TW202342435A - Triazolamide compound, preparation method therefor, and use thereof - Google Patents

Abstract

Disclosed in the present invention are a triazolamide compound, a preparation method therefor, and a use thereof. Specifically, disclosed are a triazolamide compound as shown in formula I or a pharmaceutically acceptable salt thereof, and a use thereof in the preparation of a drug for treating and/or preventing HDAC-related diseases. The diseases may be cancers.

Description

Triazolamide compounds and their preparation methods and uses

This application claims priority to Chinese patent application 2022103172254 with a filing date of March 28, 2022, and Chinese patent application 2022114611861 with a filing date of November 21, 2022. This application cites the full text of the above-mentioned Chinese patent application.

The invention relates to a triazolamide compound and its preparation method and use.

A large number of studies have shown that histone deacetylase (HDAC) is overexpressed in a variety of tumor cells and plays an important role in the occurrence and development of tumors. HDACs are a class of epigenetic enzymes that regulate the acetylation levels of histones as well as many non-histone proteins. HDACs related to the transcription level are mainly located in the nucleus. They hydrolyze the ε-amine group on the side chain of the lysine residue in histones through the catalytic active center, and then exert the deacetylation function, making the histones positively charged and interacting with DNA. Tightly binds, ultimately leading to gene silencing; inhibiting its effect will relax the chromatin conformation, which is beneficial to gene expression (Kazantsev, Thompson, Nat Rev Drug Discov 2008, 7(10): 854-868).

There are 18 subtypes of HDAC, which can be divided into four subfamilies, Class I to IV, based on homology (Ho et al., J Med Chem 2020, 63(21): 12460-12484). Class I includes HDAC1, 2, 3 and 8; Class II includes HDAC4, 5, 6, 7, 9 and 10; Class III is often called Sirtuins, including SIRT1-7; Class IV only has HDAC11. Class II can be divided into Class IIa (HDAC4, 5, 7 and 9) and Class IIb (HDAC 6 and 10). According to different catalytic activity mechanisms, HDACs can be divided into two major categories, among which Sirtuins1-7 are nicotinamide adenine dinucleotide (NAD ⁺ )-dependent, while HDAC1-11 are Zn ²⁺ -dependent. HDAC usually refers to HDAC1-11.

HDAC inhibitors are small molecule compounds that inhibit HDAC activity. Currently, there are five HDAC inhibitors that have been approved for marketing, including Vorinostat (SAHA), Panobinostat (LBH-589), Belinostat (PXD-101), Romidepsin (FK-228) and chidamide are mainly used to treat cutaneous T-cell lymphoma, relapsed or refractory peripheral T-cell lymphoma, etc. These inhibitors, except chidamide and romidepsin, are pan-HDAC inhibitors and are not subtype selective. In addition, there are many HDAC inhibitors in the research stage and have the potential to be used in the treatment of lymphoma, solid tumors and hematological tumors. Current HDAC inhibitors have poor therapeutic efficacy against solid tumors, which may be related to low activity requiring high doses, lack of subtype specificity, in vivo pharmacokinetic and pharmacodynamic limitations, endogenous tumor resistance mechanisms, and dose-dependent side effects. (such as thrombocytopenia) and other related factors (Hogg et al., Nat Rev Drug Discov 2020, 19(11): 776-800).

Hydroxamic acid HDACs inhibitors are currently the most widely studied class of compounds with the most structural types. Hydroxamic acid has a strong chelating ability with Zn ²⁺ , so hydroxamic acid HDAC inhibitors have strong activity and are usually not selective (pan-HDAC inhibitors). Benzyl anilines are another common ZBG group that have received widespread attention. Compared with hydroxamic acid HDAC inhibitors, benzoaniline HDAC inhibitors have certain selectivity for Class I HDACs. Representative compounds among benzoaniline HDAC inhibitors are chidamide, MS275 and MGCD0103. Among them, MGCD0103 has good oral anti-tumor activity, with the strongest effect on HDAC1, 2 to 10 times weaker activity on HDAC2, 3 and 11, and no inhibitory activity on HDAC4, 5, 6, 7 and 8 (Fournel et al., Mol Cancer Ther 2008, 7(4): 759-768).

In terms of mechanism of action, HDAC inhibitors can regulate multiple message transmission pathways and produce anti-tumor activity by changing gene expression and protein activity. The main mechanisms include: cell cycle arrest, induction of apoptosis, induction of autophagy, and inhibition of angiogenesis. Promote ROS production, etc. (Li et al., Front Cell Dev Biol 2020, 8, 576946). In addition, studies have shown that subtype-selective HDAC inhibitors such as MGCD0103 can change the tumor microenvironment and promote anti-tumor immunity (Briere et al., Cancer Immunol Immunother 2018, 67(3): 381-392).

The tumor microenvironment (TME) has immunosuppressive properties. Key drivers of immune evasion in the TME include tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), which not only mediate immunosuppression but also promote metastasis and resistance to immunotherapy. Studies have shown that some HDAC inhibitors can upregulate the expression of costimulatory molecules such as MHC and CD80/86 (Deng et al., Mol Cancer Ther 2019, 18(5): 900-908), while promoting the expression of non-classical MHC such as CD1d and promoting antigen Presented, thereby enhancing immune recognition and activation of NK cells (Tiper et al., Cancer Immunol Immunother 2016, 65(11): 1411-1421). Class I HDAC inhibitors have been shown to upregulate PD-L1 and PD-L2 in tumor cells, thereby synergistically enhancing the activity of anti-PD-L1 drugs (Woods et al., Cancer Immunol Res 2015, 3(12): 1375-1385 ), can be used as a potential tumor immunotherapy drug. The combination of HDAC inhibitors with radiotherapy, chemotherapy, molecular target therapy and immunotherapy drugs also has very broad prospects. Multiple clinical trials of the combination of HDAC inhibitors with immunotherapy drugs are in progress.

However, existing HDAC inhibitors have shortcomings such as low selectivity, obvious side effects, and poor pharmacokinetic properties, which seriously limit their clinical application. Therefore, the design and development of new HDAC inhibitors has important application value for the treatment of tumors.

The technical problem to be solved by the present invention is to provide a triazolamide compound with a novel structure and its preparation method and use in order to overcome the single defect of HDAC inhibitors in the prior art. The triazolamide compounds provided by the invention have good HDAC inhibitory activity and can inhibit the proliferation of tumor cells. Some compounds have good pharmacokinetic properties and can inhibit the growth of subcutaneous transplanted tumors of MC38 colon cancer in mice, and have a significant inhibitory effect on the growth of subcutaneous transplanted tumors of human HCT-116 colon cancer in mice. The compound can overcome the drug-resistant effect of FLT3 inhibitors, and the combined use of FLT3 inhibitors has a synergistic effect on drug-resistant acute leukemia.

The present invention provides a triazolamide compound represented by formula I or a pharmaceutically acceptable salt thereof, , wherein Ring A is a 6-14-membered aryl group, a 6-14-membered aryl group substituted by one or more R ^7a , a 5-10-membered heteroaryl group, or a 5-10-membered aryl group substituted by one or more R ^7b heteroaryl, or ; In the 5-10-membered heteroaryl group and the 5-10-membered heteroaryl group substituted by one or more R ^7b , the heteroatom is selected from N, O and S. One or more, the number of heteroatoms is 1-4; when there are multiple substituents, they are the same or different; R ^7a and R ^7b are independently halogen, -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkyl substituted by one or more halogens or -(CH ₂ ) _n -N(R ^8a R ^8b ); L is a chemical bond or ; R ⁵ is hydrogen, halogen or C ₁ -C ₆ alkyl; R ⁶ is hydroxyl, 6-14-membered aryl or 6-14-membered aryl substituted by one or more R ⁹ ; when the substituent is multiple when, the same or different; R ⁹ is -N (R ^9a R ^9b ) or halogen; R ¹ , R ² , R ³ , R ⁴ , R ^8a , R ^8b , R ^9a and R ^9b are independently hydrogen or C ₁ -C ₆ alkyl; n is 0, 1, 2 or 3; The carbon atom with "*" indicates that when it is a chiral carbon atom, it is S configuration, R configuration or their mixture.

In the present invention, when Ring A is a 6-14-membered aryl group or a 6-14-membered aryl group substituted by one or more R ^7a , the 6-14-membered aryl group may be substituted by one or more R ^7a The 6-14-membered aryl group in the 6-14-membered aryl group is preferably a 6-10-membered aryl group, such as phenyl, or .

In the present invention, when ring A is a 5-10-membered heteroaryl group or a 5-10-membered heteroaryl group substituted by one or more R ^7b , the 5-10-membered heteroaryl group may be substituted by one or more R 7b In the 5-10-membered heteroaryl group substituted by R ^7b , the 5-10-membered heteroaryl group is preferably pyridyl or quinolyl, for example , or .

In the present invention, when R ⁵ , R ^7a , R ^7b and R ⁹ are independently halogen, the halogen is preferably fluorine, chlorine, bromine or iodine, such as fluorine, chlorine or bromine.

In the present invention, when R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^7a , R ^7b , R ^8a , R ^8b , R ^9a and R ^9b are independently C ₁ -C ₆ alkyl, then The C ₁ -C ₆ alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl or third butyl, such as methyl, ethyl or Isopropyl.

In the present invention, when R ^7a and R ^7b are independently C ₁ -C ₆ alkoxy groups, the C ₁ -C ₆ alkoxy groups are preferably C ₁ -C ₃ alkoxy groups, such as methoxy groups Or ethoxy.

In the present invention, when R ^7a and R ^7b are independently C ₂ -C ₆ alkynyl groups, the C ₂ -C ₆ alkynyl groups are preferably C ₂ -C ₄ alkynyl groups, such as ethynyl groups.

In the present invention, when R ^7a and R ^7b are independently C ₁ -C ₆ alkyl groups substituted by one or more halogens, the C ₁ -C ₆ alkyl groups substituted by one or more halogens are preferably C ₁ -C ₃ alkyl substituted by one or more halogens, for example trifluoromethyl.

In the present invention, when R ⁶ is a 6-14-membered aryl group or a 6-14-membered aryl group substituted by one or more R ^9s , the 6-14-membered aryl group may be substituted by one or more R ^7a The 6-14-membered aryl group in the 6-14-membered aryl group is preferably a 6-10-membered aryl group, such as phenyl.

In certain preferred embodiments of the present invention, certain groups of the triazolamide compounds represented by Formula I are defined as follows (the unmentioned groups are the same as those described in any scheme of this application), Ring A is a 6-14-membered aryl group, a 6-14-membered aryl group substituted by one or more R ^7a , a 5-10-membered heteroaryl group, or .

In certain preferred embodiments of the present invention, certain groups of the triazolamide compounds represented by Formula I are defined as follows (the unmentioned groups are the same as those described in any scheme of this application), R ⁵ is hydrogen.

In certain preferred embodiments of the present invention, certain groups of the triazolamide compounds represented by Formula I are defined as follows (the unmentioned groups are the same as those described in any scheme of this application), R ⁶ is hydroxyl, or a 6-14 membered aryl group substituted by one or more R ⁹ .

In certain preferred embodiments of the present invention, certain groups of the triazolamide compounds represented by Formula I are defined as follows (the unmentioned groups are the same as those described in any scheme of this application), R ^8a and R ^8b are independently C ₁ -C ₆ alkyl.

In certain preferred embodiments of the present invention, certain groups of the triazolamide compounds represented by Formula I are defined as follows (the unmentioned groups are the same as those described in any scheme of this application), R ^9a and R ^9b are independently hydrogen.

In certain preferred embodiments of the present invention, certain groups of the triazolamide compounds represented by Formula I are defined as follows (the unmentioned groups are the same as those described in any scheme of this application), n is 0 or 1.

In certain preferred embodiments of the present invention, certain groups of the triazolamide compounds represented by Formula I are defined as follows (the unmentioned groups are the same as those described in any scheme of this application), Ring A is a 6-14-membered aryl group, a 6-14-membered aryl group substituted by one or more R ^7a , a 5-10-membered heteroaryl group, or ; When there are multiple substituents, they may be the same or different; R ^7a is halogen, -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkynyl, substituted by one or more A halogen-substituted C ₁ -C ₆ alkyl group or -(CH ₂ ) _n -N(R ^8a R ^8b ); L is a chemical bond or ; R ¹ , R ² , R ³ and R ⁴ are independently hydrogen or C ₁ -C ₆ alkyl; R ⁵ is hydrogen; R ⁶ is hydroxyl, or a 6-14-membered aromatic substituted by one or more R ⁹ group; R ^8a and R ^8b are independently C ₁ -C ₆ alkyl; R ⁹ is -N (R ^9a R ^9b ) or halogen; R ^9a and R ^9b are independently hydrogen; n is 0 or 1.

In certain preferred embodiments of the present invention, certain groups of the triazolamide compounds represented by Formula I are defined as follows (the unmentioned groups are the same as those described in any scheme of this application), Ring A is phenyl, , , , , , , , , , , , , , , , , , , , , , , , or .

In certain preferred embodiments of the present invention, certain groups of the triazolamide compounds represented by Formula I are defined as follows (the unmentioned groups are the same as those described in any scheme of this application), R ¹ and R ² are independently H or methyl.

In certain preferred embodiments of the present invention, certain groups of the triazolamide compounds represented by Formula I are defined as follows (the unmentioned groups are the same as those described in any scheme of this application), R ³ and R ⁴ are independently H or ethyl.

In certain preferred embodiments of the present invention, certain groups of the triazolamide compounds represented by Formula I are defined as follows (the unmentioned groups are the same as those described in any scheme of this application), R ⁶ is hydroxyl group, or .

In certain preferred embodiments of the present invention, the triazolamide compound represented by Formula I is selected from any of the following structures, isomers thereof or mixtures thereof: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

The present invention also provides a pharmaceutical composition, which includes the above-mentioned triazolamide compound represented by Formula I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient.

The selection of pharmaceutical excipients varies depending on the route of administration and action characteristics, and can usually be conventional fillers, diluents, adhesives, wetting agents, disintegrants, lubricants, emulsifiers, suspending agents, etc. .

The present invention also provides the use of the above-mentioned triazolamide compounds represented by Formula I and pharmaceutically acceptable salts thereof as HDAC inhibitors.

The present invention also provides a pharmaceutical combination, which includes the above-mentioned triazolamide compound represented by Formula I or a pharmaceutically acceptable salt thereof and a PD-1 or PD-L1 antibody.

The pharmaceutical combination is a pharmaceutical composition containing a triazolamide compound as shown in Formula I as described above and a PD-1 or PD-L1 antibody, and each component is provided independently in the form of a set or other different Premixed form, such as a combination of drugs to be administered by sequential administration.

In certain preferred embodiments of the present invention, the PD-1 antibody can be InVivoMab anti-mouse PD-1 (Bio X Cell), Nivolumab, or Pembrolizumab , Cemiplimab, Toripalimab, Cindilimab and Camrelizumab; the PD-L1 antibody can be atezolizumab ( Atezolizumab, Avelumab, and Durvalumab. The drug combination may be compound I-38 and PD-1 antibody nivolumab, pembrolizumab, cemiplimab, toripalimab Toripalimab, Cindilimab, or Camrelizumab; or with the PD-L1 antibody Atezolizumab, Avelumab, or Duvalumab Combination of monoclonal antibodies (Durvalumab).

In certain preferred embodiments of the present invention, the triazolamide compound represented by Formula I or a pharmaceutically acceptable salt thereof, and the PD-1 or PD-L1 monoclonal antibody are administered separately.

The present invention also provides a pharmaceutical combination, which includes the above-mentioned triazolamide compound represented by Formula I or a pharmaceutically acceptable salt thereof, and a FLT3 inhibitor. The pharmaceutical combination may be a pharmaceutical composition containing a triazolamide compound as shown in Formula I and a FLT3 inhibitor as described above, and each component may be in a package form or other forms that are not premixed in advance. For example, a combination of drugs administered in a sequential manner.

In certain preferred embodiments of the present invention, the FLT3 inhibitor is Quizartinib, Crenolanib, Gilteritinib or Sorafenib, for example Quizatinib. The pharmaceutical combination may be a combination of compound I-38 and a FLT3 inhibitor (such as quizartinib, claranib, gilitinib or sorafenib), preferably compound I-38 and quizartinib combination.

The present invention also provides the above-mentioned triazolamide compounds represented by formula I and their pharmaceutically acceptable salts in the preparation and combination treatment and/or prevention of PD-1 or PD-L1 monoclonal antibodies. Applications in drugs for HDAC-related diseases.

The present invention also provides the use of the above-mentioned triazolamide compounds represented by Formula I and their pharmaceutically acceptable salts in the preparation of drugs for the treatment and/or prevention of HDAC-related diseases.

The triazolamide compound represented by Formula I, its pharmaceutically acceptable salt or the pharmaceutical combination as described above can be a therapeutically effective amount.

The disease may be cancer. The cancer may be head and neck cancer (such as thyroid cancer, nasopharyngeal cancer, meningeal cancer or intracranial metastasis), respiratory system cancer (such as small cell lung cancer or non-small cell lung cancer), digestive system cancer (such as liver cancer, gastric cancer , esophageal, rectal, colon or pancreatic cancer), urinary tract cancer (such as kidney, bladder, prostate or testicular cancer), bone cancer, gynecological cancer (such as breast, cervical or ovarian cancer), Cancers of the blood system (such as leukemia, lymphoma, or myeloma) or other types of cancer (such as melanoma, glioma, or skin cancer).

The triazolamide compound shown in formula I, its pharmaceutically acceptable salt or the pharmaceutical combination as described above can be administered to the subject by any suitable route, preferably oral, injection (intravenous, intramuscular, subcutaneous and coronary), sublingual, nasal, inhalational or topical routes, preferably orally.

In the present invention, if stereoisomers exist in the triazolamide compounds represented by formula I or pharmaceutically acceptable salts thereof, they can be expressed as single stereoisomers or their mixtures (for example, external racemate) exists. The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotation chromatography, column chromatography, gas chromatography, high-pressure liquid chromatography, etc.), and can also It is obtained by chiral separation through bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.

In the present invention, if a tautomer exists in the triazolamide compound represented by Formula I or a pharmaceutically acceptable salt thereof, it may exist in the form of a single tautomer or a mixture thereof. , preferably in the form of a more stable tautomer.

The present invention also provides a method for preparing the triazolamide compounds shown in Formula I as described above. The preparation method includes the following scheme one or scheme two: Scheme one: When R ⁶ is a hydroxyl group, in the organic In a solvent, in the presence of a base, the compound represented by formula II is reacted with hydroxylamine hydrochloride as shown below to obtain the triazolamide compound represented by formula I, ; Option 2: When R ⁶ is When, in an organic solvent, in the presence of a condensing agent and a base, the compound represented by formula III and the compound represented by formula IV are subjected to a condensation reaction as shown below, to obtain the compound represented by formula I Triazolamide compounds, ; Wherein, ring A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and L are defined as above.

The reaction operations and conditions in Scheme 1 and Scheme 2 can be conventional operations and conditions in this type of reaction in the art, and the preferred methods of the present invention are as follows.

In the first embodiment, the organic solvent may be an alcoholic solvent, such as methanol. The organic solvent may be used in an amount that does not affect the reaction.

In the first embodiment, the base may be an alkali metal hydroxide, such as potassium hydroxide.

In the first embodiment, the molar ratio of the base to the hydroxylamine hydrochloride may be 1-3:1, such as 1.5:1.

In the first embodiment, the molar ratio of the hydroxylamine hydrochloride to the compound represented by formula II may be 1-100:1, for example, 45:1.

In the first embodiment, the reaction temperature may range from -40°C to the boiling temperature of the organic solvent, such as room temperature.

In the first embodiment, the progress of the reaction can be detected using conventional monitoring methods in the field (such as TLC, HPLC or NMR). Generally, when the compound represented by Formula II disappears or no longer reacts, it is used as the indicator. reaction endpoint. The reaction time may be from 5 minutes to 24 hours, such as 1 hour.

In the second embodiment, the organic solvent may be an amide solvent, such as N,N-dimethylformamide (DMF). The organic solvent may be used in an amount that does not affect the reaction.

In the second embodiment, the base may be an organic base, such as N,N-diisopropylethylamine (DIPEA).

In the second embodiment, the molar ratio of the base to the compound represented by formula III may be 1-3:1, for example, 2:1.

In the second embodiment, the condensation agent may be a carbodiimide condensation agent, a phosphorus cationic condensation agent or a urea cationic condensation agent. The carbodiimide-type condensation agent is preferably N,N'-dicyclohexylcarbodiimide (DCC) or N,N'-diisopropylcarbodiimide (DIC). The phosphorus cationic condensing agent is preferably Carter's condensing agent (BOP) or PyBOP. The urea cationic condensing agent is preferably HATU, TBTU or TOTU.

