CN118084884A

CN118084884A - NLRP3 inflammation small inhibitor containing biphenyl or phenyl substituted aromatic heterocyclic nucleus, and preparation method and application thereof

Info

Publication number: CN118084884A
Application number: CN202410088664.1A
Authority: CN
Inventors: 江余祺; 李晓杨; 黄超; 孙思敏; 徐文方; 陈媛媛
Original assignee: Qingdao Haiji Biomedical Co ltd; Ocean University of China; Qingdao Marine Biomedical Research Institute Co Ltd
Current assignee: Qingdao Haiji Biomedical Co ltd; Ocean University of China; Qingdao Marine Biomedical Research Institute Co Ltd
Priority date: 2024-01-22
Filing date: 2024-01-22
Publication date: 2024-05-28

Abstract

The invention discloses a compound shown in a general formula (I), or an optical isomer, a diastereoisomer, a racemate or pharmaceutically acceptable salt and deuterated substances thereof, and a preparation method and application thereof. The compound shown in the general formula (I) provided by the invention has obvious activity of inhibiting NLRP3 inflammation corpuscles, and partial compounds are in hundreds of nanomoles and are superior to the reported compounds of the same type, namely glibenclamide and JC124. In addition, in vivo anti-inflammatory experiments, representative compounds A20 and A28 can remarkably inhibit the release of IL-1 beta in LPS-induced acute peritonitis of mice without affecting the release of another inflammatory factor TNF-alpha, and the compounds can specifically inhibit NLRP3 inflammatory corpuscles and have certain selectivity.

Description

NLRP3 inflammation small inhibitor containing biphenyl or phenyl substituted aromatic heterocyclic nucleus, and preparation method and application thereof

Technical Field

The invention relates to the technical field of chemical synthesis medicines, in particular to an NLRP3 inflammation small inhibitor containing biphenyl or phenyl substituted aromatic heterocyclic parent nucleus, a preparation method and application thereof.

Background

NLRP3 inflammatory corpuscles are a cytoplasmic polyprotein complex, an important component of the innate immune system. Aberrant activation of NLRP3 inflammatory bodies is closely related to the development and progression of a variety of diseases (Int J Mol Sci,2020,21,5758) such as: cold-related periodic syndrome (also known as NLRP 3-related auto-inflammatory disease), alzheimer's disease, parkinson's disease, gout, rheumatoid arthritis, inflammatory bowel disease, atypical pneumonia, atherosclerosis, nonalcoholic steatohepatitis, multiple sclerosis and chronic obstructive pulmonary disease, traumatic brain injury, heart failure, coronary artery disease, osteoarthritis, and the like (Nat Rev immunol.2017,17, 208-214). The development of inhibitors of NLRP3 inflammatory corpuscles is considered a potential strategy for the treatment of the above-mentioned diseases, and is of great interest and favor in the academia and pharmaceutical industry (J Med chem.2021,64, 101-122). NLRP3 inflammatory corpuscles mainly comprise three parts, the sensor protein (NLRP 3), the adapter protein (ASC), and the effector protein Pro-caspase-1 (Trends Biochem Sci,2016,41 (12): 1012-1021), respectively. NLRP3 inflammatory corpuscles can be activated by a number of factors including exogenous pathogen-associated molecular patterns (Pathogen associated molecular patterns, PAMPs) of viral RNA, microbial toxins and bacterial surface components, and endogenous damage-associated molecular patterns (Damage associated molecular patterns, DAMPs) of uric acid crystals, ATP, aluminum adjuvants and beta-amyloid peptides, the typical NLRP3 inflammatory corpuscle activation pathway comprising both initiation and activation. In the starting stage, some Toll-like receptors induce nuclear transcription factors NF- κB to activate, resulting in up-regulation of NLRP3, pro-IL-18 and Pro-IL-1β gene expression, and accumulating materials for inflammatory body assembly; once the NLRP3 inflammatory body is activated, rapid assembly into a macromolecular complex induces Pro-caspase-1 self-cleavage, leading to maturation and release of the Pro-inflammatory factors IL-1 beta, IL-18, and also cleaves GASDERMIN D, perforating it at the cell membrane, leading to release of Pro-inflammatory factors from the cytoplasm to the extracellular space, ultimately leading to apoptosis (Adv immunol 2020,145, 55-93).

Through research in recent 10 years, some small molecule inhibitors against the NLRP3 inflammatory body pathway have been found, about 10 candidate molecules enter the clinical stage, and these molecules are basically sulfonylurea MCC950 analogues, and no inhibitor drugs are currently marketed (J Med chem.2023,66,14447-14473;J Med Chem.2023,66,12966-12989). The compound reported by analysis has the defects of single structural framework and insufficient activity. The benzenesulfonyl urea compound MCC950 is the highest active NLRP3 inflammasome inhibitor found so far, the IC ₅₀ inhibiting IL-1β production is 7.5nM, but it is terminated for phase II clinical of rheumatoid arthritis due to its severe hepatotoxicity (Nat Rev Drug discovery.2018, 17, 588-606), after which a large number of MCC950 analogues are reported, although their activity is comparable to MCC950, but they have the disadvantages of unstable structure, easy decomposition and short half-life, importantly, they may have human hepatotoxicity similar to MCC950, which is difficult to predict in preclinical studies, and the development of such molecules presents challenges (ACS omega.2022,7, 8158-8162). The NLRP3 inflammation small body inhibitor reported at present has a single structural skeleton, most of compounds with better activity are MCC950 analogues, and the structural homogenization is serious. While the activity of sulfonylureas is on the order of tens of nanomoles, most other compounds are on the order of micromoles, with the activity remaining to be further enhanced (Eur J Med chem.2020,185, 111822). Therefore, there is an urgent need to find NLRP3 inflammatory body inhibitors with diverse structures, higher activity and higher safety, and provide better strategies for treating NLRP3 inflammatory body-related diseases.

