1H),6.73(td,J=7.7,1.5Hz,1H),3.75(s,2H),2.64(q,J=7.6Hz,2H),1.25(dd,J=14.8,7.2Hz,3H).

[0173] Step 3: The preparation method is the same as that of M1-3, yielding (2-oxo-2-((3-(4-ethylphenoxy)phenyl)amino)ethyl)carbamate tert-butyl ester (M22-3, 46-97-40) as a white oil with a yield of 84.0%. 1 H NMR (400MHz, CDCl3): δ8.49(s,1H),8.42(dd,J=8.1,1.4Hz,1H),7.14–7.18(m,2H),7.06–7.10(m,1H),6.97–7.01(m,1H),6.90–6.9 4(m,2H),6.82(dd,J=8.1,1.3Hz,1H),5.21(s,1H),3.92(d,J=5.6Hz,2H),2.63(q,J=7.6Hz,2H),1.38(s,9H),1.23(t,J=7.6Hz,3H).

[0174] Step 4: The preparation method is the same as that of M1-4. The target compound 2-amino-N-(3-(4-ethylphenoxy)phenyl)acetamide (M22,46-103-31) is obtained as a colorless oil with a yield of 100.0%. 1¹H NMR (400MHz, CDCl₃): δ 9.91 (s, 1H), 8.50 (d, J = 8.1Hz, 1H), 7.16 (d, J = 8.4Hz, 2H), 7.11 (t, J = 7.7Hz, 2H), 7.01 (t, J = 7.8Hz, 1H), 6.94 (dd, J = 8.4, 3.1Hz, 2H), 6.87 (d, J = 8.1Hz, 1H), 3.46 (s, 2H), 2.63 (dt, J = 7.6, 5.3Hz, 2H), 1.25 (dd, J = 7.7, 3.3Hz, 3H). Synthetic intermediate M23: 2-amino-N-(3-(4-propylphenoxy)phenyl)acetamide (46-102-37)

[0175]

[0176] Step 1: The preparation method is the same as that of M1-1, yielding a pale yellow oily substance of 1-nitro-2-(4-propylphenoxy)benzene (M23-1,46-82-30) with a yield of 98.1%. 1 H NMR (400MHz, CDCl3): δ7.93(d,J=8.1Hz,1H),7.47(t,J=7.9Hz,1H),7.16(dd,J=16.7,8.1Hz ,3H),6.97(d,J=8.3Hz,3H),2.58(t,J=7.6Hz,2H),1.60–1.69(m,2H),0.95(t,J=7.3Hz,3H).

[0177] Step 2: The preparation method is the same as that of M1-2, yielding 2-(4-propylphenoxy)aniline (M23-2,46-88-38) as a colorless oil with a yield of 88.96%. 1 H NMR (400MHz, CDCl3): δ7.12–7.15(m,2H),6.97–7.01(m,1H),6.90–6.94(m,2H),6.86(ddd,J=15.4,7.9, 1.5Hz,2H),6.71–6.75(m,1H),3.76(s,2H),2.56–2.59(m,2H),1.60–1.70(m,2H),0.97(t,J=7.3Hz,3H).

[0178] Step 3: The preparation method is the same as that of M1-3, to obtain (2-oxo-2-((3-(4-propylphenoxy)phenyl)amino)ethyl)carbamate tert-butyl ester (M23-3, 46-96-38) as a colorless oil with a yield of 94.04%. 1H NMR (400MHz, CDCl3): δ8.49(s,1H),8.42(dd,J=8.1,1.3Hz,1H),7.14(d,J=8.5 Hz, 2H), 7.07 (dd, J=11.3, 4.2Hz, 1H), 6.99 (dd, J=11.4, 4.1Hz, 1H), 6.92 (dd, J= 9.0,2.2Hz,2H),6.82(dd,J=8.1,1.2Hz,1H),5.22(s,1H),3.92(d,J=5.5Hz,2H ), 4.06 (d, J = 7.2Hz, 2H), 1.58-1.67 (m, 3H), 1.38 (s, 9H), 0.94 (t, J = 7.3Hz, 3H).

[0179] Step 4: The preparation method is the same as that of M1-4. The target compound 2-amino-N-(3-(4-propylphenoxy)phenyl)acetamide (M23,46-102-30) is obtained as a colorless oil with a yield of 91.46%. 1 H NMR (400MHz, CDCl3): δ9.88(s,1H),8.49(dd,J=8.1,1.6Hz,1H),7.15(dd,J=6.7,4.7Hz,2H),7.10(dd,J=7.9,1.3Hz,1H),7.00(td,J=7.8,1.6Hz,1H),6. 94(t,J=2.8,1H),6.92(t,J=2.0,1H),6.87(dd,J=8.1,1.4Hz,1H),3.45(s,2 H), 2.56 (t, J = 7.2, 2H), 1.63 (dd, J = 15.1, 7.5Hz, 2H), 0.94 (t, J = 7.3Hz, 3H).

[0180] Synthetic intermediate M24: (R)-2-amino-N-(2-phenoxyphenyl)propionamide (42-4-30)

[0181]

[0182] Step 1: The preparation method is the same as that of M1-3, yielding (R)-(1-oxo-1-((2-phenoxyphenyl)amino)propyl-2-yl)carbamate tert-butyl ester (M24-1, 29-199-35) as a pure white solid with a yield of 88.1%. 1H NMR (400MHz, CDCl3): δ8.62(s,1H),8.42(d,J=8.0Hz,1H),7.33(t,J=7.7Hz,2H),7.07–7.13 (m,2H),7.00(d,J=8.4Hz,3H),6.85(d,J=8.1Hz,1H),4.31(s,1H),1.38(s,3H),1.36(s,9H).

[0183] Step 2: The preparation method is the same as that of M1-4. The target compound (R)-2-amino-N-(2-phenoxyphenyl)propionamide (M24,42-4-30) is obtained as a transparent oil with a yield of 79.74%. 1 H NMR (400MHz, CDCl3): δ9.97(s,1H),8.48(d,J=8.1Hz,1H),7.32(t,J=7.7Hz,2H),7.17–7.07(m,2H) ,7.00(dd,J=13.3,5.4Hz,3H),6.91(d,J=8.1Hz,1H),3.55(q,J=7.0Hz,1H),1.33(d,J=7.0Hz,3H).

[0184] Synthetic intermediate M25: (S)-2-amino-N-(2-phenoxyphenyl)propionamide (42-3-35)

[0185]

[0186] Step 1: The preparation method is the same as that of M1-3, yielding (S)-(1-oxo-1-((2-phenoxyphenyl)amino)propyl-2-yl)carbamate tert-butyl ester (M25-1,29-198-35) as a pure white solid with a yield of 86.97%. 1 H NMR (400MHz, CDCl3): δ8.67(s,1H),8.41(dd,J=8.1,1.2Hz,1H),7.31(t,J=8.0Hz,2H),7.05-7.12 (m,2H),6.98(t,J=6.4Hz,3H),6.83(dd,J=8.1,0.9Hz,1H),4.31(s,1H),1.35(s,8H),1.34(s,3H).

[0187] Step 2: The preparation method is the same as that of M1-4. 200.9 mg of the target compound (S)-2-amino-N-(2-phenoxyphenyl)propionamide (M25,42-3-35) was obtained as a transparent oil, with a yield of 81.42%. 1H NMR (400MHz, CDCl3): δ9.95(s,1H),8.45–8.49(m,1H),7.31–7.35(m,2H),7.10–7.16(m,2H ),7.00–7.05(m,3H),6.91–6.93(m,1H),3.57(dd,J=6.6,2.4Hz,1H),1.35(d,J=6.9Hz,3H).

[0188] Synthetic intermediate M26: (R)-2-amino-3-methyl-N-(2-phenoxyphenyl)butyramide (42-5-27)

[0189]

[0190] Step 1: The preparation method is the same as that of M1-3, yielding (R)-(3-methyl-1-oxo-1-((2-phenoxyphenyl)amino)but-2-yl)carbamate tert-butyl ester (M26-1, 29-200-40) as a transparent oil with a yield of 48.09%. 1 H NMR (400MHz, CDCl3): δ8.42(dd,J=8.1,1.4Hz,1H),8.32(s,1H),7.30–7.34(m,2H),7.08–7.13(m,2H),6.98–7.03(m,3H),6 .86(dd,J=8.1,1.0Hz,1H),4.07–4.11(m,1H),2.16–2.24(m,1H)1.39(s,9H),0.94(d,J=6.8Hz,3H),0.86(d,J=6.9Hz,3H).

[0191] Step 2: The preparation method is the same as that of M1-4. The target compound (R)-2-amino-3-methyl-N-(2-phenoxyphenyl)butyramide (M26,42-5-27) is obtained as a transparent oil with a yield of 79.75%. 1 H NMR (400MHz, CDCl3): δ9.96(s,1H),8.50(dd,J=8.1,1.5Hz,1H),7.29–7.35(m,2H),7.13–7.17(m,1H),7.09(t,J=7.4Hz,1H),6.97 –7.05(m,3H),6.93(dd,J=8.1,1.4Hz,1H),3.33(d,J=3.6Hz,1H),2.33–2.41(m,2H),0.97(d,J=7.0Hz,3H),0.76(d,J=6.9Hz,3H).

[0192] Synthetic intermediate M27: (S)-2-amino-3-methyl-N-(2-phenoxyphenyl)butyramide (42-6-28)

[0193]

[0194] Step 1: The preparation method is the same as that of M1-3, yielding (S)-(3-methyl-1-oxo-1-((2-phenoxyphenyl)amino)but-2-yl)carbamate tert-butyl ester (M27-1,29-201-39) as a transparent oil with a yield of 55.24%. 1 H NMR (400MHz, CDCl3): δ8.43(dd,J=8.1,1.6Hz,1H),8.27(s,1H),7.32–7.37(m,2H),7.10–7.15(m,2H),6.94–7.06(m,3 H),6.85–6.90(m,1H),4.06–4.09(m,1H),2.15–2.27(m,1H),1.39(s,9H),0.95(d,J=6.8Hz,3H),0.87(d,J=6.9Hz,3H).

[0195] Step 2: The preparation method is the same as that of M1-4. The target compound (S)-2-amino-3-methyl-N-(2-phenoxyphenyl)butyramide (M27,42-6-28) is obtained as a transparent oil with a yield of 91.73%. 1 H NMR (400MHz, CDCl3): δ9.95(s,1H),8.50(dd,J=8.1,1.5Hz,1H),7.30–7.35(m,2H),7.13–7.17(m,1H),7.09(t,J=7.4Hz,1H),7.03(td,J=7.8,1.5 Hz, 1H), 6.99 (d, J = 7.8Hz, 2H), 6.93 (dd, J = 8.1, 1.4Hz, 1H), 3.33 (d, J = 3. 6Hz,1H),2.31–2.42(m,1H),0.97(d,J=7.0Hz,3H),0.76(d,J=6.9Hz,3H).