In the second embodiment, the molar ratio of the condensation agent to the compound represented by Formula III may be 1-3:1, such as 2:1.

In the second embodiment, the molar ratio of the compound represented by formula IV to the compound represented by formula III may be 1-3:1, for example, 2:1.

In the second embodiment, the temperature of the condensation reaction may be -40°C to the boiling temperature of the organic solvent, such as room temperature.

In Scheme 2, the progress of the condensation reaction shown can be detected using conventional monitoring methods in the field (such as TLC, HPLC or NMR), generally when the compound represented by Formula III disappears or no longer reacts. as the end point of the reaction. The time of the condensation reaction may be 1-48 hours, such as 12-24 hours.

The present invention also provides a compound, which has any of the following structures: , or ; Wherein, ring A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and L are defined as above.

In certain preferred embodiments of the present invention, the compound represented by Formula II has any of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In certain preferred embodiments of the present invention, the compound represented by formula III has any of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In the present invention, unless otherwise stated, terms are defined as follows.

Unless otherwise stated, the following definitions as used herein shall apply. For the purposes of this invention, chemical elements correspond to the CAS edition of the Periodic Table of the Elements, and to Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999" and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007" , the entire contents of which are incorporated herein by reference.

In this specification, groups and their substituents may be selected by those skilled in the art to provide stable moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes substituents that are chemically equivalent when the structural formula is written from right to left.

Certain chemical groups defined herein are preceded by a simplified notation to represent the total number of carbon atoms present in the group. For example, C ₁ -C ₆ alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5 or 6 carbon atoms. The total number of carbon atoms in the simplified notation does not include carbons that may be present in substituents of the group in question.

In this article, the numerical range defined in the substituent such as 0 to 4, 1-4, 1 to 3, etc. indicates the integer within the range, such as 1-6 is 1, 2, 3, 4, 5, 6.

According to the convention in this technical field, " ” is used to depict the bond at the point of attachment of a group moiety or substituent to the core or backbone structure.

According to the convention in this technical field, the "-" at the end of a group means that the group is connected to other fragments in the molecule through this site. For example, CH ₃ -C(=O)- refers to acetyl.

The term "one or more" or "one or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

The term "comprising" is an open-ended expression, that is, it includes the contents specified in the present invention, but does not exclude other aspects.

The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable .

Generally speaking, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Further, when the group is substituted by more than one substituent, the substituents are independent of each other, that is, the one or more substituents may be different from each other or may be the same. of. Unless otherwise indicated, a substituent group may be substituted at each substitutable position of the substituted group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be identically or differently substituted at each position.

In various parts of this specification, substituents of the compounds disclosed herein are disclosed according to group type or range. In particular, the present invention includes each and every individual subcombination of the individual members of these radical classes and ranges. For example, the term "C ₁ -C ₆ alkyl" or "C ₁ - ₆ alkyl" specifically refers to the independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl base; "C _1-4 alkyl" specifically refers to independently disclosed methyl, ethyl, C ₃ alkyl (i.e. propyl, including n-propyl and isopropyl), C ₄ alkyl (i.e. butyl, including n-butyl, isobutyl, 2nd butyl and 3rd butyl).

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "alkyl" as used herein refers to a straight or branched saturated hydrocarbon chain, such as a straight or branched saturated hydrocarbon chain containing from 1 to 20 carbon atoms. The term " _Cx - _Cyalkyl " refers to a straight or branched chain saturated hydrocarbon containing x to y carbon atoms. For example, "C ₁ -C ₈ alkyl" refers to a linear or branched saturated hydrocarbon containing 1 to 8 carbon atoms. Representative examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, iso-butyl Pentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl .

The term "alkoxy" refers to the group ^-ORX , where ^RX is alkyl as defined above.

The term "alkynyl" refers to a straight or branched hydrocarbon chain radical having at least one triple bond, consisting only of carbon atoms and hydrogen atoms, having, for example, 2 to 12 (preferably 2 to 8, more preferably 2 to 6 (most preferably 2 to 4) carbon atoms, and are connected to the rest of the molecule by a single bond, including but not limited to ethynyl, 1-propynyl, n-propargyl, but-1-ynyl, butyl -2-alkynyl, pentyl-1-ynyl or pentyl-1,4-diynyl, etc.

The term "aryl" refers to an aromatic group consisting of a conjugated hydrocarbon ring system composed of carbon atoms that satisfies the 4n+2 rule, and each ring is aromatic. In one embodiment, "aryl" refers to an aromatic group having 6 to 18 (preferably 6 to 10) carbon atoms. Examples of aryl groups include, but are not limited to, phenyl or naphthyl, and the like.

The term "heteroaryl" means a conjugated ring system group having carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Preferably, the 5-10 membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms selected from N, O and S, and more preferably contains 1, 2, 3 or 4 heteroatoms selected from N, 5-6 membered heteroaryl group with O and S heteroatoms. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, diazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridyl, pyrrole, benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazolyl, indazolyl, isoxazolyl, thiadiazolyl, Isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolinyl, diazonaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carboline Base, phenanthridinyl, phenanthrolinyl, acridinyl, phenanthrolinyl, isothiazolyl, benzothiazolyl, benzisothiazolyl, benzothienyl, oxtriazolyl, cinnolinyl, quinazole Phenyl, indolyl, o-phenanthroline, isoxazolyl, phenoxanyl, phenothioxazolyl, benzoxazolyl or benzisoxazolyl.

"Pharmaceutically acceptable salts" used in the present invention refer to organic salts and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as documented in SM Berge et al. , describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977 , 66: 1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amine groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and Organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods described in books and literature such as ion exchange to obtain these salts . Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, and camphorate , camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate , gluconate, hemisulfate, enanthate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lactosurate, lactate, laurate, lauryl sulfate, malic acid Salt, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pectate, pectate, persulfate, 3-benzene Propionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates the formation of quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternary ammonization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and others. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations that counter counter ion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, _{C1 -8} Sulfonates and aromatic sulfonates.

The term "pharmaceutical excipients" refers to the excipients and additives used in the production of drugs and preparation of prescriptions. It is all substances other than active ingredients included in pharmaceutical preparations. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).

The term "pharmaceutical combination" refers to a pharmaceutical composition containing an HDAC inhibitor and a PD-1 or PD-L1 antibody, in which each component is provided independently in the form of a set or other forms that are not premixed, such as by sequential administration. The combination of drugs administered.

The term "therapeutically effective amount" refers to an amount of a compound administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.

The term "treatment" means any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that causes the disease; (3) alleviating one or more of the biological manifestations of the disease; or the development of multiple biological manifestations.

The term "prevention" refers to reducing the risk of developing a disease.

The term "subject" refers to any animal, preferably a mammal, most preferably a human, that has been or is about to be treated. Mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.

On the basis of common sense in the field, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive and progressive effect of the present invention is that the present invention provides a class of triazolamide compounds with novel structures, which have good HDAC inhibitory activity and can inhibit the proliferation of tumor cells. Some compounds have good pharmacokinetic properties and can inhibit the growth of subcutaneous transplanted tumors of MC38 colon cancer in mice, and have a significant inhibitory effect on the growth of subcutaneous transplanted tumors of human HCT-116 colon cancer in mice.

The present invention is further described below by means of examples, but the present invention is not limited to the scope of the described examples. Experimental methods that do not indicate specific conditions in the following examples should be selected according to conventional methods and conditions, or according to product specifications.

Example 1-2: Preparation of Compounds I-1 and I-2

Step 1: Dissolve cyanoacetic acid (1.89 g, 22 mmol) in dichloromethane (200 mL), add HATU (10.13 g, 27 mmol), and drop triethylamine (6.2 mL, 44 mmol) in an ice bath. , stir for 15 minutes, add 4-aminomethylbenzoic acid methyl ester hydrochloride (4.02 g, 20 mmol) and react at room temperature overnight. Extract with dichloromethane, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, concentrate, and purify with ethanol to obtain white solid sn01006 (4 g, yield 86%). ¹ H NMR (800 MHz, deuterated chloroform) δ 8.03 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 6.49 (s, 1H), 4.54 (d, J = 5.9 Hz, 2H), 3.92 (s, 3H), 3.44 (s, 2H). HRMS (ESI) C ₁₂ H ₁₃ N ₂ O ₃ ⁺ [M + H] ⁺ Calculated: 233.0921, Found: 233.0937.

Step 2: Dissolve aniline (481 mg, 5.2 mmol) with 3 mL concentrated hydrochloric acid and 1 mL water, and drop 2 mL of sodium nitrite solution (660 mg, 9.7 mmol) into it under ice bath conditions, and keep stirring in the ice bath. After 30 minutes, slowly drop it into a mixed solution of sn01006 (1.00 g, 4.3 mmol), sodium acetate trihydrate (10 g, 73 mmol), ethanol and water. After continuing to stir for 1 h, filter, and wash the filter cake with ethanol to obtain light yellow solid sn01009 (1.2 g, yield 83%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 13.84 (s, 1H), 9.11 (t, J = 6.0 Hz, 1H), 7.94 – 7.92 (m, 2H), 7.47 (d, J = 8.3 Hz, 2H), 7.40 – 7.37 (m, 4H), 7.17 – 7.13 (m, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.84 (s, 3H). HRMS (ESI) C ₁₈ H ₁₇ N ₄ O ₃ ⁺ [M+H] ⁺ calculated: 337.1295, found: 337.1312.

Step 3: Dissolve sn01009 (1.18 g, 3.5 mmol), hydroxylamine hydrochloride (300 mg, 4.3 mmol), anhydrous potassium acetate (425 mg, 4.3 mmol) in ethanol (100 mL), and reflux at 100°C for 2 h. After the reaction was completed, it was filtered while hot and concentrated under reduced pressure to obtain sn01016 (0.6 g, yield 46%) as a yellow viscous solid. ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 13.50 (s, 1H), 10.24 (s, 1H), 8.90 (t, J = 6.4 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H) , 7.45 (d, J = 8.3 Hz, 2H), 7.39 (s, 2H), 7.35 (t, J = 7.9 Hz, 2H), 7.02 (t, J = 7.3 Hz, 1H), 6.71 (s, 2H) , 4.51 (d, J = 6.3 Hz, 2H), 3.84 (s, 3H). HRMS (ESI) C ₁₈ H ₂₀ N ₅ O ₄ ⁺ [M+H] ⁺ Calculated value: 370.1510, Found value: 370.1510.

Step 4: Dissolve sn01016 (600 mg, 1.6 mmol) in anhydrous DMF (10 mL), then add triethylamine (0.25 mL, 1.79 mmol) dropwise, and reflux at 180°C for 1 h. Extract with ethyl acetate and wash with saturated brine. The organic phase is dried with anhydrous sodium sulfate and concentrated. The residue is separated and purified by flash column chromatography (ethyl acetate/petroleum ether = 1/2). The oil obtained is purified by beating with ethanol. , obtained light yellow solid sn01021 (300 mg, yield 53%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.04 (t, J = 6.2 Hz, 1H), 7.93 (d, J = 8.2 Hz, 4H), 7.56 – 7.52 (m, 2H), 7.48 (d, 13 C ^NMR ( 201 MHz, deuterated chloroform) δ 166.9, 162.2, 153.9, 143.4, 139.4, 130.2(2C), 129.5, 129.4(2C), 127.6(2C), 127.5, 126.8, 118.5(2C), 52.3 , 42.7. HRMS ( ESI) C ₁₈ H ₁₈ N ₅ O ₃ ⁺ [M+H] ⁺ calculated: 352.1404, found: 352.1404.

Step 5: Dissolve hydroxylamine hydrochloride (1.07 g) in anhydrous methanol (5.52 mL) to obtain solution A. Dissolve potassium hydroxide (1.29 g) in anhydrous methanol (3.22 mL) to obtain solution B. Drop A into B and ice it. Stir in the bath for 30 min, filter to obtain the free hydroxylamine solution, and drop it into a bottle containing sn01021 (120 mg, 0.34 mmol). First, ice bath and then stir at room temperature for 1 h. Use hydrogen chloride in 1,4-dioxane solution (2 mol/L) to adjust the pH of the reaction solution to weak alkalinity, concentrate under reduced pressure, extract with ethyl acetate, concentrate the organic phase, and then puree with ethanol to obtain a light yellow solid. I-1 (100 mg, yield 83%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.17 (s, 1H), 9.02 (t, J = 6.2 Hz, 1H), 8.98 (s, 1H), 7.93 (d, J = 7.6 Hz, 2H) , 7.71 (d, J = 8.3 Hz, 2H), 7.56 – 7.52 (m, 2H), 7.40 (d, J = 8.2 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 5.96 (s, 2H), 4.49 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.2, 161.6, 154.4, 142.9, 139.0, 131.4, 129.6(2C), 127.3(2C), 127.2, 127.0(2C), 126.7, 117.8(2C), 41.7. HRMS (ESI) C ₁₇ H ₁₇ N ₆ O ₃ ⁺ [M+H] ⁺ Calculated: 353.1357, Found: 353.1353. HPLC: 98.5%.

Step 6: Dissolve sn01021 (100 mg, 0.3 mmol) in ethanol (50 mL), add potassium hydroxide solution (600 mg potassium hydroxide, 10 mL water), and reflux at 100°C for 2 h. The reaction solution was adjusted to acidity with dilute hydrochloric acid, and a brown solid sn01028 precipitated. The next reaction was carried out directly without purification.

Step 7: Dissolve the raw material sn01028 in anhydrous DMF (10 mL), add HATU (228 mg, 0.6 mmol), DIPEA (0.1 mL, 0.6 mmol), stir for 15 minutes and then add o-phenylenediamine (65 mg, 0.6 mmol) into the chamber. Warm reaction overnight. Extract with ethyl acetate and wash with saturated brine. The organic phase is dried with anhydrous sodium sulfate and concentrated. The residue is separated and purified by flash column chromatography (ethyl acetate/petroleum ether = 3/1). The oil obtained is purified by beating with ethanol. , obtained white solid I-2 (60 mg, yield 47%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ δ 9.67 (s, 1H), 9.08 (t, J = 6.3 Hz, 1H), 7.98 – 7.92 (m, 4H), 7.58 – 7.52 (m, 2H) , 7.46 (d, J = 8.1 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 6.98 (t, J = 7.0 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.63 (t, J = 7.4 Hz, 1H), 5.99 (s, 2H), 4.53 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO - d ₆ ) δ 165.2, 161.6, 154.4, 143.2, 142.5, 139.0, 133.2, 129.6(2C), 127.9(2C), 127.2(2C), 127.1, 126.7, 126.7, 126.5, 123 .7, 117.8(2C), 116.7 , 116.4, 41.7. HRMS (ESI) C ₂₃ H ₂₂ N ₇ O ₂ ⁺ [M+H] ⁺ calculated: 428.1829, found: 418.1823. HPLC: 97.1%.

Example 3: Compound I-3

Step 1: Replace o-phenylenediamine in step 7 of Example 1-2 with "2-Boc-amino-4-fluoroaniline", and the other required raw materials and reagents are the same to obtain intermediate YWZ-02-085- 1 , light yellow oil (51 mg, yield 31%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 7.94 – 7.89 (m, 4H), 7.53 – 7.49 (m, 1H), 7.45 – 7.40 (m, 4H), 7.31 (t, J = 7.4 Hz, 1H ), 7.21 – 7.16 (m, 2H), 7.14 (s, 1H), 6.83 (t, J = 8.2 Hz, 1H), 5.29 (s, 1H), 4.68 (d, J = 6.2 Hz, 2H), 1.49 (s, 9H). HRMS (ESI) C ₂₈ H ₂₉ FN ₇ O ₄ ⁺ [M+H] ⁺ Calculated: 546.2260, Found: 546.2271.

Step 2: Dissolve YWZ-02-085-1 (60 mg, 0.1 mmol) in ethyl acetate, add concentrated hydrochloric acid (0.06 mL), stir at room temperature overnight, adjust the pH to neutral, extract with ethyl acetate, and saturate. Wash with brine, dry the organic phase over anhydrous sodium sulfate, and concentrate. The residue is separated and purified by flash column chromatography (ethyl acetate/petroleum ether = 1/1) to obtain brown solid I-3 (20 mg, yield 41%). ). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.57 (s, 1H), 9.05 (t, J = 6.1 Hz, 1H), 7.94 (t, J = 7.4 Hz, 4H), 7.55 (t, J = 7.9 Hz, 2H), 7.46 (d, J = 7.9 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.14 – 7.10 (m, 1H), 6.58 – 6.53 (m, 1H), 6.38 ( t, J = 7.1 Hz, 1H), 4.53 (d, J = 6.1 Hz, 2H). HRMS (ESI) C ₂₃ H ₂₁ FN ₇ O ₂ ⁺ [M+H] ⁺ Calculated: 446.1735, Found: 446.1740 . HPLC: 95.6%.

Example 4-5: Preparation of Compounds I-4 and I-5

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "p-methoxyaniline", and the other required raw materials and reagents are the same to obtain light yellow solid sn01040 (400 mg, yield 66%). ¹ H NMR (800 MHz, deuterated chloroform) δ 8.03 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 9.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.03 ( t, J = 5.7 Hz, 1H), 6.95 (d, J = 9.0 Hz, 2H), 4.96 (s, 2H), 4.70 (d, J = 6.2 Hz, 2H), 3.91 (s, 3H), 3.84 ( s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.7, 158.3, 154.2, 145.3, 132.7, 129.2(2C), 128.1, 127.5(2C), 125.9, 119.3(2C), 1 14.6 (2C), 55.5, 52.0, 41.7. HRMS (ESI) C ₁₉ H ₂₀ N ₅ O ₄ [M+H] ⁺ Calculated: 382.1510, Found: 382.1513.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn01040 , and the other required raw materials and reagents are the same to obtain brown solid I-4 (59 mg, yield 45%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.17 (s, 1H), 8.95 (t, J = 6.3 Hz, 1H), 7.86 – 7.81 (m, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.11 – 7.07 (m, 2H), 5.89 (s, 2H), 4.48 (d, J = 6.2 Hz, 2H), 3.81 (s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.2, 161.6, 158.3, 154.2, 142.9, 132.7, 131.3, 127.2(2C), 126.9(2C), 125.9, 119.3(2C), 114.7(2C) , 55.5 , 41.6. HRMS (ESI) Calculated for C ₁₈ H ₁₉ N ₆ O ₄ ⁺ [M+H] ⁺ : 383.1462, Found: 383.1467. HPLC: 99.2%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn01040 , and use the same remaining raw materials and reagents to obtain sn01042 . The next step of reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn01042 , and the other required raw materials and reagents are the same to obtain white solid I-5 (41 mg, yield 30%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.63 (s, 1H), 8.98 (t, J = 6.3 Hz, 1H), 7.94 (d, J = 7.9 Hz, 2H), 7.85 (d, J = 9.1 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 7.10 (d, J = 9.1 Hz, 2H), 6.97 (t, J = 7.6 Hz , 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.60 (t, J = 7.4 Hz, 1H), 5.90 (s, 2H), 4.94 (s, 2H), 4.52 (d, J = 6.2 Hz , 2H), 3.81 (s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.2, 161.7, 158.3, 154.2, 143.2, 143.0, 133.2, 132.7, 127.8(2C), 127.1(2C), 126.7, 126.5, 125.9, 123.4, 119.3(2C), 116.3, 116.2, 114.7(2C), 55.5, 41.7. HRMS (ESI) C ₂₄ H ₂₄ N ₇ O ₃ ⁺ [M+H] ⁺ Calculated: 458.1935, Actual value: 458.1938. HPLC: 99.2%.