Disclosure of Invention

In view of the above problems, a first object of the present invention is to provide an inhibitor which exhibits excellent inhibitory effect on NLRP3 inflammatory bodies and has excellent effect of treating NLRP 3-related diseases.

A second object of the present invention is to provide a method for producing the above NLRP3 inflammasome inhibitor compound, which synthesizes a desired compound with a low cost, easily available raw material, high yield, and stable properties of the compound.

A third object of the present invention is to provide the use of the above compounds for the preparation of inhibitors of NLRP3 inflammatory bodies and for the treatment of NLRP 3-related diseases.

In order to develop potential NLRP3 inflammation small body inhibitors and treat NLRP3 inflammation small body related diseases, the invention designs and forms a class of NLRP3 inflammation small body inhibitors with a mother nucleus of biphenyl or phenyl aromatic heterocycle based on the intensive study of the deficiency of the current NLRP3 inflammation small body inhibitors, and in vitro experiments prove that the compounds can inhibit the activation-mediated IL-1 beta release of the NLRP3 inflammation small body, thereby being capable of treating diseases related to NLRP3 inflammation small body activation, such as: neurological disorders and brain injuries such as Alzheimer's disease, parkinson's disease, multiple sclerosis, traumatic brain injury, huntington's disease; inflammatory diseases such as inflammatory bowel disease, acute pneumonia, atypical pneumonia, rheumatic arthritis, rheumatoid arthritis, gouty arthritis, osteoarthritis, nonalcoholic hepatitis, acute, chronic gastritis, acute, chronic nephritis, peritonitis, autoimmune encephalitis, sepsis, septic shock; metabolic diseases such as gout, non-alcoholic fatty liver, type II diabetes; cardiovascular diseases including heart failure, atherosclerosis, acute myocardial infarction, and coronary artery disease; liver fibrosis, lung fibrosis, chronic obstructive pulmonary disease, asthma, depression, cold porphyrin-related periodic syndrome, and systemic lupus erythematosus.

In a first aspect, the present invention provides an NLRP3 inflammasome inhibitor using biphenyl or phenyl aromatic heterocycle as a mother nucleus, wherein the inhibitor has a compound shown in the general formula (1), or an optical isomer, diastereoisomer, racemate or pharmaceutically acceptable salt, deuterated product thereof:

Wherein, Selected from/>

Wherein n=0-1;

Wherein the R ₁ substituents are selected from Wherein A is selected from C1-C8 aliphatic alkane, C2-C8 aliphatic alkyne, C2-C8 aliphatic alkene, C3-C12 cycloalkane, five-membered aromatic heterocycle or benzene ring or six-membered aromatic heterocycle;

The R ₂ and R ₃ substituents are in various positions on the biphenyl or phenyl-substituted aromatic heterocyclic skeleton, wherein R ₂ is selected from H, Wherein X ₃ is selected from O, S; wherein n=0-1; wherein R ₄ substituent is H, halogen, hydroxy, methoxy;

wherein R ₃ is selected from H,

Wherein the R ₅ substituent is H, OH, Halogen, C1-C6 alkyl, wherein n=0-6;

Wherein R ₆ substituent is H and halogen;

Wherein the R ₇ substituent is H, CF ₃、CN、NO₂, OH and halogen.

In some embodiments, the R ₁ is preferablyWherein n=0-6;

Further preferred are: r ₁ is Wherein n=0-6;

Most preferably: r ₁ is

In some embodiments, the R ₂ is preferably selected fromWherein X ₁ is selected from O, S, wherein n = 0-1;

preferably: r ₂ is

Most preferably: r ₂ is

In some embodiments, R ₃ is preferably H,

Wherein the R ₅ substituent is H,

Wherein R ₆ substituent is H and halogen;

Further preferred is: r ₃ is

Most preferably, R ₃ is

In some specific embodiments, the compound has the following structural formula:

Unless specifically defined, the compounds and salts provided in the present invention may also contain all isotopes of atoms present in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers.

As used herein, "halogen" refers to F, cl, br or I. In some embodiments, the halogen is F, cl or Br. In some embodiments, halogen is F. In some embodiments, the halogen is Cl. In some embodiments, the halogen is Br. In some embodiments, halogen is I.

The number and kind of halogen in the haloalkyl group are not limited, such as trifluoromethyl, difluoromethyl, trifluoroethyl, etc.

The aliphatic alkyl group is preferably a C1-C6 alkyl group such as a straight-chain alkyl group, a spirocycloalkyl group, a bridged cycloalkyl group, an alkylene group, an alkynylalkyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group.

The C1-C6 substituted alkyl is preferably an aliphatic alkyl including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and the like.

Aromatic alkyl groups include, without limitation: substituted or unsubstituted benzyl, phenethyl, benzisopropyl, and phenylpropyl.

The aromatic ring is selected from, but not limited to, substituted or unsubstituted benzene rings, naphthalene rings, biphenyl rings, and the like.

The aromatic heterocycle is selected from, but not limited to, a substituted or unsubstituted thiophene ring, furan ring, pyridine ring, pyrrole ring quinoline ring, isoquinoline ring, benzofuran ring, and the like.