[0196] Synthetic intermediate M28: 3-amino-N-(2-phenoxyphenyl)propionamide (42-2-36)

[0197]

[0198] Step 1: The preparation method is the same as that of M1-3, yielding (3-oxo-3-((2-phenoxyphenyl)amino)propyl)carbamate tert-butyl ester (M28-1,29-197-40) as a pure white solid with a yield of 86.03%.1 H NMR (400MHz, CDCl3): δ8.33(dd,J=43.3,16.1Hz,1H),7.80(d,J=32.6Hz,1H),7.34(d,J=7.6Hz,1H),7.07–7.16(m,1H ),6.96(d,J=27.8Hz,3H),6.75–6.99(m,1H),3.40(d,J=27.9Hz,2H),2.52(d,J=28.6Hz,2H),1.36(d,J=34.2Hz,9H).

[0199] Step 2: The preparation method is the same as that of M1-4, and the target compound 3-amino-N-(2-phenoxyphenyl)propionamide (M28,42-2-36) is a pure white solid with a yield of 61.8%. 1 H NMR (400MHz, CDCl3): δ9.91(s,1H),8.43(dd,J=8.2,1.4Hz,1H),7.29–7.34(m,2H),7.14(td,J=7.9,1.4Hz,1H),7.08(t,J=7.4H z,1H),7.02(td,J=7.8,1.5Hz,1H),6.94(dt,J=9.3,1.9Hz,2H),6.90–6.92(m,2H),2.98(t,J=6.0Hz,1H),2.45(t,J=6.0Hz,1H).

[0200] Synthetic intermediate M29: 4-amino-N-(2-phenoxyphenyl)butyramide (42-1-40)

[0201]

[0202] Step 1: The preparation method is the same as that of M1-3, yielding (4-oxo-4-((2-phenoxyphenyl)amino)butyl)carbamate tert-butyl ester (M29-1, 29-196-39) as a pure white solid with a yield of 88.58%. 1H NMR (400MHz, CDCl3): δ8.28–8.40(m,1H),8.07(d,J=31.1Hz,1H),7.32–7.36(m,1H),7.21–7.25(m,1H),6.99–7.14(m,2H),6.91(dd,J=11.5,8.0Hz ,2H),6.75(dd,J=11.8,8.6Hz,1H),4.81(d,J=34.0Hz,1H),3.11(dd,J=3 5.7,5.5Hz,2H),2.25–2.40(m,2H),1.72–1.86(m,2H),1.28–1.39(m,9H).

[0203] Step 2: The preparation method is the same as that of M1-4, to obtain the target compound 4-amino-N-(2-phenoxyphenyl)butyramide (M29,42-1-40) as a pure white solid with a yield of 54.6%. 1 H NMR (400MHz, CDCl3): δ8.41(d,J=8.1Hz,1H),8.31(s,1H),7.32–7.37(m,2H),7.09–7.15(m,2H),6.983–7 .02(m,3H),6.85(dd,J=8.0,1.1Hz,1H),2.76(t,J=6.7Hz,2H),2.45(t,J=7.2Hz,2H),1.78–1.85(m,2H).

[0204] Synthetic intermediate M30: (S)-2-amino-3-((tert-butyldimethylsilyl)oxy)-N-(2-phenoxyphenyl)propionamide (42-37-37)

[0205]

[0206] Step 1: Weigh (tert-butyloxycarbonyl)-L-serine (300 mg, 1.46 mmol) into a reaction flask containing DMF. Slowly add imidazole (298.2 mg, 4.38 mmol) to the above mixture. Lower the system temperature to 0°C, and slowly add a mixture of tert-butylchlorodimethylsilane (265.2 mg, 1.75 mmol) and THF. After the addition is complete, react at room temperature for 6 hours. After the reaction is complete, adjust the pH of the reaction solution to 4 with dilute HCl, wash with ethyl acetate and brine, and finally collect the organic layer to obtain the crude product N-(tert-butyloxycarbonyl)-O-(tert-butyldimethylsilyl)-L-serine (M30-1, 42-109-30), a pale yellow oil, 400 mg, yield 86%.

[0207] Step 2: Add M30-1 (344 mg, 1.1 mmol) to a 50 mL round-bottom flask and add 4 mL of DCM as the reaction solvent. Lower the reaction temperature to 0 °C, then slowly add isobutyl chloroformate (163.9 mg, 1.2 mmol). After the addition is complete, slowly add N-methylmorpholine (220.2 mg, 1.2 mmol). After reacting at this temperature for 30 min, add M1-2 (400.0 mg, 2.2 mmol). React at room temperature for 12 h. After the reaction is complete, wash the reaction solution with dilute HCl, neutralize the excess acid with sodium carbonate aqueous solution, then add water to the system. Extract the mixture with dichloromethane (100 mL x 2), dry the combined organic phase with anhydrous sodium sulfate, and finally concentrate under vacuum. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 10) and concentrated to give 800 mg of (S)-(3-((tert-butyldimethylsilyl)oxy)-1-oxo-1-((2-phenoxyphenyl)amino)propyl-2-yl)carbamate (M30-2,42-32-31) as a pale yellow oil, with a yield of 76.9%. 1 H NMR (400MHz, CDCl3): δ8.80(s,1H),8.45(dd,J=8.1,1.5Hz,1H),7.32–7.37(m,2H),7.08–7.15(m,2H),6.99–7.03(m,3H),6.82(dd,J=8.1 ,1.3Hz,1H),5.39(s,1H),4.27(s,1H),4.09(dt,J=10.2,4.9Hz,1H),3.73(dd,J=9.6,6.2Hz,1H),1.39(s,9H),0.82(s,9H),0.07(s,6H).

[0208] Step 3: The preparation method is the same as that of M1-4. The target compound (S)-2-amino-3-((tert-butyldimethylsilyl)oxy)-N-(2-phenoxyphenyl)propionamide (M30,42-37-36) is obtained as a transparent oil with a yield of 91.4%. 1 HNMR (400MHz, CDCl3): δ9.97(s,1H),8.47(dd,J=8.1,1.6Hz,1H),7.31–7.36(m,2H),7.09–7.14(m,2H),7.00–7.02 (m,3H),6.89(dd,J=8.1,1.4Hz,1H),3.82–3.81(m,2H),3.58(t,J=5.1Hz,1H),0.84(s,9H),0.03(d,J=7.4Hz,6H).

[0209] Synthetic intermediate M31: (R)-2-amino-3-((tert-butyldimethylsilyl)oxy)-N-(2-phenoxyphenyl)propionamide (42-95-30)

[0210]

[0211] Step 1: Weigh (tert-butyloxycarbonyl)-D-serine (300 mg, 1.46 mmol) into a reaction flask containing DMF. Slowly add imidazole (298.2 mg, 4.38 mmol) to the above mixture. Lower the system temperature to 0°C, and slowly add a mixture of tert-butylchlorodimethylsilane (265.2 mg, 1.75 mmol) and THF. After the addition is complete, react at room temperature for 6 hours. After the reaction is complete, adjust the pH of the reaction solution to 4 with dilute HCl, wash with ethyl acetate and brine, and finally collect the organic layer to obtain the crude product N-(tert-butyloxycarbonyl)-O-(tert-butyldimethylsilyl)-D-serine (M31-1, 42-91-38), a pale yellow oil, 340 mg, yield 73%.

[0212] Step 2: The preparation method is the same as that of M30-2, to obtain (R)-(3-((tert-butyldimethylsilyl)oxy)-1-oxo-1-((2-phenoxyphenyl)amino)propyl-2-yl)carbamate tert-butyl ester (M31-2,42-92-35) as a transparent oil with a yield of 24.8%. 1 H NMR (400MHz, CDCl3): δ8.79(s,1H),8.45(dd,J=8.1,1.4Hz,1H),7.32–7.37(m,2H),7.08–7.15(m,2H),6.99–7.03(m,3H),6.82(dd,J=8 .1,1.2Hz,1H),5.39(s,1H),4.27(s,1H),4.09–4.11(m,1H),3.73(dd,J=9.5,6.1Hz,1H),1.39(s,9H),0.82(s,9H),0.04(t,J=1.2,6H).

[0213] Step 3: The preparation method is the same as that of M1-4. The target compound (R)-2-amino-3-((tert-butyldimethylsilyl)oxy)-N-(2-phenoxyphenyl)propionamide (M31,42-95-30) is a pure white solid with a yield of 74.1%. 1HNMR (400MHz, CDCl3): δ10.00(s,1H),8.47(dd,J=8.1,1.5Hz,1H),7.31–7.36(m,2H),7.09–7.15(m,2H),6.99–7.04(m, 3H), 6.89 (dd, J = 8.1, 1.4Hz, 1H), 3.85 (dd, J = 5.1, 3.1Hz, 2H), 3.55 (t, J = 5.1Hz, 1H), 0.85 (s, 9H), 0.04 (d, J = 7.4Hz, 6H).

[0214] Synthetic intermediate M32: (S)-2-amino-3-methoxy-N-(2-phenoxyphenyl)propionamide (42-67-31)

[0215]

[0216] Step 1: Weigh (tert-butyloxycarbonyl)-L-serine (300 mg, 1.46 mmol) into a reaction flask containing THF. Lower the system temperature to 5°C, slowly add NaH (56 mg, 2.34 mmol), and stir for 20 min after addition. Then, slowly add iodomethane (227.9 mg, 1.61 mmol) to the above mixture at 0°C. React at 0°C for 6 h. After the reaction is complete, slowly pour the mixture into ice water. Extract the aqueous phase with 100 mL of toluene. Adjust the pH of the reaction solution to 4 with dilute HCl. Wash with ethyl acetate and brine. Finally, collect the organic layer to obtain the crude product N-(tert-butyloxycarbonyl)-O-methyl-L-serine (M32-1, 42-60-35), a pale yellow oil, 300 mg, yield 100%.

[0217] Step 2: The preparation method is the same as that of M30-2, yielding (S)-(3-methoxy-1-oxo-1-((2-phenoxyphenyl)amino)propyl-2-yl)carbamate tert-butyl ester (M32-2,42-93-36) as a colorless, transparent oil with a yield of 18.5%. 1 HNMR (400MHz, CDCl3): δ9.05 (s, 1H), 8.45 (d, J = 8.1Hz, 1H), 7.34 (t, J = 7.7Hz, 2H), 7.13 (dt, J = 11.1, 5.7Hz, 2H), 7.01 (dd, J = 15.4, 8. 0Hz,3H),6.88(d,J=8.1Hz,1H),5.42(d,J=37.6Hz,1H),4.36(s,1H),3.85–3.87(m,1H),3.43–3.47(m,1H),3.26(s,3H),1.40(s,9H).

[0218] Step 3: The preparation method is the same as that of M1-4. 8 mg of the target compound (S)-2-amino-3-methoxy-N-(2-phenoxyphenyl)propionamide (M32,46-67-31) as a pure white solid was obtained, with a yield of 54.1%. 1 H NMR (400MHz, CDCl3): δ10.04(s,1H),8.47(d,J=7.9Hz,1H),7.34(t,J=7.6Hz,2H),7.10–7.15(m,2 H),7.02(dd,J=11.4,8.3Hz,3H),6.90(d,J=8.0Hz,1H),3.64–3.67(m,3H),3.33(d,J=4.0Hz,3H).

