Arylamine derivative as well as preparation method and application thereof

Abstract

The invention belongs to the field of medicinal chemistry, and relates to an arylamine derivative as well as a preparation method and application thereof. The structural general formula of the arylamine derivative is a compound or a salt of the compound as shown in a formula I. The compound disclosed by the invention can inhibit an Hsp110 pathway to play a role in resisting vascular remodeling, and can be used for preparing medicines for treating pulmonary arterial hypertension and pulmonary vascular remodeling.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry and relates to an aromatic amine derivative and a preparation method and application thereof. Background Art

[0002] Pulmonary arterial hypertension (PAH) is a heterogeneous clinical pulmonary vascular disease with a high mortality rate. If left untreated, it can lead to progressive dyspnea, exercise intolerance, right ventricular failure, and even death. Therefore, PAH remains a serious global health burden. The current clinical treatment strategy is to reduce pulmonary vascular pressure. Although this strategy can effectively alleviate clinical symptoms and improve quality of life, it does not reduce clinical mortality. With the deepening understanding of the pathobiology of PAH, vascular remodeling has been recognized as a fundamental pathological feature of PAH over the past decade. Pulmonary vascular remodeling, driven by abnormal vascular cell proliferation and migration, plays a major role in the progression of PAH. These abnormalities lead to thickening of the pulmonary vascular wall, reduction in internal diameter, decreased vascular elasticity, and ultimately vascular fibrosis. In fact, significant research results have been achieved in the treatment of PAH by inhibiting vascular remodeling.

[0003] Heat shock protein 110 (Hsp110, also known as Hsp105 or HSPH1) is expressed at elevated levels in the serum of PAH patients and in the lungs and pulmonary arteries of PAH rats. Hsp110 contributes to abnormal proliferation and migration of HPAECs by increasing p-STAT3 and c-Myc. Furthermore, Hsp110 induces proliferation and autophagy in PASMCs. Therefore, inhibiting Hsp110 may modulate vascular remodeling and potentially treat the disease.

[0004] However, to date, there are no compounds targeting Hsp110 for the treatment of PAH.

[0005] WO2019057969 discloses the following compound:

[0006]

[0007] A is selected from

[0008] The derivatives are farnesoid X receptor (FXR) and / or peroxisome proliferator-activated receptor delta (PPARδ) agonists and are used to treat atherosclerosis or dyslipidemia associated with upregulated sphingomyelin levels in humans or animals.

[0009] WO2009043495 discloses the following compounds:

[0010]

[0011] A is an unsubstituted 1,4-methylene group, and R1 is a saturated 6-membered monocyclic heterocyclic group. The derivative is used for treating pain.

[0012] WO2000002851 discloses the following compounds:

[0013]

[0014] A1 is phenylene, R1 is phenyl or C1-C7 alkyl, R2 is selected from benzene or C1-C7 substituted by fluorine, hydroxyl, alkoxy, ester, amino 10 Alkyl, R3 is selected from hydrogen, halogen, alkoxy or alkyl. The derivative is used to treat cardiovascular diseases such as hypertension, angina pectoris, cardiac insufficiency, thrombosis, etc. Summary of the Invention

[0015] The purpose of the present invention is to provide an aromatic amine derivative having the ability to inhibit Hsp110 activity, and a preparation method and application thereof.

[0016] In order to achieve the above object, the technical solution of the present invention is as follows:

[0017] An aromatic amine derivative, the compound or salt of which has the general structural formula shown in Formula I:

[0018]

[0019] Wherein, X is selected from Y is selected from

[0020] R1 is selected from trifluoromethyl, -aryl-R6, -(5-10 membered heteroaryl)-R6; R6 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, trihalomethyl, cyano, -NHCO-(C1-C8 alkyl), the position is one or more of ortho, meta, and para, and the number of substituents is 1-5;

[0021] R2 and R3 are independently selected from hydrogen, halogen, trihalomethyl, -O-R7; R7 is selected from hydrogen, C1-C8 alkyl;

[0022] R4 and R5 are independently selected from -(CH2) n COOR8, -(CH2) n CONHR8, -SO2NHR8, -SO2NR9R8, -NHSO2R8, -(CH2) n CONH(CH2) m COOR8, hydrogen, C1-C8 alkyl;

[0023] n and m are independently selected from integers of 0-8; R8 and R9 are independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C3-C8 aliphatic heterocyclic group; the substituents on the substituted C1-C8 alkyl, substituted aryl, and substituted 5-10 membered heteroaryl are independently selected from halogen, hydroxyl, amino, thiol, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-substituted C1-C6 alkyl, and halo-substituted C1-C6 alkoxy; the position where the aryl or 5-10 membered heteroaryl is substituted may be ortho, meta, or para; the number of substituents may be 0-5.

[0024] In a preferred embodiment, the trihalomethyl group is selected from trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl.

[0025] In a preferred embodiment, n is an integer of 0-5, and m is an integer of 0-6.

[0026] In a preferred embodiment, the aryl group is benzene; and the 5-10 membered heteroaryl group is selected from the group consisting of furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, purinyl, carbazolyl, acridinyl, piperonyl, oxazole, and isoxazole.

[0027] In a preferred embodiment, the C3-C8 aliphatic heterocyclic group is selected from: oxirane, aziridine, thiirane, oxetane, azetidine, thietane, tetrahydrofuran, tetrahydropyrrole, tetrahydrothiophene, tetrahydropyran, piperidine, dioxane, piperazine, hexahydropyrazine, tetrahydrothiopyran, morpholine, and thiophene.

[0028] In a preferred embodiment, -Y-R1 is selected from:

[0029]

[0030] In a preferred embodiment, R4 or R5 are independently selected from:

[0031]

[0032] In a preferred embodiment, R6 is selected from -CF3, -C(CH3)3, -OCH3, -OCF3, -NHCOCH3,

[0033] In a preferred embodiment, the number of substituents is 1-3.

[0034] In a preferred embodiment, the substitution is at the para position of the phenyl ring or the 5-10 membered heteroaryl group.

[0035] In a preferred embodiment, the salt of the compound of formula I is sodium salt, potassium salt, ammonium salt, lithium salt, magnesium salt, or calcium salt.

[0036] An aromatic amine derivative, the compound or salt of which has the general structural formula shown in Formula I:

[0037]

[0038] Wherein, X is selected from Y is selected from

[0039] R1 is selected from trifluoromethyl, -aryl-R6, -(5-10 membered heteroaryl)-R6; R6 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, trihalomethyl, cyano, -NHCO-(C1-C8 alkyl), the position is one or more of ortho, meta, and para, and the number of substituents is 1-5;

[0040] R2 and R3 are independently selected from hydrogen, halogen, trihalomethyl, -O-R7; R7 is selected from hydrogen, C1-C8 alkyl;

[0041] R4 and R5 are independently selected from -(CH2) n COOR8, -(CH2) n CONHR8, -SO2NHR8, -SO2NR9R8, -NHSO2R8, -(CH2) n CONH(CH2) m COOR8, hydrogen, C1-C8 alkyl;

[0042] n and m are independently selected from integers of 0-8; R8 and R9 are independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C3-C8 aliphatic heterocyclic group; the substituents on the substituted C1-C8 alkyl, substituted aryl, and substituted 5-10 membered heteroaryl are independently selected from halogen, hydroxyl, amino, thiol, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-substituted C1-C6 alkyl, and halo-substituted C1-C6 alkoxy; the position where the aryl or 5-10 membered heteroaryl is substituted may be ortho, meta, or para; the number of substituents may be 0-5.

[0043] In a preferred embodiment, n is an integer of 0-5, and m is an integer of 0-6.

[0044] In a preferred embodiment, the trihalomethyl group is selected from trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl.

[0045] In a preferred embodiment, the aryl group is selected from benzene; and the 5-10 membered heteroaryl group is selected from furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, purinyl, carbazolyl, acridinyl, piperonyl, oxazole, and isoxazole.

[0046] In a preferred embodiment, the C3-C8 aliphatic heterocyclic group is selected from: oxirane, aziridine, thiirane, oxetane, azetidine, thietane, tetrahydrofuran, tetrahydropyrrole, tetrahydrothiophene, tetrahydropyran, piperidine, dioxane, piperazine, hexahydropyrazine, tetrahydrothiopyran, morpholine, and thiophene.

[0047] In a preferred embodiment, -Y-R1 is selected from:

[0048]

[0049] In a preferred embodiment, R4 or R5 are independently selected from:

[0050]

[0051] In a preferred embodiment, R6 is selected from -CF3, -C(CH3)3, -OCH3, -OCF3, -NHCOCH3,

[0052] In a preferred embodiment, the number of substituents is 1-3.

[0053] In a preferred embodiment, the substitution is at the para position of the phenyl ring or the 5-10 membered heteroaryl group.

[0054] In a preferred embodiment, the salt of the compound of formula I is sodium salt, potassium salt, ammonium salt, lithium salt, magnesium salt, or calcium salt.

[0055] In another aspect, the compounds of the present invention include compounds defined herein that are labeled with various isotopes, for example, where a radioactive isotope is present, such as 3 H, 14 C and 18 Those compounds of F, or in which non-radioactive isotopes are present, such as 2 H and13 Compounds of C.

[0056] In one preferred embodiment, the aromatic amine derivative comprises the following structure:

[0057]

[0058]

[0059] The present invention also claims a method for preparing the aromatic amine derivatives, which, when X is a methyleneoxy group, comprises the following steps:

[0060] reacting a benzyl bromide raw material with an o-nitrophenol raw material, reducing the obtained nitro product to obtain an amino intermediate, and reacting the amino intermediate with an acyl chloride or sulfonyl chloride compound to obtain the aromatic amine derivative;

[0061] The structure of brombenzyl raw materials is:

[0062] The structure of the nitro product is:

[0063] The structure of the amino intermediate is:

[0064] The structure of aromatic amine derivatives is:

[0065] In one preferred embodiment, the synthetic route of the aromatic amine derivatives is:

[0066]

[0067] The present invention also claims a method for preparing the aromatic amine derivatives, which, when X is an amide, comprises the following steps:

[0068] The amino intermediate obtained by the ring-opening reaction of the amine compound and the isatoic anhydride raw material reacts with the acyl chloride or sulfonyl chloride compound to obtain the aromatic amine derivative;

[0069] The structure of amine compounds is:

[0070] The structure of isatoic anhydride raw materials is:

[0071] The structure of the amino intermediate is:

[0072] The structure of aromatic amine derivatives is:

[0073] In one preferred embodiment, the synthetic route of the aromatic amine derivatives is:

[0074]

[0075] The present invention also claims a method for preparing the aromatic amine derivatives, which, when X is an amide, comprises the following steps:

[0076] The ring-closed intermediate obtained by the reaction of anthranilic acid raw materials and acyl chloride raw materials is reacted with aniline raw materials to obtain the aromatic amine derivative;

[0077] The structure of anthranilic acid raw materials is:

[0078] The structure of the ring-closure intermediate is:

[0079] The structure of aniline raw materials is:

[0080] The structure of aromatic amine derivatives is:

[0081] In one preferred embodiment, the synthetic route of the aromatic amine derivatives is:

[0082]

[0083] The present invention also claims a method for preparing the aromatic amine derivatives, which, when X is an amide, comprises the following steps:

[0084] The benzoic acid intermediate obtained by the reaction of anthranilic acid raw materials and sulfonyl chloride raw materials reacts with aniline raw materials to obtain aromatic amine derivatives;

[0085] The structure of anthranilic acid raw materials is:

[0086] The structure of sulfonyl chloride raw materials is:

[0087] The structure of benzoic acid intermediates is:

[0088] The structure of aniline raw materials is:

[0089] The structure of aromatic amine derivatives is:

[0090] In one preferred embodiment, the synthetic route of the aromatic amine derivatives is:

[0091]

[0092] The present invention also claims protection for a pharmaceutical composition comprising the aromatic amine derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and excipient.

[0093] In one preferred embodiment, the pharmaceutically acceptable excipients include solvents, diluents, other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc.

[0094] In one preferred embodiment, the pharmaceutical composition can be in the form of liquid, solid, semi-solid, gel or spray.

[0095] In a preferred embodiment, the pharmaceutical composition can be administered by any suitable means, and can be administered to humans or other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically, etc., depending on the severity of the disease.

[0096] The present invention also claims the use of the aromatic amine derivatives or pharmaceutically acceptable salts thereof in the preparation of Hsp110 inhibitors.

[0097] The present invention also claims to protect the use of the aromatic amine derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for treating pulmonary hypertension.

[0098] The present invention also claims the use of the aromatic amine derivatives or pharmaceutically acceptable salts thereof in preparing drugs for pulmonary vascular remodeling.

[0099] The beneficial effects of the present invention are:

[0100] 1. The compounds involved in the present invention have novel structures;

[0101] 2. The compounds of the present invention can inhibit the Hsp110 pathway to exert anti-vascular remodeling effects and can be used to prepare drugs for the treatment of pulmonary hypertension and pulmonary vascular remodeling.