Example 6-7: Preparation of Compounds I-6 and I-7

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "p-chloroaniline", and the other required raw materials and reagents are the same to obtain light yellow solid sn01041 (360 mg, yield 58%). ¹ H NMR (800 MHz, deuterated chloroform) δ 8.03 (d, J = 8.2 Hz, 2H), 7.87 (d, J = 8.9 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.40 ( 13 C _ ^_ NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.4, 154.5, 145.2, 137.7, 131.2, 129.6(2C), 129.3(2C), 128.2, 127.5(2C), 127.0, 119.3(2C), 52 .0, 41.7 . HRMS (ESI) Calculated for C ₁₈ H ₁₇ ClN ₅ O ₃ [M+H] ⁺ : 386.1014, Found: 386.1009.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn01041 , and the other required raw materials and reagents are the same to obtain brown solid I-6 (76 mg, yield 58%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.17 (s, 1H), 9.06 (t, J = 6.2 Hz, 1H), 8.98 (s, 1H), 7.92 (d, J = 8.9 Hz, 2H) , 7.71 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 6.01 (s, 2H), 4.49 (d, J = 6.1 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.1, 161.4, 154.5, 142.8, 137.7, 131.4, 131.2, 129.6(2C), 127.2(2C), 127.1, 126.9(2C) ), 119.3(2C), 41.7. HRMS (ESI) Calculated for C ₁₇ H ₁₆ ClN ₆ O ₃ ⁺ [M+H] ⁺ 387.0967, found: 387.0969. HPLC: 96.0%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn01041 , and use the same remaining raw materials and reagents to obtain sn01043 . The next step of reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn01043 , and the other required raw materials and reagents are the same to obtain white solid I-7 (89 mg, yield 64%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.63 (s, 1H), 9.09 (t, J = 6.3 Hz, 1H), 7.96 – 7.90 (m, 4H), 7.62 (d, J = 9.0 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 6.97 (t, J = 8.3 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H) , 6.61 (t, J = 7.4 Hz, 1H), 6.02 (s, 2H), 5.01 (s, 2H), 4.53 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.1, 161.4, 154.5, 143.0, 137.7, 133.2, 131.2, 130.4, 129.6(2C), 127.8(2C), 127.13(2C), 127.11, 126.7, 126.5, 123.4, 119.3(2C), 116.3, 116.2, 41.7. HRMS (ESI) Calculated for C ₂₃ H ₂₁ ClN ₇ O ₂ ⁺ [M+H] ⁺ : 462.1440, found: 462.1441. HPLC: 99.7%.

Example 8-9: Preparation of Compounds I-8 and I-9

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "p-fluoroaniline", and the other required raw materials and reagents are the same to obtain light yellow solid sn01055 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.07 (t, J = 6.2 Hz, 1H), 7.95 – 7.92 (m, 4H), 7.47 (d, J = 8.4 Hz, 2H), 7.40 (t, J = 8.8 Hz, 2H), 5.98 (s, 2H), 4.53 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.5 , 160.8 (d, J = 244.3 Hz), 154.4, 145.2, 135.5, 129.3(2C), 128.2, 127.5(2C), 126.7, 119.8 (d, J = 8.5 Hz, 2C), 116.4 (d, J = 23.4 Hz, 2C), 52.0, 41.7. HRMS (ESI) C ₁₈ H ₁₇ FN ₅ O ₃ [M+H] ⁺ Calculated: 370.1310, Found: 370.1317.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn01055 , and the other required raw materials and reagents are the same to obtain brown solid I-8 (34 mg, yield 27%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.17 (s, 1H), 9.02 (t, J = 6.2 Hz, 1H), 7.95 – 7.91 (m, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.42 – 7.38 (m, 4H), 5.97 (s, 2H), 4.49 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.1, 161.5, 160.8 ( d, J = 244.3 Hz), 154.4, 142.8, 135.6, 131.4, 127.2(2C), 126.9, 126.7(2C), 119.8 (d, J = 8.6 Hz, 2C), 116.4 (d, J = 23.3 Hz, 2C ), 41.7. HRMS (ESI) Calculated for C ₁₇ H ₁₆ FN ₆ O ₃ ⁺ [M+H] ⁺ : 371.1262, Found: 371.1254. HPLC: 98.4%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn01055 , and use the same remaining raw materials and reagents to obtain sn01056 . The next reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn01056 , and the other required raw materials and reagents are the same to obtain light yellow solid I-9 (75 mg, yield 56%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.63 (s, 1H), 9.06 (t, J = 6.3 Hz, 1H), 7.96 – 7.93 (m, 4H), 7.46 (d, J = 8.1 Hz, 2H), 7.41 (t, J = 8.8 Hz, 2H), 7.17 (d, J = 7.7 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H) , 6.61 (t, J = 7.4 Hz, 1H), 5.97 (s, 2H), 4.91 (s, 2H), 4.53 (d, J = 6.2 Hz, 2H). ¹³ C NMR (800 MHz, DMSO- d ₆ ) δ 165.2, 161.5, 160.8 (d, J = 244.3 Hz), 154.4, 143.1, 135.6 (d, J = 2.6 Hz), 133.2, 127.8(2C), 127.1(2C), 126.74, 126.71, 126.6 6, 126.5, 123.4, 119.8 (d, J = 8.6 Hz, 2C), 116.4 (d, J = 23.3 Hz, 2C), 116.3, 116.2, 41.7. HRMS (ESI) C ₂₃ H ₂₁ FN ₇ O ₂ ⁺ [M+H] ⁺ Calculated value: 446.1735, measured value: 446.1736. HPLC: 96.0%.

Example 10-11: Preparation of Compounds I-10 and I-11

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "4-amino-N,N-dimethylaniline", and the remaining required raw materials, The reagents were the same and a light yellow solid sn01073 was obtained. ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 8.92 (t, J = 6.2 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 9.1 Hz, 2H), 7.46 13 _ _ ^_ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.8, 154.0, 149.5, 145.4, 129.2(2C), 129.1, 128.1, 127.4(2C), 125.0, 119.0(2C), 112.2(2C), 5 2.0, 41.6, 40.0(2C). HRMS (ESI) C ₂₀ H ₂₃ N ₆ O ₃ [M+H] ⁺ Calculated: 395.1826, Found: 395.1822.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn01073 , and the other required raw materials and reagents are the same to obtain light gray solid I-10 (42 mg, yield 31%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.17 (s, 1H), 8.99 (s, 1H), 8.88 (t, J = 6.2 Hz, 1H), 7.74 (d, J = 9.1 Hz, 2H) , 7.71 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 6.83 (d, J = 9.1 Hz, 2H), 5.82 (s, 2H), 4.48 (d, J = 6.2 Hz, 2H), 2.95 (s, 6H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 162.9, 161.8, 154.0, 149.5, 143.0, 131.3, 129.1, 127.2(2C), 126.9(2C), 125.1, 119.1(2C), 112.2(2C), 41.6, 40.1(2C). HRMS (ESI) C ₁₉ H ₂₂ N ₇ O ₃ ⁺ calculated value: 396.1179, found value: 396.1776. HPLC: 97.2%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn01073 , and use the same remaining raw materials and reagents to obtain sn01075 . The next reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn01075 , and the other required raw materials and reagents are the same to obtain light yellow solid I-11 (33 mg, yield 23%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.68 (s, 1H), 8.94 (t, J = 6.3 Hz, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.76 – 7.73 (m, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.85 – 6.79 (m, 3H), 6.66 – 6.62 (m, 1H), 5.84 (s, 2H), 4.51 (d, J = 6.3 Hz, 2H), 2.95 (s, 6H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.2, 161.8, 154.0, 149.5, 143.3, 143.0, 133.1, 129.1, 127.8(2C), 127.1(2C), 126.7, 126.4, 125.1, 123.4, 119.1(2C), 116.3, 116.2, 112. 2(2C), 41.7, 40.1(2C) . HRMS (ESI) Calculated for C ₂₅ H ₂₇ N ₈ O ₂ ⁺ [M+H] ⁺ : 471.2251, Found: 471.2261. HPLC: >99.9%.

Example 12-13: Preparation of Compounds I-12 and I-13

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "3-amino-pyridine", and the other required raw materials and reagents are the same to obtain white solid sn01065 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.16 – 9.12 (m, 2H), 8.59 – 8.55 (m, 1H), 8.25 – 8.22 (m, 1H), 7.94 (d, J = 8.3 Hz, 1H 13 _ ^_ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.3, 154.6, 147.9, 145.1, 139.1, 135.4, 129.3(2C), 128.2, 127.5(2C), 127.5, 125.0, 124.3, 52 .0, 41.7. HRMS ( ESI) C ₁₇ H ₁₇ N ₆ O ₃ [M+H] ⁺ calculated: 353.1357, found: 353.1350.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn01065 , and the other required raw materials and reagents are the same to obtain light yellow solid I-12 (95 mg, yield 79%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.17 (s, 1H), 9.15 (d, J = 2.5 Hz, 1H), 9.10 (t, J = 6.2 Hz, 1H), 8.99 (s, 1H) , 8.57 (d, J = 4.7 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.61 – 7.58 (m, 1H), 7.40 (d, J = 8.2 Hz, 2H), 6.07 (s, 2H), 4.50 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.1, 161.3, 154.6, 147.9, 142.7, 139.1, 135.4, 131.4, 127.5, 127.3(2C), 127.0(2C), 125.1, 124.4, 41.7. HRMS (ESI) C ₁₆ H ₁₆ N ₇ O ₃ ⁺ [M+H] ⁺ calculated value: 354.1309, measured value :354.1316. HPLC: 99.0%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn01065 , and use the same other required raw materials and reagents to obtain sn01087 , and proceed directly to the next reaction without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn01087 , and the other required raw materials and reagents are the same to obtain light brown solid I-13 (30 mg, yield 23%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.64 (s, 1H), 9.16 (d, J = 2.6 Hz, 1H), 9.13 (t, J = 6.3 Hz, 1H), 8.59 – 8.55 (m, 1H), 8.25 – 8.23 (m, 1H), 7.95 (d, J = 7.9 Hz, 2H), 7.62 – 7.59 (m, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.61 (t, J = 7.3 Hz, 1H), 6.08 (s, 2H), 4.54 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.2, 161.3, 154.6, 147.9, 143.1, 143.0, 139.1, 135.4, 133.2, 127.9(2C), 12 7.6, 127.2(2C), 126.7, 126.5, 125.0, 124.4, 123.4, 116.3, 116.2, 41.8. HRMS (ESI) C ₂₂ H ₂₁ N ₈ O ₂ ⁺ [M+H] ⁺ Calculated value: 429.1782, Found value: 429.1772. HPLC: 96.8%.

Example 14-15: Preparation of Compounds I-14 and I-15

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "4-bromoaniline", and the other required raw materials and reagents are the same to obtain yellow solid sn01094 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.11 (t, J = 6.2 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 9.0 Hz, 2H), 7.75 13 _ _ ^_ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.4, 154.5, 145.2, 138.1, 132.5(2C), 129.3(2C), 128.2, 127.5(2C), 127.1, 119.6(2C), 119.5, 5 2.0, 41.7. HRMS (ESI) Calculated for C ₁₈ H ₁₇ BrN ₅ O ₃ [M+H] ⁺ : 430.0509, found: 430.0534.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn01094 , and the other required raw materials and reagents are the same to obtain brown solid I-14 (52 mg, yield 35%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.17 (s, 1H), 9.07 (t, J = 6.3 Hz, 1H), 8.99 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H) , 7.77 – 7.68 (m, 4H), 7.39 (d, J = 7.9 Hz, 2H), 6.01 (s, 2H), 4.48 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.1, 161.3, 154.4, 142.7, 138.1, 132.5(2C), 131.3, 127.2(2C), 127.1, 126.9(2C), 119.6(2C), 119.5, 41.7. HRMS (ESI) C _{1 7} H ₁₆ Calculated for BrN ₆ O ₃ ⁺ [M+H] ⁺ : 431.0462, Found: 431.0459. HPLC: 97.3%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn01094 , and use the same remaining raw materials and reagents to obtain sn01097 . The next step of reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn01097 , and the other required raw materials and reagents are the same to obtain white solid I-15 (79 mg, yield 52%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.63 (s, 1H), 9.10 (t, J = 6.3 Hz, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.88 – 7.83 (m, 2H), 7.78 – 7.72 (m, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 6.79 ( 13 C _ ^_ NMR (201 MHz, DMSO- d ₆ ) δ 165.2, 161.4, 154.5, 143.1, 143.0, 138.1, 133.2, 132.5(2C), 127.8(2C), 127.1(2C), 126.7, 126.5, 123.4, 122.1, 119.6( 2C), 119.5, 116.3, 116.2, 41.7. HRMS (ESI) C ₂₃ H ₂₁ BrN ₇ O ₂ ⁺ [M+H] ⁺ Calculated: 506.0935, Found: 506.0942. HPLC: 98.8%.

Example 16-17: Preparation of Compounds I-16 and I-17

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "4-ethoxyaniline", and the other required raw materials and reagents are the same to obtain a light yellow solid sn01095 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 8.99 (t, J = 6.3 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 9.1 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 9.1 Hz, 2H), 5.89 (s, 2H), 4.52 (d, J = 6.2 Hz, 2H), 4.09 – 4.05 (m, 2H) , 3.84 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.7, 157.6, 154.2, 145.3, 132.5, 129.2(2C), 128.1, 127.5(2C), 125.8, 119.3(2C), 115.1(2C), 63.5, 52.0, 41.7, 14.6. HRMS (ESI) C ₂₀ H ₂₂ N ₅ O ₄ [M+H] ⁺ Calculated: 396.1666, Actual value: 396.1665.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn01095 , and the other required raw materials and reagents are the same to obtain light brown solid I-16 (112 mg, yield 83%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.17 (s, 1H), 8.98 (s, 1H), 8.95 (t, J = 6.3 Hz, 1H), 7.82 (d, J = 9.0 Hz, 2H) , 7.71 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 9.1 Hz, 2H), 5.88 (s, 2H), 4.48 (d, J = 6.1 Hz, 2H), 4.10 – 4.05 (m, 2H), 1.34 (t, J = 6.9 Hz, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.1, 161.6, 157.6, 154.2, 142.9, 132.5, 131.3, 127.2(2C), 126.9(2C), 125.9, 119.3(2C), 115.1(2C), 63.5, 41.6, 14.6. HRMS (ESI) C ₁₉ H ₂₁ N ₆ O ₄ ⁺ [M+H] ⁺ Calculated value: 397.1619, measured value: 396.1617. HPLC: 96.5%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn01095 , and use the same remaining raw materials and reagents to obtain sn01098 . The next step of reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn01098 , and the other required raw materials and reagents are the same to obtain white solid I-17 (19 mg, yield 13%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.63 (s, 1H), 8.98 (t, J = 6.3 Hz, 1H), 7.94 (d, J = 7.7 Hz, 2H), 7.83 (d, J = 9.1 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.5 Hz, 1H), 7.08 (d, J = 9.1 Hz, 2H), 6.97 (t, J = 7.6 Hz , 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.61 (t, J = 7.3 Hz, 1H), 5.89 (s, 2H), 4.95 (s, 2H), 4.52 (d, J = 6.2 Hz , 2H), 4.10 – 4.06 (m, 2H), 1.34 (t, J = 7.0 Hz, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.2, 161.7, 157.6, 154.2, 143.2, 143.1, 133.2, 132.6, 127.8(2C), 127.1(2C), 126.7, 126.5, 125.9, 123.4, 119.3(2C), 116.3, 116.1, 115.1(2C), 63.5, 41.7, 14.6. I) C ₂₅ H ₂₆ Calculated for N ₇ O ₃ ⁺ [M+H] ⁺ : 472.2092, found: 472.2086. HPLC: 96.6%.

Example 18-19: Preparation of Compounds I-18 and I-19

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "4-isopropylaniline", and the other required raw materials and reagents are the same to obtain a white flocculent Solid sn01109 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.04 (t, J = 6.3 Hz, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.6 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 5.95 (s, 2H), 4.54 (d, J = 6.2 Hz, 2H), 3.85 (s, 3H), 3.01 – 2.88 (m, 1H), 1.23 (d, J = 6.9 Hz, 6H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.6, 154.3, 147.5, 145.3, 137.0, 129.2(2C), 128.1, 127.5(2C), 127.3(2C), 126.3, 117.8(2C), 52.0, 41.7, 33.0, 23.7(2C). HRMS (ESI) C ₂₁ H ₂₄ N ₅ O ₃ [M+H] ⁺ calculated :394.1874, actual measured value: 394.1882.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn01109 , and the other required raw materials and reagents are the same to obtain white solid I-18 (85 mg, yield 63%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 8.99 (s, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 7.4 Hz, 2H), 7.48 – 7.29 (m, 4H), 5.93 (s, 2H), 4.48 (d, J = 5.5 Hz, 2H), 2.97 – 2.90 (m, 1H), 1.22 (d, J = 6.9 Hz, 6H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.1, 161.6, 154.2, 147.5, 142.8, 137.1, 131.3, 127.3(2C), 127.2(2C), 126.9(2C), 126.3, 117.8(2C), 41.6, 33.0, 23.7(2C) . HRMS (ESI) Calculated for C ₂₀ H ₂₃ N ₆ O ₃ ⁺ [M+H] ⁺ : 395.1826, Found: 395.1831. HPLC: 99.5%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn01109 , and use the same remaining raw materials and reagents to obtain sn01114 . The next step of reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn01114 , and the other required raw materials and reagents are the same to obtain white solid I-19 (65 mg, yield 46%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.63 (s, 1H), 9.02 (t, J = 6.3 Hz, 1H), 7.95 (d, J = 7.9 Hz, 2H), 7.85 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 6.97 (t, J = 7.6 Hz , 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.60 (t, J = 7.4 Hz, 1H), 5.94 (s, 2H), 4.94 (s, 2H), 4.53 (d, J = 6.2 Hz , 2H), 2.98 – 2.92 (m, 1H), 1.23 (d, J = 6.9 Hz, 6H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.2, 161.6, 154.2, 147.5, 143.2, 143.0, 137.1, 133.2, 127.8(2C), 127.3(2C), 127.1(2C), 126.7, 126.5, 126.3, 123.4, 117.8(2C), 116.4, 116.2, 41.7, 33.0, 23.8(2C). HRMS (ESI) C Calculated for ₂₆ H ₂₈ N ₇ O ₂ ⁺ [M+H] ⁺ : 470.2299, found: 470.2294. HPLC: 99.7%.

Example 20-21: Preparation of Compounds I-20 and I-21

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "3-chloroaniline", and the other required raw materials and reagents are the same to obtain brown solid sn01123 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.14 (t, J = 6.2 Hz, 1H), 7.97 (t, J = 2.0 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.87 – 7.83 (m, 1H), 7.56 (t, J = 8.1 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.43 – 7.41 (m, 1H), 6.05 (s, 2H), 4.54 ( d, J = 6.2 Hz, 2H), 3.83 (s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.3, 154.5, 145.1, 139.9, 134.0, 131.4, 129.3(2C), 128.2 , 127.5(2C), 127.3, 126.7, 117.4, 116.1, 52.0, 41.7. HRMS (ESI) C ₁₈ H ₁₇ ClN ₅ O ₃ [M+H] ⁺ calculated value: 386.1014, found value: 386.1012.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn01123 , and the other required raw materials and reagents are the same to obtain white solid I-20 (96 mg, yield 73%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ δ 11.21 (s, 1H), 9.25 – 8.88 (m, 2H), 7.97 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 8.1 Hz, 1H), 7.46 – 7.37 (m, 3H), 6.05 (s, 2H), 4.50 (d, J = 6.0 Hz, 2H) . ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.1, 161.3, 154.5, 142.7, 139.9, 134.0, 131.4, 131.4, 127.3, 127.2(2C), 127.0(2C), 126.7, 117. 4, 116.2, 41.7. HRMS (ESI) Calculated for C ₁₇ H ₁₆ ClN ₆ O ₃ ⁺ [M+H] ⁺ : 387.0967, found: 387.0987. HPLC: 99.1%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn01123 , and use the same remaining raw materials and reagents to obtain sn01124 . The next reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn01124 , and the other required raw materials and reagents are the same to obtain light yellow solid I-21 (97 mg, yield 70%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 12.34 (s, 1H), 11.85 (t, J = 6.3 Hz, 1H), 10.68 (t, J = 2.1 Hz, 1H), 10.66 (d, J = 8.0 Hz, 2H), 10.59 – 10.54 (m, 1H), 10.27 (t, J = 8.1 Hz, 1H), 10.17 (d, J = 8.1 Hz, 2H), 10.14 – 10.11 (m, 1H), 9.88 ( d, J = 7.6 Hz, 1H), 9.70 – 9.64 (m, 1H), 9.51 – 9.46 (m, 1H), 9.30 (t, J = 7.2 Hz, 1H), 8.76 (s, 2H), 7.61 (s , 2H), 7.24 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.2, 161.3, 154.5, 143.1, 143.0, 139.9, 134.0, 133.2, 131.4, 127.9( 2C ), 127.4, 127.2(2C), 126.7, 126.7, 126.5, 123.4, 117.4, 116.3, 116.18, 116.16, 41.7. HRMS (ESI) C ₂₃ H ₂₁ ClN ₇ O ₂ ⁺ [M+H] ⁺ Calculated: 462.144 0 , measured value: 462.1412. HPLC: >99.9%.