[0219] Synthetic intermediate M33: (R)-2-amino-3-methoxy-N-(2-phenoxyphenyl)propionamide (42-190-34)

[0220]

[0221] Step 1: Weigh (tert-butyloxycarbonyl)-D-serine (500 mg, 2.44 mmol) into a reaction flask containing THF. Lower the system temperature to -10℃, slowly add NaH (117.1 mg, 2.44 mmol), stir for 20 min after addition, and slowly add iodomethane (346.2 mg, 4.88 mmol) to the above mixture at 0℃. React at 45℃ for 6 h. After the reaction is complete, cool to room temperature, adjust the pH of the reaction solution to neutral with dilute HCl, concentrate THF under vacuum, wash with ethyl acetate and brine, and finally collect the organic layer to obtain crude product N-(tert-butyloxycarbonyl)-O-methyl-D-serine (M33-1, 42-176-43) pale yellow oil, 390 mg, yield 72.9%.

[0222] Step 2: The preparation method is the same as that of M30-2, to obtain pure white oily droplets of (R)-(3-methoxy-1-oxo-1-((2-phenoxyphenyl)amino)propyl-2-yl)carbamate (M33-2,42-188-39), with a yield of 15.4%. 1HNMR (400MHz, CDCl3): δ8.45(d,J=9.3Hz,1H),7.76–8.01(m,1H),7.35(t,J=7.7Hz,2H),7.13(dd,J=16.2,7.6Hz,2H),6.96-7.05(m, 2H),6.86(d,J=8.1Hz,1H),5.39(d,J=8.1Hz,1H),4.40–4.12(m,1H),3.58(dd,J=9.3,3.0Hz,1H),3.33(d,J=0.6Hz,3H),1.44(s,9H).

[0223] Step 3: The preparation method is the same as that of phase M1-4. Pure white droplets of the target compound (R)-2-amino-3-methoxy-N-(2-phenoxyphenyl)propionamide (M33,42-190-34) were obtained with a yield of 75.0%. 1 H NMR (400MHz, CDCl3): δ9.98 (s, 1H), 8.45 (d, J = 8.2Hz, 1H), 7.33 (t, J = 7.9Hz, 2H), 7.11 (t, J = 7.5Hz, 2H), 7.0 1(t,J=9.1Hz,3H),6.89(d,J=8.0Hz,1H),3.76(dd,J=11.6,6.4Hz,1H),3.66(d,J=5.3Hz,2H),3.30(s,3H).

[0224] Synthetic intermediate M34: 2-amino-N-(3-phenoxyphenyl)acetamide (42-82-33)

[0225]

[0226] Step 1: The preparation method is the same as that of M1-1, yielding 1-nitro-3-phenoxybenzene (M34-1,42-75-30) as a white solid with a yield of 38.97%. 1 H NMR (400MHz, CDCl3): δ7.93(ddd,J=8.2,2.1,0.9Hz,1H),7.78(t,J=2.3Hz,1H),7.48(t,J =8.2Hz,1H),7.39–7.42(m,2H),7.31–7.34(m,2H),7.20–7.24(m,1H),7.05–7.08(m,2H).

[0227] Step 2: The preparation method is the same as that of M2-2, yielding 3-phenoxyaniline (M34-2, 42-78-30) as an orange-yellow oil with a yield of 76.3%. 1H NMR (400MHz, CDCl3): δ7.32–7.37(m,2H),7.11(dd,J=11.4,4.6Hz,2H),7.05(dd,J=5 .3,3.5Hz,2H),6.43(ddd,J=7.2,3.6,2.2Hz,2H),6.34(t,J=2.2Hz,1H),3.54(s,2H).

[0228] Step 3: The preparation method is the same as that of M1-3, yielding a transparent solid of (2-oxo-2-((3-phenoxyphenyl)amino)ethyl)carbamate (M34-3, 42-80-38), with a yield of 85.66%. 1 H NMR (400MHz, CDCl3): δ8.18–8.19(m,1H),8.15–8.17(m,1H),7.39–7.44(m,2H ),7.22–7.26(m,1H),7.06–7.09(m,2H),6.99–7.01(m,1H),6.97–6.99(m,1H).

[0229] Step 4: The preparation method is the same as that of M1-4, to obtain the target compound 2-amino-N-(3-phenoxyphenyl)acetamide (M34,42-82-33) as a white solid with a yield of 83.97%. 1 H NMR (400MHz, CDCl3): δ9.44(s,1H),7.35(t,J=7.9Hz,4H),7.29(d,J=8.2Hz,1H ),7.12(t,J=7.4Hz,1H),7.03(d,J=7.8Hz,2H),6.75–6.77(m,1H),3.44(s,2H).

[0230] Synthetic intermediate M35: 2-amino-N-(3-(4-propylphenoxy)phenyl)acetamide (42-86-35)

[0231]

[0232] Step 1: The preparation method is the same as that of M1-1, yielding 1-nitro-4-phenoxybenzene (M35-1,42-77-35) as a white solid with a yield of 38.97%. 1 H NMR (400MHz, CDCl3): δ8.18–8.19(m,1H),8.15–8.17(m,1H),7.39–7.44(m,2H ),7.22–7.26(m,1H),7.06–7.09(m,2H),6.99–7.01(m,1H),6.97–6.99(m,1H).

[0233] Step 2: The preparation method is the same as that of M2-2, yielding 4-phenoxyaniline (M35-2, 42-79-40) as an orange-yellow oil with a yield of 76.3%. 1 H NMR (400MHz, CDCl3): δ7.22–7.26(m,2H),6.96–6.99(m,1H),6.89(dd,J=5.8,2.0Hz,2H),6.82–6.85(m,2H),6.61–6.64(m,2H),3.40(s,2H).

[0234] Step 3: The preparation method is the same as that of M1-3, yielding a transparent solid of (2-oxo-2-((4-phenoxyphenyl)amino)ethyl)carbamate (M35-3, 42-80-38) with a yield of 85.66%. 1 H NMR (400MHz, CDCl3): δ8.77(s,1H),7.30(t,J=7.9Hz,2H),7.23(dd,J=14.6,7.0Hz,2H),7.08(t,J=7 .4Hz,1H),6.98(d,J=8.1Hz,2H),6.71–6.73(m,1H),5.67(s,1H),3.91(d,J=4.2Hz,2H),1.42(s,9H).

[0235] Step 4: The preparation method is the same as that of M1-4, to obtain the target compound 2-amino-N-(4-phenoxyphenyl)acetamide (M35,42-86-35) as a white solid with a yield of 83.97%. 1 H NMR (400MHz, CDCl3): δ9.41 (s, 1H), 7.56 (d, J = 7.2Hz, 2H), 7.31 (t, J = 7.1Hz, 2H), 7.07 (t, J = 7.3Hz, 1H), 6.99 (d, J = 6.2Hz, 4H), 3.45 (s, 2H).

[0236] Final product 1: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-benzofuran-2-carboxamide (1,33-2-42)

[0237]

[0238] Step 1: Add benzofuran-2-carboxylic acid S2 (50.0 mg, 0.3 mmol) to a 50 mL round-bottom flask, and add 6 mL of toluene as the reaction solvent. Then, slowly add SOCl2 (81.0 μL, 0.6 mmol) dropwise. Reflux at 110 °C for 2 h. After the reaction is complete, concentrate under reduced pressure to remove SOCl2. Add intermediate M1 (28-195-40, 50.0 mg, 0.2 mmol) and DIPEA (108.0 μL, 0.6 mmol) along with 2 mL of toluene. React at 80 °C for 4 h. After the reaction is complete, concentrate the reaction solution using a rotary evaporator. Add water (50 mL) to quench the reaction. Extract the mixture with dichloromethane (100 mL x 2). Dry the combined organic phases with anhydrous sodium sulfate and finally concentrate under vacuum. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 1 / 3) and concentrated to give 24.8 mg of the target compound (1,33-2-42) as a white solid, with a yield of 21.8%. 1 H NMR (400MHz, CDCl3): δ8.30–8.20(m,2H),7.49(d,J=7.8Hz,1H),7.31(dd,J=14.8,6.8Hz,2H),7.25(s,1H),7.14(t,J=7.3Hz,1H) ,7.07(dd,J=14.2,6.5Hz,2H),6.96(d,J=7.6Hz,1H),6.87(t,J=6.7Hz,2H),6.74(dd,J=14.7,8.0Hz,3H),4.15(d,J=5.4Hz,2H).

[0239] Final product 2: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-benzo[b]thiophene-2-carboxamide (2,33-10-41)

[0240]

[0241] Step 1: The preparation method is the same as that of the final product 1. The target compound (2,33-10-41) is a yellowish-white solid with a yield of 33.8%. 1H NMR (400MHz, CDCl3): δ8.63(s,1H),8.38(dd,J=7.9,1.0Hz,1H),7.81(dd,J=16.1,8.9Hz,3H),7.54(s,1H),7.41(dd,J=5.5,3.9Hz,1H),7. 27(d,J=5.9Hz,1H),7.24(s,1H),7.08(m,J=9.4,7.4,4.6Hz,3H),6.96(d,J=7.8Hz,2H),6.90(dd,J=8.0,1.2Hz,1H),4.29(d,J=5.3Hz,2H).

[0242] Final product 3: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-benzo[b]thiophene-3-carboxamide (3,33-11-40)

[0243]

[0244] Step 1: The preparation method is the same as that of the final product 1. The target compound (3,33-11-40) is a yellowish-white solid with a yield of 16.9%. 1 H NMR (400MHz, CDCl3): δ8.52(s,1H),8.37(d,J=8.0Hz,1H),7.86–7.80(m,1H),7.78(d,J=0.9Hz,1H),7.44–7.33(m, 3H),7.26(s,1H),7.24(s,1H),7.12–7.02(m,3H),6.95(d,J=8.2Hz,2H),6.88(d,J=8.0Hz,1H),4.33–4.22(m,2H).

[0245] Final product 4: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-benzofuran-3-carboxamide (4,33-12-40)

[0246]

[0247] Step 1: The preparation method is the same as that of the final product 1. The target compound (4,33-12-40) is a yellow solid with a yield of 46.6%. 1H NMR (400MHz, DMSO-d6): δ9.52(s,1H),8.78–8.69(m,1H),8.50(s,1H),8.05(d,J=7.3Hz,1H),7.96(dd,J=7.6,0.8Hz,1H),7.58(d,J =8.0Hz,1H),7.33–7.23(m,4H),7.08–6.99(m,3H),6.88(dd,J=8.6,0.9Hz,2H),6.82(dd,J=7.9,1.5Hz,1H),4.04(d,J=5.9Hz,2H).

[0248] Final product 5: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-1H-indole-3-carboxamide (5,33-14-40)

[0249]

[0250] Step 1: The preparation method is the same as that of the final product 1. The target compound (5,33-14-40) is a white solid with a yield of 25.8%. 1 H NMR (400MHz, DMSO-d6): δ11.41(s,1H),9.33(s,1H),8.18(s,1H),7.96(d,J=7.6Hz,1H),7.87(d,J=7.9Hz,1H),7.81(d ,J=2.9Hz,1H),7.22(d,J=8.0Hz,1H),7.11–7.06(m,2H),6.95–6.85(m,5H),6.74–6.67(m,3H),3.84(d,J=5.3Hz,2H).