[0102] 3. The carboxylic acid, carboxylic acid derivative, sulfonamide, and sulfonamide derivative fragments of the compounds described herein exhibited superior Hsp110 inhibitory activity when located at the R5 position compared to those located at the R4 position (17b, 17e, 22h, and 22i). Furthermore, when the R1 position was a tert-butyl or trifluoromethyl substituted benzene ring, the activity was superior to that of a naphthalene ring substituent (17i and GF053). BRIEF DESCRIPTION OF THE DRAWINGS

[0103] Figure 1 is the effect of compound 17i in Example 65 on Hsp110 and its downstream proteins; wherein Figure 1A is the expression of Hsp110 and its downstream proteins detected by Western blot after treatment with different concentrations of compound 17i; Figure 1 B. Figure 1 C. Figure 1 D is a bar graph of the quantitative analysis of Western blot data of Hsp100, p-YAP, and p-TAZ proteins, respectively;

[0104] Figure 2 The following is a bar graph showing HE staining (100 μm) of lung tissue of rats in each group after treatment with compound 17i in Example 66 and quantitative analysis, wherein Figure 2 A is the HE staining picture of lung tissue of rats in each group. Figure 2 B is a bar graph of the quantitative analysis of the percentage of median thickness of the pulmonary artery;

[0105] Figure 3 The effect of compound 22k in Example 65 on Hsp110 and its downstream proteins; Figure 3 A is the Western blot detection of the expression of Hsp110 and its downstream proteins after treatment with different concentrations of compound 22k; Figure 3 B. Figure 3 C. Figure 3 D is a bar graph of the quantitative analysis of Western blot data of Hsp100, p-YAP, and p-TAZ proteins, respectively;

[0106] Figure 4 The bar graph is a graph of HE staining (100 μm) and quantitative analysis of lung tissue of rats in each group after treatment with compound 22k in Example 66, wherein Figure 4 A is the HE staining picture of lung tissue of rats in each group. Figure 4 B is a bar graph showing the quantitative analysis of the median thickness percentage of the pulmonary artery. DETAILED DESCRIPTION

[0107] Hereinafter, the composition and effect of the present invention will be described in more detail through preparation examples, embodiments and experimental examples. However, the following preparation examples, embodiments and experimental examples are provided only for the purpose of illustrating the present invention, and therefore the present invention is not limited thereto.

[0108] The term "unsubstituted" as used herein means having no substituents or being substituted only with hydrogen.

[0109] Some of the terms used in this invention are defined as follows:

[0110] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0111] "=O" refers to an oxo group.

[0112] "-CF3" refers to trifluoromethyl.

[0113] "-CO-NH-" is "-amide-".

[0114] "-NH-CO-" is "-aminoacyl-".

[0115] "Carbonyl" means

[0116] "Alkyl," when used as a group or part of a group, refers to a straight-chain or branched aliphatic hydrocarbon group. Preferred alkyl groups are C1-C14 alkyl groups; more preferred are C1-C10 alkyl groups; and most preferred are C1-C6 alkyl groups, unless otherwise indicated. Examples of straight-chain or branched C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, hexyl, and the like.

[0117] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, or spirocyclic carbon ring. Rings consisting of 3-9 carbon atoms are preferred. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0118] "Heteroalkyl" refers to a straight-chain or branched alkyl group containing at least one heteroatom selected from S, O, and N in the main chain. Preferably, the heteroalkyl group contains 2-14 atoms. Heteroalkyl groups include, but are not limited to, ethers, thioethers, alkyl esters, secondary or tertiary alkylamines, and alkylsulfinic acids.

[0119] "Heterocycloalkyl" refers to a group in which one or more (preferably 1, 2, or 3) carbon atoms in the "cycloalkyl" group defined above are replaced by oxygen, nitrogen, phosphorus, boron, selenium, silicon, or sulfur atoms (preferably oxygen, sulfur, or nitrogen). The heterocycloalkyl and alkyl moieties are as defined herein. Preferably, the group contains 1-3 heteroatoms. Preferred rings are 3-14 membered rings (i.e., 3-14 membered heterocycloalkyls), and more preferably, 4-7 membered rings (i.e., 4-7 membered heterocycloalkyls). Heterocycloalkyls include, but are not limited to, pyrrolidinyl, dihydropyrrolyl, tetrahydropyrrolyl, dihydropyrazolyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, oxirane, azirane, or 2-pyrazolinyl, as well as lactams, lactones, cyclic imides, and cyclic anhydrides. Heterocycloalkyls may be substituted with one or more substituents.

[0120] "Acyl" includes (alkyl-CO)- and (aryl-CO)- groups, unless otherwise indicated. Alkyl and aryl are as defined herein. Examples of acyl include, but are not limited to, acetyl, propionyl, isobutyryl, and benzoyl.

[0121] "Amide" includes (alkyl-CONH)- and (aryl-CONH)- groups, unless otherwise specified. Alkyl and aryl are as defined herein. Examples of amide include, but are not limited to, acetamido, propionamido, butyramido, isobutyramido, and benzamido.

[0122] "Alkoxy" refers to a group of (alkyl-O)-. The "alkyl" part thereof is defined in the relevant text. The alkoxy group is preferably a C1-C8 alkoxy group, more preferably a C1-C6 alkoxy group. Examples of the alkoxy group include, but are not limited to: methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, isohexyloxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, etc. In addition, "alkoxycarbonyl" means a group in which the "alkoxy" defined above is bonded to a carbonyl group, for example, methoxycarbonyl, ethoxycarbonyl, etc.

[0123] "Aryl" as a group or part of a group refers to: (1) an aromatic monocyclic or fused ring; preferably an aromatic carbocyclic ring (a cyclic structure in which all the ring atoms are carbon) having 5-12 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl and naphthyl; (2) partially saturated carbocyclic rings, such as phenyl and a C5-7 cycloalkyl or C5-7 cycloalkenyl group fused together to form a cyclic structure. Examples include, but are not limited to, tetrahydronaphthyl, indenyl, or hydroindenyl. Aryl groups may be substituted with one or more substituents.

[0124] "Heteroaryl" refers to a monocyclic or condensed polycyclic aromatic heterocyclic group, preferably an aromatic group having one or more (preferably 3 to 14, more preferably 5 to 10, particularly preferably 5 or 6) carbon atoms, and one or more (preferably 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N) as ring atoms, preferably a 4-15 membered heteroaryl group, more preferably a 5-7 membered heteroaryl group. Examples of the heteroaryl group include furyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, pyridinyl, imidazolyl, 3-phenylpyrrolyl, thiazolyl-oxazolyl, tetrazolyl, isoxazolyl, indazolyl, pyridazinyl, quinolyl, purinyl, carbazolyl, acridinyl, pyrimidinyl, 2,3'-bifuranyl and isoquinolyl.

[0125] Unless otherwise specified, the subunit of the present invention refers to a divalent group, that is, a group in which one hydrogen atom in a monovalent group is replaced by a valency. For example, "heteroalkylene" refers to a heteroalkyl group in which one hydrogen atom is replaced by a valence; "heterocyclylene" refers to a heterocyclyl group in which one hydrogen atom is replaced by a valence; "arylene" refers to an aryl group in which one hydrogen atom is replaced by a valence; "alkylene" refers to an alkyl group in which one hydrogen atom is replaced by a valence; "alkenylene" refers to an alkenyl group in which one hydrogen atom is replaced by a valence; "cycloalkylene" refers to a cycloalkyl group in which one hydrogen atom is replaced by a valence; "heteroarylene" refers to a heteroaryl group in which one hydrogen atom is replaced by a valence; "heterocycloalkylene" refers to a heterocycloalkyl group in which one hydrogen atom is replaced by a valence; "heterocycloalkenylene" refers to a heterocycloalkenyl group in which one hydrogen atom is replaced by a valence; "alkyleneoxy" refers to an alkoxy group in which one hydrogen atom is replaced by a valence; "alkenyleneoxy" refers to an alkenyloxy group in which one hydrogen atom is replaced by a valence; "alkynyleneoxy" refers to an alkynyloxy group in which one hydrogen atom is replaced by a valence, and the like. Wherein, the definitions of the above-mentioned heterocyclic group, aryl, alkyl, alkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, etc. can be found in the relevant definitions herein.

[0126] The present invention includes compounds represented by general formula (I) and their various possible isomeric forms, including diastereoisomers, mirror image isomers, tautomers, and geometric isomers of "E" or "Z" configuration isomers. Any chemist with a certain level of basic knowledge can isolate the above optically pure or stereoisomerically pure compounds.

[0127] The term "pharmaceutically acceptable salt" refers to certain salts of the above-mentioned compounds that can maintain their original biological activity and are suitable for medical use. Pharmaceutically acceptable salts of the compounds represented by general formula (I) are formed in two forms: one is a salt formed with an acid; the other is a salt formed with an alkali or an alkali metal. Acids that form pharmaceutically acceptable salts with the compounds represented by general formula (I) include inorganic acids and organic acids. Suitable inorganic acids include hydrochloric acid, sulfuric acid and phosphoric acid. Suitable organic acids can be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic acids and sulfonic acids; examples include but are not limited to formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, glycine, arginine, citric acid, fumaric acid, alkylsulfonic acid, aromatic sulfonic acid, etc. Alkali metals that form pharmaceutically acceptable salts with the compound represented by general formula (I) include lithium, sodium, potassium, magnesium, calcium, aluminum, zinc, etc.; bases that form pharmaceutically acceptable salts with the compound represented by general formula (I) include choline, diethanolamine, morpholine, etc.

[0128] The compounds of the present invention may be used alone or in combination with one or more other drugs; or in combination with surgery or radiotherapy; or formulated with pharmaceutically acceptable carriers, diluents, or excipients to form a specific dosage form for administration. The specific dosage form depends on the route of administration.

[0129] The parenteral injection drug formulation of the present invention comprises a pharmaceutically acceptable sterile aqueous solution or non-aqueous solution, a dispersant, a suspending agent or an emulsifier, and a powder injection which is prepared into an injectable sterile aqueous solution before use.

[0130] If desired, and for more effective distribution, the compounds of the invention can be incorporated into slow-release or targeted-delivery systems such as polymer matrices, liposomes, and microspheres.

[0131] Solid dosage forms for oral administration include capsules, tablets, troches, powders and granules. In these solid dosage forms, the active compound represented by general formula (I) is mixed with at least one inert and pharmaceutically acceptable excipient or carrier. These excipients or carriers include sodium citrate or dicalcium phosphate and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and salicylic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; d) dissolution delaying agents, such as paraffin; e) absorption accelerators, such as quaternary ammonium compounds; f) wetting agents, such as cetyl alcohol and glyceryl monostearate; g) adsorbents, such as kaolin and bentonite; and h) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols.

[0132] Solid dosage forms of tablets, dragees, capsules, troches, and granules can be prepared with coatings or shells.

[0133] The active compound can also be administered in microencapsulated form. If desired, one or more of the above-mentioned excipients can be present.

[0134] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, etc. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, stabilizers and emulsifiers, such as ethyl alcohol, ethyl carbonate, ethyl acetate, benzoic acid alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuranol, polyethylene glycol and fatty acid esters of sorbitan, etc.

[0135] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0136] The suspension may contain, in addition to the active compound, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters.

[0137] Compositions for rectal or vaginal administration are preferably in the form of suppositories. These can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers.

[0138] Dosage forms for topical administration of the compounds of this invention include powders, patches, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives, buffers or propellants.

[0139] The synthesis method of the compound of the present invention is as follows:

[0140]

[0141] Compounds 5a-g, 6a-g, and 7a-f were prepared according to Scheme 1. In the presence of potassium carbonate, 4-chloro-2-nitrophenol was O-alkylated with ethyl 4-(bromoethyl)benzoate 2a or 4-((4-(bromoethyl)phenyl)sulfonyl)line 2b to afford benzyl phenyl ethers 3a-b, which were then reduced to afford anilines 4a-b. 7a-f were obtained by substitution of 4b with a chlorine derivative or a sulfonyl chloride derivative n. Substitution of 4a with a chlorine derivative or a sulfonyl chloride derivative n afforded 5a-g, followed by alkaline hydrolysis to afford 6a-g.

[0142]

[0143] In DMF, ethyl 3-aminophenylpropionate 8 was anthranilated with isovaleric anhydride derivatives 9a-b to give 10a-b. 10a-b were then N-sulfonated with sulfonyl chloride derivatives and then alkaline hydrolyzed to give 11a-d and 12a-d, respectively.

[0144]

[0145] Key intermediates 15a-h were obtained by reacting commercially substituted 2-aminobenzoic acids 13a-c with chloro derivatives 14a-e. 15a-h and aniline derivatives 16a-f were refluxed in pyridine to afford target compounds 17a-m.

[0146]

[0147] Intermediates 20a-b are obtained by reacting 2-aminobenzoic acid starting materials with sulfonyl chloride starting materials, and then undergo amide condensation with aniline starting materials 21a-i to obtain products 22a-m. 23a-b are obtained by hydrolysis of 22a and 22g.

[0148]

[0149] The starting material 24 is condensed with a fatty amine to give intermediates 25a-f, which are then hydrolyzed to give products 26a-f.

[0150]

[0151] Key intermediates 29a-e were obtained by reacting commercially substituted 2-aminobenzoic acid 27 with chloro derivatives 28a-e. 29a-e and aniline starting material 30 were refluxed in pyridine to afford target compounds 31a-e.