The phrase "pharmaceutically acceptable" is employed in the present invention to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

Wherein pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by converting the existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; and alkali metal salts or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts of the present application include, for example, conventional non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids, including primarily inorganic acid salts such as sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, hydrochloric acid, boric acid, sulfamic acid and the like; or organic acids such as acetic acid, propionic acid, butyric acid, valproic acid, camphoric acid, caproic acid, caprylic acid, suberic acid, carbonic acid, cinnamic acid, glycolic acid, trifluoroacetic acid, adipic acid, pyruvic acid, salicylic acid, methanesulfonic acid, alginic acid, 2-hydroxypropionic acid, stearic acid, lactic acid, citric acid, oxalic acid, malonic acid, succinic acid, pyroglutamic acid, ascorbic acid, aspartic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, hydroxymaleic acid, palmitic acid, cinnamic acid, isobutyric acid, lauric acid, mandelic acid, maleic acid, fumaric acid, malic acid, tartaric acid, sulfanilic acid, 2-acetoxy-benzoic acid, 2-hydroxy-1, 2, 3-propanetrioic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, formic acid, fumaric acid, mucic acid, gentisic acid, ethylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfinic acid, hydroxyethanesulfonic acid, ethanedisulfonic acid, 4- (carbobenzoxy) butyric acid, dichloroacetic acid, 1, 2-ethanedisulfonic acid, camphorsulfonic acid, 2, 10-dihydroxybenzoic acid, 2-hydroxybenzoic acid, 2-hydroxy-1, 2-hydroxybenzoic acid, 4-hydroxy-naphtalene-1, and trans-2-hydroxybenzoic acid. Pharmaceutically acceptable salts of the present application can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with stoichiometric amounts of the appropriate base or acid in water or in an organic solvent or in a mixture of both; in general, non-aqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol) or acetonitrile (MeCN) are preferred.

In a second aspect, the present invention also provides a process for the preparation of a compound of formula (1) as described above, or an optical isomer, diastereomer, racemate or a pharmaceutically acceptable salt, deuterate thereof, comprising the steps of:

(1) When R ₁ is In this case, the method for producing a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof comprises the steps of:

Taking the compound 1 as a starting material, and reacting with an amino compound to obtain an intermediate 2; the intermediate 2 reacts with a substituted or unsubstituted boric acid aromatic ring or aromatic heterocyclic analogue under the catalysis of tetra (triphenylphosphine) palladium to obtain an intermediate 3; further carrying out reductive amination reaction on the intermediate 3 and a substituted aldehyde compound to generate an intermediate 4; and finally, carrying out condensation reaction on the intermediate 4 and substituted carboxylic acid to obtain a target compound 5 (a compound of the general formula (I)).

(2) When R ₁ isIn this case, the method for producing a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof comprises the steps of:

taking a compound 6 as a starting material, and carrying out condensation reaction with an amino compound to obtain an intermediate 7; intermediate 7 reacts with substituted or unsubstituted boric acid aromatic ring or aromatic heterocyclic analogue under the catalysis of tetra (triphenylphosphine) palladium to obtain intermediate 8; further carrying out reductive amination reaction on the intermediate 8 and a substituted aldehyde compound to generate an intermediate 9; finally, the intermediate 9 and the substituted carboxylic acid undergo condensation reaction to obtain the target compound 10.

In a third aspect, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) as described above or an optical isomer thereof, or a pharmaceutically acceptable salt, deuterate and a pharmaceutically acceptable diluent or carrier thereof. The content of the compound or the optical isomer thereof, or the pharmaceutically acceptable salt, solvate, deuterated compound or prodrug thereof is 0.1-99.9wt%.

In a fourth aspect, the present invention provides the use of a compound of formula (I) as described above, or an optical isomer thereof, or a pharmaceutically acceptable salt, deuterate thereof, in the preparation of an NLRP3 inflammation small inhibitor.

In a fifth aspect, the present invention also provides the use of a compound of formula (I) as described above or an optical isomer thereof, or a pharmaceutically acceptable salt, deuterate thereof, in the manufacture of a medicament for the treatment of a disease associated with abnormal activation of NLRP3 inflammatory bodies.

The diseases related to NLRP3 inflammation and abnormal activation of the corpuscles comprise Alzheimer's disease, parkinson's disease, multiple sclerosis, traumatic brain injury, huntington disease and other neurological diseases and brain injury; inflammatory diseases such as inflammatory bowel disease, acute pneumonia, atypical pneumonia, rheumatic arthritis, rheumatoid arthritis, gouty arthritis, osteoarthritis, nonalcoholic hepatitis, acute and chronic gastritis, acute and chronic nephritis, peritonitis, autoimmune encephalitis, sepsis, and infection shock; metabolic diseases such as gout, non-alcoholic fatty liver, type II diabetes, etc.; cardiovascular diseases such as heart failure, atherosclerosis, acute myocardial infarction, and coronary artery disease; liver fibrosis, pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, depression, cold-related periodic syndrome or systemic lupus erythematosus.

The invention has the beneficial effects that: the invention has the beneficial effects that the drug design based on the NLRP3 inflammation small body inhibitor provides a new chemical entity for treating NLRP3 inflammation small body abnormal activation related diseases.

1. The invention provides an NLRP3 inflammation small inhibitor with a novel skeleton of biphenyl or phenyl substituted aromatic heterocycle as a parent nucleus, which aims at the defects of the existing NLRP3 inflammation small inhibitor on the basis of the prior art.

2. The compound provided by the invention has remarkable inhibitory activity on IL-1 beta release mediated by NLRP3 inflammatory corpuscle activation, and the IC ₅₀ of part of the compounds is better than the reported compounds of the same type, namely glibenclamide and JC124 at hundreds of nanomoles. Meanwhile, the representative compounds A20 and A28 can obviously inhibit the generation of inflammatory factor IL-1 beta in acute peritonitis of mice induced by LPS, and have no inhibition effect on another inflammatory factor TNF-alpha, which indicates that the compounds A20 and A28 selectively inhibit NLRP3 inflammatory small body passages.