[0251] Final product 6: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-1H-benzo[d]imidazol-2-carboxamide (6,33-15-41)

[0252]

[0253] Step 1: The preparation method is the same as that of the final product 1. The target compound (6,33-15-41) is a white solid with a yield of 16.1%. 1¹H NMR (400MHz, CDCl₃): δ 9.87 (s, 1H), 8.50 (d, J = 8.1Hz, 1H), 7.38–7.27 (m, 3H), 7.23–6.94 (m, 7H), 6.92–6.85 (m, 1H), 3.43 (d, J = 10.8Hz, 2H). Final product 7: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-indole-2-carboxamide (7, 33-23-38)

[0254]

[0255] Step 1: The preparation method is the same as that of the final product 1. The target compound (7,33-23-38) is a white solid with a yield of 64.5%. 1 H NMR (400MHz, DMSO-d6): δ11.55(s,1H),9.50(s,1H),8.83(t,J=5.9Hz,1H),8.03(d,J=7.7Hz,1H),7.55(d,J=8.0Hz,1H),7.37(d,J =8.3Hz,1H),7.28–7.22(m,2H),7.13–6.96(m,6H),6.90(dd,J=8.6,1.0Hz,2H),6.83(dd,J=7.9,1.5Hz,1H),4.05(d,J=6.0Hz,2H).

[0256] Final product 8: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-1H-indole-6-carboxamide (8,33-1-42)

[0257]

[0258] Step 1: The preparation method is the same as that of the final product 1. The target compound (8,33-1-42) is a white solid with a yield of 25.4%. 1 H NMR (400MHz, CDCl3): δ8.71(s,1H),8.63(d,J=11.7Hz,1H),8.40(d,J=8.2Hz,1H),8.04(d,J=8.2Hz,1H),7.56–7.52(m,1H),7.32 (d,J=8.5Hz,1H),7.25–7.22(m,2H),7.11–7.01(m,4H),6.91(t,J=7.7Hz,2H),6.87(dd,J=8.1,1.1Hz,1H),4.27(t,J=4.7Hz,2H).

[0259] Final product 9: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-benzo[d]thiazol-6-carboxamide (9,33-4-40)

[0260]

[0261] Step 1: The preparation method is the same as that of the final product 1. The target compound (9,33-4-40) is a grayish-white solid with a yield of 32.4%. 1 H NMR (400MHz, CDCl3): δ9.09 (s, 1H), 8.50 (s, 1H), 8.38 (d, J = 7.9Hz, 1H), 8.25 ( d,J=8.0Hz,1H),7.81(d,J=7.5Hz,1H),7.71(d,J=5.3Hz,1H),7.52(dd,J=8.1 ,4.1Hz,1H),7.23(d,J=8.0Hz,1H),7.10(d,J=6.8Hz,1H),7.03(dd,J=18.7,8 .5Hz,3H),6.92(d,J=8.1Hz,2H),6.86(d,J=8.0Hz,1H),4.35(d,J=5.1Hz,2H).

[0262] Final product 10: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-benzo[d]thiazol-5-carboxamide (10, 33-5-41)

[0263]

[0264] Step 1: The preparation method is the same as that of the final product 1. The target compound (10,33-5-41) is a white solid with a yield of 46.3%. 1 H NMR (400MHz, CDCl3): δ9.10(s,1H),8.57(s,2H),8.40(d,J=8.1Hz,1H),7.98(d,J=8.4Hz,1H),7.87(dd,J=8.4,1.4Hz,1H),7.55–7.48(m,1H), 7.30–7.26(m,1H),7.24(s,1H),7.13(dd,J=11.0,4.5Hz,1H),7.08–7. 02(m,2H),6.97–6.93(m,2H),6.90–6.87(m,1H),4.32(t,J=4.9Hz,2H).

[0265] Final product 11: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-benzo[d]thiophene-5-carboxamide (11, 33-6-43)

[0266]

[0267] Step 1: The preparation method is the same as that of the final product 1. The target compound (11, 33-6-43) is a white solid with a yield of 49.1%. 1 H NMR (400MHz, CDCl3): δ8.63(s,1H),8.39(d,J=8.0Hz,1H),8.22(d,J=1.0Hz,1H),7.86(d,J =8.4Hz,1H),7.70(dd,J=8.4,1.5Hz,1H),7.52–7.49(m,1H),7.35–7.30(m,2H),7.27(s,1H) ,7.26(s,1H),7.07(tt,J=7.3,6.3Hz,3H),6.98–6.93(m,2H),6.88(dd,J=8.1,1.3Hz,1H),4.31(d,J=5.3Hz,2H). Final product 12: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-benzo[d]furan-5-carboxamide (12,33-8-40)

[0268]

[0269] Step 1: The preparation method is the same as that of the final product 1. The target compound (12,33-8-40) is a yellowish-white solid with a yield of 16.9%. 1 H NMR (400MHz, CDCl3): δ8.57(s,1H),8.39(d,J=7.2Hz,1H),8.02(d,J=1.1Hz,1H),7.73–7.67(m,2H),7.48(d,J=8.6Hz,1H),7.28(s,1H) ,7.14–7.09(m,2H),7.08–7.02(m,2H),6.95(d,J=7.8Hz,2H),6.88(dd,J=8.1,1.0Hz,1H),6.78(d,J=1.4Hz,1H),4.29(d,J=5.3Hz,2H).

[0270] Final product 13: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-1H-indazole-6-carboxamide (13, 33-18-40)

[0271]

[0272] Step 1: The preparation method is the same as the synthesis of final product 1. The target compound (13,33-18-40) was obtained. The organic layer was taken, dried with anhydrous Na2SO4, concentrated under reduced pressure, and purified by normal-phase silica gel column chromatography. 10.0 mg of white solid was obtained, with a yield of 16.1%. 1 HNMR (400MHz, CDCl3): δ8.65(s,1H),8.38(d,J=7.9Hz,1H),8.19(s,2H),8.04(s,1H),7.36–7.26(m, 3H),7.07(m,J=27.7,7.6Hz,4H),6.95(d,J=7.9Hz,2H),6.88(d,J=8.0Hz,1H),4.31(d,J=4.6Hz,2H).

[0273] Final product 14: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-1H-indole-6-carboxamide (14, 33-19-40)

[0274]

[0275] Step 1: The preparation method is the same as that of the final product 1. The target compound (14,33-19-40) is a white solid with a yield of 16.1%. 1 H NMR (400MHz, CDCl3): δ8.82(s,1H),8.56(s,1H),8.39(d,J=7.9Hz,1H),7.87(s,1H),7.60(d,J=8.3Hz,1H),7.50(t,J=7.1Hz,1H),7 .28(d,J=6.8Hz,1H),7.24(d,J=7.1Hz,1H),7.15–7.03(m,4H),6.92(d,J=8.0Hz,2H),6.87(d,J=8.0Hz,1H),4.30(d,J=4.1Hz,2H).

[0276] Final product 15: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-1H-indazole-6-carboxamide (15, 33-21-41)

[0277]

[0278] Step 1: The preparation method is the same as that of the final product 1. The target compound (17,33-21-41) is a white solid with a yield of 13.9%. 1H NMR (400MHz, CDCl3): δ8.57(s,2H),8.40(d,J=8.1Hz,1H),7.91(d,J=8.6Hz,1H),7.48(d,J=6.9Hz,1H),7.33–7.27(m,3H),7.1 8(s,1H),7.15–7.09(m,2H),7.05(dd,J=14.4,6.7Hz,1H),6.96(t,J=7.3Hz,2H),6.86(d,J=8.1Hz,1H),4.33(d,J=5.0Hz,2H).

[0279] Final product 16: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-1H-indazole-6-carboxamide (16, 33-22-41)

[0280]

[0281] Step 1: The preparation method is the same as that of the final product 1. The target compound (16,33-22-38) is a white solid with a yield of 26.9%. 1 H NMR (400MHz, CDCl3): δ8.54(s,1H),8.38(d,J=7.8Hz,1H),8.07(s,2H),7.74(d,J=8.4Hz,1H),7.56(d,J=8.3Hz,1H),7.37(d ,J=5.7Hz,1H),7.29(d,J=7.9Hz,1H),7.15–7.00(m,4H),6.96(d,J=7.9Hz,2H),6.87(d,J=7.9Hz,1H),4.31(d,J=5.0Hz,2H).

[0282] Final product 17: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-1H-indazole-7-carboxamide (17, 33-24-38)

[0283]

[0284] Step 1: The preparation method is the same as that of the final product 1. The target compound (17,33-24-35) is a white solid with a yield of 32.9%. 1¹H NMR (400MHz, CDCl₃): δ 8.88 (s, 1H), 8.37 (d, J = 7.8Hz, 1H), 8.06 (s, 1H), 7.87 (d, J = 7.8Hz, 1H), 7.69 (d, J = 6.6Hz, 1H), 7.61 (s, 1H), 7.25–7.21 (m, 2H), 7.13 (d, J = 7.1Hz, 2H), 7.04 (s, 2H), 6.93–6.86 (m, 3H), 4.43 (s, 2H). Final product 18: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-2,1,3-benzoxazadiazole-5-carboxamide (18, 33-29-42)

[0285]

[0286] Step 1: The preparation method is the same as that of the final product 1. The target compound (18,33-29-42) is a white solid with a yield of 72.6%. 1 H NMR (400MHz, DMSO-d6): δ9.54(s,1H),9.25(t,J=5.7Hz,1H),8.44(d,J=1.1Hz,1H),8.05(d,J=9.4Hz,1H),8.01(d,J=7.4Hz,1H),7.85(dd ,J=9.4,1.3Hz,1H),7.28–7.23(m,2H),7.07–6.99(m,3H),6.89(dd,J=8.6,1.0Hz,2H),6.81(dd,J=7.9,1.6Hz,1H),4.07(d,J=5.7Hz,2H).

[0287] Final product 19: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-benzo[d]oxazol-5-carboxamide (19, 33-31-44)

[0288]

[0289] Step 1: The preparation method is the same as that of the final product 1. 40.0 mg of the target compound (19,33-31-44) yellowish-white solid was obtained, with a yield of 61.5%. 1H NMR (400MHz, DMSO-d6): δ9.48(s,1H),8.97(t,J=5.7Hz,1H),8.78(s,1H),8.22(d,J=1.2Hz,1H),8.04(d,J=7.7Hz,1H),7.88(dd,J=8.6,1.6 Hz,1H),7.77(d,J=8.6Hz,1H),7.28–7.23(m,2H),7.07–6.98(m,3H),6.90–6.86(m,2H),6.81(dd,J=7.9,1.6Hz,1H),4.04(d,J=5.8Hz,2H).

[0290] Final product 20: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-benzofuran-6-carboxamide (20, 14-181-41)

[0291]

[0292] Step 1: The preparation method is the same as that of the final product 1. The target compound (20,14-181-41) is a yellowish-white solid with a yield of 16.2%. 1 H NMR (400MHz, CDCl3): δ8.50–8.39(m,2H),7.95(s,1H),7.75(d,J=2.2Hz,1H),7.63–7.62(m,1H),7.31–7.27(m,2H),7. 16–7.02(m,4H),6.96(d,J=7.8Hz,2H),6.89(dd,J=8.1,1.1Hz,1H),6.82(dd,J=2.1,0.7Hz,1H),4.31(d,J=5.3Hz,2H).