[0152] Example 1

[0153] Ethyl 4-((4-chloro-2-((4-fluorophenyl)sulfonamido)phenoxy)methyl)benzoate (Compound 5a)

[0154] Synthesis of Intermediate 3a: 4-Chloro-2-nitrophenol (2.00 g, 11.523 mmol) and 2a (2.80 g, 11.523 mmol) were stirred in DMF (10 mL). KCO (1.59 g, 11.523 mmol) was added, and the mixture was stirred at room temperature. The mixture was extracted with water and EA, and dried over MgSO. The organic layer was concentrated in vacuo. The resulting residue was recrystallized from EA to afford a pale yellow solid in 98.8% yield. 1 H NMR (400MHz, DMSO-d6) δ8.07(d,J=2.7Hz,1H),8.00(d,J=8.2Hz,2H),7.75(dd,J=9.0,2.7Hz,1H),7.58(d,J =8.1Hz,2H),7.47(d,J=9.0Hz,1H),5.43(s,2H),4.32(q,J=7.1Hz,2H),1.32(t,J=7.0Hz,3H).HRMS(ESI)m / z calcd for[C 16 H 14 ClNO5+Na] + 358.0458; found:358.0448.

[0155] Synthesis of Intermediate 4a: Intermediate 3a (3.863 g, 11.506 mmol) and NH4Cl (1.231 g, 22.995 mmol) were stirred in ethanol (50 mL). Reduced iron powder (1.930 g, 34.56 mmol) was added and stirred at 80°C. After completion of the reaction, the mixture was filtered through celite, and the organic layer was concentrated in vacuo. The resulting residue was recrystallized from ethyl acetate to afford a brown solid in a yield of 86.59%. 1 H NMR (400MHz, DMSO-d6) δ8.02–7.93(m,2H),7.66–7.59(m,2H),6.81(d,J=8.6Hz,1H),6.70(d,J=2.6Hz,1H),6 .47(dd,J=8.5,2.6Hz,1H),5.16(d,J=8.2Hz,4H),4.31(q,J=7.1Hz,2H),1.32(t,J=7.1Hz,3H).HRMS(ESI)m / z calcd for[C 16 H 16 ClNO3+H] + 306.0897; found:306.0899.

[0156] Synthesis of Compound 5a: Intermediate 4a (0.278 g, 0.91 mmol) was dissolved in 20 mL of dichloromethane, pyridine (0.1 ml, 1.24 mmol) was added, and 4-fluorobenzenesulfonyl (0.177 g, 0.91 mmol) was slowly added dropwise. The mixture was stirred at room temperature. The reaction was monitored by thin-layer chromatography. After completion of the reaction, the product was purified by column chromatography (DCM / MeOH) to obtain a white solid in an 87% yield. HPLC purity: 97%. 1 H NMR (400MHz, DMSO-d6) δ9.21(s,1H),8.00(s,1H),7.95(d,J=8.2Hz,2H),7.80(d,J=8.9Hz,2H) ,7.63(d,J=8.1Hz,2H),7.15(d,J=4.1Hz,2H),6.76(d,J=9.0Hz,2H),5.32(s,2H),3.01(s,5H). 13C NMR(126MHz,DMSO-d6)δ165.96,165.69,163.69,150.61,142.21,137.09,137.07,130.08,130.00,129.65,1 29.47,127.51,127.00,126.99,126.17,124.59,116.68,116.49,114.90,69.49,61.19,14.61.HRMS(ESI)m / z calcd for[C 22 H 19 ClFNO5S+H] + 464.0735; found:464.0731.

[0157] Example 2

[0158] 4-((4-chloro-2-((4-fluorophenyl)sulfonamido)phenoxy)methyl)benzoic acid (Compound 6a)

[0159] Compound 6a was synthesized by dissolving 5a (0.368 g, 0.79 mmol) in 30 mL of ethanol and adding 6 mL of 1N sodium hydroxide. The mixture was stirred at room temperature. The reaction was monitored by thin-layer chromatography. The reaction mixture was completely dried by spin-drying, adjusted to pH 1-3 with dilute hydrochloric acid, and extracted with EA to afford a pale yellow solid in 70% yield. Purity: 99%. 1 H NMR (500MHz, DMSO-d6) δ13.00(s,1H),10.01(s,1H),7.90(d,J=7.9Hz,2H),7.71(d,J=3.2Hz,2H ),7.34(d,J=7.9Hz,2H),7.29(s,1H),7.27–7.21(m,2H),7.18(s,1H),6.97(s,1H),4.99(s,2H). 13 C NMR (126MHz, DMSO-d6) δ167.57,165.69,163.70,150.66,141.78,137.11,137.08,130.54,130.07,130.0 0,129.67,127.38,127.02,126.96,126.23,124.55,116.68,116.50,114.84,69.54.HRMS(ESI)m / zcalcd for[C 20 H 15 ClFNO5S+H] + 436.0422; found:436.0423.

[0160] Example 3

[0161] Ethyl 4-((2-((4-acetamidophenyl)sulfonylamino)-4-chlorophenoxy)methyl)benzoate (Compound 5c)

[0162] Compound 5c was prepared from 4a and 4-acetamidobenzenesulfonyl chloride using a method similar to that used to synthesize 5a with a yield of 87% and a purity of 99%. 1 H NMR(500MHz,Chloroform-d)δ8.03(d,J=8.8Hz,2H),7.71(d,J=9.5Hz,2H),7.63(s,1H),7.59(d,J=8.3Hz,2H),7.42(s,1H),7 .20(d,J=7.8Hz,2H),6.98(d,J=13.3Hz,2H),6.67(s,1H),4.98(s,2H),4.42(d,J=7.6Hz,2H),2.25(s,3H),1.46–1.42(m,3H). 13 C NMR (126MHz, DMSO-d6) δ169.40,165.96,150.25,143.62,142.27,134.14,129.62,129.47,128.25,1 27.48,127.45,126.43,125.38,124.53,118.74,114.84,69.53,61.18,24.56,14.63.HRMS(ESI)m / z calcd for[C 24 H 23 ClN2O6S+H] + 503.1044; found:503.1045.

[0163] Example 4

[0164] 4-((2-((4-Acetylaminophenyl)sulfonylamino)-4-chlorophenoxy)methyl)benzoic acid (Compound 6c)

[0165] The yield of compound 6c was 98%, using 5c ​​as the starting material and a method similar to that used to synthesize 6a. Purity: 98%. 1 HNMR(500MHz,DMSO-d6)δ12.96(s,1H),10.30(s,1H),9.76(s,1H),7.87(d,J=7.8Hz,2H),7.62(q, J=8.4Hz,4H),7.28(d,J=7.8Hz,3H),7.14(d,J=8.8Hz,1H),6.91(s,1H),5.02(s,2H),2.07(s,3H). 13C NMR(126MHz,DMSO-d6)δ169.45,167.57,150.22,143.66,141.82,134.13,130.50,129.67,12 8.25,127.45,127.31,126.41,125.31,124.50,118.75,114.75,69.52,24.57.HRMS(ESI)m / z calcd for[C 22 H 19 ClN2O6S+H] + 475.0731; found:475.0733.

[0166] Example 5

[0167] Ethyl 4-((4-chloro-2-(5-chlorothiophene-2-carboxamido)phenoxy)methyl)benzoate (Compound 5d)

[0168] Compound 5d was prepared from 4a and 2-chloro-5-thiophene chloride in 45% yield using a procedure similar to that used to synthesize 5a. Purity: 99%. 1 H NMR(400MHz,Chloroform-d)δ8.53(s,1H),8.31(s,1H),8.13(d,J=8.0Hz,2H),7.51(d,J=8.0Hz,2H),7.25 (s,1H),7.03(s,1H),6.96(s,1H),6.89(s,1H),5.23(s,2H),4.43(d,J=7.1Hz,2H),1.44(t,J=7.1Hz,3H). 13 C NMR (126MHz, DMSO-d6) δ165.92,159.38,150.32,142.62,138.81,134.58,129.85,129.71,129.6 5,128.87,128.05,127.55,126.36,125.63,124.65,115.18,69.94,61.20,14.61.HRMS(ESI)m / z calcd for[C 21 H 17 Cl2NO4S+H] + 450.0334; found:450.0323.

[0169] Example 6

[0170] 4-((4-chloro-2-(5-chlorothiophene-2-carboxamido)phenoxy)methyl)benzoic acid (Compound 6d)

[0171] The yield of compound 6d was 32%, and the synthesis process was similar to that of 6a using 5d as the starting material. The purity was 96%. 1 H NMR(500MHz,DMSO-d6)δ12.99(s,1H),9.92(s,1H),7.92(d,J=7.8Hz,2H),7.89(s,1H), 7.68(s,1H),7.59(d,J=7.9Hz,2H),7.30(s,1H),7.25(s,1H),7.16(s,1H),5.30(s,2H). 13 CNMR(126MHz,DMSO-d6)δ167.52,159.39,150.38,142.22,138.80,134.57,130.62,129.87,129. 85,128.88,128.01,127.44,126.39,125.65,124.59,115.14,69.95,56.49,19.03.HRMS(ESI)m / z calcd for[C 19 H 13 Cl2NO4S+H] + 422.0021; found:422.0020.

[0172] Example 7

[0173] Ethyl 4-((4-chloro-2-((5-chlorothiophene)-2-sulfonamido)phenoxy)methyl)benzoate (Compound 5e)

[0174] Compound 5e was prepared from 4a and 2-chloro-5-thiophenesulfonyl chloride in a similar manner to that used for the synthesis of 5a, with a yield of 83% and a purity of 99%. 1 H NMR(500MHz,Chloroform-d)δ8.08(d,J=8.6Hz,2H),7.64(s,1H),7.32–7.29(m,1H),7.27(s,1H),7.06(d,J= 6.1Hz,2H),6.88(s,1H),6.76(s,1H),5.32(s,1H),5.05(s,2H),4.42(d,J=7.1Hz,2H),1.43(t,J=7.2Hz,3H). 13C NMR(126MHz,DMSO-d6)δ165.97,151.23,142.16,139.47,135.49,132.32,129.71,129.50,1 28.17,127.68,127.59,126.96,126.36,124.62,115.03,69.67,61.20,14.63.HRMS(ESI)m / z calcd for[C 20 H 17 Cl2NO5S2+H] + 486.0003; found:486.0008.

[0175] Example 8

[0176] 4-((4-chloro-2-((5-chlorothiophene)-2-sulfonamido)phenoxy)methyl)benzoic acid (Compound 6e)

[0177] Compound 6e was prepared using a method similar to that used to synthesize 6a, starting from 5e, in a 93% yield with a purity of 99%. 1 H NMR(500MHz,DMSO-d6)δ12.94(s,1H),10.28(s,1H),7.94(d,J=8.0Hz,2H),7 .43(d,J=8.7Hz,2H),7.35–7.23(m,3H),7.06(d,J=9.1Hz,2H),5.06(s,2H). 13 C NMR(101MHz,DMSO-d6)δ167.59,151.29,141.73,139.45,135.52,132.32,130.59,12 9.70,128.16,127.73,127.47,127.05,126.29,124.58,114.97,69.73.HRMS(ESI)m / z calcd for[C 18 H 13 Cl2NO5S2+H] + 457.9690; found:457.9688.

[0178] Example 9

[0179] Ethyl 4-[(4-chloro-2-(4-fluorobenzamido)phenoxy)methyl]benzoate (Compound 5g)

[0180] Compound 5g was prepared in 91% yield from 4a and 4-fluorobenzoyl chloride using a procedure similar to that used for the synthesis of 5a. Purity: 97%. 1H NMR (500MHz, DMSO-d6) δ9.75(s,1H),8.03(d,J=3.0Hz,2H),7.95(d,J=8.0Hz,2H),7.83(s,1H),7.63(d,J=8.0Hz,2H),7. 40(d,J=8.9Hz,2H),7.23(dd,J=8.8,2.7Hz,1H),7.15(s,1H),5.32(s,2H),4.31(d,J=7.1Hz,2H),1.32(t,J=7.1Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ165.94,165.51,164.76,163.86,149.94,142.72,131.14,131.12,130.84,130.78,129.7 2,129.69,128.94,127.58,125.81,124.89,124.63,116.07,115.92,115.00,69.88,61.21,14.62.HRMS(ESI)m / z calcd for[C 23 H 19 ClFNO4+H] + 428.1065; found:428.1064.

[0181] Example 10

[0182] 4-[(4-Chloro-2-(4-fluorobenzamido)phenoxy)methyl]benzoic acid (Compound 6g)

[0183] The yield of compound 6g was 98%, and the synthesis process was similar to that of 6a using 5g of compound as starting material. Purity: 98%. 1 H NMR(500MHz,DMSO-d6)δ12.96(s,1H),9.75(s,1H),8.03(d,J=3.1Hz,2H),7.93(d,J=8.2Hz,2H), 7.84(s,1H),7.61(d,J=8.1Hz,2H),7.40(d,J=8.8Hz,2H),7.22(s,1H),7.16(s,1H),5.31(s,2H). 13C NMR (126MHz, DMSO-d6) δ167.53,165.68,164.77,163.69,149.94,142.28,131.17,131.15,130.83,130.76 ,130.65,129.87,128.95,127.47,125.78,124.81,124.61,116.07,115.90,114.96,69.95.HRMS(ESI)m / z calcd for[C 21 H 15 ClFNO4+H] + 400.0752; found:400.0748.

[0184] Example 11

[0185] N-(5-chloro-2-((4-(morpholinesulfonyl)benzyl)oxy)phenyl)-4-fluorobenzenesulfonamide (Compound 7a)

[0186] Compound 7a was prepared in 67% yield from 4b and 4-fluorobenzenesulfonyl chloride using a procedure similar to that used to synthesize 5a. Purity: 98%. 1 H NMR (500MHz, DMSO-d6) δ10.01(s,1H),7.72(dd,J=8.6,4.7Hz,4H),7.53(d,J=8.3Hz,2H),7.30(s ,1H),7.24(t,J=8.8Hz,3H),7.02(s,1H),5.03(s,2H),3.65(t,J=4.8Hz,4H),2.92–2.84(m,4H). 13 C NMR(101MHz,DMSO-d6)δ165.91,163.42,150.70,142.56,137.18,137.15,134.02,130.10,130.01,128.0 5,128.02,127.18,126.96,126.51,124.73,116.69,116.46,114.92,69.24,65.75,46.37.HRMS(ESI)m / z calcd for[C 23 H 22 ClFN2O6S2+H] + 541.0670; found:541.0672.