Drawings

FIG. 1 is a graph showing the effect of compounds A20 (10 mg/kg), A28 (10 mg/kg) and MCC950 (10 mg/kg) on IL-1β production by LPS-induced C57BL/6 mice.

FIG. 2 is a graph showing the effect of Compounds A20 (10 mg/kg), A28 (10 mg/kg) and MCC950 (10 mg/kg) on TNF-. Alpha.production by LPS-induced C57BL/6 mice.

Detailed Description

It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The invention comprises a pharmaceutical composition comprising a therapeutic amount of a compound of the invention, and one or more pharmaceutically acceptable carriers and/or excipients. Carriers include, for example, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof, as discussed in more detail below. The composition may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired. The composition may be a liquid, suspension, emulsion, tablet, pill, capsule, sustained release formulation or powder. The composition may be formulated as a suppository with conventional binders and carriers such as triglycerides. Oral formulations may include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Depending on the formulation required, the formulation may be designed to mix, granulate and compress or dissolve the ingredients. In another approach, the composition may be formulated as nanoparticles or enteric pellets.

The pharmaceutical carrier used may be solid or liquid.

Typical solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. The solid carrier may comprise one or more substances which may act simultaneously as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it may also be an encapsulating material. In powders, the carrier is a finely divided solid which is admixed with the finely divided active ingredient. The active ingredient is mixed in a suitable ratio in a tablet with a carrier having the necessary compression properties, compressed in the desired shape and size. The powders and tablets preferably contain up to 99% active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, low melting waxes or ion exchange resins.

Typical liquid carriers include syrup, peanut oil, olive oil, water and the like. Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, tinctures and sealed compositions. The active ingredient may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of the two or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, pigments, viscosity regulators, stabilizing or osmotic pressure regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as described above, e.g., cellulose derivatives, preferably carboxymethyl cellulose sodium salt solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., ethylene glycol) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). The carrier for parenteral administration may also be oils such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid compositions for parenteral administration. The liquid carrier for the pressurized composition may be a halocarbon or other pharmaceutically acceptable propellant. Sterile solution or suspension liquid pharmaceutical compositions may be used, for example, for intravenous, intramuscular, intraperitoneal or subcutaneous injection. The injection can be performed in a single push or gradually, such as 30 minutes of intravenous infusion. The compounds may also be administered orally in the form of liquid or solid compositions.

The carrier or excipient may include time delay materials known in the art, such as glyceryl monostearate or glyceryl distearate, and may also include waxes, ethylcellulose, hydroxypropyl methylcellulose, methyl methacrylate, and the like. When the formulation is for oral administration, it is recognized that PHOSALPG-50 (phospholipid (phospholipid) concentrated with 1, 2-propanediol, 0.01% tween 80 in a. Nattermann & cie.gmbh) is useful for the formulation of acceptable oral formulations of other compounds, which can be adapted for the formulation of various compounds of the invention.

A wide variety of pharmaceutical forms may be used in administering the compounds of the present invention. If a solid carrier is used, the formulation may be in the form of enteric coated tablets, enteric pellets or lozenges or troches placed in hard gelatin capsules. The amount of solid support varies to a large extent but is preferably from about 25mg to about 1.0g. If a liquid carrier is used, the formulation may be a syrup, emulsion, soft capsule, sterile injectable solution or suspension in an ampoule or vial or nonaqueous liquid suspension.

Various delivery systems are known and may be used for administration of compounds or other various formulations including tablets, capsules, injectable solutions, capsules in liposomes, microparticles, microcapsules, and the like. Methods of introduction include, but are not limited to, cutaneous, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, pulmonary, epidural, ocular and (generally preferred) oral routes. The compounds may be administered by any convenient or other appropriate route, for example by infusion or bolus injection, by absorption through epithelial or mucosal routes (e.g., oral mucosa, rectal and intestinal mucosa, etc.), or by drug-loaded stents, and may be administered with other bioactive agents. The administration may be systemic or local.

In order to enable those skilled in the art to more clearly understand the technical scheme of the present application, the technical scheme of the present application will be described in detail with reference to specific embodiments.

The test materials used in the examples of the present invention are all conventional in the art and are commercially available.

The preparation method of the compound of the general formula (1) in the invention is shown below, and each substituent is defined as the summary of the invention.

Synthetic route ^a for Compounds A01-A08:

^a Reagents and conditions: (a) n-propylamine, triethylamine (TEA), 1.5h at room temperature; (b) Tetrakis (triphenylphosphine) palladium (Pd [ P (C ₆H₅)₃]₄), 2mol/L potassium carbonate (K ₂CO₃),N₂, 1, 4-dioxane, 105 ℃ C., reflux 3 h), (C) bromoethane, dimethylformamide, 100 ℃ C., 2 h), (d) sodium cyanoborohydride (NaBH ₃ CN), methanol (MeOH), room temperature 2h, (e) bis (2-oxo-3-oxazolidinyl) phosphinic chloride (Bop-Cl), TEA, dichloromethane (DCM), room temperature 6h.

Synthetic route ^a for Compound A09-A24:

^a Reagents and conditions: (a) n-propylamine, TEA, room temperature for 1.5h; (b) Pd [ P (C ₆H₅)₃]₄,2mol/L K₂CO₃,N₂, 1, 4-dioxane, 105 ℃ C., reflux for 3h; (C) NaBH ₃ CN, meOH, room temperature for 2h; (d) Bop-Cl, TEA, DCM, room temperature for 6h.