Example 22-23: Preparation of Compounds I-22 and I-23

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "3-methoxyaniline", and the other required raw materials and reagents are the same to obtain a light yellow solid sn01122 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.07 (t, J = 6.2 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.53 – 7.51 (m, 1H), 7.49 – 7.46 ( m, 3H), 7.44 (t, J = 8.2 Hz, 1H), 6.95 – 6.92 (m, 1H), 5.97 (s, 2H), 4.54 (d, J = 6.2 Hz, 2H), 3.83 (d, J = 3.3 Hz, 6H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.5, 160.0, 154.3, 145.2, 140.0, 130.5, 129.3(2C), 128.2, 127.5(2C), 126.7, 112.9, 109.9, 103.3, 55.4, 52.1, 41.7. HRMS (ESI) C ₁₉ H ₂₀ N ₅ O ₄ [M+H] ⁺ Calculated: 382.1510, Found: 382.1505.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn01126 , and the other required raw materials and reagents are the same to obtain white solid I-22 (117 mg, yield 90%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.21 (s, 1H), 9.05 (t, J = 6.2 Hz, 1H), 9.01 (s, 1H), 7.73 (d, J = 8.2 Hz, 2H) , 7.51 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 2.2 Hz, 1H), 7.43 (t, J = 8.2 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H), 6.99 – 6.88 (m, 1H), 5.98 (s, 2H), 4.50 (d, J = 6.2 Hz, 2H), 3.83 (s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.2, 161.5 HRMS (ESI) C ₁₈ H ₁₉ N ₆ O ₄ ⁺ [M +H] ⁺ Calculated value: 383.1462, measured value: 383.1477. HPLC: 96.1%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn01122 , and use the same remaining raw materials and reagents to obtain sn01126 . The next reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn01043 , and the other required raw materials and reagents are the same to obtain white solid I-23 (64 mg, yield 46%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.64 (s, 1H), 9.07 (t, J = 6.3 Hz, 1H), 7.96 (d, J = 7.9 Hz, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.50 (t, J = 2.1 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.44 (t, J = 8.2 Hz, 1H), 7.18 (d, J = 7.6 Hz , 1H), 6.97 (t, J = 7.6 Hz, 1H), 6.96 – 6.93 (m, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.61 (t, J = 7.4 Hz, 1H), 5.99 (s, 2H), 4.93 (s, 2H), 4.55 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.2, 161.5, 160.1 , 154.3, 143.1, 143.0, 140.1, 133.2, 130.5, 127.9(2C), 127.2(2C), 126.8, 126.7, 126.5, 123.4, 116.4, 116.2, 112.9, 110.0, 103.4, 55.5, 41.7. HRMS (ESI) C Calculated for ₂₄ H ₂₄ N ₇ O ₃ ⁺ [M+H] ⁺ : 458.1953, found: 458.1941. HPLC: 96.0%.

Example 24-25: Preparation of Compounds 1-24 and 1-25

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "4-ethynylaniline", and the other required raw materials and reagents are the same to obtain light brown solid sn01133 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.11 (t, J = 6.3 Hz, 1H), 7.94 – 7.91 (m, 4H), 7.64 (d, J = 8.8 Hz, 2H), 7.47 (d, ¹³ C NMR (201 MHz , DMSO- d ₆ ) δ 166.1, 161.4, 154.5, 145.1, 138.7, 133.1(2C), 129.3(2C), 128.2, 127.5(2C), 127.3, 120.1, 117.8(2C), 82.8, 81.9, 52 .0, 41.7. HRMS ( ESI) C ₂₀ H ₁₈ N ₅ O ₃ [M+H] ⁺ calculated: 376.1404, found: 376.1395.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn01133 , and the other required raw materials and reagents are the same to obtain light brown solid I-24 (76 mg, yield 83%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.22 (s, 1H), 9.10 (t, J = 5.8 Hz, 1H), 9.01 (s, 1H), 7.92 (d, J = 8.5 Hz, 2H) , 7.73 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 6.04 (s, 2H), 4.50 (d, J = 6.0 Hz, 2H), 4.30 (s, 1H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.1, 161.3, 154.5, 142.8, 138.7, 133.1(2C), 131.4, 127.3(2C), 127.2( 2C), 127.0, 120.1, 117.8(2C), 82.8, 81.9, 41.7. HRMS (ESI) C ₁₉ H ₁₇ N ₆ O ₃ ⁺ [M+H] ⁺ calculated: 377.1357, found: 377.1352. HPLC: 96.3%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn01133 , and use the same remaining raw materials and reagents to obtain sn01135 . The next step of reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn01135 , and the other required raw materials and reagents are the same to obtain white solid I-25 (82 mg, yield 60%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.64 (s, 1H), 9.12 (t, J = 6.2 Hz, 1H), 7.99 – 7.89 (m, 4H), 7.66 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 7.6 Hz, 1H), 6.97 (t, J = 7.3 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H) , 6.60 (t, J = 7.4 Hz, 1H), 6.05 (s, 2H), 4.93 (s, 2H), 4.54 (d, J = 6.2 Hz, 2H), 4.30 (s, 1H). ¹³ C NMR ( 201 MHz, DMSO- d ₆ ) δ 165.2, 161.4, 154.5, 143.1, 143.0, 138.8, 133.2, 133.1(2C), 127.9(2C), 127.3, 127.2(2C), 126.7, 126.5, 1 23.4, 120.1, 117.8( 2C), 116.3, 116.2, 82.8, 81.9, 41.8. HRMS (ESI) C ₂₅ H ₂₂ N ₇ O ₂ ⁺ [M+H] ⁺ calculated: 452.1829, found: 452.1820. HPLC: 99.5%.

Example 26-27: Preparation of Compounds 1-26 and 1-27

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "4-trifluoromethylaniline", and the other required raw materials and reagents are the same to obtain a white solid sn01113 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.18 (t, J = 6.2 Hz, 1H), 8.10 (d, J = 8.6 Hz, 2H), 7.99 – 7.86 (m, 4H), 7.48 (d, J = 8.3 Hz, 2H), 6.11 (s, 2H), 4.54 (d, J = 6.2 Hz, 2H), 3.83 (s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.3 HRMS ( ESI) Calculated for C ₁₉ H ₁₇ F ₃ N ₅ O ₃ [M+H] ⁺ : 420.1278, found: 420.1270.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn01113 , and the other required raw materials and reagents are the same to obtain white solid I-26 (76 mg, yield 53%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.19 (s, 1H), 9.15 (t, J = 6.2 Hz, 1H), 9.00 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H) , 7.92 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 7.9 Hz, 2H), 7.41 (d, J = 7.9 Hz, 2H), 6.10 (s, 2H), 4.50 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.1, 161.2, 154.6, 142.7, 141.5, 131.4, 128.0(2C), 127.3(2C), 127.0(2C), 126.8, 124. 8, 123.4, 118.0(2C), 41.7. HRMS (ESI) C ₁₈ H ₁₆ F ₃ N ₆ O ₃ ⁺ [M+H] ⁺ Calculated: 421.1230, Found: 421.1233. HPLC: 97.7%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn01113 , and use the same remaining raw materials and reagents to obtain sn01142 . The next step of reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn01142 , and the other required raw materials and reagents are the same to obtain white solid I-27 (94 mg, yield 63%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.63 (s, 1H), 9.19 (t, J = 6.3 Hz, 1H), 8.12 (d, J = 8.4 Hz, 2H), 8.00 – 7.87 (m, 4H), 7.47 (d, J = 7.9 Hz, 2H), 7.18 (d, J = 7.8 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H) , 6.60 (t, J = 7.6 Hz, 1H), 6.12 (s, 2H), 4.94 (s, 2H), 4.55 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.1, 161.2, 154.6, 143.1, 143.0, 141.5, 133.2, 128.0, 127.9(2C), 127.2(2C), 127.0, 126.7, 126.5(2C), 124.8, 123.4, 1 23.4, 118.0(2C), 116.3, 116.2, 41.8. HRMS (ESI) Calculated for C ₂₄ H ₂₁ F ₃ N ₇ O ₂ ⁺ [M+H] ⁺ : 496.1703, found: 496.1718. HPLC: 97.7%.

Example 28-29: Preparation of Compound 1-28 and Compound 1-29

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "4-amino-N,N-dimethylbenzylamine", and the remaining required The raw materials and reagents were the same, and brown solid sn01148 was obtained. ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.11 (t, J = 5.5 Hz, 1H), 8.04 – 7.88 (m, 4H), 7.74 (d, J = 7.9 Hz, 2H), 7.47 (d, 13 C ^_ NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.5, 154.4, 145.2, 139.4, 132.4, 132.3(2C), 129.3(2C), 128.2, 127.5(2C), 127.1, 117.7(2C), 58 .9, 52.1 , 41.7, 41.6(2C). HRMS (ESI) C ₂₁ H ₂₅ N ₆ O ₃ [M+H] ⁺ Calculated: 409.1983, Found: 409.1980.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn01148 , and the other required raw materials and reagents are the same to obtain white solid I-28 (112 mg, yield 80%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.20 (s, 1H), 9.04 – 8.98 (m, 2H), 7.87 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 5.95 (s, 2H), 4.49 (d, J = 6.2 Hz, 2H), 3.43 (s, 2H), 2.16 (s, 6H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.1, 161.5, 154.3, 142.9, 137.9, 132.6, 131.3, 129.8(2C), 127.2(2C), 127.0(2C) ), 126.5, 117.6(2C), 62.6, 44.9(2C), 41.7. HRMS (ESI) C ₂₀ H ₂₄ N ₇ O ₃ ⁺ [M+H] ⁺ calculated value: 410.1935, measured value: 410.1938. HPLC: 99.0%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn01148 , and use the same remaining raw materials and reagents to obtain sn01149 . The next step of reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn01142 , and the other required raw materials and reagents are the same to obtain white foamy solid I-29 (57 mg, yield 39%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.64 (s, 1H), 9.06 (t, J = 6.2 Hz, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 7.7 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 7.4 Hz, 1H), 6.98 (t, J = 7.4 Hz , 1H), 6.79 (d, J = 7.8 Hz, 1H), 6.61 (t, J = 6.9 Hz, 1H), 6.03 (s, 2H), 4.54 (d, J = 6.1 Hz, 2H), 4.32 (s , 2H), 2.75 (s, 6H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.1, 161.4, 154.4, 143.0, 142.7, 139.6, 133.2, 132.4(2C), 128.8, 127.8(2C), 127.3, 127.1(2C), 126.6, 126.5, 123.5, 120.7, 117.9(2C), 116.3, 59.1, 41.8(2C), 41.7. HRMS (ESI) C ₂₆ H ₂₉ N ₈ O ₂ ⁺ [M+H] ⁺ Calculated value: 485.2408, measured value: 485.2406. HPLC: 95.2%.

Example 30-31: Preparation of Compounds I-30 and I-31

Step 1: Dissolve the raw material methyl p-formyl benzoate (5.0 g, 31 mmol) in dichloromethane (120 mL), add (S)-tert-butylsulfinamide (4.4 g, 37 mmol) and Cesium carbonate (13 g, 37 mmol), heated to reflux for 18 hours. The solvent was removed under reduced pressure, the residue was extracted with ethyl acetate, washed with saturated brine, the organic phase was dried with anhydrous sodium sulfate, concentrated, and the residue was separated and purified by flash column chromatography (ethyl acetate/petroleum ether = 1/10). A white solid sn01130S (5.78 g, yield 71%) was obtained. ¹ H NMR (800 MHz, deuterated chloroform) δ 8.63 (s, 1H), 8.13 (d, J = 8.2 Hz, 2H), 7.91 (d, J = 8.2 Hz, 2H), 3.95 (s, 3H), 1.28 (s, 9H). HRMS (ESI) Calculated for C ₁₃ H ₁₈ NO ₃ S [M+H] ⁺ : 268.1002, Found: 268.1017.

Step 2: Dissolve diethylzinc (1.7 mL, 1.7 mmol) in anhydrous tetrahydrofuran (5 mL) at room temperature, and add ethylmagnesium bromide (1.5 mL, 1.5 mmol). After stirring for 30 minutes, cool to -78°C. Dissolve sn01130S (267 mg, 1.0 mmol) in anhydrous tetrahydrofuran (1.5 mL) and add it. Maintain the temperature and stir for 4 hours before returning to room temperature. Dilute with saturated ammonium chloride solution, extract with ethyl acetate, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, concentrate, and use flash column chromatography to separate and purify the residue (ethyl acetate/petroleum ether = 1/2) to obtain Colorless oil sn01137S . ¹ H NMR (800 MHz, deuterated chloroform) δ 8.01 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 4.36 – 4.31 (m, 1H), 3.91 (s, 3H ), 3.41 (d, J = 3.6 Hz, 1H), 2.08 – 2.01 (m, 1H), 1.82 – 1.73 (m, 1H), 1.23 (s, 9H), 0.80 (t, J = 7.4 Hz, 3H) . HRMS (ESI) Calculated for C ₁₅ H ₂₄ NO ₃ S [M+H] ⁺ : 298.1471, Found: 298.1486.

Step 3: Dissolve the raw material sn01137S (1.2 g, 4.2 mmol) in dichloromethane (5 mL), add 2 N hydrochloric acid/methanol (10 mL) under ice bath conditions, stir at room temperature for 3 hours, and concentrate under reduced pressure to obtain light yellow The oily substance sn01144S was directly used in the next reaction without purification.

Step 4: Follow the method of step 1 described in Example 1-2, replace 4-aminomethylbenzoic acid methyl ester hydrochloride with sn01144S , and the other required raw materials and reagents are the same to obtain white solid sn01145S (550 mg, collected rate 31%). ¹ H NMR (800 MHz, deuterated chloroform) δ 8.01 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 6.43 (d, J = 7.5 Hz, 1H), 4.89 ( q, J = 7.5 Hz, 1H), 3.91 (s, 3H), 3.41 – 3.34 (m, 2H), 1.91-1.83 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H). HRMS (ESI ) C ₁₄ H ₁₇ N ₂ O ₃ [M+H] ⁺ calculated: 261.1234, found: 261.1240.

Step 5-7: Follow the method of step 2-4 described in Example 1-2, replace sn01006 in step 2 with sn01145S , and the other required raw materials and reagents are the same to obtain light yellow solid sn01157S . ¹ H NMR (800 MHz, Methanol- d ₄ ) δ 8.01 (d, J = 7.4 Hz, 2H), 7.98 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.47 (t, J = 7.1 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 5.04 (t, J = 6.6 Hz, 1H), 3.88 (s, 3H), 2.01 – 1.90 (m, 2H) , 1.01 (t, J = 7.3 Hz, 3H). ¹³ C NMR (201 MHz, Methanol- d ₄ ) δ 168.4, 163.7, 155.8, 149.9, 140.8, 130.7(2C), 130.3(2C), 130.1, 128.3, 127.99, 127.96(2C), 119.4(2C), 56.0, 52.5, 29.9, 11.5. HRMS (ESI) C ₂₀ H ₂₂ N ₅ O ₃ [M+H] ⁺ Calculated: 380.1717, Found: 380.1719.

Step 8: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn01157S , and use the same other raw materials and reagents to obtain light yellow vesicular solid I-30 (91 mg, yield 70%). ¹ H NMR (800 MHz, Methanol- d ₄ ) δ 8.0 (d, J = 7.8 Hz, 2H), 7.7 (d, J = 8.3 Hz, 2H), 7.5 (d, J = 8.2 Hz, 2H), 7.5 (t, J = 7.9 Hz, 2H), 7.3 (t, J = 7.4 Hz, 1H), 5.1 – 5.0 (m, 1H), 2.0 – 1.9 (m, 2H), 1.2 (t, J = 7.1 Hz, 1H), 1.0 (t, J = 7.3 Hz, 3H). ¹³ C NMR (201 MHz, Methanol- d ₄ ) δ 168.0, 163.7, 155.8, 148.3, 140.8, 132.3, 130.3(2C), 128.35, 128.32(2C) ), 128.05(2C), 128.01, 119.4(2C), 56.0, 30.0, 11.5. HRMS (ESI) C ₁₉ H ₂₁ N ₆ O ₃ ⁺ [M+H] ⁺ calculated: 381.1670, found: 381.1670. HPLC: 99.2%. Optical rotation: = –220 ( c 0.1, MeOH).

Step 9: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn01157S , and use the same remaining raw materials and reagents to obtain sn01160S . The next step of reaction is carried out directly without purification.

Step 10: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn01160S , and the other required raw materials and reagents are the same to obtain light yellow vesicular solid I-31 (73 mg, yield 53%). ¹ H NMR (800 MHz, Methanol- d ₄ ) δ 8.03 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 7.51 – 7.46 (m, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.08 (t, J = 7.7 Hz, 1H), 6.91 (d, J = 13 C ^_ NMR (201 MHz, Methanol- d ₄ ) δ 168.7, 163.7, 155.8, 148.5, 143.7, 140.8, 134.4, 130.3(2C), 129.0(2C), 128.5, 128.4, 128.1, 128.0(2C) , 127.6, 125.3, 119.7, 119.4(2C), 118.7, 56.1, 30.0, 11.5. HRMS (ESI) C ₂₅ H ₂₆ N ₇ O ₂ ⁺ [M+H] ⁺ Calculated: 456.2142, Found: 456.2149. HPLC: 96.2%. Optical rotation: = –167 ( c 0.1, MeOH).

Example 32-33: Preparation of Compounds I-32 and I-33

Use the same method as Example 30-31 to prepare I-30 and I-31, replace (S)-tert-butylsulfenamide with (R)-tert-butylsulfinamide in step 1, Compounds I-32 and I-33 can be prepared. sn01145R , white solid. ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 8.73 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 4.74 (q, J = 7.7 Hz, 1H), 3.84 (s, 3H), 3.75 – 3.65 (m, 2H), 1.75 – 1.62 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H). HRMS ( ESI) C ₁₄ H ₁₇ N ₂ O ₃ [M+H] ⁺ calculated: 261.1234, found: 261.1254. sn01157R , light yellow oily substance. ¹ H NMR (800 MHz, Methanol- d ₄ ) δ 8.04-8.03 (m, 2H), 8.02 – 8.00 (m, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.52 – 7.48 (m, 2H ), 7.36 (t, J = 7.4 Hz, 1H), 5.06-5.04 (m, 1H), 3.90 (s, 3H), 2.08 – 1.91 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H) . ¹³ C NMR (201 MHz, Methanol- d ₄ ) δ 168.4, 163.8, 155.8, 150.0, 140.9, 130.8(2C), 130.3(2C), 130.2, 128.4, 128.01, 127.98(2C), 119. 4(2C), 56.1, 52.6, 30.0, 11.6. Compound I-32 , white solid. ¹ H NMR (800 MHz, Methanol- d ₄ ) δ 8.01 (d, J = 7.9 Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.47 (t, J = 7.9 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 5.05 – 4.99 (m, 1H), 2.01 – 1.88 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H). ¹³ C NMR (201 MHz, Methanol- d ₄ ) δ 168.0, 163.7, 155.8, 148.3, 140.8, 132.3, 130.3(2C), 128.35, 128.32(2C), 128.05(2C), 128.00, 119.4(2C ), 56.0, 30.0, 11.5. HRMS (ESI) C ₁₉ H ₂₁ N ₆ O ₃ ⁺ [M+H] ⁺ Calculated: 381.1670, Found: 381.1666. HPLC: 99.5%. Optical rotation: = + 216 ( c 0.1 , MeOH). Compound I-33 , light yellow vesicular solid. ¹ H NMR (800 MHz, Methanol- d ₄ ) δ 8.02 (d, J = 8.0 Hz, 2H), 7.96 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 7.4 Hz, 2H), 7.47 (t, J = 7.2 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.90 (d , J = 7.9 Hz, 1H), 6.77 (t, J = 7.5 Hz, 1H), 5.08 – 5.03 (m, 1H), 2.01 – 1.92 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H) . ¹³ C NMR (201 MHz, Methanol- d ₄ ) δ 173.0, 168.6, 163.7, 155.8, 148.5, 143.7, 140.8, 134.3, 130.3(2C), 129.0(2C), 128.5, 128.3, 128 .0(2C), 127.6 , 125.3, 119.6, 119.4(2C), 118.7, 56.0, 30.0, 11.6. HRMS (ESI) C ₂₅ H ₂₆ N ₇ O ₂ ⁺ [M+H] ⁺ calculated value: 456.2142, measured value: 456.2138. HPLC: 96.5%. Optical rotation: = + 178 ( c 0.1, MeOH).

Example 34-35: Preparation of Compound 1-34 and Compound 1-35

Step 1: Add sodium hydride (140 mg, 5.8 mmol) to tetrahydrofuran (10 mL), then add the raw material 4-bromomethylcinnamate methyl ester (1.35 g, 5.3 mmol), and then add bis( tert-butoxycarbonyl)amine (1.27 g, 5.8 mmol, 10 mL THF), stir in ice bath for 20 minutes, then rise to room temperature and react for 14 hours. Extract with ethyl acetate and wash with saturated brine. The organic phase is dried with anhydrous sodium sulfate and concentrated. The residue is separated and purified by flash column chromatography (ethyl acetate/petroleum ether = 1/10) to obtain white solid sn01152a (1.46 g, Yield 95%). ¹ H NMR (800 MHz, deuterated chloroform) δ 7.67 (d, J = 16.0 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 6.42 ( d, J = 16.0 Hz, 1H), 4.78 (s, 2H), 3.80 (s, 3H), 1.45 (s, 9H). HRMS (ESI) C ₁₆ H ₂₁ NNaO ₄ [M+Na] ⁺ Calculated: 314.1363, measured value: 314.1368.