[0293] Final product 21: N-(2-oxo-2-((2-phenoxyphenyl)amino)ethyl)-benzo[d]thiazol-6-carboxamide (21, 32-8-33)

[0294]

[0295] Step 1: The preparation method is the same as that of the final product 1. The target compound (21,32-8-33) is yellowish-white and oily, with a yield of 67.7%. 1H NMR (400MHz, CDCl3): δ9.11(s,1H),8.75(s,1H),8.36(dd,J=5.8,1.5Hz,2H),8.08(d,J=8.5Hz,1H),7.86(dd,J=8.6,1.6Hz,1H),7.65 (t,J=4.8Hz,1H),7.26(s,1H),7.24(s,1H),7.11–7.01(m,3H),6.96–6.92(m,2H),6.87(dd,J=8.0,1.4Hz,1H),4.31(d,J=5.3Hz,2H).

[0296] Final product 22: N-(2-((2-(2-methoxyphenoxy)phenyl)amino)-2-oxoethyl)benzothiophene-5-carboxamide (22,29-81-40)

[0297]

[0298] Step 1: The preparation method is the same as that of the final product 1. The target compound (22,29-81-40) is a pale yellow oil with a yield of 23.8%. 1 H NMR (400MHz, CDCl3): δ8.69(s,1H),8.34(d,J=7.2Hz,1H),8.23(s,1H),7.81(d,J=8.4 Hz,1H),7.71(dd,J=8.4,1.4Hz,1H),7.45(d,J=5.4Hz,1H),7.40(t,J=4.8Hz,1H),7.2 4(d,J=2.4Hz,1H),7.07–7.11(m,1H),7.02(dd,J=11.4,4.3Hz,1H),6.96(d,J=8.1Hz, 2H), 6.88 (d, J = 7.7Hz, 2H), 6.74 (d, J = 8.0Hz, 1H), 4.32 (d, J = 5.1Hz, 2H), 3.67 (s, 3H).

[0299] Final product 23: N-(2-((2-(3-methoxyphenoxy)phenyl)amino)-2-oxoethyl)benzothiophene-5-carboxamide (23,29-82-41)

[0300]

[0301] Step 1: The preparation method is the same as that of the final product 1. The target compound (23,29-82-41) is a pale yellow oil with a yield of 23.8%. 1H NMR (400MHz, CDCl3): δ8.68(s,1H),8.37(d,J=8.0Hz,1H),8.21(s,1H),7.84(d,J= 8.4Hz,1H),7.70(t,J=8.2Hz,1H),7.49(d,J=5.4Hz,1H),7.42(s,1H),7.31(d,J=5. 4Hz,1H),7.12(dd,J=19.5,7.9Hz,2H),7.03(t,J=7.7Hz,1H),6.91(d,J=8.0Hz,1H ),6.59(d,J=9.2Hz,1H),6.49(d,J=7.4Hz,2H),4.29(d,J=5.2Hz,2H),3.66(s,3H).

[0302] Final product 24: N-(2-((2-(4-methoxyphenoxy)phenyl)amino)-2-oxoethyl)benzothiophene-5-carboxamide (24,29-83-38)

[0303]

[0304] Step 1: The preparation method is the same as that of the final product 1. The target compound (24,29-83-38) is a pure white solid with a yield of 34.6%. 1 H NMR (400MHz, CDCl3): δ8.81(s,1H),8.34(dd,J=7.8,1.5Hz,1H),8.21(d,J=0.9 Hz,1H),7.80(d,J=8.4Hz,1H),7.70(dd,J=8.4,1.5Hz,1H),7.65(d,J=4.9Hz,1H ),7.46(d,J=5.4Hz,1H),7.25(d,J=5.6Hz,1H),6.99(ddt,J=9.0,7.5,3.9Hz,2H ),6.87(d,J=9.1Hz,2H),6.74–6.78(m,3H),4.32(d,J=5.4Hz,2H),3.72(s,3H).

[0305] Final product 25: N-(2-oxo-2-((2-(o-tolyloxy)phenyl)amino)ethyl)benzothiophene-5-carboxamide (25,29-84-32)

[0306]

[0307] Step 1: The preparation method is the same as that of the final product 1. The target compound (25,29-84-32) is a pure white solid with a yield of 10.3%. 1H NMR (400MHz, CDCl3): δ8.70(s,1H),8.39(d,J=7.9Hz,1H),8.22(s,1H),7.85(d,J=8.3Hz, 1H),7.71(dd,J=8.4,1.3Hz,1H),7.50(d,J=5.4Hz,1H),7.37(d,J=4.6Hz,1H),7.30(d,J= 5.3Hz,1H),7.18(d,J=7.3Hz,1H),7.13(t,J=7.5Hz,1H),7.02–7.07(m,2H),6.97(t,J=7. 7Hz, 1H), 6.82 (d, J = 8.0Hz, 1H), 6.65 (d, J = 8.0Hz, 1H), 4.35 (d, J = 5.3Hz, 2H), 2.17 (s, 3H).

[0308] Final product 26: N-(2-oxo-2-((2-(m-formyloxy)phenyl)amino)ethyl)benzothiophene-5-carboxamide (26, 29-85-40)

[0309]

[0310] Step 1: The preparation method is the same as that of the final product 1. The target compound (26,29-85-40) is a transparent solid with a yield of 10.3%. 1 H NMR (400MHz, CDCl3): δ8.62(s,1H),8.38(d,J=8.0Hz,1H),8.21(s,1H),7.85( d,J=8.4Hz,1H),7.70(dd,J=8.4,1.3Hz,1H),7.50(d,J=5.4Hz,1H),7.35(s,1 H),7.31(d,J=5.4Hz,1H),7.07–7.16(m,2H),7.02(dd,J=10.9,4.5Hz,1H),6. 87(d,J=7.9Hz,2H), 6.74(d,J=7.6Hz,2H), 4.30(d,J=5.3Hz,2H), 2.23(s,3H).

[0311] Final product 27: N-(2-oxo-2-((2-(p-tolyloxy)phenyl)amino)ethyl)benzothiophene-5-carboxamide (27,29-113-30)

[0312]

[0313] Step 1: The preparation method is the same as that of the final product 1. The target compound (27,29-113-30) is a pale yellow solid with a yield of 60.3%. 1H NMR (400MHz, CDCl3): δ8.64(s,1H),8.38(d,J=7.9Hz,1H),8.23(s,1H),7.85(d,J=8.4Hz,1H),7.71(d,J=8.4Hz,1H),7.50(d,J=5.4Hz,1 H),7.40(d,J=4.9Hz,1H),7.31(d,J=5.4Hz,1H),7.06(dt,J=11.1,5.3Hz,4H),6.84(d,J=8.3Hz,3H),4.32(d,J=5.1Hz,2H),2.27(s,3H).

[0314] Final product 28: N-(2-((2-(2-bromophenoxy)phenyl)amino)-2-oxoethyl)benzothiophene-5-carboxamide (28, 39-39-35)

[0315]

[0316] Step 1: The preparation method is the same as that of the final product 1. The target compound (28,39-39-35) is a light yellow oil with a yield of 66.5%. 1 H NMR (400MHz, CDCl3): δ8.75(s,1H),8.38(d,J=8.0Hz,1H),8.20(s,1H),7.88(d,J=8.4Hz,1H),7.68(d,J=8.4Hz,1H),7.52(d,J=5.4H z,1H),7.35(d,J=5.4Hz,2H),7.19–7.12(m,2H),7.10–7.03(m,3H),6.91(d,J=8.0Hz,1H),6.90–6.84(m,1H),4.30(d,J=5.3Hz,2H).

[0317] Final product 29: N-(2-((2-(3-bromophenoxy)phenyl)amino)-2-oxoethyl)benzothiophene-5-carboxamide (29, 29-155-36)

[0318]

[0319] Step 1: The preparation method is the same as that of the final product 1. The target compound (29,29-155-36) is a pale yellow solid with a yield of 62.2%. 1H NMR (400MHz, CDCl3): δ8.93(s,1H),8.35(d,J=7.1Hz,1H),8.20(s,1H),7.84(d,J=8.4Hz,1H),7.64–7.69(m,2H),7.49(d,J=5.4Hz,1H),7. 30(d,J=5.4Hz,1H),7.11(dd,J=10.5,4.3Hz,2H),7.02–7.08(m,3H),6.89–6.90(m,1H),6.83(dd,J=8.1,1.7Hz,1H),4.29(d,J=5.4Hz,2H).

[0320] Final product 30: N-(2-((2-(4-bromophenoxy)phenyl)amino)-2-oxoethyl)benzothiophene-5-carboxamide (30, 29-140-37)

[0321]

[0322] Step 1: The preparation method is the same as that of the final product 1. The target compound (30,29-140-37) is a white solid with a yield of 71.6%. 1 H NMR (400MHz, CDCl3): δ8.83 (s, 1H), 8.58 (d, J = 1.1Hz, 1H), 8.35–8.37 (m, 1H), 8. 20(s,1H),7.87(d,J=8.4Hz,1H),7.67(d,J=7.8Hz,1H),7.43(d,J=5.4Hz,1H),7 .31(dd,J=13.3,7.1Hz,3H),7.12(dd,J=11.3,4.3Hz,1H),7.05(td,J=7.9,1.3H z,1H),6.87(dd,J=8.0,1.1Hz,1H),6.79(d,J=8.8Hz,2H),4.33(d,J=5.2Hz,2H).

[0323] Final product 31: N-(2-(2-(1-isopropyl-1H-pyrazol-4-yl)phenoxy)phenyl)amino)-2-oxoethyl)benzothiophene-5-carboxamide (31,39-56-30)

[0324]

[0325] Step 1: The preparation method is the same as that of the final product 1. The target compound (31,39-56-30) is a light yellow-white oil with a yield of 76.1%. 1H NMR (400MHz, CDCl3): δ8.65(s,1H),8.38(d,J=7.8Hz,1H),8.13(s,1H),7.82(d,J=8.3Hz,1H),7. 76(d,J=14.0Hz,2H),7.62(d,J=8.3Hz,1H),7.50(d,J=5.4Hz,2H),7.29(d,J=5.4Hz,1H),7.16(d ,J=6.9Hz,1H),7.12(dd,J=8.1,3.8Hz,3H),7.01(t,J=7.3Hz,1H),6.83(dd,J=6.0,3.2Hz,1H),6 .78(d,J=7.9Hz,1H), 4.42(dt,J=13.1,6.5Hz,1H), 4.28(d,J=4.4Hz,2H), 1.43(d,J=6.5Hz,6H).

[0326] Final product 32: N-(2-((2-(3-(1-isopropyl-1H-pyrazol-4-yl)phenoxy)phenyl)amino)-2-oxoethyl)benzothiophene-5-carboxamide (32,39-44-30)

[0327]

[0328] Step 1: The preparation method is the same as that of the final product 1. The target compound (32,39-44-30) is a light yellow-white oil with a yield of 23.0%. 1 H NMR (400MHz, CDCl3): δ8.62(s,1H),8.40(d,J=8.1Hz,1H),8.20(s,1H),7.83(d,J=8.4Hz,1H),7.67– 7.70(m,2H),7.58(s,1H),7.49(d,J=5.4Hz,1H),7.29(d,J=5.4Hz,1H),7.25(d,J=5.3Hz,1H),7.20(t ,J=8.5Hz,2H),7.12(dd,J=15.2,7.1Hz,2H),7.04(dd,J=10.9,4.6Hz,1H),6.91(dd,J=8.1,1.1Hz,1 H),6.77(d,J=7.8Hz,1H),4.50(dt,J=13.3,6.6Hz,1H),4.32(d,J=5.0Hz,2H),1.52(d,J=6.7Hz,6H).