[0187] Example 12

[0188] N-(4-(N-(5-chloro-2-((4-(morpholinesulfonyl)benzyl)oxy)phenyl)aminosulfonyl)phenyl)acetamide (Compound 7b)

[0189] Compound 7b was prepared from 4b and 4-acetamidobenzenesulfonyl chloride in a similar manner to that used for the synthesis of 5a, with a yield of 57% and a purity of 98%. 1 H NMR (500MHz, DMSO-d6) δ10.32(s,1H),9.79(s,1H),7.70–7.60(m,6H),7.44(d,J=7.9Hz,2H),7.31(s,1H),7. 16(d,J=8.3Hz,1H),6.94(d,J=8.8Hz,1H),5.77(s,1H),5.08(s,2H),3.65(s,4H),2.85(s,4H),2.07(s,3H). 13 C NMR(101MHz,DMSO-d6)δ169.53,165.10,160.79,150.13,143.63,142.66,136.01,134.20,134.00,128.84,128.30,128.05,128.00 ,127.48,127.38,126.49,125.38,124.69,120.74,118.85,114.81,69.23,65.73,65.70,55.36,46.36,24.57,16.81.HRMS(ESI)m / z calcd for[C 25 H 26 ClN3O7S2+H] + 580.0979; found:580.0983.

[0190] Example 13

[0191] 5-Chloro-N-(5-chloro-2-((4-(morpholinesulfonyl)benzyl)oxy)phenyl)thiophene-2-sulfonamide (Compound 7d)

[0192] Compound 7d was prepared from 4b and 2-chloro-5-thiophenesulfonyl chloride in 45% yield using a procedure similar to that used to synthesize 5a. Purity: 99%. 1H NMR (500MHz, DMSO-d6) δ10.31(s,1H),7.74(d,J=8.2Hz,2H),7.62(d,J=8.1Hz,2H),7.35–7. 25(m,3H),7.09(d,J=13.4Hz,2H),5.10(s,2H),3.65(t,J=4.7Hz,4H),2.89(t,J=4.7Hz,4H). 13 C NMR(101MHz,DMSO-d6)δ151.32,142.53,139.45,135.51,133.99,132.36,128.13,128.1 1,128.08,127.90,127.36,126.25,124.75,115.01,69.42,65.74,46.39.HRMS(ESI)m / z calcd for[C 21 H 20 Cl2N2O6S3+H] + 562.9939; found:562.9942.

[0193] Example 14

[0194] N-(5-chloro-2-((4-(morpholinesulfonyl)benzyl)oxy)phenyl)-4-(5-methyl-2-oxopyridin-1(2H)-yl)benzamide (Compound 7e)

[0195] Compound 7e was prepared from 4b and 4-(5-methyl-2-pyridone-1(2H))benzoyl chloride in a 73% yield using a procedure similar to that used to synthesize 5a. Purity: 98%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.89(s,1H),8.06(d,J=8.5Hz,2H),7.88(d,J=2.6Hz,1H),7.77(q,J=8.4Hz,4H),7.59(d,J=8.5Hz,2H),7.50(s,1H),7.43(dd,J=9.4,2.5 Hz,1H),7.27(d,J=8.8Hz,1H),7.19(d,J=8.9Hz,1H),6.47(d,J=9.3Hz,1H),5.37(s,2H),3.67–3.57(m,4H),2.91–2.79(m,4H),2.07(s,3H). 13C NMR(101MHz,DMSO-d6)δ165.08,160.76,149.89,144.10,143.80,143.08,136.03,134.11,134.07,128.92,128.84, 128.30,127.38,125.89,124.85,124.76,120.75,114.98,114.86,69.68,65.70,55.39,46.37,16.81.HRMS(ESI)m / z calcd for[C 30 H 29 ClN3O6S+H] + 594.1466; found:594.1468.

[0196] Example 15

[0197] N-(5-chloro-2-((4-(morpholinesulfonyl)benzyl)oxy)phenyl)-4-fluorobenzamide (Compound 7f)

[0198] Compound 7f was prepared in 39% yield from 4b and 4-fluorobenzoyl chloride using a procedure similar to that used to synthesize 5a. Purity: 98%. 1 H NMR(500MHz,DMSO-d6)δ9.78(s,1H),8.08–7.97(m,2H),7.83(s,1H),7.76(q,J=8.3Hz,4H),7.39(d,J=8.9Hz,2H ),7.26(dd,J=8.8,2.7Hz,1H),7.17(d,J=8.9Hz,1H),5.36(s,2H),3.62(t,J=4.7Hz,4H),2.84(t,J=4.7Hz,4H). 13 C NMR(101MHz,DMSO-d6)δ165.92,164.79,163.44,149.99,143.10,134.06,131.15,131.12,130.88,130.78,1 28.95,128.28,128.25,125.90,124.99,124.74,116.08,115.87,114.98,69.65,65.70,46.35.HRMS(ESI)m / z calcd for[C 24 H 22 ClFN2O5S+H] + 505.1000;found:505.1001.

[0199] Example 16

[0200] 3-(3-(5-chloro-2-((4-fluorophenyl)sulfonamido)benzamido)phenyl)propanoic acid (Compound 12a)

[0201] Synthesis of Intermediate 10a: Ethyl 3-(3-aminophenyl)propionate 8 (1.210 g, 6.261 mmol) and 5-chloroindanedioic anhydride 9a (1.700 g, 8.604 mmol) were stirred in ethanol (25 mL) at 80°C. The reaction was purified by column chromatography. After completion of the reaction, the product was purified by column chromatography (PE / EA) and the organic layer was concentrated in vacuo to afford a white solid in a yield of 35.56%. 1 HNMR(400MHz, DMSO-d6)δ10.05(s,1H),7.67(d,J=2.4Hz,1H),7.58(t,J=1.9Hz,1H),7.56–7.50(m,1H),7.28–7.17(m,2H),6.96(dt,J=7.6,1.4Hz ,1H),6.78(d,J=8.8Hz,1H),6.47(s,2H),4.05(q,J=7.1Hz,2H),2.84(t,J=7.5Hz,2H),2.61(t,J=7.5Hz,2H),1.16(t,J=7.1Hz,3H).HRMS(ESI) m / z calcd for[C 18 H 19 ClN2O3+H] + 347.1162; found:347.1167.

[0202] Synthesis of Intermediate 11a: Intermediate 10a (0.320 g, 0.923 mmol) and pyridine (0.5 mL, 6.22 mmol) were stirred in dichloromethane (10 mL), and benzenesulfonyl chloride (2.3 g, 13 mmol) was added at room temperature. The reaction mixture was stirred for 3 hours, and the organic layer was concentrated in vacuo. Purification by column chromatography (PE / EA) gave a yield of 66.67%. 1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),10.35(s,1H),7.87–7.71(m,3H),7.59(dd,J =8.8,2.5Hz,1H),7.53(t,J=1.9Hz,1H),7.50–7.45(m,1H),7.43(d,J=8.8Hz,1H),7 .30(td,J=8.3,7.8,5.7Hz,3H),7.04(dt,J=7.6,1.3Hz,1H),4.07(q,J=7.1Hz,2H) ,2.88(t,J=7.5Hz,2H),2.64(t,J=7.5Hz,2H),1.18(t,J=7.1Hz,3H).HRMS(ESI)m / z calcd for[C 24 H 22 ClFN2O5S+H] + 505.1000;found:505.1000.

[0203] Synthesis of Compound 12a: Dissolve 11a (0.399 g, 0.79 mmol) in 30 mL of ethanol, add 6 mL of 1N sodium hydroxide, and stir at room temperature to synthesize Compound 12a. Monitor the reaction by thin-layer chromatography. After complete drying, the reaction mixture is adjusted to pH 1-3 with dilute hydrochloric acid and extracted with EA to obtain a pale yellow solid with a yield of 94% and a purity of 99%. 1 H NMR(500MHz,DMSO-d6)δ12.12(s,1H),10.50(s,1H),10.33(s,1H),7.85–7.75(m,3H),7.59(s,1H),7.50(s, 1H),7.48(s,1H),7.42(s,1H),7.34–7.24(m,3H),7.05(s,1H),2.84(d,J=7.6Hz,2H),2.57(d,J=7.6Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ174.15,166.25,165.32,163.74,141.85,138.59,135.77,135.43,132.30,130.49,130.3 9,129.32,129.25,129.03,127.80,124.85,124.60,121.12,119.11,117.18,116.95,35.60,30.86.HRMS(ESI)m / z calcd for[C 22 H 18 ClFN2O5S+H] +477.0687; found:477.0687.

[0204] Example 17

[0205] 3-(3-(5-chloro-2-((5-chlorothiophene)-2-sulfonamido)benzamido)phenyl)propanoic acid (Compound 12b)

[0206] The yield of compound 12b was 82%, and the purity was 98%. 1 H NMR(500MHz,DMSO-d6)δ12.17(s,1H),10.65(s,1H),10.41(s,1H),7.84(s,1H),7.63(s,1H),7.56 –7.37(m,4H),7.28(s,1H),7.12(s,1H),7.04(s,1H),2.83(d,J=7.6Hz,2H),2.57(d,J=7.6Hz,2H). 13 C NMR(126MHz,DMSO-d6)δ174.12,165.15,141.85,138.70,137.72,136.51,135.00,133.58,132.2 6,130.02,129.35,129.05,128.62,125.46,124.79,121.01,119.00,35.60,30.87.HRMS(ESI)m / z calcd for[C 20 H 16 Cl2N2O5S2+H] + 498.9956; found:498.9958.

[0207] Example 18

[0208] 3-(3-(2-(4-(trifluoromethyl)benzamido)benzamido)phenyl)propanoic acid (Compound 12c)

[0209] Compound 12c was obtained in 17% yield using a method similar to that used to synthesize 12a, starting from 11c. Purity: 99%. 1H NMR (500MHz, DMSO-d6) δ12.17(s,1H),11.77(s,1H),10.51(s,1H),8.40(s,1H),8.11(d,J=8.1Hz,2H),7.95(d,J=8.4Hz,3H) ,7.64(s,1H),7.58(s,1H),7.55(s,1H),7.33(s,1H),7.28(s,1H),7.03(s,1H),2.84(d,J=7.6Hz,2H),2.56(d,J=7.6Hz,2H). 13 C NMR (126MHz, DMSO-d6) δ174.14,167.66,164.01,141.84,138.96,138.59,132.62,129.50,129.04,128.5 1,126.43,126.40,126.37,126.34,124.66,124.25,122.21,121.40,119.44,35.54,30.82.HRMS(ESI)m / z calcd for[C 24 H 19 F3N2O4+Na] + 479.1195; found:479.1197.

[0210] Example 19

[0211] 3-(3-(3-(2-(2-(4-fluorobenzamido)benzamido)phenyl)propanoic acid (Compound 12d)

[0212] The yield of compound 12d was 26%, and the method of synthesizing compound 12a was similar to that of 11d. The purity was 99%. 1 HNMR(500MHz,DMSO-d6)δ12.18(s,1H),11.67(s,1H),10.50(s,1H),8.45(s,1H),8.00(d,J=8.6Hz,2H),7.93(s,1H),7.61(d,J=1 1.9Hz,2H),7.54(s,1H),7.42(d,J=8.8Hz,2H),7.29(d,J=7.7Hz,2H),7.03(s,1H),2.84(d,J=7.6Hz,2H),2.56(d,J=7.6Hz,2H). 13C NMR (126MHz, DMSO-d6) δ174.15,167.80,165.74,164.07,163.76,141.84,138.98,138.92,132.65,131.47,131.45,130.3 1,130.23,129.47,129.06,124.68,123.86,123.61,121.93,121.47,119.50,116.46,116.28,35.54,30.83.HRMS(ESI)m / z calcd for[C 23 H 19 FN2O4+Na] + 429.1227; found:429.1246.

[0213] Example 20

[0214] 3-(3-(3-(5-chloro-2-(4-fluorobenzamido)benzamido)phenyl)propanoic acid (Compound 17b)

[0215] Compound 17b was prepared in 49% yield from 15a and 3-(3-aminophenyl)propionic acid 16b. Intermediate 15a (3.0 g, 10.91 mmol) was dissolved in 30 ml of pyridine, and 3-(3-aminophenyl)propionic acid 16b (1.80 g, 10.91 mmol) was added. The mixture was refluxed at 115°C. The reaction was monitored by thin-layer chromatography. After completion of the reaction, pyridine was removed by spin distillation and the product was purified by column chromatography (DCM / MEOH). A white solid was obtained in 49% yield with a purity of 98%. 1 H NMR (400MHz, DMSO-d6) δ12.17(s,1H),11.55(s,1H),10.57(s,1H),8.39(s,1H),7.97(t,J=7.1Hz,3H),7.69(s,1H),7. 57(s,1H),7.52(s,1H),7.42(d,J=8.8Hz,2H),7.29(s,1H),7.04(s,1H),2.84(d,J=7.5Hz,2H),2.56(d,J=7.6Hz,2H). 13C NMR(101MHz,DMSO-d6)δ174.15,166.33,164.17,163.57,141.88,138.74,137.74,132.22,131.22,131.19,130.4 1,130.32,129.08,127.76,125.55,124.85,123.83,121.44,119.46,116.50,116.28,35.54,30.81.HRMS(ESI)m / z calcd for[C 23 H 18 ClFN2O4+Na] + 463.0837; found:463.0832.