Step 2: Dissolve sn01152a (1.46 g, 5.0 mmol) in ethyl acetate, add concentrated hydrochloric acid (3.3 mL), stir at room temperature overnight, and filter to obtain white solid sn01152 (797 mg, yield 83%). Purify and proceed directly to the next reaction. ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 8.37 (s, 2H), 7.78 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 16.0 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 6.70 (d, J = 16.1 Hz, 1H), 4.12 – 4.00 (m, 2H), 3.73 (s, 3H). HRMS (ESI) C ₁₁ H ₁₄ NO ₂ [M+H] ⁺ Calculated value: 192.1019, measured value: 192.1024.

Step 3: Follow the method of step 1 described in Example 1-2, replace 4-aminomethylbenzoic acid methyl ester hydrochloride with sn01152 , and other required raw materials and reagents are the same to obtain white solid sn01153 (1.59 g, collected rate 74%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 8.75 (t, J = 5.7 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.65 (d, J = 16.0 Hz, 1H), 7.31 HRMS _ _ (ESI) Calculated for C ₁₄ H ₁₄ N ₂ NaO ₃ [M+Na] ⁺ : 281.0897, found: 281.0893.

Step 4-6: Follow the method of step 2-4 described in Example 1-2, replace sn01006 with sn01153 , and the other required raw materials and reagents are the same to obtain white solid sn01159 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.01 (t, J = 6.2 Hz, 1H), 7.95 – 7.90 (m, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 16.0 Hz, 1H), 7.56 – 7.50 (m, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 6.60 (d, J = 16.0 Hz, 1H), 5.97 (s, 2H), 4.49 (d, J = 6.2 Hz, 2H), 3.71 (s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 166.7, 161.5, 154.3, 144.3, 142.2 _, 139.0, 132.6, 129.5(2C), 128.4(2C), 127.9(2C), 127.1, 126.7, 117.7(2C), 117.3, _51.4 , _{41.7 .} +H] ⁺ Calculated value: 378.1561, measured value: 378.1568.

Step 7: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn01159 , and the other required raw materials and reagents are the same to obtain light yellow oily substance I-34 (52 mg, yield 40%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 10.75 (s, 1H), 9.06 – 8.97 (m, 2H), 7.93 (d, J = 8.0 Hz, 2H), 7.57 – 7.50 (m, 4H), 7.43 (d, J = 15.8 Hz, 1H), 7.39 – 7.35 (m, 3H), 6.44 (d, J = 15.8 Hz, 1H), 5.97 (s, 2H), 4.47 (d, J = 6.1 Hz, 2H ). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 162.8, 161.5, 154.3, 141.1, 138.9, 138.1, 133.4, 129.5(2C), 127.9(2C), 127.5(2C), 127.1, 126.7, 118.7, 117.7(2C), 41.7. HRMS (ESI) C ₁₉ H ₁₉ N ₆ O ₃ ⁺ [M+H] ⁺ Calculated: 379.1513, Found: 379.1522. HPLC: 98.1%.

Step 8: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn01159 , and use the same remaining raw materials and reagents to obtain sn01163 . The next step of reaction is carried out directly without purification.

Step 9: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn01163 , and the other required raw materials and reagents are the same to obtain light yellow solid I-35 (83 mg, yield 61%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.40 (s, 1H), 9.02 (t, J = 6.3 Hz, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.57 – 7.52 (m, 3H), 7.41 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H) , 6.92 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 15.7 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 6.58 (t, J = 7.6 Hz, 1H), 5.98 (s, 2H), 5.00 (s, 2H), 4.50 (d, J = 6.1 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 163.5, 161.5, 154.3, 141.5, 141.3, 139.4, HRMS (ESI) C ₂₅ H ₂₄ Calculated for N ₇ O ₂ ⁺ [M+H] ⁺ : 454.1986, found: 454.1987. HPLC: 99.7%.

Example 36: Preparation of compound 1-36

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "p-aminobenzonitrile", and the other required raw materials and reagents are the same to obtain yellow solid sn01112 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.19 (t, J = 6.2 Hz, 1H), 8.06 – 8.04 (m, 2H), 8.03 – 8.00 (m, 2H), 7.95 – 7.88 (m, 2H ), 7.47 (d, J = 8.4 Hz, 2H), 6.15 (s, 2H), 4.54 (d, J = 6.2 Hz, 2H), 3.83 (s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.2, 154.7, 145.0, 141.6, 134.1(2C), 129.3(2C), 128.3, 128.2, 127.5(2C), 118.4, 118.0(2C), 108.9, 52.1, 41. 7. HRMS (ESI) C Calculated for ₁₉ H ₁₇ N ₆ O ₃ [M+H] ⁺ : 377.1357, Found: 377.1355.

Step 4: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn01112 , and use the same other raw materials and reagents to obtain sn01138 . The next step of reaction is carried out directly without purification.

Step 5: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn01138 , and the other required raw materials and reagents are the same to obtain white solid I-36 (55 mg, yield 40%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.63 (s, 1H), 9.19 (t, J = 6.2 Hz, 1H), 8.07 – 8.05 (m, 2H), 8.04 – 8.02 (m, 2H), 7.95 (d, J = 7.9 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 6.97 (t, J = 8.3 Hz, 1H), 6.78 ( 13 C _ ^_ NMR (201 MHz, DMSO- d ₆ ) δ 165.1, 161.1, 154.7, 143.1, 142.9, 141.6, 134.1(2C), 133.2, 128.4, 127.8(2C), 127.1(2C), 126.7, 126.5, 123.3, 118.4, 118.0(2C), 116.3, 116.1, 108.9, 41.8. HRMS (ESI) C ₂₄ H ₂₁ N ₈ O ₂ ⁺ [M+H] ⁺ Calculated: 453.1782, Found: 457.1783. HPLC: 95.7%.

Examples 37-38: Preparation of Compounds 1-37 and 1-38

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "2-chloroaniline", and the other required raw materials and reagents are the same to obtain light yellow solid sn02017 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.04 (t, J = 6.2 Hz, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.72 – 7.70 (m, 2H), 7.58 – 7.52 ( m, 2H), 7.46 (d, J = 8.2 Hz, 2H), 5.92 (s, 2H), 4.50 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.6, 154.2, 145.2, 137.4, 130.9, 130.7, 129.2(2C), 128.4, 128.1, 128.0, 127.5(2C), 127.1, 126.9, 52.0, 41.7. HRMS (ESI) C ₁₈ H ₁₇ ClN ₅ O ₃ [M+H] ⁺ calculated: 386.1014, found: 386.1012.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn02017 , and the other required raw materials and reagents are the same to obtain white solid I-37 (97 mg, yield 74%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.15 (s, 1H), 9.02 – 8.95 (m, 2H), 7.74 – 7.67 (m, 4H), 7.59 – 7.51 (m, 2H), 7.37 (d , J = 8.0 Hz, 2H), 5.89 (s, 2H), 4.45 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.1, 161.5, 154.1, 142.8, 137.4 , 131.3(2C), 130.9, 130.7, 128.4, 128.2, 128.1, 127.2(2C), 126.9, 126.9, 41.7. HRMS (ESI) C ₁₇ H ₁₆ ClN ₆ O ₃ ⁺ [M+H] ⁺ Calculated value: 387.0967 , measured value: 387.0961. HPLC: 96.4%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn02017 , and use the same remaining raw materials and reagents to obtain sn02018 . The next step of reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn02018 , and the other required raw materials and reagents are the same to obtain light yellow solid I-38 (72 mg, yield 52%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.60 (s, 1H), 9.03 (d, J = 6.3 Hz, 1H), 7.93 (d, J = 7.9 Hz, 2H), 7.74 – 7.69 (m, 2H), 7.59 – 7.52 (m, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 6.96 (t, J = 6.9 Hz, 1H), 6.78 ( 13 C _ ^_ NMR (201 MHz, DMSO- d ₆ ) δ 165.1, 161.5, 154.2, 143.1, 143.1, 137.4, 133.2, 130.9, 130.7, 128.4, 128.1, 128.1, 127.8(2C), 127.1(2 C), 127.0, 126.6, 126.4 , 123.4, 116.3, 116.1, 41.7. HRMS (ESI) C ₂₃ H ₂₁ ClN ₇ O ₂ ⁺ [M+H] ⁺ Calculated: 462.1440, Found: 462.1397. HPLC: 98.2%.

Example 39-40: Preparation of Compound 1-39 and Compound 1-40

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "3,4-dichloroaniline", and the other required raw materials and reagents are the same to obtain a white solid sn02023 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.16 (t, J = 6.2 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.86 – 7.84 (m, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 6.08 (s, 2H), 4.53 (d, J = 6.2 Hz, 2H) , 3.83 (s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.2, 154.5, 145.0, 138.3, 132.1, 131.6, 129.2(2C), 129.0, 128.2, 127.6, 12 7.5(2C) , 119.1, 117.5, 52.0, 41.7. HRMS (ESI) C ₁₈ H ₁₆ Cl ₂ N ₅ O ₃ [M+H] ⁺ Calculated: 420.0625, Found: 420.0628.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn02023 , and the other required raw materials and reagents are the same to obtain white solid I-39 (115 mg, yield 80%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.20 (s, 1H), 9.13 (t, J = 5.7 Hz, 1H), 8.99 (s, 1H), 8.10 (d, J = 2.2 Hz, 1H) , 7.87 – 7.84 (m, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 6.08 (s, 2H), 4.49 (d, J = 3.0 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.1, 161.1, 154.5, 142.6, 138.3, 132.0, 131.6, 131.4, 129.0, 127.6, 1 27.2( 2C), 126.9(2C), 119.1, 117.5, 41.6. HRMS (ESI) C ₁₇ H ₁₅ Cl ₂ N ₆ O ₃ ⁺ [M+H] ⁺ Calculated: 421.0577, Found: 421.0574. HPLC: 99.3%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn02023 , and use the same remaining raw materials and reagents to obtain sn02024 . The next step of reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn02024 , and the other required raw materials and reagents are the same to obtain light yellow solid I-40 (36 mg, yield 24%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.62 (s, 1H), 9.16 (t, J = 6.2 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 7.8 Hz, 2H), 7.88 – 7.84 (m, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H) , 6.97 (t, J = 7.0 Hz, 1H), 6.78 (d, J = 7.1 Hz, 1H), 6.60 (t, J = 7.4 Hz, 1H), 6.09 (s, 2H), 4.88 (s, 2H) , 4.54 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.1, 161.1, 154.5, 143.0, 142.9, 138.3, 133.2, 132.1, 131.6, 129.0, 127. 8(2C) , 127.7, 127.1(2C), 126.6, 126.4, 123.3, 119.1, 117.5, 116.2, 116.1, 41.7. HRMS (ESI) C ₂₃ H ₂₀ Cl ₂ N ₇ O ₂ ⁺ [M+H] ⁺ Calculated value: 496.1050, Actual value: 496.1054. HPLC: 98.4%.

Example 41-42: Preparation of Compound 1-41 and Compound 1-42

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "2-aminonaphthalene", and the other required raw materials and reagents are the same to obtain brown solid sn02034 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.14 (t, J = 6.2 Hz, 1H), 8.40 (d, J = 1.7 Hz, 1H), 8.18 – 8.14 (m, 1H), 8.10 (d, J = 8.9 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 6.03 (s, 2H), 4.56 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.5, 154.5, 145.2, 136.4, 132.9, 131.6, 129.5, 129.2(2C), 128.1, 128.0, 127.8, 12 7.5(2C) , 127.3, 126.9, 126.3, 117.0, 115.0, 52.0, 41.7. HRMS (ESI) C ₂₂ H ₂₀ N ₅ O ₃ [M+H] ⁺ Calculated: 402.1561, Found: 402.1583.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn02034 , and the other required raw materials and reagents are the same to obtain gray solid I-41 (135 mg, yield 70%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.17 (s, 1H), 9.09 (t, J = 6.3 Hz, 1H), 8.98 (s, 1H), 8.39 (s, 1H), 8.16 (d, J = 8.9 Hz, 1H), 8.10 (d, J = 8.9 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 6.02 (s, 2H), 4.52 (d, J = 6.1 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.6, 162.0, 154.9, 143.3, 136.9, 133.4, 132.1, 131.9, 130.0, 128.5, 128.3, 127. 8(2C) , 127.7(2C), 127.4, 126.8, 126.0, 117.5, 115.5, 42.2. HRMS (ESI) C ₂₁ H ₁₉ N ₆ O ₃ ⁺ [M+H] ⁺ Calculated value: 403.1513, Found value: 403.1516. HPLC: 98.7%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn02034 , and use the same remaining raw materials and reagents to obtain sn02035 . The next step of reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn02035 , and the other required raw materials and reagents are the same to obtain white solid I-42 (96 mg, yield 62%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.64 (s, 1H), 9.13 (t, J = 6.2 Hz, 1H), 8.45 – 8.36 (m, 1H), 8.21 – 8.15 (m, 1H), 8.11 (d, J = 9.0 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.99 – 7.95 (m, 3H), 7.60 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 7.6 Hz, 1H), 6.97 (t, J = 8.1 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.60 (t, J = 7.4 Hz, 1H), 6.04 (s, 2H), 5.18 (s, 2H), 4.57 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.1, 162.3, 161.5, 154.5, 143.1, 143.0, 133.2, 132.9, 131.6, 129.5, 128.0, 127.8(2C), 127.3, 127.1(2C), 127.0 , 126.6, 126.4, 126.3, 123.4, 117.0, 116.2, 116.3, 116.1, 115.0, 41.7. HRMS (ESI) C ₂₇ H ₂₄ N ₇ O ₂ ⁺ [M+H] ⁺ Calculated: 478.1986, Found: 478.1988. HPLC: 97.9%.

Example 43-44: Preparation of Compound 1-43 and Compound 1-44

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "8-aminoquinoline", and the other required raw materials and reagents are the same to obtain brown solid sn02043 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 8.99 (t, J = 6.2 Hz, 1H), 8.96 – 8.95 (m, 1H), 8.55 – 8.51 (m, 1H), 8.22 – 8.18 (m, 1H ), 8.02 – 7.99 (m, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.76 (t, J = 7.8 Hz, 1H), 7.68 – 7.64 (m, 1H), 7.46 (d, J = 8.2 Hz, 2H), 5.83 (s, 2H), 4.50 (d, J = 6.3 Hz, 2H), 3.84 (s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.9, 154.0 HRMS (ESI) C ₂₁ H ₁₉ N ₆ O ₃ [M+H] ⁺ Calculated value: 403.1513, Found value: 403.1520.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn02043 , and the other required raw materials and reagents are the same to obtain white solid I-43 (135 mg, yield 98%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.16 (s, 1H), 9.01 – 8.92 (m, 3H), 8.54 (d, J = 8.2 Hz, 1H), 8.21 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.70 (d, J = 8.1 Hz, 2H), 7.68 – 7.65 (m, 1H), 7.38 ( d, J = 8.1 Hz, 2H), 5.81 (s, 2H), 4.45 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.1, 161.9, 154.0, 151.6, HRMS (ESI) C ₂₀ H ₁₈ N ₇ O ₃ ⁺ [M+ H] ⁺ calculated value: 404.1466, measured value: 404.1461. HPLC: 97.6%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn02043 , and use the same remaining raw materials and reagents to obtain sn02044 . The next reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn02044 , and the other required raw materials and reagents are the same to obtain white solid I-44 (96 mg, yield 67%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.60 (s, 1H), 8.99 – 8.95 (m, 2H), 8.55 – 8.53 (m, 1H), 8.21 (d, J = 7.5 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 7.9 Hz, 2H), 7.77 (t, J = 7.8 Hz, 1H), 7.69 – 7.64 (m, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 7.9 Hz, 1H), 6.59 (t, J = 7.4 Hz, 1H), 5.82 (s, 2H), 4.88 (s, 2H), 4.49 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.2, 161.9, 154.0, 151.6, 143.3, 143.0, 142.4, 137.1, 136.4, 133.2, 130.1, 128.6, 127.8(2C), 127.5, 127.2(2C), 126.6, 126.6, 126.4, 125.9, 1 23.4, 122.5, 116.3, 116.1, 41.7. HRMS ( ESI) C ₂₆ H ₂₃ N ₈ O ₂ ⁺ [M+H] ⁺ calculated: 479.1938, found: 479.1939. HPLC: 99.8%.

Example 45-46: Preparation of Compound 1-45 and Compound 1-46

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "3,4-methylenedioxyaniline", and the other required raw materials and reagents are the same. Obtained yellow solid sn02050 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 8.99 (t, J = 5.6 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.48 – 7.45 (m, 3H), 7.42 – 7.40 ( m, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.11 (s, 2H), 5.91 (s, 2H), 4.53 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.5, 154.1, 148.0, 146.4, 145.2, 133.8, 129.2(2C), 128.1, 127.5(2C), 126.0, 111.2, 108.4, 101.9, 99.5, 52.0 , 41.6. HRMS (ESI) C ₁₉ H ₁₈ N ₅ O ₅ [M+H] ⁺ Calculated: 396.1302, Found: 396.1298.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn02050 , and the other required raw materials and reagents are the same to obtain yellow solid I-45 (123 mg, yield 92%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.17 (s, 1H), 8.99 (s, 1H), 8.96 (t, J = 6.2 Hz, 1H), 7.71 (d, J = 8.2 Hz, 2H) , 7.46 (d, J = 2.1 Hz, 1H), 7.42 – 7.40 (m, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.4 Hz, 1H), 6.12 (s, 2H), 5.91 (s, 2H), 4.48 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.1, 161.5, 154.1, 148.0, 146.4, 142.8, 133.8, 131.3 , 127.2(2C), 126.9(2C), 126.0, 111.2, 108.5, 102.0, 99.5, 41.6. HRMS (ESI) C ₁₈ H ₁₇ N ₆ O ₅ ⁺ [M+H] ⁺ calculated value: 397.1255, measured value: 397.1253. HPLC: 97.4%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn02050 , and use the same other required raw materials and reagents to obtain sn02051 , and proceed directly to the next reaction without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn02051 , and the other required raw materials and reagents are the same to obtain white solid I-46 (36 mg, yield 25%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.62 (s, 1H), 8.99 (t, J = 6.2 Hz, 1H), 7.94 (d, J = 7.9 Hz, 2H), 7.47 – 7.44 (m, 3H), 7.43 – 7.40 (m, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.78 ( d, J = 8.0 Hz, 1H), 6.59 (t, J = 7.4 Hz, 1H), 6.12 (s, 2H), 5.92 (s, 2H), 4.88 (s, 2H), 4.52 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.1, 161.5, 154.1, 148.0, 146.4, 143.1, 143.0, 133.8, 133.2, 127.8(2C), 127.1(2C), 126.6 , 126.4, 126.0, 123.4, 116.3, 116.1, 111.2, 108.4, 102.0, 99.5, 41.7. HRMS (ESI) C ₂₄ H ₂₂ N ₇ O ₄ ⁺ [M+H] ⁺ Calculated: 472.1728, Found: 472.1736. HPLC: 99.0%.