[0329] Final product 33: N-(2-((2-(4-(1-isopropyl-1H-pyrazole-4-yl)phenoxy)phenyl)amino)-2-oxoethyl)benzothiophene-5-carboxamide (33,29-125-36)

[0330]

[0331] Step 1: The preparation method is the same as that of the final product 1. The target compound (33,29-125-36) is a light white solid with a yield of 89.2%. 1 H NMR (400MHz, DMSO-d6): δ9.65(d,J=65.4Hz,1H),9.01(s,1H),839–8.51(m,1H),8.16(d d,J=17.3,8.4Hz,2H),8.07–8.11(m,2H),7.85(ddd,J=15.8,13.0,5.7Hz,3H),7.59–7.6 2(m,1H),7.52–7.54(m,2H),7.09(dt,J=14.0,7.4Hz,2H),6.96(d,J=8.6Hz,1H),6.91( d,J=7.7Hz,1H),4.46–4.53(m,1H),4.14(dd,J=10.4,5.9Hz,2H),1.44(d,J=6.6Hz,6H).

[0332] Final product 34: N-(2-(2-(1-cyclopropyl-1H-pyrazol-4-yl)phenoxy)phenyl)amino)-2-oxoethyl)benzothiophene-5-carboxamide (34,46-72-37)

[0333]

[0334] Step 1: The preparation method is the same as that of the final product 1. The target compound (34,46-72-37) is a pure white solid with a yield of 55.0%. 1 H NMR (400MHz, CDCl3): δ9.02(d,J=62.5Hz,1H),8.32(dd,J=28.4,7.9Hz,1H),8.11(d,J=7.3Hz,1H),7.76 (d,J=6.4Hz,2H),7.71(d,J=2.4Hz,1H),7.68(s,1H),7.60(dd,J=13.9,5.8Hz,1H),7.47(q,J=6.1Hz,2H ),7.22(t,J=5.2Hz,1H),7.14(dd,J=5.9,3.4Hz,1H),7.05–7.09(m,2H),6.97–7.02(m,1H),6.80–6.74( m,1H),6.67(d,J=2.2Hz,1H),4.26–4.29(m,2H),3.37–3.46(m,1H),0.96–1.02(m,2H),085–0.89(m,2H).

[0335] Final product 35: N-(2-oxo-2-(2-(2-(1-propyl-1H-pyrazol-4-yl)phenoxy)phenyl)amino)ethyl)benzothiophene-5-carboxamide (35,46-113-32)

[0336]

[0337] Step 1: The preparation method is the same as that of the final product 1. The target compound (35,46-113-32) is a pure white solid with a yield of 63.0%. 1 H NMR (400MHz, CDCl3): δ8.78(s,1H),8.36–8.38(m,1H),8.13(s,1H),7.80(d,J=8.4Hz,1H),7. 74(d,J=15.8Hz,2H),7.62(d,J=8.3Hz,1H),7.50(dd,J=7.4,4.8Hz,2H),7.34(d,J=5.3Hz,1H) ,7.27(d,J=6.5Hz,1H),7.06–7.13(m,3H),6.97–7.01(m,1H),6.80–6.83(m,1H),6.75–6.77( m,1H),4.26(d,J=5.0Hz,2H),3.94(t,J=7.1Hz,2H),1.73–1.82(m,2H),0.79(t,J=7.4Hz,3H).

[0338] Final product 36: N-(2-oxo-2-((2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)phenoxy)phenyl)amino)ethyl)benzothiophene-5-carboxamide (36,46-115-35)

[0339]

[0340] Step 1: The preparation method is the same as that of the final product 1. The target compound (36,46-115-35) is a pure white solid with a yield of 48.8%. 1H NMR (400MHz, CDCl3): δ8.86(s,1H),8.32–8.34(m,1H),8.10(s,1H),7.91(s,1H),7.8 1(s,1H),7.79(d,J=8.4Hz,1H),7.59(d,J=8.3Hz,1H),7.48(dd,J=9.0,5.5Hz,2H),7. 40(s,1H),7.25(s,1H),7.05–7.17(m,3H),6.99–7.02(m,1H),6.83(dd,J=7.8,1.3Hz, 1H), 6.77 (dd, J=8.0, 1.0Hz, 1H), 4.60 (q, J=8.4Hz, 2H), 4.27 (dd, J=13.7, 6.0Hz, 2H).

[0341] Final product 37: N-(2-(2-(1-(oxecyclobutane-3-yl)-1H-pyrazol-4-yl)phenoxy)phenyl)amino)-2-oxoethyl)benzothiophene-5-carboxamide (37, 46-107-35)

[0342]

[0343] Step 1: The preparation method is the same as that of final product 1. The target compound (37,46-107-35) is a pure white solid with a yield of 42.0%. 1 H NMR (400MHz, CDCl3): δ8.89(s,1H),8.36(d,J=8.0Hz,1H),8.09(s,1H),7.91(s,1H),7.83(s,1H),7.79(d ,J=8.4Hz,1H),7.58(d,J=8.4Hz,1H),7.54(dd,J=5.9,3.4Hz,1H),7.50(d,J=5.4Hz,1H),7.34(d,J=5.1H z,1H),7.24(s,1H),7.12–7.17(m,2H),7.08(t,J=7.7Hz,1H),6.99(t,J=7.7Hz,1H),6.86(dd,J=5.2,4.0 Hz, 1H), 6.74 (d, J = 8.1Hz, 1H), 5.27 (dd, J = 13.2, 6.4Hz, 1H), 4.91 (p, J = 7.1Hz, 4H), 4.27 (d, J = 5.4Hz, 2H).

[0344] Final product 38: N-(2-(2-(1-(difluoromethyl)-1H-pyrazol-4-yl)phenoxy)phenyl)amino)-2-oxoethyl)benzothiophene-5-carboxamide (38, 46-111-32)

[0345]

[0346] Step 1: The preparation method is the same as that of the final product 1. The target compound (38,46-111-32) is a pure white solid with a yield of 80.5%. 1 H NMR (400MHz, CDCl3): δ8.87(s,1H),8.37(dd,J=8.1,1.3Hz,1H),8.18(s,1H),8.09(s, 1H),7.92(s,1H),7.80(d,J=8.4Hz,1H),7.58(d,J=8.4Hz,1H),7.51(d,J=5.4Hz,1H),7 .46(dd,J=7.6,1.6Hz,1H),7.27–7.29(m,2H),7.15–7.19(m,1H),7.08–7.14(m,3H),7 .02(ddd,J=15.3,11.0,3.8Hz,1H), 6.82(dd,J=8.7,1.7Hz,2H), 4.27(d,J=5.4Hz,2H).

[0347] Final product 39: N-(2-((2-(4-fluorophenoxy)phenyl)amino)-2-oxoethyl)benzothiophene-5-carboxamide (39, 46-118-32)

[0348]

[0349] Step 1: The preparation method is the same as that of the final product 1. The target compound (39,46-118-32) is a white solid with a yield of 90.57%. 1 H NMR (400MHz, CDCl3): δ8.92(s,1H),8.34(dd,J=7.8,1.8Hz,1H),8.19(d,J=1.3Hz,1H),7.80(d,J=8.4Hz,1H),7.74(t,J=5.2Hz,1H),7.69(dd,J=8.4 ,1.6Hz,1H),7.48(d,J=5.4Hz,1H),7.25(d,J=4.5Hz,1H),6.98–7.07(m,2 H),6.85–6.93(m,4H),6.80(dd,J=7.8,1.6Hz,1H),4.32(d,J=5.4Hz,2H).

[0350] Final product 40: N-(2-((2-(4-chlorophenoxy)phenyl)amino)-2-oxoethyl)benzothiophene-5-carboxamide (40, 46-65-40)

[0351]

[0352] Step 1: The preparation method is the same as that of the final product 1. The target compound (40,46-65-40) is a pale white solid with a yield of 24.8%. 1 H NMR (400MHz, CDCl3): δ8.94(s,1H),8.34(d,J=7.2Hz,1H),8.17(s,1H),7.82(d,J=8.4Hz,1H),7.65–7.69(m,2H),7.49(d,J=5 .4Hz,1H),7.27–7.29(m,1H),7.14(d,J=8.8Hz,2H),7.012–7.09(m,2H),6.84(dd,J=14.0,8.7Hz,3H),4.30(d,J=5.4Hz,2H).

[0353] Final product 41: N-(2-oxo-2-((2-(4-(trifluoromethyl)phenoxy)phenyl)amino)ethyl)benzothiophene-5-carboxamide (41, 46-104-36)

[0354]

[0355] Step 1: The preparation method is the same as that of the final product 1. The target compound (41,46-104-36) is a pure white solid with a yield of 94.8%. 1 H NMR (400MHz, CDCl3): δ8.82(s,1H),8.39(dd,J=8.1,1.3Hz,1H),8.19(d,J=1.3Hz,1H),7.86(d,J=8.4Hz,1H),7.61–7.63(m,1H),7.53(d,J=5.4 Hz,1H),7.46(d,J=8.6Hz,2H),7.33(d,J=5.5Hz,2H),7.16–7.20(m,1H),7.07–7.11(m,1H),6.96(dd,J=12.7,4.8Hz,3H),4.28(d,J=5.5Hz,2H).

[0356] Final product 42: N-(2-((2-(4-ethylphenoxy)phenyl)amino)-2-oxoethyl)benzothiophene-5-carboxamide (42, 46-105-33)

[0357]

[0358] Step 1: The preparation method is the same as that of the final product 1. The target compound (42,46-105-33) is a colorless oil with a yield of 83.1%. 1H NMR (400MHz, CDCl3): δ8.72 (s, 1H), 8.35 (dd, J = 7.9, 1.7Hz, 1H), 8.21 (d, J = 1.3Hz, 1H),7.80(d,J=8.4Hz,1H),7.69(dd,J=8.4,1.6Hz,1H),7.54(t,J=5.1Hz,1H),7.46 (d,J=5.4Hz,1H),7.25(d,J=5.1Hz,1H),7.04–7.07k(m,3H),6.97–7.02(m,1H),6.8 2–6.87(m,3H),4.28(t,J=7.5Hz,2H),2.56(q,J=7.6Hz,2H),1.18(t,J=7.6Hz,3H).

[0359] Final product 43: N-(2-oxo-2-((2-(4-propylphenoxy)phenyl)amino)ethyl)benzothiophene-5-carboxamide (43,46-106-37)

[0360]

[0361] Step 1: The preparation method is the same as that of the final product 1. The target compound (43,46-106-37) is a colorless and transparent solid with a yield of 98.6%. 1 H NMR (400MHz, CDCl3): δ8.60 (s, 1H), 8.38 (dd, J = 7.9, 1.2Hz, 1H), 8.25 (s, 1H), 7. 85(d,J=8.4Hz,1H),7.72(d,J=8.4Hz,1H),7.50(d,J=5.4Hz,1H),7.36(s,1H),7. 31(d,J=5.4Hz,1H),7.06–7.09(m,3H),6.99–7.03(m,1H),6.84–6.90(m,3H),4. 32(d,J=5.0Hz,2H),2.50–2.53(m,2H),1.55–1.64(m,2H),0.93(t,J=7.3Hz,3H).