Synthetic route ^a for Compounds A25-A31:

Synthetic route ^a for Compounds A32-A37:

Synthetic route ^a for Compounds A38-A47:

Synthetic route ^a for Compounds A48-A49:

Synthetic route ^a for compound a 50:

^a Reagents and conditions: (a) ammonia water, THF, 6h at room temperature; (b) Pd [ P (C ₆H₅)₃]₄,2mol/L K₂CO₃,N₂, 1, 4-dioxane, 105 ℃ C.) refluxing for 3h, (C) N, N' -carbonyldiimidazole, 1, 8-diazabicyclo [5.4.0] undec-7-ene, N ₂, THF, room temperature for 4h, (d) hydrochloric acid EA or trifluoroacetic acid, DCM, room temperature for 2h, (e) NaBH ₃ CN, meOH, room temperature for 2h, (f) Bop-Cl, TEA, DCM, room temperature for 6h.

Specific examples:

the present invention will be described in detail by way of specific examples, but the purpose and purpose of these exemplary examples are only for illustrating the present invention, and are not intended to limit the actual scope of the present invention in any way.

Preparation of intermediate 5-chloro-2-propoxybenzaldehyde (2):

5-chloro-2-hydroxybenzaldehyde (500 mg,3.2 mmol) was put in a 50mL eggplant-shaped bottle, 10mL of Dimethylformamide (DMF) was added thereto for dissolution, K ₂CO₃ (1.1 g,8 mmol) was further added thereto, and the mixture was stirred for 10 minutes, bromoethane (578 mg,5.12 mmol) was added thereto and reacted at 100℃for 2 hours. The reaction was detected to be complete by thin layer chromatography. Adding 10mL of ethyl acetate into the reaction solution, repeatedly washing with water for 3-5 times, adding saturated sodium chloride (NaCl, 5 mL) into the organic phase for 3 times, then adding a proper amount of anhydrous sodium sulfate (Na ₂SO₄) into the organic phase for drying, concentrating after 15-20min to obtain a crude product intermediate 2, and adding the crude product into the next step (light yellow solid, 550mg, yield) without column chromatography separation 86.7％).¹H-NMR(400MHz,DMSO-d₆)δ10.28(s,1H),7.64(dd,J＝9.0,2.5Hz,1H),7.57(d,J＝2.5Hz,1H),7.24(d,J＝9.1Hz,1H),4.10–4.03(m,2H),1.81–1.70(m,2H),0.99–0.94(m,3H).

Preparation of the target compound:

Example 1: synthesis of N- (5-chloro-2-propoxybenzyl) -N- (2- (5- (N-propylaminosulfonyl) thiophen-2-yl) benzyl) benzofuran-2-carboxamide (A01):

Synthesis of 5-bromo-N-propylthiophene-2-sulfonamide (4):

n-propylamine (27 mg,0.38 mmol) was placed in a 25mL eggplant-shaped bottle, 2mL of Dichloromethane (DCM) was added for dissolution, triethylamine (TEA, 80. Mu.L, 0.57 mmol) was added after cooling in ice bath, 5-bromothiophene-2-sulfonyl chloride (100 mg,0.38 mmol) was added after stirring for 10min, and the reaction was carried out at room temperature overnight. The reaction was detected to be complete by thin layer chromatography. Saturated sodium bicarbonate (NaHCO ₃, 5 mL), 1mol/L hydrochloric acid (HCl, 5 mL) and saturated sodium chloride (NaCl, 5 mL) are sequentially added into the reaction solution for 1 time, then an appropriate amount of anhydrous sodium sulfate (Na ₂SO₄) is added into the organic phase for drying for 15-20min, and then the mixture is concentrated to obtain a crude product intermediate 4, and the crude product can be put into the next step without column chromatography separation. (white solid, 96mg, yield) 88.9％).¹H-NMR(400MHz,DMSO-d₆)δ7.90(t,J＝5.8Hz,1H),7.38(d,J＝4.0Hz,1H),7.30(d,J＝4.0Hz,1H),2.81–2.72(m,2H),1.44–1.30(m,2H),0.78(t,J＝7.4Hz,3H).

B.synthesis of 5- (2-aminomethyl) phenyl-N-propylthiophene-2-sulfonamide (5):

Intermediate 4 (500 mg,1.75 mmol), (2- (aminomethyl) phenyl) boronic acid (344 mg,2.275 mmol) and tetrakis (triphenylphosphine) palladium (202 mg,0.175 mmol) were placed in a 50mL three-necked flask, 1, 4-dioxane (10 mL) was added to dissolve, and then 2mol/L aqueous potassium carbonate solution (K ₂CO₃, 3 mL) was added to the reaction solution, and the mixture was refluxed for 3 hours at 105℃under nitrogen. The reaction was detected to be complete by thin layer chromatography. The organic solvent in the reaction solution was evaporated to dryness. Ethyl acetate was added to dissolve, and then washed 1 time with saturated sodium bicarbonate (NaHCO ₃, 8 mL), 1mol/L hydrochloric acid (HCl, 8 mL), and saturated sodium chloride (NaCl, 8 mL) in this order. Then adding a proper amount of anhydrous sodium sulfate (Na ₂SO₄) into the organic phase, drying for 15-20min, concentrating, and separating by column chromatography to obtain an intermediate 5. (pale yellow oil, 400mg, yield) 73.8％,PE/EA＝10/1).¹H-NMR(400MHz,DMSO-d₆)δ8.92(s,2H),7.99(s,1H),7.77(d,J＝7.7Hz,1H),7.63(d,J＝3.5Hz,1H),7.60–7.52(m,1H),7.49(s,2H),7.33(d,J＝3.5Hz,1H),4.07(s,2H),2.86(t,J＝7.2Hz,2H),1.51–1.38(m,2H),0.84(t,J＝7.4,1.9Hz,3H).