[0216] Example 21

[0217] 2-(3-(5-chloro-2-(4-fluorobenzamido)benzamido)phenyl)acetic acid (Compound 17d)

[0218] Compound 17d was prepared from 15a and 2-(3-aminophenyl)acetic acid 16d in 27% yield using a procedure similar to that used to synthesize 17b. Purity: 99%. 1 H NMR(500MHz,DMSO-d6)δ12.32(s,1H),11.62(s,1H),10.64(s,1H),8.44(s,1H),8.09–7.88( m,3H),7.68(s,1H),7.62(d,J=8.2Hz,2H),7.42(s,2H),7.26(d,J=8.3Hz,2H),3.56(s,2H). 13 C NMR(101MHz,DMSO-d6)δ173.23,166.35,166.05,164.08,163.57,137.87,137.24,132.28,131.63,131.18 ,131.15,130.37,130.27,130.09,129.04,127.68,125.19,123.65,121.64,116.53,116.31.HRMS(ESI)m / z calcd for[C 22 H 16 ClFN2O4+Na] + 449.0680; found:449.0676.

[0219] Example 22

[0220] 3-(4-(4-(5-chloro-2-(4-fluorobenzamido)benzamido)phenyl)propanoic acid (Compound 17e)

[0221] Compound 17e was prepared from 15a and 3-(4-aminophenyl)propionic acid 16e in a 32% yield using a procedure similar to that used to synthesize 17b. Purity: 99%. 1 H NMR (400MHz, DMSO-d6) δ12.11(s,1H),11.62(s,1H),10.57(s,1H),8.43(s,1H),7.97(t,J=7.1Hz,3H),7.70(s ,1H),7.59(d,J=8.5Hz,2H),7.43(d,J=8.8Hz,2H),7.23(d,J=8.5Hz,2H),2.82(d,J=7.6Hz,2H),2.53(s,2H). 13 CNMR(126MHz,DMSO-d6)δ174.21,166.28,165.80,164.08,163.82,137.87,137.55,136.69,132.24,131.20,131.1 8,130.35,130.27,129.02,128.89,127.67,125.19,123.63,121.70,116.50,116.32,35.76,30.33.HRMS(ESI)m / z calcd for[C 23 H 18 ClFN2O4+Na] + 463.0837; found:463.0835.

[0222] Example 23

[0223] 3-(3-(5-chloro-2-(5-chlorothiophene-2-carboxamido)benzamido)phenyl)propanoic acid (Compound 17g)

[0224] Compound 17g was prepared from 15b and 3-(3-aminophenyl)propionic acid 16b in a similar manner to that used for the synthesis of 17a in a 64% yield. Purity: 99%. 1H NMR (400MHz, DMSO-d6) δ12.13(s,1H),11.55(s,1H),10.57(s,1H),8.22(s,1H),7.97(s,1H),7.66(d,J=9. 2Hz,2H),7.58(s,1H),7.52(s,1H),7.28(d,J=4.1Hz,2H),7.04(s,1H),2.83(d,J=7.5Hz,2H),2.55(s,2H). 13 C NMR(101MHz,DMSO-d6)δ174.16,166.07,158.90,141.86,138.84,138.78,137.00,134.86,132.18,12 9.33,129.12,129.08,128.12,125.98,124.80,124.16,121.37,119.39,35.58,30.84.HRMS(ESI)m / z calcd for[C 21 H 16 Cl2N2O4S+Na] + 485.0106; found:485.0101.

[0225] Example 24

[0226] 3-(3-(3-(5-chloro-2-(4-(trifluoromethyl)benzamido)benzamido)phenyl)propanoic acid (Compound 17i)

[0227] Compound 17i was prepared in 32% yield from 15d and 3-(3-aminophenyl)propionic acid 16b in a similar manner to that used for the synthesis of 17b. Purity: 99%. 1 H NMR (500MHz, DMSO-d6) δ12.15(s,1H),11.63(s,1H),10.58(s,1H),8.36(s,1H),8.10(d,J=7.8Hz,2H),7.96(d,J=8.6H z,3H),7.70(s,1H),7.59(s,1H),7.52(s,1H),7.26(s,1H),7.02(s,1H),2.83(d,J=7.2Hz,2H),2.55(d,J=7.4Hz,2H). 13C NMR(101MHz,DMSO-d6)δ174.13,166.18,164.09,141.86,138.78,138.50,137.38,132.18,129.0 6,128.56,128.14,126.37,125.99,124.81,124.07,121.37,119.39,35.53,30.81.HRMS(ESI)m / z calcd for[C 24 H 18 ClF3N2O4+Na] + 513.0805; found:513.0792.

[0228] Example 25

[0229] 3-(3-(2-(2-(4-(4-(tert-butyl)benzamido)-4-chlorobenzamido)phenyl)propanoic acid (Compound 17k)

[0230] Compound 17k was prepared in 30% yield from 15f and 3-(3-aminophenyl)propionic acid 16b using a procedure similar to that used for the synthesis of 17b. Purity: 98%. 1 H NMR (500MHz, DMSO-d6) δ12.16(s,1H),11.94(s,1H),10.56(s,1H),8.68(s,1H),7.98(s,1H),7.85(d,J=8.4Hz,2H),7.59(d, J=8.5Hz,3H),7.51(s,1H),7.35(s,1H),7.30(s,1H),7.05(s,1H),2.85(d,J=7.6Hz,2H),2.55(d,J=7.6Hz,2H),1.30(s,9H). 13 C NMR (126MHz, DMSO-d6) δ174.13,167.13,165.19,155.79,141.89,140.85,138.63,137.24,131.76,131.19,129. 09,127.42,126.29,124.92,123.15,121.69,120.85,120.61,119.72,35.53,35.22,31.30,30.81.HRMS(ESI)m / z calcd for[C 27 H 27 ClN2O4+Na] + 501.1557; found:501.1558.

[0231] Example 26

[0232] 3-(3-(3-(4-(4-chloro-2-(4-(trifluoromethyl)benzamido)benzamido)phenyl)propanoic acid (Compound 171)

[0233] Compound 171 was prepared from 15 g of 17a and 3-(3-aminophenyl)propionic acid 16b in a similar manner to that used for 17b. The yield was 13% and the purity was 96%. 1 H NMR (500MHz, DMSO-d6) δ12.15(s,1H),11.95(s,1H),10.57(s,1H),8.54(s,1H),8.10(d,J=8.1Hz,2H),8.02–7.93(m ,3H),7.56(s,1H),7.52(s,1H),7.42(s,1H),7.28(s,1H),7.04(s,1H),2.84(d,J=7.6Hz,2H),2.55(d,J=7.6Hz,2H). 13 CNMR(126MHz,DMSO-d6)δ174.12,166.85,164.24,141.88,140.08,138.71,138.37,137.02,132.51,131.23,129.0 8,128.57,126.49,126.46,124.86,123.89,123.18,122.19,121.53,121.34,119.58,35.52,30.79.HRMS(ESI)m / z calcd for[C 24 H 18 ClF3N2O4+Na] + 513.0805; found:513.0798.

[0234] Example 27

[0235] 3-(3-(4-methoxy-2-(4-(trifluoromethyl)benzamido)benzamido)phenyl)propanoic acid (Compound 17m)

[0236] Compound 17m was prepared in 35% yield from 15h and 3-(3-aminophenyl)propionic acid 16b using a procedure similar to that used for the synthesis of 17b. Purity: 98%. 1H NMR(500MHz,DMSO-d6)δ12.50(s,1H),12.15(s,1H),10.38(s,1H),8.29(s,1H),8.12(d,J=8.1Hz,2H),8.04–7.93(m,3H),7 .55(s,1H),7.51(s,1H),7.28(s,1H),7.03(s,1H),6.87(s,1H),3.88(s,3H),2.85(d,J=7.6Hz,2H),2.56(d,J=7.6Hz,2H). 13 C NMR(126MHz,DMSO-d6)δ174.15,167.86,163.97,162.77,141.82,141.51,138.81,138.74,131.21,129.02,1 28.39,126.55,126.52,124.68,121.82,119.87,114.15,109.32,106.37,56.01,35.54,30.80.HRMS(ESI)m / z calcd for[C 25 H 21 F3N2O5-H] - 485.1324; found:485.1333.

[0237] Example 28

[0238] Methyl 2-(3-(2-((4-(tert-butyl)phenyl)sulfonamido)-5-chlorobenzamido)phenyl)acetate (22a)

[0239] Using 20a and 21a as starting materials, 20a was dissolved in DMF with stirring. HATU and DIPEA were added and stirred at room temperature for 15 minutes. 21a was then added and stirred at room temperature for 6 hours. Water was added to precipitate a solid which was filtered and dried to produce compound 22a in a 54% yield with a purity of 98%. 1 H NMR (600MHz, DMSO-d6) δ10.54(s,1H),10.37(s,1H),7.85(d,J=2.5Hz,1H),7.70–7.67(m,2H),7.62(t,J=1.9Hz,1H),7.59(dd,J=8.8,2.5Hz,1H) ,7.53(ddd,J=8.1,2.2,1.1Hz,1H),7.51–7.46(m,3H),7.32(t,J=7.8Hz, 1H),7.07(dt,J=7.7,1.2Hz,1H),3.70(s,2H),3.64(s,3H),1.18(s,9H). 13C NMR(151MHz,DMSO-d6)δ171.95,165.56,156.85,138.60,136.37,136.33,135.27,132.47,129.19,129.09,1 28.78,127.13,126.73,126.50,126.01,123.82,122.12,119.96,52.23,40.75,35.28,31.04.HRMS(ESI)m / z calcd for:[C 26 H 27 ClN2O5S+H] + :515.1407,found:515.1411.

[0240] Example 29

[0241] 2-((4-(tert-Butyl)phenyl)sulfonamido)-5-chloro-N-(4-aminosulfonylphenyl)benzamide (22b)

[0242] Using 20a and 21b as starting materials and following the synthesis method of 22a, 22b was obtained with a yield of 42% and a purity of 98%. 1 HNMR(500MHz,DMSO-d6)δ10.63(s,1H),10.38(s,1H),7.85(d,J=2.5Hz,1H),7.83(s,4H),7.72–7.68(m ,2H),7.60(dd,J=8.9,2.4Hz,1H),7.54–7.50(m,2H),7.43(d,J=8.8Hz,1H),7.32(s,2H),1.21(s,9H). 13 C NMR(151MHz,DMSO-d6)δ165.76,156.85,141.64,139.90,136.46,136.05,132.53,129.3 6,128.96,127.31,127.18,126.92,126.71,124.16,120.81,35.31,31.09.HRMS(ESI)m / z calcd for:[C 23 H 24 ClN3O5S2+H] + :522.0924,found:522.0931.

[0243] Example 30

[0244] 2-((4-(tert-Butyl)phenyl)sulfonamido)-5-chloro-N-(4-(N-methylaminosulfonyl)phenyl)benzamide (22c)

[0245] Using 20a and 21c as starting materials and following the synthesis method of 22a, 22c was obtained with a yield of 32% and a purity of 98%. 1 HNMR(500MHz,DMSO-d6)δ10.65(s,1H),10.28(s,1H),7.90–7.85(m,2H),7.83(d,J=2.5Hz,1H),7.81–7.76(m,2H),7.70–7.66(m,2H ),7.60(dd,J=8.8,2.5Hz,1H),7.52–7.48(m,2H),7.43(d,J=8.8Hz,1H),7.39(q,J=5.0Hz,1H),2.43(d,J=5.0Hz,3H),1.18(s,9H). 13 C NMR(126MHz,DMSO-d6)δ165.77,156.80,142.26,136.48,135.93,134.75,132.49,129.31,1 29.11,128.06,127.65,127.16,126.67,124.60,120.93,35.27,31.06,29.10.HRMS(ESI)m / z calcd for:[C 24 H 26 ClN3O5S2+H] + :536.1081,found:536.1085.

[0246] Example 31

[0247] Ethyl 2-(4-(4-(tert-butyl)phenyl)sulfonamido)-5-chlorobenzamido)phenyl)acetate (22 g)

[0248] Compound 20a and 21g were used as starting materials. Following the synthesis method of compound 22a, compound 22g was obtained with a yield of 59% and a purity of 98%. 1 HNMR (600MHz, DMSO-d6) δ10.57(s,1H),10.37(s,1H),7.85(d,J=2.5Hz,1H),7.72–7.65(m,2H),7.59(dq,J=9.1 ,2.5Hz,3H),7.52–7.47(m,3H),7.29–7.24(m,2H),4.09(q,J=7.1Hz,2H),3.65(s,2H),1.19(d,J=3.9Hz,12H). 13C NMR(151MHz,DMSO-d6)δ171.59,165.51,156.86,137.22,136.43,136.37,132.48,131.05,129.95,129.17 ,128.76,127.12,126.74,126.40,123.74,121.41,60.73,40.32,35.29,31.06,14.57.HRMS(ESI)m / zcalcd for:[C 27 H 29 ClN2O5S+H] + :529.1564,found:529.1570.