Examples 47-48: Preparation of Compounds 1-47 and 1-48

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "6-aminoquinoline", and the other required raw materials and reagents are the same to obtain a light yellow solid sn02058 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.17 (t, J = 6.2 Hz, 1H), 8.93 – 8.90 (m, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.43 (d, J = 2.4 Hz, 1H), 8.40 – 8.37 (m, 1H), 8.18 (d, J = 9.1 Hz, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.61 – 7.58 (m, 1H), 7.50 (d, J = 8.4 Hz, 2H), 6.08 (s, 2H), 4.56 (d, J = 6.2 Hz, 2H), 3.83 (s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.4, 154.6, 150.7, 146.4, 145.1, 136.5, 136.2, 130.7, 129.2(2C), 128.2, 128.0, 127.5(2C), 127.3, 122.5, 120.3, 115.0, 52.0, 41.7. HRMS (ESI) C ₂₁ H ₁₉ N ₆ O ₃ [M+H] ⁺ Calculated: 403.1513, Found: 403.1511.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn02058 , and the other required raw materials and reagents are the same to obtain light pink solid I-47 (56 mg, yield 42%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.19 (s, 1H), 9.13 (t, J = 6.2 Hz, 1H), 8.99 (s, 1H), 8.93 – 8.91 (m, 1H), 8.49 ( d, J = 7.9 Hz, 1H), 8.43 (d, J = 2.4 Hz, 1H), 8.40 – 8.38 (m, 1H), 8.18 (d, J = 9.1 Hz, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.62 – 7.59 (m, 1H), 7.42 (d, J = 8.3 Hz, 2H), 6.07 (s, 2H), 4.52 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.1, 161.4, 154.6, 150.7, 146.4, 142.7, 136.5, 136.3, 131.4, 130.7, 128.0, 127.4, 127.2(2C), 126.9(2C), 12 2.6, 120.4, 115.0, 41.7. HRMS (ESI) Calculated for C ₂₀ H ₁₈ N ₇ O ₃ ⁺ [M+H] ⁺ : 404.1466, found: 404.1471. HPLC: 98.9%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn02058 , and use the same remaining raw materials and reagents to obtain sn02063 . The next step of reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn02063 , and the other required raw materials and reagents are the same to obtain light orange solid I-48 (124 mg, 86%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.62 (s, 1H), 9.16 (t, J = 6.2 Hz, 1H), 8.94 – 8.91 (m, 1H), 8.50 (d, J = 8.2 Hz, 1H), 8.44 (d, J = 2.3 Hz, 1H), 8.41 – 8.38 (m, 1H), 8.19 (d, J = 9.1 Hz, 1H), 7.96 (d, J = 7.9 Hz, 2H), 7.62 – 7.60 (m, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.7 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.59 (t, J = 7.5 Hz, 1H), 6.07 (s, 2H), 4.88 (s, 2H), 4.56 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.2, 161.4, 154.6, 150.7, 146.4, 143.1, 143.0, 136.5, 136.2, 133.2, 130.7, 128.0, 127.8(2C), 127.4, 127.2(2C) , 126.6, 126.4, 123.4, 122.5, 120.4, 116.3, 116.1, 115.0, 41.8. HRMS (ESI) C ₂₆ H ₂₃ N ₈ O ₂ ⁺ [M+H] ⁺ Calculated: 479.1938, Found: 479.1928. HPLC: 99.5%.

Examples 49-50: Preparation of Compounds 1-49 and 1-50

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "3,5-dichloroaniline", and the other required raw materials and reagents are the same to obtain light brown Solid sn02062 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.19 (t, J = 6.2 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.87 (d, J = 1.8 Hz, 2H), 7.58 13 _ _ ^_ C NMR (201 MHz, DMSO- d ₆ ) δ 166.0, 161.1, 154.5, 145.0, 140.3, 135.0(2C), 129.2(2C), 128.2, 127.9, 127.5(2C), 126.0, 116.0(2C), 5 2.0, 41.7. HRMS (ESI) Calculated for C ₁₈ H ₁₆ Cl ₂ N ₅ O ₃ [M+H] ⁺ : 420.0625, found: 420.0616.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn02062 , and the other required raw materials and reagents are the same to obtain light brown solid I-49 (103 mg, yield 72%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.16 (s, 1H), 9.16 (t, J = 6.2 Hz, 1H), 8.99 (s, 1H), 7.89 (d, J = 1.8 Hz, 2H) , 7.72 (d, J = 8.2 Hz, 2H), 7.62 (t, J = 1.8 Hz, 1H), 7.39 (d, J = 8.2 Hz, 2H), 6.11 (s, 2H), 4.49 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.0, 161.0, 154.5, 142.5, 140.4, 135.1(2C), 131.6, 128.0, 127.2(2C), 126.9(2C), 126. 0, 116.1(2C), 41.7. HRMS (ESI) C ₁₇ H ₁₅ Cl ₂ N ₆ O ₃ ⁺ [M+H] ⁺ Calculated: 421.0577, Found: 421.0576. HPLC: 97.6%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn02062 , and use the same other raw materials and reagents to obtain sn02066 . The next step of reaction is carried out directly without purification.

Step 6: Follow the method of Step 7 described in Example 1-2, replace sn01028 with sn02066 , and the other required raw materials and reagents are the same to obtain white solid I-50 (82 mg, yield 55%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.62 (s, 1H), 9.19 (t, J = 6.3 Hz, 1H), 7.95 (d, J = 7.9 Hz, 2H), 7.90 (d, J = 1.8 Hz, 2H), 7.62 (t, J = 1.9 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 7.8 Hz, 1H), 6.96 (t, J = 8.3 Hz , 1H), 6.78 (d, J = 9.0 Hz, 1H), 6.59 (t, J = 7.4 Hz, 1H), 6.12 (s, 2H), 4.88 (s, 2H), 4.54 (d, J = 6.2 Hz , 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.1, 161.0, 154.5, 143.1, 142.9, 140.4, 135.1(2C), 133.2, 128.0, 127.8(2C), 127.1(2C), 12 6.6, 126.4, 126.0, 123.3, 116.3, 116.1, 116.1(2C), 41.7. HRMS (ESI) C ₂₃ H ₂₀ Cl ₂ N ₇ O ₂ ⁺ [M+H] ⁺ Calculated: 496.1050, Found: 496.1060. HPLC: 99.3%.

Examples 51-52: Preparation of Compounds I-51 and I-52

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "1-aminonaphthalene", and the other required raw materials and reagents are the same to obtain light yellow solid sn02033 . ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.10 (t, J = 6.2 Hz, 1H), 8.29 – 8.25 (m, 1H), 8.10 – 8.06 (m, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.67 – 7.62 (m, 3H), 7.48 (d, J = 8.3 Hz, 2H), 5.98 (s, 2H), 4.54 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.7, 154.3, 145.3, 136.0, 133.9, 129.24, 129.20(2C), 128.3, 128 .1, 127.48(2C), 127.46, 126.8, 126.8, 126.5, 125.3, 123.3, 122.5, 52.0, 41.7. HRMS (ESI) C ₂₂ H ₂₀ N ₅ O ₃ [M+H] ⁺ Calculated: 402.1561, Found: 420.15 59 .

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn02033 , and use the same other raw materials and reagents to obtain light brown solid I-51 (119 mg, yield 87%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.00 (t, J = 6.3 Hz, 1H), 8.27 – 8.24 (m, 1H), 8.11 – 8.05 (m, 2H), 7.83 (d, J = 7.3 Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.67 – 7.62 (m, 3H), 7.29 (d, J = 8.0 Hz, 2H), 5.95 (s, 2H), 4.45 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 163.7, 161.6, 154.3, 140.4, 136.0, 134.5, 133.9, 129.2, 128.3, 127.5, 127.0, 126.8, 1 26.7(2C), 126.6 , 126.2(2C), 125.3, 123.4, 122.5, 41.8. HRMS (ESI) C ₂₁ H ₁₉ N ₆ O ₃ ⁺ [M+H] ⁺ Calculated value: 403.1513, Found value: 403.1511. HPLC: 98.0%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn02033 , and use the same other required raw materials and reagents to obtain sn02039 . The next reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn02039 , and the other required raw materials and reagents are the same to obtain light yellow solid I-52 (108 mg, yield 75%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.61 (s, 1H), 9.09 (t, J = 6.1 Hz, 1H), 8.28 – 8.24 (m, 1H), 8.12 – 8.07 (m, 2H), 7.94 (d, J = 7.9 Hz, 2H), 7.84 (d, J = 7.0 Hz, 1H), 7.68 – 7.63 (m, 3H), 7.47 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.59 (t, J = 7.4 Hz, 1H), 5.96 (s, 2H), 4.88 (s, 2H), 4.53 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.2, 161.7, 154.3, 143.2, 143.0, 136.0, 133.9, 133.2, 129.3, HRMS ( ESI) C ₂₇ H ₂₄ N ₇ O ₂ ⁺ [M+H] ⁺ Calculated value: 478.1986, Measured value: 478.1976. HPLC: 97.7%.

Example 53-54: Preparation of Compound 1-53 and Compound 1-54

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "3-fluoroaniline", and the other required raw materials and reagents are the same to obtain sn02096 as a white solid. ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.11 (t, J = 6.2 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.78 – 7.74 (m, 1H), 7.72 – 7.67 ( m, 1H), 7.61 – 7.56 (m, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.23 – 7.19 (m, 1H), 6.04 (s, 2H), 4.54 (d, J = 6.2 Hz , 2H), 3.84 (s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 162.4 (d, J = 244.2 Hz), 161.3, 154.4, 145.1, 140.2 (d, J = 10.6 Hz ), 131.6 (d, J = 9.3 Hz), 129.3(2C), 128.2, 127.5(2C), 127.2, 113.7 (d, J = 21.1 Hz), 113.6 (d, J = 2.6 Hz), 105.0 (d, J = 27.1 Hz), 52.0, 41.7. HRMS (ESI) C ₁₈ H ₁₇ FN ₅ O ₃ [M+H] ⁺ Calculated: 370.1310, Found: 370.1315.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn02096 , and the other required raw materials and reagents are the same to obtain white solid I-53 (51 mg, yield 40%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.04 (t, J = 5.6 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 3H), 7.61 – 7.55 (m, 1H), 7.33 (d, J = 7.7 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 6.03 (s, 2H), 4.47 (d, J = 5.8 Hz, 2H) . ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 163.8, 162.5 (d, J = 244.6 Hz), 161.2, 154.4, 141.3, 140.2 (d, J = 10.8 Hz), 133.2, 131.6 (d, J = 9.4 Hz), 127.3, 127.0(2C), 126.5(2C), 113.7, 113.6, 105.0 (d, J = 26.8 Hz), 41.7. HRMS (ESI) C ₁₇ H ₁₆ FN ₆ O ₃ ⁺ [M+H] ⁺ Calculated value: 371.1262, measured value: 371.1280. HPLC: 99.1%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn02096 , and use the same remaining raw materials and reagents to obtain sn02097 . The next step of reaction is carried out directly without purification.

Step 6: Follow the method of Step 7 described in Example 1-2, replace sn01028 with sn02097 , and use the same raw materials and reagents as the rest to obtain white solid I-54 (127 mg, yield 95%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.62 (s, 1H), 9.11 (t, J = 6.3 Hz, 1H), 7.95 (d, J = 7.9 Hz, 2H), 7.79 – 7.74 (m, 1H), 7.73 – 7.69 (m, 1H), 7.63 – 7.56 (m, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.25 – 7.20 (m, 1H), 7.17 (d, J = 7.6 Hz , 1H), 6.99 – 6.93 (m, 1H), 6.80 – 6.76 (m, 1H), 6.59 (t, J = 7.2 Hz, 1H), 6.04 (s, 2H), 4.88 (s, 2H), 4.54 ( d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.1, 162.5 (d, J = 244.2 Hz), 161.3, 154.4, 143.1, 143.0, 140.2 (d, J = 10.9 Hz), 133.2, 131.6 (d, j = 9.3 Hz), 127.8 (2c), 127.3, 127.1 (2C), 126.7, 126.5, 123.4, 116.3, 113.7 (d, j = 21.1 Hz), 113.6 (D , J = 2.3 Hz), 105.0 (d, J = 27.3 Hz), 41.7. HRMS (ESI) C ₂₃ H ₂₁ FN ₇ O ₂ ⁺ [M+H] ⁺ Calculated: 446.1735, Found: 446.1748. HPLC: 95.9%.

Examples 55-56: Preparation of Compounds 1-55 and 1-56

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "2,3-dichloroaniline", and the other required raw materials and reagents are the same to obtain a brown solid sn02102 . ¹ H NMR (800 MHz, DMSO- d ₆ ) 9.07 (t, J = 6.2 Hz, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.87 – 7.82 (m, 1H), 7.73 – 7.70 (m , 1H), 7.56 (t, J = 8.1 Hz, 1H), 7.45 (d, J = 8.3 Hz, 2H), 5.96 (s, 2H), 4.50 (d, J = 6.2 Hz, 2H), 3.84 (s , 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) 166.1, 161.4, 154.3, 145.2, 139.0, 133.0, 131.4, 129.2(2C), 128.8, 128.1, 127.5(2C), 127.4, 1 27.2, 126.9, 52.0, 41.7. HRMS (ESI) Calculated for C ₁₈ H ₁₆ Cl ₂ N ₅ O ₃ [M+H] ⁺ : 420.0625, found: 420.0634.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn02102 , and the other required raw materials and reagents are the same to obtain light brown solid I-55 (113 mg, yield 79%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.17 (s, 1H), 9.03 (t, J = 6.2 Hz, 1H), 8.99 (s, 1H), 7.87 – 7.84 (m, 1H), 7.72 – 7.69 (m, 3H), 7.57 (t, J = 8.1 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H), 5.94 (s, 2H), 4.45 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) 164.1, 161.4, 154.3, 142.8, 139.0, 133.0, 131.4, 131.3, 128.8, 127.4, 127.3, 127.2(2C), 126.9(2C), 1 26.9, 41.7. HRMS ( ESI) C ₁₇ H ₁₅ Cl ₂ N ₆ O ₃ ⁺ [M+H] ⁺ calculated: 421.0577, found: 421.0579. HPLC: 98.8%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn02102 , and use the same remaining raw materials and reagents to obtain sn02103 . The next step of reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn02103 , and the other required raw materials and reagents are the same to obtain white solid I-56 (55 mg, yield 37%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.61 (s, 1H), 9.07 (t, J = 6.3 Hz, 1H), 7.94 (d, J = 7.8 Hz, 2H), 7.88 – 7.83 (m, 1H), 7.74 – 7.70 (m, 1H), 7.57 (t, J = 8.1 Hz, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.2 Hz, 1H), 6.98 – 6.95 (m, 1H), 6.82 – 6.75 (m, 1H), 6.60 (t, J = 7.2 Hz, 1H), 5.96 (s, 2H), 4.88 (s, 2H), 4.50 (d, J = 6.3 Hz , 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.1, 161.4, 154.3, 143.1, 143.1, 139.0, 133.2, 133.0, 131.4, 128.8, 127.8(2C), 127.4, 127 .3, 127.2(2C) , 127.0, 126.6, 126.4, 123.3, 116.3, 116.1, 41.7. HRMS (ESI) C ₂₃ H ₂₀ Cl ₂ N ₇ O ₂ ⁺ [M+H] ⁺ Calculated value: 496.1050, Found value: 496.1054. HPLC: 99.5%.

Examples 57-58: Preparation of Compounds 1-57 and 1-58

Step 1-3: Follow the method of step 2-4 described in Example 1-2, replace the aniline in step 2 with "2-fluoroaniline", and the other required raw materials and reagents are the same, and a brown solid sn02095 is obtained. ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.03 (t, J = 6.2 Hz, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.81 (t, J = 7.2 Hz, 1H), 7.53 – 7.44 (m, 4H), 7.40 – 7.35 (m, 1H), 5.96 (s, 2H), 4.51 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 166.1, 161.5, 154.4, 153.7 (d, J = 253.1 Hz), 145.2, 130.0 (d, J = 7.8 Hz), 129.2(2C), 128.1, 127.5(2C), 127.2, 125.1 ( d, J = 3.6 Hz), 125.0, 117.5, 117.4, 52.0, 41.7. HRMS (ESI) C ₁₈ H ₁₇ FN ₅ O ₃ [M+H] ⁺ calculated: 370.1310, found: 370.1313.

Step 4: Follow the method of step 5 described in Example 1-2, replace sn01021 with sn02095 , and the other required raw materials and reagents are the same to obtain light brown solid I-57 (88 mg, yield 70%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 11.16 (s, 1H), 9.01 – 8.96 (m, 2H), 7.81 (t, J = 7.8 Hz, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.53 – 7.47 (m, 2H), 7.40 – 7.36 (m, 3H), 5.95 (s, 2H), 4.47 (d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 164.1, 161.4, 154.4, 153.8 (d, J = 253.5 Hz), 142.8, 131.3, 130.0 (d, J = 7.4 Hz), 127.5 (d, J = 9.2 Hz), 127.3, 127.2(2C), 126.9, 125.1 (d, J = 3.7 Hz), 125.1(2C), 117.5 (d, J = 19.6 Hz), 41.7. HRMS (ESI) C ₁₇ H ₁₆ FN ₆ O ₃ ⁺ [M+H] ⁺ calculated :371.1262, actual measured value: 371.1280. HPLC: 98.3%.

Step 5: Follow the method of step 6 described in Example 1-2, replace sn01021 with sn02095 , and use the same remaining raw materials and reagents to obtain sn02111 . The next reaction is carried out directly without purification.

Step 6: Follow the method of step 7 described in Example 1-2, replace sn01028 with sn02111 , and the other required raw materials and reagents are the same to obtain white solid I-58 (86 mg, yield 64%). ¹ H NMR (800 MHz, DMSO- d ₆ ) δ 9.62 (s, 1H), 9.03 (t, J = 6.3 Hz, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.82 (t, J = 7.3 Hz, 1H), 7.53 – 7.47 (m, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.40 – 7.37 (m, 1H), 7.17 (d, J = 7.6 Hz, 1H), 6.97 ( t, J = 6.9 Hz, 1H), 6.78 (d, J = 6.8 Hz, 1H), 6.60 (t, J = 7.2 Hz, 1H), 5.97 (s, 2H), 4.89 (s, 2H), 4.52 ( d, J = 6.2 Hz, 2H). ¹³ C NMR (201 MHz, DMSO- d ₆ ) δ 165.2, 161.4, 154.4, 153.8 (d, J = 253.3 Hz), 143.1, 133.2, 130.0 (d, J = 7.8 Hz), 127.8(2C), 127.5 (d, J = 9.1 Hz), 127.3, 127.1(2C), 126.6, 126.4, 125.1 (d, J = 3.8 Hz), 125.1, 123.3, 117.5, 117.4, 116.3, 1 16.1 , 41.8. HRMS (ESI) Calculated for C ₂₃ H ₂₁ FN ₇ O ₂ ⁺ [M+H] ⁺ : 446.1735, Found: 446.1743. HPLC: 97.4%.

Biological Test Example 1 : Inhibitory activity of compounds of the present invention on HDAC

The specific operation method is as follows: (1) Prepare experimental buffer (50 mM Tris PH, 0.01% Tween-20, 50 mM NaCl); (2) Prepare the compound to be tested into a DMSO solution with a corresponding 10 mM concentration, and then use DMSO Dilute to 1 mM, then 3 times gradient dilution, 10 concentration points; (3) Use Echo to transfer different concentrations of the compounds to be tested to a 384-well plate (Perkin Elmer, Cat. No. 6007279), 250 nL per well ( The final DMSO content is 1%); (4) Use the buffer in step (1) to prepare a solution of histone deacetylase. The final concentration of HDAC1 (BPS bioscience, Cat. No. 50051) is 4 nM; HDAC2 ( BPS, Cat. No. 50002); HDAC3 (BPS, Cat. No. 50003); HDAC4 (BPS, Cat. No. 50004); HDAC5 (BPS, Cat. No. 50005); HDAC6 (BPS bioscience, Cat. No. . 50056) at a final concentration of 5 nM; HDAC7 (BPS, Cat. No. 50007); HDAC8 (BPS, Cat. No. 50008); HDAC9 (BPS, Cat. No. 50009); HDAC10 (BPS, Cat. No. 50009); 50010); (5) Use the buffer in step (1) to prepare a mixed solution of the substrate (LGK(Ac)-AMC, Trypsin). For the determination of HDAC1 activity: the concentration of LGK(Ac)-AMC (Gill Biochemical) is 8 μM, Trypsin concentration is 0.05 μM; (6) Add 15 μL of the enzyme solution prepared in step (4) to each well of the test 384-well plate, and for the low control group, add 15 μL of the buffer in step (1). Centrifuge at 1000 rpm for 1 minute, and then incubate at room temperature for 15 minutes; (7) Add 10 μL of the enzyme solution prepared in step (5) to each well of the test 384-well plate, centrifuge at 1000 rpm for 1 minute, and then incubate at room temperature for 60 minutes ; (8) Use Synergy MX to read the values (maximum excitation light: 355 nm, maximum emission light: 460 nm); (9) Use GraphPad Prism5 to process the data and calculate the IC ₅₀ value.

Among them, SAHA (CAS: 149647-78-9), MGCD0103 (CAS: 726169-73-9) and chidamide (CAS: 1616493-44-7) are commercially available.