Synthesis of 5- (2- ((5-chloro-2-propoxybenzylamino) methyl) phenyl) -N-propylthiophene-2-sulfonamide (6):

Intermediate 5 (560 mg,1.84 mmol) and intermediate 2 (284 mg,1.84 mmol) were placed in a 50mL eggplant-shaped bottle and dissolved in methanol (MeOH, 15 mL). The reaction was carried out at room temperature for 2 hours. Then, methyl orange and cyano sodium borohydride (NaBH ₃ CN,2g,11.04 mmol) are added after the reaction liquid is cooled in an ice bath, and hydrochloric acid methanol solution (1:1) is added dropwise to adjust the PH to 3-5. The reaction is carried out for 1 to 2 hours at room temperature. The reaction was detected to be complete by thin layer chromatography. The reaction mixture was evaporated to dryness, saturated NaHCO ₃ (10 mL) was added to adjust pH to 8-9, and then EA was added to extract (8 mL. Times.3). The organic phase was then washed 1 time with saturated NaCl. Then adding a proper amount of anhydrous sodium sulfate (Na ₂SO₄) into the organic phase, drying for 15-20min, concentrating, and separating by column chromatography to obtain an intermediate 6. (pale yellow solid, 800mg, yield) 88.4％,PE/EA＝7：1).¹H-NMR(400MHz,DMSO-d₆)δ7.81(t,J＝5.8Hz,1H),7.56–7.51(m,1H),7.48(d,J＝3.8Hz,1H),7.42–7.36(m,2H),7.35–7.29(m,2H),7.27(d,J＝3.8Hz,1H),7.17(dd,J＝8.7,2.7Hz,1H),6.90(d,J＝8.8Hz,1H),3.86(t,J＝6.3Hz,2H),3.65(d,J＝18.0Hz,4H),2.82–2.74(m,2H),1.69–1.58(m,2H),1.44–1.33(m,2H),0.88(t,J＝7.4Hz,3H),0.78(t,J＝7.4Hz,3H).

Synthesis of d.N- (5-chloro-2-propoxybenzyl) -N- (2- (5- (N-propylaminosulfonyl) thiophen-2-yl) benzyl) benzofuran-2-carboxamide (A01):

Benzofuran-2-carboxylic acid (724 mg,0.15 mmol) was placed in a 25mL eggplant-shaped bottle, DCM (2 mL) was added for dissolution, triethylamine (26. Mu.L, 0.18 mmol) and bis (2-oxo-3-oxazolidinyl) hypophosphorous acid chloride (Bop-Cl, 76mg,0.3 mmol) were added after cooling in ice bath, intermediate 4 (60 mg,0.12 mmol) was added after 30min of reaction, and the reaction was carried out overnight at room temperature. The reaction was detected to be complete by thin layer chromatography. To the reaction solution were successively added saturated sodium bicarbonate (NaHCO ₃, 8 mL), 1mol/L hydrochloric acid (HCl, 8 mL), and saturated sodium chloride (NaCl, 8 mL), each washed 1 time. Then adding a proper amount of anhydrous sodium sulfate (Na ₂SO₄) into the organic phase, drying for 15-20min, concentrating, and separating by column chromatography to obtain the target compound A01. (white solid, 50mg, yield) 52.6％).¹H NMR(400MHz,DMSO-d₆)δ7.83(t,J＝5.9Hz,1H),7.75–7.62(m,1H),7.51–7.23(m,9H),7.11(s,3H),6.86(s,1H),5.01(s,1H),4.81–4.47(m,3H),3.78(s,2H),2.80–2.65(m,2H),1.52–1.32(m,4H),0.85–0.70(m,6H).¹³C NMR(126MHz,DMSO-d₆)δ155.80,154.44,148.52,131.74,128.24,127.18,127.01,124.15,123.01,113.65,112.11,69.92,60.19,44.95,22.70,11.56,10.69.

Example 2: 2-bromo-N- (5-chloro-2-propoxybenzyl) -N- (2- (5- (N-propylaminosulfonyl) thiophene-2-phenyl) acetamide (A02)

Synthetic method reference example 1, total yield 39.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.89–7.79(m,1H),7.53–7.34(m,3H),7.34–7.13(m,4H),7.09–6.99(m,1H),6.94–6.85(m,1H),4.72–4.59(m,1H),4.52–4.29(m,4H),4.14(s,1H),3.82(t,J＝6.4Hz,1H),3.76(t,J＝6.4Hz,1H),2.79–2.72(m,2H),1.64–1.44(m,2H),1.44–1.33(m,2H),0.87–0.76(m,6H).¹³C NMR(126MHz,DMSO-d₆)δ173.02,155.76,146.64,141.92,135.79,131.77,130.94,129.98,129.54,128.92,128.35,128.16,127.60,127.41,126.39,124.30,113.67,69.99,60.69,55.37,48.04,46.26,44.98,22.72,22.31,11.58,10.77.

Example 3: n- (5-chloro-2-propoxybenzyl) -N- (2- (5- (N-propylaminosulfonyl) thiophen-2-yl) benzyl) cyclopropanecarboxamide (A03)

Synthetic method reference example 1, total yield 44.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.91–7.77(m,1H),7.53–7.45(m,1H),7.40–7.27(m,3H),7.25–7.04(m,3H),6.97–6.80(m,2H),4.82(s,1H),4.57(s,2H),4.35(s,1H),3.84(t,J＝6.3Hz,1H),3.75(t,J＝6.5Hz,1H),2.76(dd,J＝12.0,6.2Hz,2H),1.99–1.79(m,1H),1.62–1.34(m,4H),0.90–0.70(m,10H).¹³C NMR(126MHz,DMSO-d₆)δ174.05,155.69,146.68,141.88,136.40,131.87,131.63,131.01,129.87,128.81,128.60,128.45,127.91,127.56,127.47,126.72,124.33,113.68,69.84,49.42,47.00,44.99,44.97,22.70,11.57,11.25,10.81,8.18.