[0249] Example 32

[0250] 2-((4-(tert-Butyl)phenyl)sulfonamido)-5-chloro-N-(3-aminosulfonylphenyl)benzamide (22h)

[0251] Compound 20a and 21h were used as starting materials. Following the synthesis method of compound 22a, compound 22h was obtained in a 44% yield with a purity of 99%. 1 HNMR (500MHz, DMSO-d6) δ10.60(s,1H),10.43(s,1H),8.29(t,J=1.9Hz,1H),7.86(d,J=2.5Hz,1H),7.77(d,J=8 .0Hz,1H),7.72–7.67(m,2H),7.59(dt,J=20.8,7.6Hz,3H),7.53–7.49(m,2H),7.47–7.42(m,3H),1.18(s,9H). 13 C NMR(126MHz,DMSO-d6)δ165.75,156.91,145.08,138.99,136.38,136.27,132.58,129.75,12 9.24,128.89,127.17,126.72,124.12,124.01,121.92,118.27,35.30,31.07.HRMS(ESI)m / z calcd for:[C 23 H 24 ClN3O5S2+H] + :522.0924,found:522.0929.

[0252] Example 33

[0253] 2-((4-(tert-Butyl)phenyl)sulfonamido)-5-chloro-N-(3-(N-methylaminosulfonyl)phenyl)benzamide (22i)

[0254] Using 20a and 21i as starting materials, and referring to the synthesis method of 22a, 22i was obtained with a yield of 48% and a purity of 98%. 1 HNMR(500MHz,DMSO-d6)δ10.65(s,1H),10.41(s,1H),8.27(t,J=1.9Hz,1H),7.90(q,J=3.1Hz,2H),7.74–7.70(m,2H),7.6 4(dd,J=8.5,2.9Hz,2H),7.60–7.57(m,2H),7.55–7.51(m,2H),7.49(d,J=8.8Hz,1H),2.51(d,J=5.0Hz,3H),1.21(s,9H). 13 C NMR(151MHz,DMSO-d6)δ165.72,140.21,139.36,136.38,136.12,134.57,132.54,131.15,130.05,1 29.26,128.98,127.17,126.69,124.56,124.32,122.67,119.10,60.22,31.04,29.14.HRMS(ESI)m / z calcd for:[C 24 H 26 ClN3O5S2+NH4] + :533.1346,found:533.1356.

[0255] Example 34

[0256] 5-Chloro-2-((5-chlorothiophene)-2-sulfonamido)-N-(3-(N-methylaminosulfonyl)phenyl)benzamide (22j)

[0257] Using 20b and 21i as starting materials, and referring to the synthesis method of 22a, 22J was obtained in a 51% yield with a purity of 98%. 1 HNMR(500MHz,DMSO-d6)δ10.71(s,1H),10.50(s,1H),8.24(t,J=2.0Hz,1H),7.92–7.87(m,1H),7.85(d,J=2.5Hz,1 H),7.67–7.59(m,2H),7.56–7.50(m,2H),7.43(dd,J=6.4,2.3Hz,2H),7.12(d,J=4.1Hz,1H),2.48(d,J=4.9Hz,3H).13 C NMR(151MHz,DMSO-d6)δ165.27,140.23,139.60,137.86,136.45,134.53,133.52,132.27,13 0.31,130.12,130.06,129.43,128.53,126.11,124.22,122.47,118.80,29.17.HRMS(ESI)m / z calcd for:[C 18 H 15 Cl2N3O5S3+H] + :519.9629,found:519.9634.

[0258] Example 35

[0259] 2-((5-Chlorothiophene)-2-sulfonamido)-N-(3-(N-methylaminosulfonyl)phenyl)-5-(trifluoromethyl)benzamide (22k)

[0260] Using 20c and 21i as starting materials, and referring to the synthesis method of 22a, 22k was obtained in a 46% yield with a purity of 98%. 1 HNMR(500MHz,DMSO-d6)δ10.91(d,J=67.7Hz,2H),8.26(s,1H),8.17(s,1H),7.90(d,J=8.3 Hz,2H),7.70–7.60(m,2H),7.60–7.50(m,3H),7.19(d,J=4.2Hz,1H),2.48(d,J=4.9Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ165.47,140.27,139.60,137.79,136.64,133.72,130.15,129.43,128.55 ,127.09,126.55,125.19,124.42,123.39,122.54,122.34,121.99,118.96,29.16.HRMS(ESI)m / z calcd for:[C 19 H 15 ClF3N3O5S3+NH4] + :571.0158,found:571.0175.

[0261] Example 36

[0262] 2-((4-(tert-Butyl)phenyl)sulfonamido)-N-(3-(N-methylaminosulfonyl)phenyl)-5-(trifluoromethyl)benzamide (22m)

[0263] Using 20d and 21i as starting materials, and referring to the synthetic method of 22a, 22m was obtained in a 29% yield. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),10.83(s,1H),8.24(t,J=2.0Hz,1H),8.19–8.12(m,1H),7.90(dd,J=15 .6,8.4Hz,2H),7.85–7.80(m,2H),7.68–7.60(m,2H),7.60–7.53(m,4H),2.47(d,J=5.0Hz,3H),1.22(s,9H). 13 C NMR(101MHz,DMSO-d6)δ166.01,157.14,141.08,140.23,139.35,136.52,130.10,129.73,127.27,127.0 0,126.86,125.60,124.83,123.96,122.90,122.78,120.66,119.34,35.36,31.09,29.14.HRMS(ESI)m / z calcd for:[C 25 H 26 F3N3O5S2+NH4] + :587.1610,found:587.1617.

[0264] Example 37

[0265] 2-((4-(tert-Butyl)phenyl)sulfonamido)-5-chloro-N-(4-(N-pyrimidin-2)sulfamoyl)benzamide (22n)

[0266] Using 20a and 21n as starting materials, and referring to the synthesis method of 22a, 22n was obtained with a yield of 41% and a purity of 98%. 1 HNMR(500MHz,DMSO-d6)δ11.65(s,1H),10.64(s,1H),10.22(s,1H),8.53(d,J=4.9Hz,2H),7.98(d,J =8.4Hz,2H),7.85-7.78(m,3H),7.67-7.55(m,3H),7.43(m,3H),7.07(t,J=4.9Hz,1H),1.12(s,9H). 13C NMR (126MHz, DMSO-d6) δ165.68,158.91,157.39×2,156.72,155.24,151.59,151.30,142.82,135.53,132.43 ,129.34×2,129.17×2,127.92,127.12×2,126.59×2,124.71,120.36,116.31,35.18,31.05×3.HRMS(ESI)m / z calcd for:[C 27 H 26 ClN5O5S2+H] + :600.1064,found:600.1150.

[0267] Example 38

[0268] 2-((4-(tert-Butyl)phenyl)sulfonamido)-5-chloro-N-(4-(N-(5-methoxypyrimidin-2)sulfamoyl)benzamide (22p)

[0269] Using 20a and 21p as starting materials, and following the synthesis method of 22a, 22p was obtained with a yield of 54% and a purity of 99%. 1 HNMR(500MHz,DMSO-d6)δ11.48(s,1H),10.64(s,1H),10.24(s,1H),8.32(s,2H),7.97(d,J =8.8Hz,2H),7.88-7.78(m,3H),7.70-7.57(m,3H),7.44(m,3H),3.80(s,3H),1.12(s,9H). 13 CNMR(126MHz,DMSO-d6)δ165.73,156.74,151.44×2,150.12,145.12,142.65,136.42,135.75,132.46,129.32,1 29.15,128.98×2,127.90,127.16×2,126.66×2,124.72,123.64,120.43×2,56.75,35.21,31.00×3.HRMS(ESI)m / z calcd for:[C 28 H 28 ClN5O6S2+H] + :630.1170,found:630.1257.

[0270] Example 39

[0271] 2-((4-(tert-Butyl)phenyl)sulfonamido)-5-chloro-N-(4-(N-(5-methylisoxazole-3-yl)sulfamoyl)benzamide (22o)

[0272] Using 20a and 21o as starting materials, and following the synthesis method of 22a, 22o was obtained in 51% yield with a purity of 98%. 1 HNMR(500MHz,DMSO-d6)δ11.43(s,1H),10.69(s,1H),10.24(s,1H),7.87(m,4H),7.79(d,J=2.5Hz,1H),7.68(d,J=8.2H z,2H),7.59(dd,J=8.8,2.5Hz,1H),7.48(d,J=8.3Hz,2H),7.41(d,J=8.8Hz,1H),6.17(s,1H),2.31(s,3H),1.15(s,9H). 13 C NMR(126MHz,DMSO-d6)δ170.74,165.77,157.98,156.77,143.16,136.47,135.76,134.54,132.47,129.34,1 29.10,128.30×2,127.91,127.18×2,126.66×2,124.60,120.86,95.83,35.24,31.02×3,12.54.HRMS(ESI)m / z calcd for:[C 27 H 27 ClN4O6S2+H] + :603.1061,found:603.1150.

[0273] Example 40

[0274] 2-(3-(2-((4-(tert-Butyl)phenyl)sulfonamido)-5-chlorobenzamido)phenyl)acetic acid (23a)

[0275] Compound 22a was dissolved in methanol, and NaOH was added. The mixture was stirred at room temperature for 2 h, dried by evaporation, and acidified with hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and dried by evaporation to afford compound 23a in a 95% yield with a purity of 98%. 1H NMR (500MHz, DMSO-d6) δ12.37(s,1H),10.54(s,1H),10.35(s,1H),7.86(d,J=2.5Hz,1H),7.69–7.66(m,2H),7.62(d,J=1.9 Hz,1H),7.59(dd,J=8.8,2.4Hz,1H),7.53–7.47(m,4H),7.31(t,J=7.9Hz,1H),7.08–7.03(m,1H),3.58(s,2H),1.18(s,9H). 13 CNMR(101MHz,DMSO-d6)δ172.99,165.55,156.88,138.46,136.41,136.30,135.94,132.46,129.18,128. 93,128.77,127.12,126.74,126.42,126.07,123.80,122.21,119.78,41.32,35.29,31.05.HRMS(ESI)m / z calcd for:[C 25 H 25 ClN2O5S+H] + :501.1251,found:501.1255.

[0276] Example 41

[0277] 2-(4-(2-((4-(tert-Butyl)phenyl)sulfonamido)-5-chlorobenzamido)phenyl)acetic acid (23b)

[0278] Referring to the synthesis method of 23a, 23b was obtained with 22b as the starting material in 95% yield. Purity: 99%. 1H NMR (500 MHz, DMSO-d6) δ 12.31 (s, 1H), 10.62 (s, 1H), 10.38 (s, 1H), 7.87 (q, J = 1.9 Hz, 1H), 7.71–7.66 (m, 2H), 7.59 (td, J = 8.1, 7.5, 1.9 Hz, 3H), 7.50 (dd, J = 9.8, 8.4 Hz, 3H), 7.27 (d, J = 8.2 Hz, 2H), 3.56 (s, 2H), 1.20 (s, 9H). 13C NMR(101MHz,DMSO-d6)δ173.12,165.52,156.88,137.00,136.51,136.38,132.49,131.70,129.9 8,129.18,128.71,127.11,126.74,126.20,123.61,121.39,40.63,35.30,31.08.HRMS(ESI)m / z calcd for:[C25H25ClN2O5S+H]+:501.1251,found:501.1251.

[0279] Example 42

[0280] 3-(3-(2-((4-(tert-Butyl)phenyl)sulfonamido)-5-chlorobenzamido)phenyl)propanoic acid (23c)

[0281] Referring to the synthesis method of 23a, 23c was obtained with 91% yield and 98% purity from 22c. 1 H NMR (400MHz, DMSO-d6) δ12.19(s,1H),10.55(s,1H),10.32(s,1H),7.85(d,J=2.5Hz,1H),7.71-7.66(m,2H),7.60(dd,J=8.8,2.5H z,1H),7.54-7.47(m,5H),7.28(t,J=7.8Hz,1H),7.04(d,J=7.7Hz,1H),2.84(t,J=7.6Hz,2H),2.56(t,J=7.6Hz,2H),1.18(s,9H). 13C NMR (101MHz, DMSO-d6) δ174.11,165.54,156.86,141.85,138.52,136.44,136.33,132.47,129.18,129.02,128. 77,127.15×2,126.74×2,126.43,124.91,123.81,121.18,119.18,35.62,35.28,31.04×3,30.85.HRMS(ESI)m / z calcd for:[C 26 H 27 ClN2O5S+H] + :515.1329,found:515.1408.

[0282] Example 43

[0283] (3-(3-(2-((4-(tert-Butyl)phenyl)sulfonamido)-5-chlorobenzamido)phenyl)propionyl)glycine (26a)

[0284] Using 24 and methyl 2-aminoacetate as raw materials, 24 was dissolved in DMF, HATU and DIEA were added, and the mixture was stirred at room temperature for 15 minutes. Then, methyl 2-aminoacetate was added. After stirring at room temperature for 6 hours, water was added. A solid precipitated. After filtration, the solid was dried, dissolved in methanol, and NaOH was added. After stirring at room temperature for 2 hours, the mixture was spin-dried and acidified with hydrochloric acid. A solid precipitated, which was filtered and dried to obtain 26a in a 45% yield. Purity: 99%. NMR (600MHz, DMSO-d6) δ12.54(s,1H),10.59(s,1H),10.34(s,1H),8.28(t,J=5.9Hz,1H ),7.87(d,J=2.5Hz,1H),7.73–7.67(m,2H),7.60(dd,J=8.8,2.5Hz,1H),7.55(d,J=1.9 Hz,1H),7.53–7.46(m,4H),7.28(t,J=7.8Hz,1H),7.04(dt,J=7.7,1.3Hz,1H),3.79(d, J=5.8Hz,2H),2.85(dd,J=9.1,6.7Hz,2H),2.48(dd,J=9.1,6.8Hz,2H),1.19(s,9H).13C NMR(151MHz,DMSO-d6)δ172.11,171.87,165.54,156.86,142.25,138.48,136.45,136.34,132.46,129.18,129.00, 128.75,127.14,126.73,126.36,124.88,123.72,121.24,119.11,41.08,37.17,35.27,31.56,31.04.HRMS(ESI)m / z calcdfor:[C28H30ClN3O6S+H]+:572.1622,found:572.1636.