[0362] Final product 44: (R)-N-(1-oxo-1-((2-phenoxyphenyl)amino)propyl-2-yl)benzothiophene-5-carboxamide (44,42-9-40)

[0363]

[0364] Step 1: The preparation method is the same as that of the final product 1. The target compound (44,42-9-40) is a pure white solid with a yield of 46.2%. 1H NMR (400MHz, CDCl3): δ8.66(s,1H),8.39(dd,J=8.1,1.3Hz,1H),8.17(d,J=1.2H z,1H),7.86(d,J=8.4Hz,1H),7.66(dd,J=8.4,1.5Hz,1H),7.51(d,J=5.4Hz,1H), 7.33(d,J=5.4Hz,1H),7.29(d,J=8.2Hz,2H),7.04–7.14(m,3H),6.96(d,J=7.9H z, 2H), 6.89 (dd, J = 8.1, 1.2Hz, 1H), 4.90 (p, J = 7.0Hz, 1H), 1.54 (d, J = 7.0Hz, 3H).

[0365] Final product 45: (S)-N-(1-oxo-1-((2-phenoxyphenyl)amino)propyl-2-yl)benzothiophene-5-carboxamide (45,42-12-35)

[0366]

[0367] Step 1: The preparation method is the same as that of the final product 1. The target compound (45,42-12-35) is a pure white solid with a yield of 48.3%. 1 H NMR (400MHz, CDCl3): δ8.64(s,1H),8.39(dd,J=8.1,1.5Hz,1H),8.16(d,J=1.4Hz,1H),7.86(d, J=8.4Hz,1H),7.65(dd,J=8.4,1.6Hz,1H),7.51(d,J=5.4Hz,1H),7.33(d,J=5.5Hz,1H),7.27–7. 34(m,1H),7.09–7.14(m,1H),7.06(dd,J=4.6,3.7Hz,1H),7.03(dd,J=7.5,1.6Hz,1H),6.95–6.9 8(m,2H),6.93(s,1H),6.89(dd,J=8.1,1.4Hz,1H),4.88(p,J=7.0Hz,1H),1.54(d,J=7.0Hz,3H).

[0368] Final product 46: (S)-N-(3-methyl-1-oxo-1-((2-phenoxyphenyl)amino)but-2-yl)benzothiophene-5-carboxamide (46,42-17-39)

[0369]

[0370] Step 1: The preparation method is the same as that of the final product 1. The target compound (46,42-17-39) is a pure white solid with a yield of 27.1%. 1 H NMR (400MHz, CDCl3): δ8.39(dd,J=8.1,1.6Hz,1H),8.32(s,1H),8.23(d,J=1.3Hz,1H),7.89(d ,J=8.4Hz,1H),7.72(dd,J=8.4,1.6Hz,1H),7.52(d,J=5.4Hz,1H),7.36(t,J=4.2Hz,1H),7.28– 7.37(m,2H),7.09–7.14(m,2H),7.05(ddd,J=9.1,6.4,2.1Hz,1H),6.98–7.00(m,3H),6.88(dd, J=8.1,1.4Hz,1H),4.68(dd,J=8.4,6.5Hz,1H),2.26–2.34(m,1H),1.04(dd,J=6.8,2.0Hz,6H).

[0371] Final product 47: (R)-N-(3-methyl-1-oxo-1-((2-phenoxyphenyl)amino)but-2-yl)benzothiophene-5-carboxamide (47,42-16-34)

[0372]

[0373] Step 1: The preparation method is the same as that of the final product 1. The target compound (47,42-16-34) is a pure white solid with a yield of 41.9%. 1 H NMR (400MHz, CDCl3): δ8.37–8.40(m,2H),8.23(d,J=1.2Hz,1H),7.88(d,J=8.4Hz,1H), 7.73(dd,J=8.4,1.5Hz,1H),7.51(d,J=5.4Hz,1H),7.35(d,J=5.4Hz,1H),7.29–7.31(m, 2H),7.09–7.13(m,2H),7.02–7.06(m,2H),6.98(d,J=7.8Hz,2H),6.88(dd,J=8.1,1.2H z,1H),4.70(dd,J=8.4,6.8Hz,1H),2.30(dq,J=13.5,6.7Hz,1H),1.04(d,J=6.8Hz,6H).

[0374] Final product 48: N-(3-oxo-3-((2-phenoxyphenyl)amino)propyl)benzothiophene-5-carboxamide (48, 42-8-35)

[0375]

[0376] Step 1: The preparation method is the same as that of the final product 1. The target compound (48,42-8-35) is a pale yellow solid with a yield of 41.8%. 1 H NMR (400MHz, CDCl3): δ8.38(dd,J=8.1,1.4Hz,1H),8.25(d,J=1.4Hz,1H),8.25(d,J=1.4H z,1H),7.88(d,J=8.4Hz,2H),7.73(dd,J=8.4,1.7Hz,1H),7.50(d,J=5.5Hz,1H),7.38(s, 1H),7.29–7.33(m,2H),7.11(dd,J=12.7,4.5Hz,2H),7.01(td,J=7.9,1.6Hz,1H),6.96–7 .00(m,2H),6.82(dd,J=8.1,1.3Hz,1H),3.84(dd,J=11.5,5.9Hz,2H),2.73–2.76(m,2H).

[0377] Final product 49: N-(4-oxo-4-((2-phenoxyphenyl)amino)butyl)benzothiophene-5-carboxamide (49, 42-7-36)

[0378]

[0379] Step 1: The preparation method is the same as that of the final product 1. The target compound (49,42-7-36) is a pure white solid with a yield of 71.9%. 1 H NMR (400MHz, CDCl3): δ8.39 (dd, J=8.1, 1.4Hz, 1H), 8.26 (d, J=1.2Hz, 1H), 8.09 (s, 1H), 7.84(d,J=8.4Hz,1H),7.73–7.75(m,1H),7.47(d,J=5.4Hz,1H),7.29–7.33(m,2H),7.16 (s,1H),7.05–7.11(m,2H),7.00(dd,J=8.0,1.5Hz,1H),6.95–6.99(m,2H),6.80(dd,J= 8.1,1.3Hz,1H),3.56(dd,J=12.2,5.8Hz,2H),2.54(t,J=6.6Hz,2H),2.01–2.08(m,2H).

[0380] Final product 50: (S)-N-(3-((tert-butyldimethylsilyl)oxy)-1-oxo-1-((2-phenoxyphenyl)amino)propyl-2-yl)benzothiophene-5-carboxamide (50,42-96-34)

[0381]

[0382] Step 1: The preparation method is the same as that of the final product 1. The target compound (50,42-96-34) is a transparent oil with a yield of 57.9%. 1 H NMR (400MHz, CDCl3): δ8.97(s,1H),8.45(dd,J=8.1,1.5Hz,1H),8.25(d,J=1.4Hz,1H),7.91(d,J=8.4Hz,1 H),7.73(dd,J=8.4,1.6Hz,1H),7.53(d,J=5.4Hz,1H),7.36(d,J=5.4Hz,1H),7.30(d,J=7.5Hz,2H),7.08–7 .14(m,2H),7.02(td,J=7.9,1.6Hz,1H),6.94(d,J=7.7Hz,2H),6.82(dd,J=8.1,1.3Hz,1H),4.78(td,J=7. 4,3.7Hz,1H),4.28(dd,J=9.8,3.7Hz,1H),3.79(dd,J=9.8,7.7Hz,1H),0.86(s,9H),0.08(d,J=4.4Hz,6H).

[0383] Final product 51: (R)-N-(3-((tert-butyldimethylsilyl)oxy)-1-oxo-1-((2-phenoxyphenyl)amino)propyl-2-yl)benzothiophene-5-carboxamide (51,42-46-36)

[0384]

[0385] Step 1: The preparation method is the same as that of the final product 1. The target compound (51,42-46-36) is a pure white solid with a yield of 100.0%. 1H NMR (400MHz, CDCl3): δ8.97(s,1H),8.45(dd,J=8.1,1.2Hz,1H),8.25(d,J=1.1Hz,1H),7.91(d,J=8.4Hz ,1H),7.73(dd,J=8.4,1.4Hz,1H),7.53(d,J=5.4Hz,1H),7.36(d,J=5.4Hz,1H),7.28(s,2H),7.08–7.14( m,2H),7.02(td,J=8.0,1.4Hz,1H),6.94(d,J=7.8Hz,2H),6.82(dd,J=8.1,1.1Hz,1H),4.78(td,J=7.3, 3.7Hz, 1H), 4.27 (dd, J = 9.8, 3.7Hz, 1H), 3.79 (dd, J = 9.7, 7.7Hz, 1H), 0.86 (s, 9H), 0.07 (d, J = 4.0Hz, 6H).

[0386] Final product 52: (S)-N-(3-methoxy-1-oxo-1-((2-phenoxyphenyl)amino)propyl-2-yl)benzothiophene-5-carboxamide (52,42-194-37)

[0387]

[0388] Step 1: The preparation method is the same as that of the final product 1. The target compound (52,42-194-37) is a transparent solid with a yield of 80.0%. 1 H NMR (400MHz, CDCl3): δ9.20 (s, 1H), 8.46 (dd, J = 8.1, 1.5Hz, 1H), 8.26 (d, J = 1.4Hz, 1H), 7.91(d,J=8.4Hz,1H),7.75(dd,J=8.4,1.6Hz,1H),7.53(d,J=5.5Hz,1H),7.37(d,J=5. 4Hz,1H),7.27–7.38(m,3H),7.16(td,J=8.0,1.4Hz,1H),7.05–7.10(m,2H),6.90–6.96 (m,3H),4.87–4.91(m,1H),4.02(dd,J=9.0,3.8Hz,1H),3.50–3.54(m,1H),3.31(s,3H).

[0389] Final product 53: (R)-N-(3-methoxy-1-oxo-1-((2-phenoxyphenyl)amino)propyl-2-yl)benzothiophene-5-carboxamide (53, 42-94-36)

[0390]

[0391] Step 1: The preparation method is the same as that of the final product 1. The target compound (53,42-94-36) is a pure white solid with a yield of 80.0%. 1 H NMR (400MHz, CDCl3): δ9.39(s,1H),8.44(d,J=8.0Hz,1H),7.81(d,J=7.7Hz,1H),7.76(s,1H),7.48(d,J=4.1Hz,1H),7.35(t,J= 6.9Hz,2H),7.28–7.30(m,2H),7.14(s,2H),7.04(d,J=5.9Hz,3H),6.93(d,J=8.0Hz,1H),3.96(s,1H),3.41(s,2H),2.96(s,3H).