Table 1. Inhibitory activity of compounds of the present invention on HDAC1 and HDAC6 compound HDAC1 IC ₅₀ , nM HDAC6 IC ₅₀ , nM compound HDAC1 IC ₅₀ , nM I-1 2.3±1.0 3.5±0.2 I-31 212±6 I-2 43±12 ＞10000 I-32 8.6±2.4 I-3 36 ＞10000 I-33 37±14 I-4 2.7±0.1 - I-34 4.0±0.8 I-5 74±11 - I-35 78±18 I-6 2.6±0.1 - I-36 91±9 I-7 102±10 - I-37 11±1 I-8 5.3±1.5 - I-38 54±6 I-9 77±1 - I-39 2.9±0.3 I-10 3.2±1.0 - I-40 276±73 I-11 64±5 - I-41 1.3±0.1 I-12 11±1 - I-42 179±65 I-13 74±1 - I-43 10±0 I-14 2.2±0.8 - I-44 43±0 I-15 112±25 - I-45 2.1±0 I-16 2.2±0.7 - I-46 50±11 I-17 78±8 - I-47 1.0 I-18 2.9±0.5 - I-48 37±5 I-19 167±48 - I-49 9.8±1.3 I-20 3.2±0.7 - I-50 223±8 I-21 115±12 - I-51 5.8±0 I-22 3.3±0.2 - I-52 56±13 I-23 68±7 - I-53 4.9 I-24 1.7±0.4 - I-54 73 I-25 78±13 - I-55 7.8 I-26 3.1±0.3 - I-56 63 I-27 178±22 - I-57 4.6 I-28 3.5±0.8 - I-58 62 I-29 90±14 - SAHA 21±4 I-30 40±20 - MGCD0103 69±9

Note: "-" means not tested.

Table 2. Selectivity of I-38 for HDAC subtypes HDAC subtypes _IC50 , nM I-38 SAHA MGCD0103 chidamide HDAC1 47 17 85 93 HDAC2 125 20 208 186 HDAC3 450 35 509 359 HDAC4 ＞10000 ＞10000 ＞10000 ＞10000 HDAC5 ＞10000 ＞10000 ＞10000 ＞10000 HDAC6 ＞10000 18 ＞10000 ＞10000 HDAC7 ＞10000 ＞10000 ＞10000 ＞10000 HDAC8 ＞10000 432 ＞10000 ＞10000 HDAC9 ＞10000 ＞10000 ＞10000 ＞10000 HDAC10 96 151 138 416

As can be seen from Table 2, compound I-38 is selective for HDAC1, 2, 3 and 10.

Biological Test Example 2 : Proliferation Inhibitory Activity of Compounds of the Invention on Tumor Cells

1. Screening of the activity of compounds in inhibiting tumor cell proliferation

Mouse colon cancer MC38 and human colon cancer HCT-116 cells were selected for measurement. Cells were grown in DMEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37°C in a 5% CO ₂ environment.

The assay methods for MC38 and HCT-116 cells are as follows.

(1) Cell plate culture a. Prepare complete culture medium and mix thoroughly. b. Select cell lines with good growth status. c. Take the cell culture bottle out of the incubator and check the cell name, culture medium type and cell generation number marked on the bottle. d. Discard the culture medium of MC38 and HCT-116 cells and digest them with trypsin. After digestion, neutralize them with serum-containing culture medium and pipet the cells to make them fall off. Use a pipette to transfer the cell suspension into a centrifuge tube and centrifuge at 800-1000 rpm for 3-5 minutes. e. Aspirate the cell supernatant in the centrifuge tube, add an appropriate volume of culture medium to the centrifuge tube, and gently pipet to resuspend the cells evenly. f. Use Vi-Cell XR cell counter to count and adjust the cell suspension to the appropriate concentration. g. Add the cell suspension into a 384-well plate with white bottom and white bottom, 36 μL/well. Label the cell name, seed plate density, date and other details, and place the culture plate in a CO ₂ incubator overnight.

(2) Cell experiment a. Use DMSO to prepare the compound to be tested to 200×, and dilute the compound 3 times with DMSO to obtain 10 concentration gradients of the compound. b. After 24 hours of cell seeding on the plate, add 1 μL of compound to 19 μL of medium to form a 10× intermediate plate, then add 4 μL of 10× corresponding compound to each well, and then incubate in a 37°C incubator for 72 hours. c. Observe cell morphology under an inverted microscope. d. Allow the cell culture plate to equilibrate at room temperature for 30 minutes, add 25 µL CTG to each well, and mix on a shaker for 10 minutes to induce cell lysis. e. Place the 384-well plate at room temperature for 10 minutes to allow the luminescence signal to stabilize, then stick a white bottom film on the bottom of the culture plate, and use Flexstation 3 to read the culture plate (relevant settings are: luminescence, integration time 500 ms) .

Calculate the cell growth inhibition rate according to the following formula: Inhibition rate = (OD value control hole - OD value administration hole)/OD value control hole × 100%. The IC ₅₀ value was calculated based on the compound concentration and corresponding inhibition rate using Graphpad prism 5.0 software. The test results are shown in Table 3.

2. Broad-spectrum anti-tumor cell proliferation activity of the compounds according to the embodiments of the present invention

To study the broad-spectrum cytotoxicity of candidate compounds I-1, I-38 and control compounds SAHA, MGCD0103 and chidamide, a total of 13 tumor cell lines from various tissue sources were selected, including: human lung cancer cells A549 and PC-9, human Cervical cancer cell HeLa, human renal cancer cell Caki-1, human pancreatic cancer cell MIAPaCa, human prostate cancer cell PC-3, human gastric cancer cell NCI-N87, human ovarian cancer cell ES-2, human breast cancer cell MDA-MB -231 and ZR-751, human chronic leukemia cells K562, human diffuse large B lymphoma cells DoHH2 and T leukemia cells Jurkat, and normal renal epithelial cells HEK293 were tested for activity. All cells were obtained from the American Type Culture Collection (ATCC). Cells were grown in RPMI1640 medium with 10% fetal bovine serum and 1% penicillin-streptomycin in an environment of 37°C and 5% _CO2 .

The measurement method is as follows.

(1) Cell plate culture a. Prepare complete culture medium and mix thoroughly. b. Select cell lines with good growth status. c. Take the cell culture dish out of the incubator and check the cell name, culture medium type and cell generation number marked on the dish. d. Discard the culture medium and digest it with trypsin. After digestion, neutralize it with serum-containing culture medium and pipette the cells to make them fall off. Use a pipette to transfer the cell suspension into a centrifuge tube and centrifuge at 500×g for 5 minutes. e. Aspirate the cell supernatant in the centrifuge tube, add an appropriate volume of culture medium to the centrifuge tube, and gently pipet to resuspend the cells evenly. f. Use Countstar cell counter to count and adjust the cell suspension to the appropriate concentration. g. Add the cell suspension into a 96-well plate with a transparent bottom and a transparent wall, 180 μL/well. Label the cell name, seed plate density, date and other details, and place the culture plate in a CO ₂ incubator overnight.

(2) Cell experiment a. Use DMSO to prepare the compound to be tested to 10 mM, add 2 μL of the compound to 198 μL of culture medium containing 1% DMSO and dilute to 100 μM. The compound was then diluted 3-fold to obtain 9 concentration gradients of the compound. b. After 12 hours of cell seeding on the plate, add 20 μL of the compound to the cell culture plate and incubate it in a 37°C incubator for 72 hours. c. Observe cell morphology under an inverted microscope. d. Discard the supernatant in the cell culture plate, add 10% TCA and fix at 4°C for 1 hour, then rinse and dry. Stain with 4 mg/mL SRB for 15 minutes, rinse with 1% acetic acid, dry, add 150 μL Tris-HCl and mix on a shaker for 40 minutes. e. Use TECAN enzyme label reader for detection (parameter setting: wavelength 510 nm).

Calculate the cell growth inhibition rate according to the following formula: Inhibition rate = 1-(OD value administration well-blank control well)/(OD value control well-blank control well)×100%. The IC ₅₀ value was calculated based on the compound concentration and corresponding inhibition rate using Graphpad prism 7.0 software. The test results are shown in Table 4.

3. Proliferative activity of the compounds of the present invention against drug-resistant acute leukemia cells

MV-4-11 human acute myeloid leukemia cells were purchased from ATCC. MV-4-11/R is a long-term culture of MV-4-11 cells in the environment of continuously increasing concentrations of the FLT3 inhibitor quizartinib, which induces the successful establishment of FMS-like tyrosine kinase 3 (Fms-like tyrosine kinase). , FLT3) inhibitor-resistant cell lines. The above cells were cultured in RPMI-1640 culture medium containing 10% FBS, and were routinely subcultured in a 37°C constant-temperature incubator containing 5% _CO2 saturated humidity.

MV-4-11 parental and MV-4-11/R drug-resistant cells in good logarithmic growth phase were seeded into a 96-well plate at an appropriate density, with 180 μL per well. 3 hours after inoculation, concentration gradient dilutions of compound I-38, MGCD0103 (CAS: 726169-73-9), MS275 (CAS: 209783-80-2) and chidamide or FLT3 inhibitor quizartinib ( Quizartinib (CAS: 950769-58-1), Gilteritinib (CAS: 1254053-43-4), Sorafenib (CAS: 284461-73-0), and Crenolanib (CAS : 670220-88-9), with 3 replicate wells for each drug concentration. After 72 hours of drug action, carefully remove 100 μL of culture medium from each well and discard, add 20 μL of MTT working solution (4 mg/mL) to each well, incubate in a 37°C cell culture incubator for 4 hours, and then add 100 μL of MTT working solution to each well. Triple solution (10% SDS, 5% isobutanol, 0.01 M hydrochloric acid) and placed in a 37°C oven overnight. Use an adjustable wavelength microplate enzyme label reader to measure the OD value at wavelengths of 570 nm and 690 nm. The OD value is the difference between OD570 and OD690. Calculate the inhibition rate of cell growth using the following formula: Calculate the inhibition rate of cell growth using the following formula: Inhibition rate = 1-(OD value dosing well-blank control well)/(OD value control well-blank control well)×100%. The IC ₅₀ value was calculated based on the compound concentration and corresponding inhibition rate using Graphpad prism 7.0 software. Resistance index (RI) = IC ₅₀ of drug-resistant cells/IC ₅₀ of parental cells. The test results are shown in Table 5.

Table 3. Activity of compounds of the present invention in inhibiting tumor cell proliferation in vitro compound MC38 IC ₅₀ , μM HCT-116 IC ₅₀ , μM compound MC38 IC ₅₀ , μM HCT-116 IC ₅₀ , μM I-1 0.28±0.02 0.10±0.02 I-32 0.79±0.06 0.23±0.02 I-2 1.35±0.68 0.39±0.01 I-33 1.69±0.05 1.08±0.06 I-4 0.30±0.04 0.10±0.01 I-34 0.82±0.02 0.13±0.02 I-5 2.00±0.24 0.39±0.02 I-35 7.31±0.25 3.27±0.38 I-6 0.21±0.01 0.48±0.38 I-36 0.70±0.11 1.16±0.01 I-7 2.51±0.42 0.52±0.14 I-37 0.77±0.11 0.81±0.04 I-8 0.68±0.15 0.22±0.01 I-38 0.66±0.13 0.58±0.05 I-9 1.88±0.18 1.16±0.65 I-39 0.64±0.26 0.53±0.11 I-10 0.12±0.01 0.11±0.01 I-40 4.62±0.78 5.02±0.56 I-11 2.92±0.38 1.84±0.98 I-41 0.08±0.02 0.080±0.020 I-12 8.92±0.37 3.92±2.91 I-42 1.79±0.37 1.45±0.13 I-13 4.16±0.16 0.94±0.07 I-43 3.32±0.38 2.14±0.02 I-14 0.27±0.06 0.41±0.31 I-44 2.52±0.27 0.87±0.07 I-15 5.33±1.12 1.80±0.15 I-45 0.15±0.02 0.10±0.01 I-16 0.090±0.010 0.15±0.11 I-46 0.71±0.17 1.04±0.13 I-17 5.61±0.46 2.55±0.26 I-47 0.060±0.020 0.050±0.010 I-18 2.19±0.57 0.13±0.01 I-48 1.85±0.44 1.77±0.31 I-19 14.71±1.84 2.76±0.58 I-49 2.89±0.23 2.78±0.49 I-20 0.31±0.01 0.11±0 I-50 6.91±0.85 9.51±1.27 I-21 0.93±0.09 0.79±0.01 I-51 0.60±0.18 0.47±0.02 I-22 0.52±0.02 0.13±0.02 I-52 0.16±0.02 0.26±0.01 I-23 0.66±0.01 0.31±0.01 I-53 2.92 1.14 I-24 0.098±0.03 0.060±0.010 I-54 6.37 2.89 I-25 1.87±0.17 1.09±0.13 I-55 8.18 3.07 I-26 0.28±0.02 0.55±0.43 I-56 7.40 2.71 I-27 5.49±0.73 2.65±0.05 I-57 1.15 0.28 I-28 0.29±0.02 0.30±0.03 I-58 1.76 0.36 I-29 5.05±0.08 0.26±0.03 SAHA 2.12 0.521 I-30 2.95±0.41 1.06±0.02 MGCD0103 1.84±0.55 0.67±0.01 I-31 3.27±0.17 1.74±0.10 chidamide 3.3 1.18±0.10

Table 4. In vitro inhibitory activity of compounds I-1 and I-38 on the proliferation of different cell lines cell lines Organizational source _IC50 , nM I-1 I-38 SAHA MGCD0103 Chidamide A549 lung cancer 403±134 1425±221 1862±45 1275±377 9432±231 PC-9 lung cancer 179±46 249±13 1181±166 345±47 1714±91 HeLa cervical cancer 180±6 644±17 1270±403 660±60 2623±521 Caki-1 renal cell carcinoma 98±3 252±85 517±72 265±53 570±95 MIAPaCa-2 pancreatic cancer 166±7 297±129 996±11 303±105 1682±371 PC-3 prostate cancer 282±26 1657±479 1791±489 1393±488 3091±1131 NCI-N87 stomach cancer 183±4 607±120 1027±146 606±40 4515±1110 ES-2 ovarian cancer 126±44 15±1 414±26 25±6 669±151 ZR-751 breast cancer 299±38 1125±51 1629±587 1132±179 ＞10000 MDA-MB-231 breast cancer 231±65 425±87 1480±389 309±44 619±104 K562 chronic myelogenous leukemia 150±50 345±26 828±247 322±109 1775±600 DoHH2 Diffuse large B-cell lymphoma 36±2 65±9 366±58 74±7 449±190 Jurkat T cell leukemia 83±13 126±40 702±111 150±22 1202±103 HEK293 renal epithelial cells 261±70 1256±285 1637±262 1338±529 6244±1283

Table 5. In vitro inhibitory activity of compound I-38 against FLT3 inhibitor-resistant acute leukemia cells MV-4-11/R Type compound _IC50 , nM resistance index MV-4-11 MV-4-11/R FLT3 inhibitors Quizatinib 0.2±0.1 181.8 ± 15.5 1009.4 Kranib 2.1±0.1 13.7±0.9 6.6 Gilitinib 1.5±0.6 47.0 ± 28.0 31.8 Sorafenib 0.7±0.1 1116.0 ± 152.7 1536.8 HDAC inhibitors I-38 95.0±14.0 61.3 ± 3.6 0.6 MGCD0103 101.0 ± 11.0 65.7 ± 2.7 0.7 Chidamide 515.0 ± 62.0 332.3 ± 28.6 0.6 MS275 657.0 ± 1.0 286.0 ± 83.0 0.4

Biological Test Example 3 : Animal Metabolism Properties of Compounds of the Invention

Test on the pharmacokinetic properties of the compound of the present invention after single administration to C57 male mice, SD male rats and male beagle dogs via intragastric administration and intravenous injection

(1) Experimental purpose After a single dose of the compound of the present invention was administered to C57 male mice, SD male rats and male beagle dogs, blood samples were collected at different time points (3 animals at each sampling point), and the plasma of the experimental animals was measured by LC-MS/MS. The concentration of the compound in the compound was calculated and the relevant pharmacokinetic parameters were calculated to examine the pharmacokinetics of the compound in mice, rats and dogs.

(2) Experimental design Male C57 mice (Suzhou Zhaoyan), male SD rats (Suzhou Zhaoyan), and male beagle dogs (Peking Mastiff) were used for experiments according to Table 6 (3 animals per group or each sampling point).

(3) Sample collection 0.030 mL of blood was taken from each mouse through the orbit each time, 0.1 mL of blood was taken from each rat through the orbit each time, and 1.0 mL of blood was taken from each beagle dog through the jugular vein. EDTA-K2 was used for anticoagulation. Collection time points They are: 0min, 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h after administration of the test substance. Blood samples were collected and placed on ice, and centrifuged within 30 minutes to separate plasma (centrifugation conditions: 5000 rpm, 10 minutes, 4°C). Store at –80°C until analysis.

(4) Data processing The data acquisition and control system software is Analyst1.5.1 software (Applied Biosystem). The sample peak integration method of the spectrum is automatic integration; the ratio of the sample peak area and the internal standard peak area is used as an indicator to perform regression with the concentration of the sample. Regression method: linear regression, weight coefficient is 1/X2. Pharmacokinetic parameters were analyzed using noncompartmental model analysis using WinNonlin Professional v6.3 (Pharsight, USA). Cmax is the measured maximum blood drug concentration, the area under the blood drug concentration-time curve AUC (0→t) is calculated by the trapezoidal method, and Tmax is the time to reach the peak blood drug concentration after administration. Experimental data are expressed as “Mean ± standard deviation” (Mean ± ICR, n ≥ 3) or “Mean” (Mean, n = 2).

(5) Experimental results The pharmacokinetic results of the compounds of the present invention are shown in Tables 7 to 10. It can be seen that the compound has good pharmacokinetic properties in C57 male mice, SD male rats and male beagle dogs.

Table 6. Dosage regimens of compounds test substance animal Group Dosage (mg/kg) Dosing concentration (mg/mL) Dosing volume (mL/kg) Collect samples Dosing method solvent I-1 mouse 1 20 2.0 10 plasma PO 5%DMSO+ 30%PEG+ 65%saline I-2 mouse 2 20 2.0 10 plasma PO I-4 mouse 3 20 2.0 10 plasma PO I-6 mouse 4 20 2.0 10 plasma PO I-41 mouse 5 20 2.0 10 plasma PO I-52 mouse 6 20 2.0 10 plasma PO I-21 mouse 7 20 2.0 10 plasma PO mouse 8 5 1.0 5 plasma IV 10%DMSO+ 30%PEG400+ 60%saline I-38 mouse 9 20 2.0 10 plasma PO 5%DMSO+ 30%PEG400+ 65%saline rat 10 20 2.0 10 plasma PO Beagles 11 5 1.0 5 plasma PO mouse 12 5 1.0 5 plasma IV 5%DMSO+ 10%solutol+ 85%saline rat 13 5 1.0 5 plasma IV Beagles 14 1 1.0 1 plasma IV MGCD0103 rat 15 20 2.0 10 plasma PO 5%DMSO+ 30%PEG400+ 65%saline Beagles 16 5 1.0 5 plasma PO rat 17 5 1.0 5 plasma IV 5%DMSO+ 10%solutol+ 85%saline Beagles 18 1 1.0 1 plasma IV

Table 7. Oral pharmacokinetic parameters of some compounds (experimental animal: mouse, dosage: 20 mg·kg ^-1 ) Pharmacokinetic parameters I-1 I-2 I-4 I-6 I-41 I-52 Terminal elimination rate K _el h ^-1 0.138 0.383 0.17 0.191 0.1 0.316 Terminal elimination half-life t _1/2 h 5.03 2.03 4.22 4.25 7 2.22 Peak time t _max h 0.25 0.139 0.083 0.139 0.139 0.25 Drug peak concentration C _max ng·mL ^-1 2715 1470 3501 1091 2578 1097 Area under the drug-time curve AUC _0-t h·ng·mL ^-1 2917 1260 2059 965 2730 940 Area under the curve AUC _0-inf h·ng·mL ^-1 7267 1297 2074 998 2842 1001 Average dwell time MRT _PO h 3.02 1.71 2.15 3.63 4.11 2.26

As can be seen from the data in Table 7, some compounds of formula I have good oral exposure in mice.

Table 8. Intravenous and oral pharmacokinetic parameters of compounds I-21 and I-38 in mice I-21 I-38 Pharmacokinetic parameters intravenous injection Oral administration intravenous injection Oral administration Dosage mg·kg ^-1 5.0 20.0 5.0 20.0 Terminal elimination rate K _el h ^-1 0.475 0.202 0.815 0.281 Terminal elimination half-life t _1/2 h 1.46 3.44 0.85 2.49 Peak time t _max h -- 0.417 -- 0.417 Drug peak concentration C _max ng·mL ^-1 3349 3385 8129 9558 Area under the drug-time curve AUC _0-t h·ng·mL ^-1 2983 5887 5864 15278 Area under the curve AUC _0-inf h·ng·mL ^-1 3044 5903 5873 15287 Clearance CL mL/min/kg 27.6 -- 14.3 -- Average dwell time MRT _PO h -- 2.56 -- 2.44 Apparent volume of distribution Vdss L/kg 2.11 -- 0.766 -- BioavailabilityF % -- 49.3 -- 65.1

Note: "--" means not applicable.

It can be seen from the data in Table 8 that compounds I-21 and I-38 have good metabolic properties in mice and high bioavailability.