[0285] Example 44

[0286] 3-(3-(3-(2-((4-(tert-butyl)phenyl)sulfonamido)-5-chlorobenzamido)phenyl)propionamido)propanoic acid (26b)

[0287] Referring to the synthesis of 26a, 26b was obtained with 24 and methyl 3-aminopropionate as starting materials in a 33% yield. Purity: 98%. 1H NMR (600 MHz, DMSO-d6) δ 12.17 (s, 1H), 10.59 (s, 1H), 10.34 (s, 1H), 8.00 (t, J = 5.6 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.73–7.67 (m, 2H), 7.59 (dd, J = 8.8, 2.5 Hz, 1H), 7.55 (t, J = 1.8 Hz, 1H ),7.52–7.45(m,4H),7.27(t,J=7.8Hz,1H),7.01(dt,J=7.7,1.2Hz,1H),3.27(td,J=6.9, 5.5Hz,2H),2.82(dd,J=8.9,6.8Hz,2H),2.39(td,J=7.6,7.0,2.7Hz,4H),1.19(s,9H).13C NMR(151MHz,DMSO-d6)δ173.38,171.73,165.54,156.86,142.31,138.47,136.45,136.33,132.46,129.19,128.96,128 .75,127.14,126.73,126.33,124.85,123.69,121.23,119.07,37.40,35.27,35.24,34.39,31.69,31.04.HRMS(ESI)m / z calcdfor:[C29H32ClN3O6S+H]+:586.1779,found:586.1790.

[0288] Example 45

[0289] 5-(3-(3-(2-((4-(tert-butyl)phenyl)sulfonamido)-5-chlorobenzamido)phenyl)propionamido)pentanoic acid (26d)

[0290] Referring to the synthesis of 26a, 26d was obtained with 24 and methyl 5-aminopentanoate as starting materials in a 29% yield. Purity: 98%. 1H NMR (600 MHz, DMSO-d6) δ 11.85 (s, 1H), 10.60 (s, 1H), 10.34 (s, 1H), 7.88 (t, J = 5.6 Hz, 1H), 7.87 (d, J = 2.5 Hz, 1H), 7.71–7.68 (m, 2H), 7.59 (dd, J = 8.8, 2.4 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.51–7.48 (m, 3H), 7.47 (dt, J = 8.4, 1.4 Hz, 1H). z,1H),7.27(t,J=7.8Hz,1H),7.01(dt,J=7.7,1.3Hz,1H),3.06(q,J=6.7Hz,2H),2.83(dd,J=8.8,6.9Hz,2H),2. 39(dd,J=8.8,6.9Hz,2H),2.21(t,J=7.3Hz,2H),1.52–1.44(m,2H),1.40(dtd,J=10.8,8.4,7.6,5.9Hz,2H).13C NMR(151MHz,DMSO-d6)δ174.84,171.43,165.54,156.86,142.36,138.46,136.47,136.34,132.47,129.19,128.94,128.73,12 7.13,126.73,126.28,124.85,123.66,121.26,119.07,38.58,37.52,35.28,33.77,31.77,31.04,29.11,22.41.HRMS(ESI)m / z calcd for:[C31H36ClN3O6S+H]+:614.2092,found:614.2105.

[0291] Example 46

[0292] 5-Chloro-N-(3-aminosulfonylphenyl)-2-(4-(trifluoromethyl)benzamido)benzamide (31a)

[0293] Starting from 29a and 30, 29a and 30 were dissolved in pyridine and refluxed in an oil bath at 115°C for 12 h. The reaction solution was spin-dried and purified by column chromatography using PE:EA as the developing solvent to obtain 31a in a 23% yield with a purity of 99%. 1H NMR (600MHz, DMSO-d6) δ11.41(s,1H),10.86(s,1H),8.30–8.22(m,2H),8.10(d,J=8.1Hz,2H),7.97(d,J=2.5Hz,1H ),7.94(d,J=8.2Hz,2H),7.90(dt,J=8.0,1.6Hz,1H),7.71(dd,J=8.8,2.5Hz,1H),7.62–7.54(m,2H),7.43(s,2H). 13 C NMR(151MHz,DMSO-d6)δ166.30,164.31,145.04,139.38,138.54,136.97,132.56,132.35,132.21,132.14,131.92,129.86,129.17,128 .67,128.41,126.99,126.93,126.35,126.32,126.30,126.27,125.18,124.73,124.18,123.37,121.76,121.57,118.24.HRMS(ESI)m / z calcd for:[C 21 H 14 ClF3N3O4S+Na] + :520.0322,found:520.0319.

[0294] Example 47

[0295] 2-(4-(tert-Butyl)benzamido)-5-chloro-N-(3-aminosulfonylphenyl)benzamide (31b)

[0296] Referring to the synthesis method of 31a, 29b and 30 were used as starting materials to obtain 31b in 41% yield. Purity: 99%. 1HNMR (400MHz, DMSO-d6) δ 11.41 (s, 1H), 10.86 (s, 1H), 8.43 (d, J = 8.9 Hz, 1H), 8.24 (t, J = 1.9 Hz, 1H), 8.00 (d, J = 2.5 Hz, 1H), 7.92 (dt, J = 7.7, 1.8 Hz, 1H), 7.87–7.82 (m, 2H), 7.69 (dd, J = 8.9, 2.5 Hz, 1H), 7.64–7.56 (m, 4H), 7.43 (s ,2H),1.31(s,9H).13CNMR(101MHz,DMSO-d6)δ166.66,165.17,155.61,145.06,139.23,137.96,132.43,131.95 ,129.89,129.13,127.54,127.49,126.18,125.10,124.40,123.78,121.89,118.45,35.22,31.33.HRMS(ESI)m / z calcd for:[C24H24ClN3O4S+Na]+:508.1074,found:508.1073.

[0297] Example 48

[0298] 5-Chloro-2-(4-cyanobenzamido)-N-(3-aminosulfonylphenyl)benzamide (31c)

[0299] Referring to the synthesis method of 31a, 31c was obtained with 29c and 30 as starting materials in a 42% yield and a purity of 98%. 1 HNMR (400MHz, DMSO-d6) δ11.38(s,1H),10.85(s,1H),8.26–8.19(m,2H),8.04(s,4H),7.96(d,J=2. 5Hz, 1H), 7.89 (dt, J=7.7, 1.8Hz, 1H), 7.70 (dd, J=8.8, 2.5Hz, 1H), 7.63–7.53 (m, 2H), 7.43 (s, 2H). 13C NMR(101MHz,DMSO-d6)δ166.23,164.10,145.04,139.37,138.71,136.82,133.32,132.18,129.86 ,129.18,128.57,128.53,127.12,124.83,124.18,121.76,118.64,118.23,114.78.HRMS(ESI)m / z calcd for:[C 21 H 15 ClN4O4S+Na] + :477.0440,found:477.0395.

[0300] Example 49

[0301] N-(4-Chloro-2-((3-aminosulfonylphenyl)carbamoyl)phenyl)-3,4,5-trimethoxybenzamide (31d)

[0302] Referring to the synthesis method of 31a, 29d and 30 were used as starting materials to obtain 31d in a 35% yield with a purity of 98%. 1 HNMR (400MHz, DMSO-d6) δ11.39(s,1H),10.85(s,1H),8.41(t,J=1.9Hz,1H),8.31(d,J=8.9Hz,1H),7.99(d,J=2.5Hz,1H),7.88(dt,J=7. 7,1.8Hz,1H),7.70(dd,J=8.8,2.5Hz,1H),7.62–7.58(m,1H),7.55(d,J=7.7Hz,1H),7.39(s,2H),7.23(s,2H),3.84(s,6H),3.73(s,3H). 13 C NMR(101MHz,DMSO-d6)δ166.45,164.82,153.31,145.05,141.07,139.43,137.57,132.32,129.98,12 9.78,129.05,127.84,126.07,124.06,123.95,121.74,118.07,105.20,60.61,56.48.HRMS(ESI)m / z calcd for:[C 23 H 22 ClN3O7S+H] + :520.0945,found:520.0945.

[0303] Example 50

[0304] The synthesized compounds were subjected to Hsp110 activity test and anti-PASMCs proliferation test

[0305] 1. Hsp110 activity test of the synthesized compounds

[0306] 1. Experimental Materials

[0307] Hsp110 enzyme (extracted from Escherichia coli), ATP-FAM (Jena Bioscience, Jena, Germany), Hsp110 buffer (25 mM Hepes, 150 mM KCl, 10 mM Mg(OAc)2, 10% glycerol and 1 mM DTT), Hepes (Sigma), KCl (Sigma), DTT (Sigma), Mg(OAc)2 (Sigma), glycerol (Sigma), Cytation5 (Bio-tek).

[0308] 2. Experimental Methods

[0309] (1) Compound solution (or DMSO) was incubated with Hsp110 protein in a buffer containing 25 mM Hepes, 150 mM KCl, 10 mM Mg(OAc)2, 10% glycerol, and 1 mM DTT at room temperature for 1 h. The compound concentration was 100 μM.

[0310] (2) Add ATP-FAM and incubate at room temperature for 1 h;

[0311] (3) Record the fluorescence shift value.

[0312] The experimental results are shown in Table 1. The results show that all target compounds can effectively inhibit the binding of ATP and Hsp110, reducing the fluorescence polarization value to below 80, thereby inhibiting the activity of Hsp110. Among them, compounds 17i and 22k have the most prominent effects, reducing the fluorescence polarization value to below 40.

[0313] 2. PASMCs anti-proliferation experiment of the synthesized compounds

[0314] 1. Experimental Materials

[0315] (1) Cell line: PASMCs

[0316] (2) Reagents and instruments: 96-well plates (Corning); DMEM medium (BI); biological safety cabinet, carbon dioxide incubator (ESCO); Counting Kit-8 (CCK-8) cell viability detection kit (Nanjing Enjing Biotechnology Co., Ltd.); Cytation 5 multifunctional imager (Bio-Tek).

[0317] 2. Experimental Methods

[0318] (1) According to the CCK-8 staining method, cells with a live cell ratio of more than 90% were used for the experiment, and the cell proliferation inhibition test was performed using the CCK-8 cell viability detection kit.

[0319] (2) Cells were digested, counted, and prepared into a concentration of 1×10 5 100 μL of cell suspension (1×10 cells / mL) was added to each well of a 96-well plate. 4 cells).

[0320] (3) The 96-well plate was placed in a 37°C, 5% CO2 incubator for 24 hours; 100 μL of the corresponding drug-containing culture medium was added to each well. A negative control group, a solvent control group, and a positive control group were set up at the same time, with 5 replicates in each group.

[0321] (4) After the 96-well plate was placed in a 37°C, 5% CO2 incubator for 48 hours, 10 μL of CCK-8 solution was added to each well, and the plate was incubated in the incubator for 4 hours. The culture medium in the wells was carefully aspirated.

[0322] (5) Measure the OD value at 450 nm using an enzyme-labeled instrument and calculate the inhibitory rate and IC of the compound on human pulmonary artery smooth muscle cells. 50 value.

[0323] (6) Dosage setting: Dose group 1: 100 μM; Dose group 2: 50 μM; Dose group 3: 25 μM; Dose group 4: 12.5 μM; Dose group 5: 6.25 μM; Dose group 6: 3.125 μM; Dose group 7: 1.5625 μM; Dose group 8: 0.78125 μM; Dose group 9: 0.390625 μM; Dose group 10: 0.1953125 μM.

[0324] (7) Data processing: Data were expressed as mean and SD, and GraphPad Prism 5.0 statistical software was used. The t-test was used for comparison between two groups. The IC of the compound was calculated by fitting the curve with the concentration as the horizontal axis and the inhibition rate as the vertical axis. 50 The absorbance OD value of each well was measured at 450 nm on a microplate reader, and the cell growth inhibition rate was calculated as follows:

[0325] Inhibition rate (%) = [(average OD value of control wells - average OD value of experimental wells) / average OD value of control wells] * 100%

[0326] Table 1 Results of the fluorescence polarization values ​​and anti-HPASMC abnormal proliferation activity of the compounds

[0327]

[0328] The structure of GFS008 is: The structure of HMR-1766 is:

[0329] The structure of 22e is: The structure of KNK437 is:

[0330] The compound GF053 with different structures in the prior art WO 2019 / 057969 A1 was selected for anti-HPASMC cell abnormal proliferation activity detection, and it was found that the anti-proliferation activity of compound GF053 on HPASMC cells was poor.

[0331] Example 51

[0332] Effects of compounds on Hsp110 downstream proteins

[0333] 1. Experimental Materials

[0334] (1) Sample: human pulmonary artery smooth muscle cells (HPASMC) or rat lung tissue

[0335] (2) Antibodies: Hsp100, p-YAP, p-TAZ, t-YAP, t-TAZ, STAT3, p-STAT3, C-Myc, and β-actin were purchased from CST.