Example 4: n- (5-chloro-2-propoxybenzyl) -N- (3- (5- (N-propylaminosulfonyl) thiophen-2-yl) benzyl) benzofuran-2-carboxamide (A04)

Synthetic method reference example 1, total yield 42.9％.¹H-NMR(400MHz,DMSO-d₆)δ7.85(t,J＝5.7Hz,1H),7.70(d,J＝7.9Hz,1H),7.62–7.54(m,2H),7.54–7.49(m,2H),7.47(d,J＝3.9Hz,1H),7.44–7.32(m,3H),7.31–7.14(m,4H),6.97–6.81(m,1H),4.99–4.81(m,2H),4.71–4.55(m,2H),3.86–3.70(m,2H),2.82–2.74(m,2H),1.60–1.33(m,4H),0.78(t,J＝7.4Hz,6H).¹³C-NMR(126MHz,DMSO-d₆)δ161.27,155.84,154.46,138.95,132.75,131.99,131.49,128.73,127.20,127.06,124.42,124.19,123.03,113.74,112.14,111.71,69.99,45.05,22.73,22.27,11.60,10.66.

Example 5: 2-bromo-N- (5-chloro-2-propoxybenzyl) -N- (3- (5- (N-propylaminosulfonyl) thiophen-2-yl) benzyl) acetamide (A05)

Synthetic method reference example 1, total yield 46.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.85(t,J＝5.8Hz,1H),7.65–7.47(m,3H),7.47–7.28(m,2H),7.26–7.17(m,1H),7.16–7.07(m,1H),6.91(d,J＝8.7Hz,1H),4.65(d,J＝9.7Hz,1H),4.59–4.45(m,2H),4.38(d,J＝5.9Hz,1H),4.30(d,J＝5.2Hz,1H),3.85–3.76(m,2H),2.82–2.73(m,2H),1.66–1.49(m,2H),1.47–1.34(m,2H),0.86–0.74(m,6H).¹³C-NMR(126MHz,DMSO-d₆)δ172.87,155.83,149.10,140.67,139.37,132.65,130.13,129.67,128.87,128.33,127.77,126.88,125.61,125.34,124.83,124.43,113.72,70.06,60.68,49.81,48.50,45.05,22.74,22.34,11.61,10.71.

Example 6: n- (5-chloro-2-propoxybenzyl) -N- (3- (5- (N-propylaminosulfonyl) thiophen-2-yl) benzyl) cyclopropanecarboxamide (A06)

Synthetic method reference example 1, total yield 47.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.89–7.83(m,1H),7.62–7.51(m,2H),7.49–7.37(m,3H),7.34(t,J＝7.7Hz,1H),7.25–7.13(m,2H),7.03(dd,J＝6.9,2.7Hz,1H),6.91(dd,J＝11.8,8.8Hz,1H),4.81(s,1H),4.64(s,1H),4.53(s,1H),4.44(s,1H),3.87–3.76(m,2H),2.83–2.76(m,2H),2.05–1.84(m,1H),1.67–1.52(m,2H),1.45–1.35(m,2H),0.86–0.69(m,10H).¹³C-NMR(126MHz,DMSO-d₆)δ173.87,155.72,149.12,140.66,139.81,132.92,132.76,130.09,128.56,128.25,127.88,127.58,125.69,125.16,124.61,124.49,124.31,113.76,70.03,50.98,45.05,44.23,22.74,22.38,11.60,11.40,10.78,10.75,8.12.

Example 7: n- (5-chloro-2-propoxybenzyl) -N- (4- (5- (N-propylaminosulfonyl) thiophen-2-yl) benzyl) benzofuran-2-carboxamide (A07)

Synthetic method reference example 1, total yield 54.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.90–7.82(m,1H),7.80–7.61(m,4H),7.60–7.49(m,3H),7.48–7.37(m,2H),7.37–7.20(m,4H),7.18–6.89(m,1H),4.93(s,1H),4.86(s,1H),4.64(s,1H),4.57(s,1H),3.87(s,1H),3.81(s,1H),2.79(d,J＝6.5Hz,2H),1.60(s,1H),1.51(s,1H),1.44–1.33(m,2H),0.83–0.68(m,6H).¹³C-NMR(126MHz,DMSO-d₆)δ161.15,155.80,154.45,140.40,138.62,132.80,128.95,127.21,127.12,127.03,124.41,124.32,124.18,123.02,113.84,112.14,111.73,70.03,45.05,30.27,29.46,22.74,14.39,11.60,10.74.

Example 8: 2-bromo-N- (5-chloro-2-propoxybenzyl) -N- (4- (5- (N-propylaminosulfonyl) thiophen-2-yl) benzyl) acetamide (A08)

Synthetic method reference example 1, total yield 58.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.83(t,J＝5.8Hz,1H),7.70(d,J＝7.8Hz,2H),7.65(d,J＝11.9Hz,2H),7.58–7.50(m,4H),7.42–7.38(m,2H),7.32(d,J＝8.1Hz,3H),7.30–7.22(m,2H),4.93(s,1H),4.86(s,1H),4.64(s,1H),4.58(s,1H),3.84(s,2H),2.84–2.75(m,2H),1.65–1.48(m,3H),1.45–1.36(m,3H),0.79(t,J＝7.4Hz,6H).¹³C-NMR(126MHz,DMSO-d₆)δ172.72,155.77,149.03,140.44,139.01,132.78,131.45,128.87,128.27,128.03,126.90,126.27,124.39,124.23,113.69,69.96,60.66,48.27,45.05,43.88,22.75,22.33,11.61.