[0392] Final product 54: N-(2-oxo-2-((3-phenoxyphenyl)amino)ethyl)benzothiophene-5-carboxamide (54, 42-108-36)

[0393]

[0394] Step 1: The preparation method is the same as that of the final product 1. The target compound (54,42-169-40) is a pure white solid with a yield of 40.28%. 1 H NMR (400MHz, DMSO-d6): δ10.20(s,1H),8.94(t,J=5.8Hz,1H),8.45(d,J=1.4Hz,1H),8.11(d,J=8.4Hz,1H),7.85–7.89(m,2H),7.57(d,J=5.5Hz,1 H),7.39(ddd,J=6.8,5.6,1.9Hz,3H),7.34(dd,J=3.4,1.7Hz,1H),7.12– 7.16(m,1H),7.02–7.04(m,2H),6.71–6.74(m,1H),4.09(d,J=5.8Hz,2H).

[0395] Final product 55: N-(2-oxo-2-((4-phenoxyphenyl)amino)ethyl)benzothiophene-5-carboxamide (55, 42-89-35)

[0396]

[0397] Step 1: The preparation method is the same as that of the final product 1. The target compound (55,42-89-35) is a pure white solid with a yield of 75.75%. 1H NMR (400MHz, DMSO-d6): δ10.14(s,1H),8.97(t,J=5.8Hz,1H),8.47(d,J=0.9Hz,1H),8.12(d,J=8.5Hz,1H),7.86–7.91(m,2H),7.64(d,J=9 .0Hz,2H),7.58(d,J=5.4Hz,1H),7.36(dd,J=10.8,5.1Hz,2H),7.09(t,J=7.4Hz,1H),6.98(dd,J=17.2,8.4Hz,4H),4.11(d,J=5.8Hz,2H).

[0398] Final product 56: (S)-N-(3-hydroxy-1-oxo-1-((2-phenoxyphenyl)amino)propyl-2-yl)benzothiophene-5-carboxamide (56, 42-99-38)

[0399]

[0400] Step 1: The preparation method is the same as that of the final product 1. The target compound (56,42-99-38) is a pure white solid with a yield of 100%. 1 H NMR (400MHz, CDCl3): δ9.37(s,1H),8.34–8.36(m,1H),8.13(s,1H),7.87(d,J= 8.4Hz,1H),7.63(d,J=8.5Hz,1H),7.53(d,J=5.5Hz,1H),7.35(d,J=5.5Hz,2H) ,7.14(t,J=7.2Hz,2H),7.06(t,J=7.0Hz,3H),6.96(d,J=8.1Hz,2H),6.92(dd, J=8.1,1.2Hz,1H),4.82(s,1H),4.38(dd,J=11.4,2.2Hz,1H),3.75–3.79(m,1H)

[0401] Final product 57: (S)-N-(3-hydroxy-1-oxo-1-((2-phenoxyphenyl)amino)propyl-2-yl)benzothiophene-5-carboxamide (57, 42-51-30)

[0402]

[0403] Step 1: The preparation method is the same as that of the final product 1. The target compound (57,42-51-30) is a pure white solid with a yield of 100%. 1H NMR (400MHz, CD3OD): δ8.25(d,J=1.6Hz,1H),8.19(dd,J=7.9,1.8Hz,1H),7.91(d,J=8.5Hz,1H),7.71(dd,J=8.5,1.7Hz,1H),7.63(d,J=5.5Hz,1H),7. 37(d,J=5.5Hz,1H),7.16–7.21(m,2H),7.03–7.12(m,2H),6.97(t,J=7.4Hz ,1H),6.82–6.86(m,3H),4.75(t,J=5.7Hz,1H),3.90(dd,J=5.7,2.3Hz,2H).

[0404] Example 2: Experimental test of anti-proliferation activity of SK-N-AS cells

[0405] Screening method: Cell Counting Kit-8 (CCK-8)

[0406] Instruments: Low-speed benchtop centrifuge (L420-A) (Hunan Xiangyi Laboratory Instrument Development Co., Ltd.); Clean bench (Zhejiang Sujing Purification Equipment Co., Ltd.); Optical microscope (Shanghai Dilun Optical Instrument Co., Ltd.); Constant temperature water bath (HH-S2) (Gongyi Yuhua Instrument Co., Ltd.)

[0407] Materials: RPMI-1640 (Solepro), premium bovine serum (Solepro), trypsin (Solepro), PBS buffer (Solepro), CCK-8 reagent (Meilun Biotechnology)

[0408] Principle: The CCK-8 cell viability assay kit contains WST-8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfonylbenzene)-2H-tetrazole monosodium salt) (CAS: 193149-74-5). In the presence of electron carriers, WST-8 is oxidized and reduced by intracellular dehydrogenases to generate a highly water-soluble orange-yellow formazan dye that dissolves in tissue culture medium. The amount of formazan generated is directly proportional to the number of viable cells and inversely proportional to cytotoxicity. For the same number of cells, the color intensity is linearly related to the cell number. The OD value is measured at 450 nm using a microplate reader, which indirectly reflects the number of viable cells. The CCK-8 method is a highly sensitive, non-radioactive colorimetric assay for determining the number of viable cells in cell proliferation or cytotoxicity experiments.

[0409] Experimental procedure:

[0410] Digest SK-N-AS cells for 1 min. Cell count was performed in MEM medium containing 10% FBS (premium bovine serum) and 1% P / S. The result was (64+60+60+57)*2 / 4*10. 4 =1.205*10 6 Cell suspension preparation (12 ml): Take 10.5 ml of 1640 medium containing 10% FBS + 1.5 ml of cell suspension. Seeding plate: 96-well plate, 100 μl / well, 10 cells per well. 4 indivual / Incubate at 37°C in a 5% CO2 incubator overnight. Prepare the reagents: Set the concentration of each compound to 10 μM (22 compounds), adding 100 μL of reagent to each well, and incubate for 24 h. Prepare a 10% CCK-8 solution containing 1% FBS and 1% P / S. Remove the reagent solution and add 100 μL of CCK-8 solution to each well. Incubate for 1.5 h. Detect using a microplate reader at 450 nm. Calculate the inhibition rate using the formula: Inhibition rate = (Control wells - Experimental wells) / (Control wells - Blank wells) * 100. For inhibition rates greater than 50%, simultaneously test the IC50. 50 value.

[0411] Table 3. Inhibition rates of 57 small molecule compounds against SK-N-AS

[0412]

[0413] — a , indicating that it has not been measured.

[0414] The above description is merely a preferred embodiment of the present invention. The present invention is not limited to the above-described embodiments. Any embodiment that achieves the technical effects of the present invention using the same means should fall within the protection scope of the present invention. Within the protection scope of the present invention, various modifications and variations can be made to the technical solutions and / or implementation methods.

Claims

1. A small molecule compound having a substituted diphenyl ether structure, characterized in that, The small molecule compound, or its enantiomer, racemate, or mixture thereof, or its pharmaceutically acceptable salt, hydrate, or solvate, comprises the structure shown in formula (I) or (II): In formula (I) or formula (II): X, Y, and Z are each independently selected from N, NH, O, S, or CH; the dashed lines in the structural segments containing X, Y, and Z represent single or double bonds, forming suitable benzo[c][1,2,5]oxadiazole; in addition, the intermediate chains shown in formulas (I) and (II) are connected to the benzene ring at any position; R1 represents substitution at any position on the benzene ring, independently selected from any of the following: H, halogen, hydroxyl, amino, nitro, substituted or unsubstituted 5-12 membered heteroaromatic rings containing N, O, or S atoms, substituted or unsubstituted 5-13 membered saturated heterocycles containing N, O, or S atoms, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or Unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkylethynyl, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C1-C4 alkylcarbonylamino, substituted or unsubstituted C1-C4 alkoxycarbonylamino, substituted or unsubstituted C1-C4 sulfonyl, substituted or unsubstituted C1-C4 alkyl-S-, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C1-C4 alkylcarbonyl, substituted or unsubstituted C1-C4 alkylaminocarbonyl. R2 represents a substituent in the intermediate linking chain and is independently selected from any of the following: H, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C1-C4 alkylethynyl, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C1-C4 alkylcarbonylamino, substituted or unsubstituted C1-C4 alkoxycarbonylamino, substituted or unsubstituted C1-C4 sulfonyl, substituted or unsubstituted C1-C4 alkyl-S-, substituted or unsubstituted C1-C4 alkylcarbonyl, substituted or unsubstituted C1-C4 alkylaminocarbonyl. n represents the number of carbon atoms in the intermediate connecting chain, and its value is an integer from 0 to 2.

2. A small molecule compound having a substituted diphenyl ether structure according to claim 1, characterized in that, The small molecule compound having a substituted diphenyl ether structure has any of the following structures:

3. A method for preparing a small molecule compound having a substituted diphenyl ether structure as described in claim 1 or 2, characterized in that, The preparation steps of the small molecule compounds shown in formulas (I) and (II) are as follows: Step 1: The compound shown in formula (I) or (II) is prepared in one step by an amidation step. The preparation route is as follows: amine S1 is mixed with the corresponding carboxylic acid S2 or S3 in a suitable solvent, phosphorus oxychloride is added, and the reaction is carried out at room temperature to obtain the compound shown in formula (I) or (II). The solvent is pyridine. Alternatively, S2 or S3 can be first prepared into acyl chlorides, and then mixed with the corresponding amine S1 in a solvent, such as tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, or N,N-dimethylformamide; a base (triethylamine, diisopropylethylamine, pyridine, or N-methylmorpholine, etc.) is added, and the reaction is carried out at room temperature, low temperature (-10℃ to 0℃), or elevated temperature (40-50℃) to obtain the small molecule compounds shown in formula (I) and formula (II).

4. An inhibitor for the treatment of cancer, characterized in that, The inhibitor includes small molecule compounds having a substituted diphenyl ether structure as described in claim 1 or 2, or their enantiomers, diastereomers, racemates, or mixtures thereof, as well as their pharmaceutically acceptable salts, hydrates, and solvates.

5. A pharmaceutical composition, characterized in that, This includes small molecule compounds having a substituted diphenyl ether structure as described in claim 1 or 2, or their enantiomers, diastereomers, racemates, or mixtures thereof, as well as one or more of their pharmaceutically acceptable salts, hydrates, and solvates, and pharmaceutically acceptable carriers.

6. The pharmaceutical composition according to claim 5, characterized in that, It also includes pharmaceutically acceptable excipients selected from the group consisting of: binders, fillers, diluents, disintegrants, suspending agents, suspending aids, sustained-release agents, lyophilization protectants, coating agents, enteric materials, lubricants, flow aids, anti-adhesion agents, sweeteners, flavoring agents, plasticizers, opacifiers, solubilizers, humectants, solvents, osmotic pressure regulators, colorants, pigments, surfactants, emulsifiers, water-soluble matrices, fat-soluble matrices, lipophilic matrices, pore-forming agents, gelling agents, preservatives, buffers, chelating agents, antioxidants, or combinations thereof.

7. The pharmaceutical composition according to claim 5, characterized in that, This pharmaceutical composition is used to prepare a medicament for treating diseases associated with the activity or expression level of anticancer agents, wherein the diseases associated with the activity or expression level of anticancer agents are selected from the group consisting of: fallopian tube cancer, prostate cancer, peritoneal cancer, breast cancer, gastric cancer, brain cancer, lung cancer, liver cancer, colorectal cancer, skin cancer, esophageal cancer, cervical cancer, ovarian cancer, bladder cancer, and pancreatic cancer.

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