[0336] (3) Drugs and reagents: Ultrasensitive ECL chemiluminescence reagent was purchased from Abbkine; goat anti-rabbit secondary antibody, developer, fixer, RIPA lysis buffer, BSA, BCA protein concentration detection kit, pre-stained protein marker were all purchased from Nanjing Enjing Biotechnology Co., Ltd.

[0337] (4) Instruments and consumables: Micro vertical electrophoresis tank (Bio-RAD); Transfer electrophoresis tank (Bio-RAD); Electrophoresis apparatus (Junyi Co., Ltd.); Decolorization shaker (Huali Da Co., Ltd.).

[0338] 2. Experimental Methods

[0339] (1) Protein sample preparation

[0340] After treatment, discard the culture medium and wash three times with PBS. Add 100 μL of RIPA lysis buffer and lyse for 30 minutes. Transfer the cells to a 0.5 mL centrifuge tube and measure the protein concentration in the supernatant using a protein quantification kit. Store the supernatant at -20°C. Denature the sample protein before loading on electrophoresis.

[0341] (2) SDS-PAGE electrophoresis

[0342] Slowly pour the separation gel along the glass, then add a layer of anhydrous ethanol to seal the gel. Once the gel has solidified, remove the water from the top of the gel and blot dry with absorbent paper. Add the stacking gel and insert the comb. Once the stacking gel has solidified, gently pull the comb upright and remove it. Load the sample, adding sufficient electrophoresis buffer. Run the gel at 70V for 20 minutes. Once the proteins have aggregated to the boundaries of the separation gel, increase the voltage to 130V. Terminate the electrophoresis just as bromophenol blue begins to run, and transfer to the membrane.

[0343] (3) Transfer

[0344] Place the soaked PVDF membrane over the desired target band, carefully removing any bubbles and preventing further movement. Cover with a sponge pad and close the transfer plate. Place the transfer plate with the PVDF membrane on the positive electrode and the gel on the negative electrode. Add transfer buffer to the transfer tank and transfer at 80V for 45 minutes. After transfer, remove the PVDF membrane, soak it in TBS, and place it in blocking buffer. Block overnight at 4°C. After blocking, incubate with the primary and secondary antibodies, and perform chemiluminescent development.

[0345] 3. Experimental Results

[0346] The results of compound 17i are as follows Figure 1 As shown. Figure 1 A is the Western blot analysis of the expression of Hsp110 and its downstream proteins after treatment with different concentrations of compound 17i; Figure 1 B. Figure 1 C. Figure 1 D is a bar graph showing quantitative Western blot analysis of Hsp100, p-YAP, and p-TAZ proteins. #### indicates p < 0.0001 compared to the negative control group (0 / -), ### indicates p < 0.001 compared to the negative control group (0 / -), and *** indicates p < 0.001 compared to the positive control group (0 / +). As shown in the figure, the target compound can effectively regulate the levels of Hsp110 downstream proteins. Compared with KNK437, the compound has a more potent Hsp110 inhibitory effect.

[0347] The results of compound 22k are as follows Figure 3 As shown. Figure 3 A is the Western blot detection of the expression of Hsp110 and its downstream proteins after treatment with different concentrations of compound 22k; Figure 3 B. Figure 3 C. Figure 3D is a bar graph showing quantitative Western blot analysis of Hsp100, p-YAP, and p-TAZ proteins. *** indicates p < 0.001 compared to the negative control (0 / -), and ### indicates p < 0.001 compared to the positive control (0 / +). As shown in the figure, the target compound can effectively regulate the levels of Hsp110 downstream proteins. Compared to riociguat, the compound has a more potent Hsp110 inhibitory effect.

[0348] The structure of Riociguat is:

[0349] Example 52

[0350] Effects of compounds on hypoxia-induced pulmonary hypertension model in rats

[0351] The hypoxia-induced pulmonary hypertension model is a classic model of pulmonary hypertension that simulates the symptoms of pulmonary hypertension and hypoxia. The purpose of this study was to observe the therapeutic efficacy of the target compound of the present invention in a 28-day hypoxia-induced pulmonary hypertension model to clarify its therapeutic effect on pulmonary hypertension.

[0352] 1. Experimental Materials

[0353] 1.1 Drug: Target compound 17i; Properties: White solid. Provided by: School of Pharmacy, Central South University. Dissolve the target compound in double-distilled water (adjust pH to approximately 4.5).

[0354] Target compound 22k; Properties: White solid. Provided by: School of Pharmacy, Central South University. Dissolve the target compound in double-distilled water (adjust pH to approximately 7.4).

[0355] 1.2 Experimental animals: Male SD rats, weighing 150 g, were purchased from Hunan Slake Jingda Experimental Animal Co., Ltd., with the experimental animal production license number: SCXK (Xiang) 2015-0017.

[0356] 2. Experimental Methods

[0357] 2.1 Experimental design

[0358] SD rats were divided into a control group, a hypoxia group (the oxygen concentration was controlled at 10% during feeding), a hypoxia + cinaciguat (10 mg / kg) group, a hypoxia + target compound (10 mg / kg), a hypoxia + target compound (30 mg / kg) group, and the positive drug (cinaciguat) and target compound groups were given the target compound by gavage, starting from the 14th day, once a day for 14 consecutive days, and the mice were killed on the 28th day.

[0359] 2.2 Detection indicators

[0360] 2.2.1 Sample preparation and test sample analysis: Weigh a sufficient amount of compound according to the weight of the mouse, adjust the pH and use double-distilled water as the solvent to prepare a drug solution of corresponding concentration.

[0361] 2.2.2 Effects on lung tissue pathology: 14 days after administration, all mice were anesthetized, and lung tissues were fixed in formalin, dehydrated, embedded in paraffin, and sliced. HE staining was performed on the HE-stained tissue sections for pathological scoring.

[0362] 2.3 Statistical methods

[0363] SPSS 20.0 was used for statistical analysis. If the variances were homogeneous, one-way ANOVA was used for statistical analysis. If the variances were unequal, the Kruskal-Wallis test was used. If the Kruskal-Wallis test was statistically significant (P < 0.05), Dunnett's test (nonparametric method) was used for comparative analysis. P < 0.05 was considered statistically significant, and P < 0.01 indicated a highly significant difference.

[0364] 3. Experimental Results

[0365] Effects of compound 17i on H&E staining pathological scores of lung tissue Figure 2 As shown, Figure 2 A is the HE staining picture of lung tissue of rats in each group. Figure 2 A is a bar graph quantitatively analyzing the percentage of median pulmonary artery thickness. Compared with the control group, the pulmonary artery thickened significantly after 28 days in the hypoxia group, indicating successful model establishment. Compared with the hypoxia group, compound 17i significantly reduced pulmonary artery ring thickness, and this reduction was even more pronounced than with the active drug riociguat, indicating that the compound significantly improved vascular remodeling compared to riociguat.

[0366] Effects of compound 22k on H&E staining pathological scores of lung tissue Figure 4 As shown, Figure 4 A is the HE staining picture of lung tissue of rats in each group. Figure 4 B is a bar graph quantitatively analyzing the percentage of median pulmonary artery thickness. Compared to the control group, the pulmonary artery thickened significantly after 28 days in the hypoxia group, demonstrating successful model establishment. Compared to the hypoxia group, compound 22k significantly reduced pulmonary artery ring thickness, and this reduction was even more pronounced than in the positive drug, riociguat, indicating that the compound significantly improved vascular remodeling compared to riociguat.

[0367] 4. Conclusion:

[0368] The aromatic amine derivatives of the present invention can significantly improve pulmonary hypertension.

Claims

1. An aromatic amine derivative, characterized in that: The compound or salt thereof has the general structural formula shown in Formula I: Wherein, X is selected from Y is selected from R1 is selected from trifluoromethyl, -aryl-R6, -(5-10 membered heteroaryl)-R6; R6 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, trihalomethyl, cyano, -NHCO-(C1-C8 alkyl), the position is one or more of ortho, meta, and para, and the number of substituents is 1-5; R2 and R3 are independently selected from hydrogen, halogen, trihalomethyl, -O-R7; R7 is selected from hydrogen, C1-C8 alkyl; R4 and R5 are independently selected from -(CH2) n COOR8, -(CH2) n CONHR8, -SO2NHR8, -SO2NR9R8, -NHSO2R8, -(CH2) n CONH(CH2) m COOR8, hydrogen, C1-C8 alkyl; n and m are independently selected from integers of 0-8; R8 and R9 are independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C3-C8 aliphatic heterocyclic group; the substituents on the substituted C1-C8 alkyl, substituted aryl, and substituted 5-10 membered heteroaryl are independently selected from halogen, hydroxyl, amino, thiol, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-substituted C1-C6 alkyl, and halo-substituted C1-C6 alkoxy; the position where the aryl or 5-10 membered heteroaryl is substituted may be ortho, meta, or para; the number of substituents may be 0-5.

2. The aromatic amine derivative according to claim 1, characterized in that The aryl group is benzene; the 5-10 membered heteroaryl group is selected from the group consisting of furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, purinyl, carbazolyl, acridinyl, piperonyl, oxazole, and isoxazole; the C3-C8 aliphatic heterocyclic group is selected from the group consisting of oxirane, aziridine, thiirane, oxetane, azetidine, thietane, tetrahydrofuran, tetrahydropyrrole, tetrahydrothiophene, tetrahydropyran, piperidine, dioxane, piperazine, hexahydropyrazine, tetrahydrothiopyran, morpholine, and thiophene.

3. The aromatic amine derivative according to claim 1, characterized in that -Y-R1 is selected from: R4 and R5 are independently selected from:

4. An aromatic amine derivative, the compound or salt of which has the general structural formula shown in Formula I: in, X is selected from Y is selected from R1 is selected from trifluoromethyl, -aryl-R6, -(5-10 membered heteroaryl)-R6; R6 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, trihalomethyl, cyano, -NHCO-(C1-C8 alkyl), the position is one or more of ortho, meta, and para, and the number of substituents is 1-5; R2 and R3 are independently selected from hydrogen, halogen, trihalomethyl, -O-R7; R7 is selected from hydrogen, C1-C8 alkyl; R4 and R5 are independently selected from -(CH2) n COOR8, -(CH2) n CONHR8, -SO2NHR8, -SO2NR9R8, -NHSO2R8, -(CH2) n CONH(CH2) m COOR8, hydrogen, C1-C8 alkyl; n and m are independently selected from integers of 0-8; R8 and R9 are independently selected from hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C3-C8 aliphatic heterocyclic group; the substituents on the substituted C1-C8 alkyl, substituted aryl, and substituted 5-10 membered heteroaryl are independently selected from halogen, hydroxyl, amino, thiol, cyano, C1-C6 alkyl, C1-C6 alkoxy, halo-substituted C1-C6 alkyl, and halo-substituted C1-C6 alkoxy; the position where the aryl or 5-10 membered heteroaryl is substituted may be ortho, meta, or para; the number of substituents may be 0-5.

5. The aromatic amine derivative according to claim 4, characterized in that R6 is selected from -CF3, -C(CH3)3, -OCH3, -OCF3, -NHCOCH3, 6. The aromatic amine derivative according to any one of claims 1 to 5, characterized in that: The aromatic amine derivatives include the following structures:

7. The method for preparing an aromatic amine derivative according to any one of claims 1 to 6, characterized in that: When X is methyleneoxy, the process comprises the following steps: reacting a benzyl bromide raw material with an o-nitrophenol raw material, reducing the obtained nitro product to obtain an amino intermediate, and reacting the amino intermediate with an acyl chloride or sulfonyl chloride compound to obtain the aromatic amine derivative; The structure of brombenzyl raw materials is: The structure of the nitro product is: The structure of the amino intermediate is: The structure of aromatic amine derivatives is:

8. The method for preparing an aromatic amine derivative according to any one of claims 1 to 6, characterized in that: When X is an amide, the preparation method of the aromatic amine derivative comprises the following steps: The amino intermediate obtained by the ring-opening reaction of the amine compound and the isatoic anhydride raw material reacts with the acyl chloride or sulfonyl chloride compound to obtain the aromatic amine derivative; The structure of amine compounds is: The structure of isatoic anhydride raw materials is: The structure of the amino intermediate is: The structure of aromatic amine derivatives is: Preferably, when X is an amide, the preparation method of the aromatic amine derivative comprises the following steps: The ring-closed intermediate obtained by the reaction of anthranilic acid raw materials and acyl chloride raw materials is reacted with aniline raw materials to obtain the aromatic amine derivative; The structure of anthranilic acid raw materials is: The structure of the ring-closure intermediate is: The structure of aniline raw materials is: The structure of aromatic amine derivatives is: Preferably, when X is an amide, the preparation method of the aromatic amine derivative comprises the following steps: The benzoic acid intermediate obtained by the reaction of anthranilic acid raw materials and sulfonyl chloride raw materials reacts with aniline raw materials to obtain aromatic amine derivatives; The structure of anthranilic acid raw materials is: The structure of sulfonyl chloride raw materials is: The structure of benzoic acid intermediates is: The structure of aniline raw materials is: The structure of aromatic amine derivatives is:

9. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the aromatic amine derivative according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and excipient.

10. Use of the aromatic amine derivative according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in the preparation of an Hsp110 inhibitor, a drug for treating pulmonary hypertension, or a drug for pulmonary vascular remodeling.

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