Table 9. Intravenous and oral pharmacokinetic parameters of compound I-38 in rats I-38 MGCD0103 Pharmacokinetic parameters veins oral veins oral Dosage mg·kg ^-1 5 20 5 20 Terminal elimination rate K _el h ^-1 0.241 0.176 0.493 0.198 Terminal elimination half-life t _1/2 h 2.92 3.99 1.41 3.54 Peak time t _max h -- 0.667 -- 0.250 Drug peak concentration C _max ng·mL ^-1 11146 6483 1900 3276 Area under the drug-time curve AUC _0-t h·ng·mL ^-1 7451 18169 1252 7700 Area under the curve AUC _0-inf h·ng·mL ^-1 7481 18219 1261 7713 Clearance CL mL/min/kg 11.7 -- 68.3 -- Average dwell time MRT _PO h -- 2.35 -- 2.24 Apparent volume of distribution Vdss L/kg 0.826 -- 3.60 -- BioavailabilityF % -- 61.0 -- 153

Note: "--" means not applicable.

It can be seen from the data in Table 9 that compound I-38 has good metabolic properties in rats, and its oral bioavailability is 61.0%.

Table 10. Intravenous and oral pharmacokinetic parameters of compound 1-38 in beagle dogs I-38 MGCD0103 Pharmacokinetic parameters veins oral veins oral Dosage mg·kg ^-1 1 5 1 5 Terminal elimination rate constant λz h ^-1 1.085 0.898 1.53 1.07 Terminal elimination half-life t _1/2 h 0.640 0.774 0.453 0.671 Peak time t _max h 0.083 0.5 0.083 0.42 Drug peak concentration C _max ng·mL ^-1 931 801 887 390 Area under the curve AUC _last h·ng·mL ^-1 710 1049 444 380 Area under the drug-time curve AUCINF_obs h·ng·mL ^-1 711 1051 446 382 Initial concentration C ₀ ng·mL ^-1 1161 -- 1170 -- Average residence timeMRT _last h 0.768 1.19 0.412 0.916 Average residence time MRT _0-∞ h 0.773 1.20 0.424 0.937 Apparent volume of distribution Vss mL/kg 1112 -- 953 -- Apparent volume of distribution V mL/kg 1350 -- 1499 -- Clearance CL mL/min/kg 1450 -- 2292 -- BioavailabilityF % - 29.6 - 17.1

Note: "--" means not applicable.

It can be seen from the data in Table 10 that compound I-38 has good metabolic properties in beagle dogs, and its oral bioavailability is 29.6%.

Biological Test Example 4 : Inhibitory activity of the compounds of the present invention on the growth of subcutaneous transplanted tumors of MC38 colon cancer in mice

(1) Experimental animals

C57BL/6 mice, 6-8 weeks old, ♀, were purchased from Beijing Huafukang Biotechnology Co., Ltd. The use and welfare of experimental animals are in compliance with the regulations of the International Laboratory Animal Assessment and Accreditation Committee (AAALAC). Monitor the health status and death of animals every day. Routine inspections include observing the effects of test substances and drugs on the daily behavioral performance of animals, such as behavioral activities, weight changes, appearance signs, etc.

(2) Experimental steps

Mouse MC38 colon cancer cells were subcutaneously inoculated into the right axilla of mice at a rate of 5.0×10 ⁵ cells/mouse. Mice were monitored daily and caliper measurements were initiated when tumors became visible. The width (W) and length (L) of each tumor were measured by calipers, using the equation V=(L×W2)/2. ^After the tumors grew to ~100 mm, the mice were randomly divided into groups (n=5-6). I-38 (60 mg/kg, 120 mg/kg) and I-1 (60 mg/kg, 90 mg/kg) were administered intragastrically once a day respectively. In the combined experiment with anti-mPD-1, I-38 (60 mg/kg, 120 mg/kg) was administered intragastrically once a day, and anti-mPD-1 (InVivoMab anti-mouse PD-1) was intraperitoneally injected twice a week. , Bio % DMSO + 40% PEG400 + 55% 5/1000 concentrated hydrochloric acid). Tumor volume and mouse body weight were recorded every two days. The evaluation index of tumor inhibition is the relative tumor inhibition rate: TGI%=(1-T/C)%=(1-average tumor growth volume of the treatment group/average tumor growth volume of the control group)×100%.

(3) Experimental results

Compound I-38 in the embodiments of the present invention has a significant inhibitory effect on the growth of subcutaneous transplanted tumors of MC38 colon cancer in mice when used alone, and the anti-tumor activity is significantly enhanced when used in combination with anti-PD-1. As shown in Figure 1, on day 15, the TGI (%) of the I-38 60 mg/kg group, 120 mg/kg group and anti-PD-1 group were 77.3% (P＜0.01) and 92.7% ( P＜0.001) and 51.7% (P＜0.05); TGI (%) after anti-PD-1 and I-38 (60 mg/kg, 120 mg/kg) were combined were 89.7% (P＜0.001) and 100.6 respectively % (P<0.001). On days 15 and 21, the tumors of 3 and 5 mice in the anti-PD-1 and I-38 120 mg/kg combination groups respectively showed complete regression (CR, Complete Regression). CR% is 50% and 84%. In addition, there was no significant difference in the weight gain of mice in each group during the entire experiment (Figure 2).

As shown in Figure 3 and Figure 4, the TGI (%) of the 60 mg/kg and 90 mg/kg groups of compound I-1 according to the embodiment of the present invention are 86.0% (P<0.01) and 96.5% (P<0.01) respectively; Compared with the control group, the body weight of mice decreased by 13.0% and 17.9% respectively.

In summary, in the C57BL/6 mouse model, compounds I-1 and I-38 of the embodiments of the present invention alone have a significant inhibitory effect on the growth of subcutaneous transplanted tumors of MC38 colon cancer in mice; I-38 and anti-mPD- 1. The combined use has a synergistic effect, and the weight of the mice in the combined group did not decrease significantly.

Biological Test Example 5 : Inhibitory activity of compound I-38 on the growth of HCT-116 human colon cancer cell xenografts in nude mice

(1) Experimental animals

BALB/c nude mice, 6-7 weeks old, ♀, were purchased from Beijing Huafukang Biotechnology Co., Ltd. The use and welfare of experimental animals are in compliance with the regulations of the International Laboratory Animal Assessment and Accreditation Committee (AAALAC). Monitor the health status and death of animals every day. Routine inspections include observing the effects of test substances and drugs on the daily behavioral performance of animals, such as behavioral activities, weight changes, appearance signs, etc.

(2) Experimental steps

Human HCT-116 colon cancer cells were subcutaneously inoculated into the right axilla of mice at a rate of 7.0×10 ⁶ cells/mouse. Mice were monitored daily and caliper measurements were initiated when tumors became visible. The width (W) and length (L) of each tumor were measured by calipers, using the equation V=(L×W2)/2. ^After the tumors grew to ~100 mm, the mice were randomly divided into groups (n = 5). I-38 (30 mg/kg; 60 mg/kg; 120 mg/kg) or MGCD0103 (120 mg/kg) were administered by gavage once a day respectively, and the control group was administered an equal amount of solvent by gavage every day. Tumor volume and mouse body weight were recorded every two days. The evaluation index of tumor inhibition is the relative tumor inhibition rate: TGI%=(1-T/C)%=(1-average tumor growth volume of the treatment group/average tumor growth volume of the control group)×100%.

(3) Experimental results

Compound I-38 according to the embodiments of the present invention has a significant inhibitory effect on the growth of subcutaneous transplanted tumors in mice with human HCT-116 colon cancer when used alone. As shown in Figure 5, on the 15th day, the TGI (%) of the I-38 30 mg/kg group, 60 mg/kg group and 120 mg/kg group were 38.9% (P＜0.01) and 65.9% (P <0.001) and 85.8% (P<0.0001), the TGI (%) of the MGCD0103 (120 mg/kg) group was 61.5%. In addition, there was no significant difference in the weight gain of mice in each group during the entire experiment (Figure 6). In summary, compound I-38 according to the embodiments of the present invention has a significant inhibitory effect on the growth of subcutaneous transplanted tumors of human HCT-116 colon cancer in nude mice, and its activity is stronger than that of MGCD0103.

Biological Test Example 6 : Inhibitory activity of compound I-38 on the growth of FLT3 inhibitor-resistant human acute myeloid leukemia MV-4-11/R nude mouse transplanted tumors

(1) Experimental animals

BALB/c nude mice, 6-7 weeks old, ♀, were purchased from Beijing Huafukang Biotechnology Co., Ltd. The use and welfare of experimental animals are in compliance with the regulations of the International Laboratory Animal Assessment and Accreditation Committee (AAALAC). Monitor the health status and death of animals every day. Routine inspections include observing the effects of test substances and drugs on the daily behavioral performance of animals, such as behavioral activities, weight changes, appearance signs, etc.

(2) Experimental steps

FLT3 inhibitor-resistant human MV-4-11/R acute leukemia cells were subcutaneously inoculated into the right axilla of mice at a rate of 1.0×10 ⁷ cells/mouse. Mice were monitored daily and caliper measurements were initiated when tumors became visible. The width (W) and length (L) of each tumor were measured by calipers, using the equation V=(L×W2)/2. ^After the tumors grew to ~100 mm, the mice were randomly divided into groups (n = 5). I-38 (120 mg/kg), MGCD0103 (120 mg/kg), quizartinib (1 mg/kg) or I-38 (120 mg/kg) + quizartinib ( 1 mg/kg), and the control group was given the same amount of solvent by gavage every day. Tumor volume and mouse body weight were recorded every two days. The evaluation index of tumor inhibition is the relative tumor inhibition rate: TGI%=(1-T/C)%=(1-average tumor growth volume of the treatment group/average tumor growth volume of the control group)×100%.

(3) Experimental results

Compound I-38 according to the embodiments of the present invention has a significant inhibitory effect on the growth of subcutaneous transplanted tumors in mice with human MV-4-11/R acute leukemia cells that are resistant to FLT3 inhibitors. As shown in Figure 7, on day 12, the TGI (%) of the I-38 (120 mg/kg) group and MGCD0103 (120 mg/kg) group were 91.1% (P＜0.00001) and 59.3% (P＜ 0.001); the quizartinib (1 mg/kg) group only had weak anti-tumor activity, with a TGI (%) of 24.8% (P>0.05). After the combination of quizartinib (1 mg/kg) and I-38 (120 mg/kg), the TGI (%) was 97.9% (P<0.00001). One mouse (1/5) in the combined group had tumor regression. No tumor shrinkage was seen in mice in the single-use group. In summary, compound I-38 according to the embodiments of the present invention has a significant inhibitory effect on the growth of subcutaneous transplanted tumors in nude mice with human acute leukemia that is resistant to FLT3 inhibitors. The activity is significantly stronger than that of MGCD0103, and the anti-tumor activity is enhanced when combined with quizartinib. .

Although specific embodiments of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. . Therefore, the protection scope of the present invention is limited by the appended patent application scope.

Other features and effects of the present invention will be clearly presented in the embodiments with reference to the drawings, in which: Figure 1 shows the changes in tumor volume after intragastric administration of compound I-38 and its combination with PD-1 antibody; Figure 2 shows the changes in body weight of mice administered compound I-38 by gavage and combined with PD-1 antibody; Figure 3 shows the changes in tumor volume after intragastric administration of Compound I-1; Figure 4 shows the changes in body weight of mice administered compound I-1 by gavage; Figure 5 shows the changes in tumor volume of subcutaneous transplanted tumors of human HCT-116 colon cancer mice after intragastric administration of Compound I-38; Figure 6 shows changes in body weight of mice with human HCT-116 colon cancer after intragastric administration of Compound I-38; and Figure 7 Changes in tumor volume of subcutaneous xenograft tumors in acute leukemia MV-4-11/R mice resistant to human FLT3 inhibitors after intragastric administration of Compound I-38 and combination with Quizartinib.

Claims (15)

A triazolamide compound represented by formula I or a pharmaceutically acceptable salt thereof, , wherein Ring A is a 6-14-membered aryl group, a 6-14-membered aryl group substituted by one or more R ^7a , a 5-10-membered heteroaryl group, or a 5-10-membered aryl group substituted by one or more R ^7b heteroaryl, or ; In the 5-10-membered heteroaryl group and the 5-10-membered heteroaryl group substituted by one or more R ^7b , the heteroatom is selected from N, O and S. One or more, the number of heteroatoms is 1-4; when there are multiple substituents, they are the same or different; R ^7a and R ^7b are independently halogen, -CN, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkyl substituted by one or more halogens or -(CH ₂ ) _n -N(R ^8a R ^8b ); L is a chemical bond or ; R ⁵ is hydrogen, halogen or C ₁ -C ₆ alkyl; R ⁶ is hydroxyl, 6-14-membered aryl or 6-14-membered aryl substituted by one or more R ⁹ ; when the substituent is multiple when, the same or different; R ⁹ is -N (R ^9a R ^9b ) or halogen; R ¹ , R ² , R ³ , R ⁴ , R ^8a , R ^8b , R ^9a and R ^9b are independently hydrogen or C ₁ -C ₆ alkyl; n is 0, 1, 2 or 3; The carbon atom with "*" indicates that when it is a chiral carbon atom, it is S configuration, R configuration or their mixture. The triazolamide compound represented by formula I or a pharmaceutically acceptable salt thereof as described in claim 1, wherein the triazolamide compound represented by formula I satisfies the following conditions: One or more of: (1) When Ring A is a 6-14-membered aryl group or a 6-14-membered aryl group substituted by one or more R ^7a , the 6-14-membered aryl group is either substituted by one or more Among the 6-14-membered aryl groups substituted by multiple R ^7a , the 6-14-membered aryl group is a 6-10-membered aryl group, such as phenyl, or ; (2) When ring A is a 5-10 membered heteroaryl group or a 5-10 membered heteroaryl group substituted by one or more R ^7b , the 5-10 membered heteroaryl group may be substituted by one or more R 7b In the 5-10-membered heteroaryl group substituted by R ^7b , the 5-10-membered heteroaryl group is pyridyl or quinolyl, for example , or ; (3) When R ⁵ , R ^7a , R ^7b and R ⁹ are independently halogen, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine, chlorine or bromine; (4) When R ¹ , R ^2. When R ³ , R ⁴ , R ⁵ , R ^7a , R ^7b , R ^8a , R ^8b , R ^9a and R ^9b are independently C _{1 -C 6 alkyl, the C 1 -C 6 alkyl} is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl or third butyl, such as methyl, ethyl or isopropyl; (5) When R ^7a When R 7b and R ^7b are independently C ₁ -C ₆ alkoxy groups, the C ₁ -C ₆ alkoxy groups are C ₁ ~ C ₃ alkoxy groups, such as methoxy or ethoxy groups; (6) When R ^7a and R ^7b are independently C ₂ -C ₆ alkynyl, the C ₂ -C ₆ alkynyl is C ₂ -C ₄ alkynyl, such as ethynyl; (7) When R ^7a and R ^7b When it is independently a C ₁ -C ₆ alkyl group substituted by one or more halogens, the C ₁ -C ₆ alkyl group substituted by one or more halogens is a C ₁ - substituted by one or more halogens. C ₃ alkyl, such as trifluoromethyl; (8) When R ⁶ is a 6-14-membered aryl group or a 6-14-membered aryl group substituted by one or more R ⁹ , the 6-14-membered aryl group The 6-14-membered aryl group in the 6-14-membered aryl group substituted by one or more R ^7a is a 6-10-membered aryl group, such as phenyl. The triazolamide compound represented by formula I or a pharmaceutically acceptable salt thereof as described in claim 1, wherein the triazolamide compound represented by formula I satisfies the following conditions: One or more of: (1) Ring A is a 6-14-membered aryl group, a 6-14-membered aryl group substituted by one or more R ^7a , a 5-10-membered heteroaryl group, or ; (2) R ⁵ is hydrogen; (3) R ⁶ is hydroxyl, or a 6-14-membered aryl group substituted by one or more R ⁹ ; (4) R ^8a and R ^8b are independently C ₁ -C ₆ Alkyl; (5) R ^9a and R ^9b are independently hydrogen; (6) n is 0 or 1. The triazolamide compound represented by formula I or a pharmaceutically acceptable salt thereof as described in claim 1, wherein the triazolamide compound represented by formula I satisfies the following conditions: One or more of: (1) Ring A is phenyl, , , , , , , , , , , , , , , , , , , , , , , , or ; (2) R ¹ and R ² are independently H or methyl; (3) R ³ and R ⁴ are independently H or ethyl; (4) R ⁶ is hydroxyl, or . The triazolamide compound represented by formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 4, wherein the triazolamide compound represented by formula I The compound is selected from any of the following structures, isomers thereof or mixtures thereof: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . The use of a triazolamide compound represented by formula I as described in any one of claims 1 to 5 and a pharmaceutically acceptable salt thereof as an HDAC inhibitor. A pharmaceutical composition, which includes a triazolamide compound represented by formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, and at least one pharmaceutical excipient. A triazolamide compound represented by formula I as described in any one of claims 1 to 5, a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim 7 in the preparation of treatment and/or or application in drugs to prevent HDAC-related diseases. A pharmaceutical combination, which includes a triazolamide compound represented by Formula I or a pharmaceutically acceptable salt thereof and a PD-1 or PD-L1 antibody as described in any one of claims 1 to 5; The PD-1 antibody can be InVivoMab anti-mouse PD-1, nivolumab, pembrolizumab, cimepilimab, toripalimab, sintilimab or carretin Lezumab; the PD-L1 antibody can be atezolizumab, avelumab or durvalumab. A triazolamide compound as shown in formula I as described in any one of claims 1 to 5, and a pharmaceutically acceptable salt thereof, in the preparation and combined treatment with PD-1 or PD-L1 antibodies. /or application in drugs to prevent HDAC-related diseases. The application as described in claim 8 or 10, wherein the HDAC-related disease is cancer; the cancer can be head and neck cancer, respiratory system cancer, digestive system cancer, urinary system cancer, bone cancer, gynecological cancer, Cancer of the blood system, melanoma, glioma or skin cancer. A preparation method of a triazolamide compound represented by formula I as described in any one of claims 1 to 5, wherein the preparation method includes the following scheme one or scheme two; Scheme one: when R ⁶ When it is a hydroxyl group, in an organic solvent and in the presence of a base, the compound represented by formula II is reacted with hydroxylamine hydrochloride as shown below to obtain the triazolamide compound represented by formula I, ; Option 2: When R ⁶ is When, in an organic solvent, in the presence of a condensing agent and a base, the compound represented by formula III and the compound represented by formula IV are subjected to a condensation reaction as shown below, to obtain the compound represented by formula I Triazolamide compounds, . The preparation method of triazolamide compounds represented by Formula I as described in claim 12, wherein the preparation method satisfies one or more of the following conditions: (1) In the first embodiment, the organic solvent is an alcohol solvent, such as methanol; (2) In the first embodiment, the base is an alkali metal hydroxide, such as potassium hydroxide; (3) In the first embodiment, the molar ratio of the base to the hydroxylamine hydrochloride is 1-3:1, such as 1.5:1; (4) In the first embodiment, the molar ratio of the hydroxylamine hydrochloride to the compound represented by formula II is 1-100:1, such as 45:1; (5) In the first embodiment, the reaction temperature ranges from -40°C to the boiling temperature of the organic solvent, such as room temperature; (6) In the second embodiment, the organic solvent is an amide solvent, such as N,N-dimethylformamide; (7) In the second embodiment, the base is an organic base, such as N,N-diisopropylethylamine; (8) In the second embodiment, the molar ratio of the base to the compound represented by formula III is 1-3:1, such as 2:1; (9) In the second embodiment, the condensation agent is a carbodiimide condensation agent, a phosphorus cationic condensation agent or a urea cationic condensation agent; the carbodiimide condensation agent is preferably N, N '-dicyclohexylcarbodiimide or N,N'-diisopropylcarbodiimide; the phosphorus cationic condensation agent is preferably Carter condensation agent or PyBOP; the urea cationic condensation agent is preferably HATU, TBTU or TOTU; (10) In the second embodiment, the molar ratio of the condensation agent to the compound represented by Formula III is 1-3:1, such as 2:1; (11) In the second embodiment, the molar ratio of the compound represented by formula IV to the compound represented by formula III is 1-3:1, such as 2:1; (12) In the second embodiment, the temperature of the condensation reaction ranges from -40°C to the boiling temperature of the organic solvent, such as room temperature. A compound that has any of the following structures: , or ; Wherein, the definitions of ring A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and L are as described in claim 1. The compound according to claim 14, wherein the compound represented by formula II is , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; The compound represented by formula III is , , , , , , , , , , , , , , , , , , , , , , , , , , , or .