Example 9: n- (5-chloro-2-propoxybenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -2-yl) methyl) benzofuran-2-carboxamide (A09)

Synthetic method reference example 1, total yield 59.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.71(dd,J＝11.9,7.6Hz,3H),7.57(d,J＝6.5Hz,2H),7.48–7.36(m,5H),7.36–7.29(m,3H),7.27(d,J＝7.6Hz,1H),7.21(d,J＝6.9Hz,1H),7.14(s,1H),6.92–6.69(m,1H),4.85(s,1H),4.63(s,1H),4.53(s,1H),4.46(s,1H),3.79(s,1H),3.73(s,1H),2.68–2.52(m,2H),1.57–1.31(m,4H),0.81–0.64(m,6H).¹³C-NMR(126MHz,DMSO-d₆)δ155.79,154.42,148.57,129.99,128.84,127.12,127.03,126.82,124.13,122.98,113.59,112.14,69.90,49.04,44.70,22.83,11.56,10.69.

Example 10: 2-bromo-N- (5-chloro-2-propoxybenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -2-ylmethyl) acetamide (A10)

Synthetic method reference example 1, total yield 42.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.73(dd,J＝13.7,7.9Hz,2H),7.66–7.55(m,1H),7.47–7.26(m,4H),7.25–7.10(m,3H),6.95–6.68(m,2H),5.52(s,3H),4.41–4.31(m,2H),4.30–4.13(m,3H),4.10–4.00(m,1H),3.83–3.71(m,2H),2.70–2.58(m,2H),1.64–1.42(m,2H),1.42–1.28(m,2H),0.87–0.70(m,6H).¹³C-NMR(126MHz,DMSO-d₆)δ172.87,155.74,144.28,139.99,134.58,130.49,130.04,128.85,128.58,128.25,127.90,127.47,127.27,126.73,126.23,124.16,113.57,69.96,60.65,47.88,45.76,44.74,22.88,22.30,11.58,10.77.

Example 11: n- (5-chloro-2-propoxybenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -2-methyl) cyclopropanecarboxamide (A11)

Synthetic method reference example 1, total yield 45.3％.¹H-NMR(400MHz,DMSO-d₆)δ7.76(d,J＝8.3Hz,1H),7.71(d,J＝8.1Hz,1H),7.67–7.55(m,1H),7.48(d,J＝8.1Hz,1H),7.45–7.31(m,3H),7.23(t,J＝6.0Hz,1H),7.20–7.10(m,2H),6.92–6.72(m,2H),4.67(d,J＝11.1Hz,1H),4.43(d,J＝14.8Hz,2H),4.30(d,J＝11.1Hz,1H),3.86–3.70(m,2H),2.73–2.59(m,2H),1.86(d,J＝10.3Hz,1H),1.67–1.55(m,1H),1.54–1.41(m,1H),1.42–1.33(m,2H),0.89–0.69(m,10H).¹³C-NMR(126MHz,DMSO-d₆)δ173.91,155.62,144.36,140.07,139.65,135.27,130.39,130.06,128.91,128.64,128.20,127.77,127.50,126.87,126.63,124.20,113.46,69.89,49.04,46.48,44.77,44.52,22.83,11.58,11.29,10.85,8.17.

Example 12: n- (5-chloro-2-propoxybenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -3-yl) methyl) benzofuran-2-carboxamide (A12)

Synthetic method reference example 1, total yield 50％.¹H-NMR(400MHz,DMSO-d₆)δ7.87–7.67(m,5H),7.65–7.48(m,4H),7.41(d,J＝10.0Hz,3H),7.34–7.12(m,4H),6.98–6.80(m,1H),4.97(s,1H),4.88(s,1H),4.70(s,1H),4.62(s,1H),3.81(s,1H),3.73(s,1H),2.74–2.61(m,2H),1.62–1.40(m,2H),1.40–1.28(m,2H),0.84–0.58(m,6H).¹³C-NMR(126MHz,DMSO-d₆)δ161.26,155.84,154.45,148.72,139.94,138.56,128.68,127.78,127.55,127.17,127.08,124.38,124.18,123.02,113.77,112.14,111.64,69.98,49.04,44.83,22.86,11.59,10.65.

Example 13: 2-bromo-N- (5-chloro-2-propoxybenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -3-yl) methyl) acetamide (A13)

Synthetic method reference example 1, total yield 44.9％.¹H-NMR(400MHz,DMSO-d₆)δ7.80(d,J＝6.6Hz,2H),7.78–7.68(m,2H),7.62–7.49(m,1H),7.48–7.40(m,1H),7.39–7.30(m,1H),7.19(dd,J＝8.7,2.7Hz,1H),7.15(t,J＝2.2Hz,1H),7.10(dd,J＝16.4,2.8Hz,1H),6.86(d,J＝8.9Hz,1H),4.67(s,1H),4.49(d,J＝10.2Hz,2H),4.39(s,1H),4.25(d,J＝4.2Hz,2H),3.79–3.71(m,2H),2.66(t,J＝7.1Hz,2H),1.60–1.46(m,2H),1.38–1.28(m,2H),0.79–0.71(m,6H).¹³C-NMR(126MHz,DMSO-d₆)δ172.88,155.93,144.17,139.99,139.32,138.97,138.40,129.87,129.45,129.09,128.85,128.42,128.28,127.84,127.54,126.94,126.69,126.45,126.08,124.43,113.68,70.09,60.82,49.04,44.84,29.02,22.87,22.30,11.60,10.70.

Example 14: n- (5-chloro-2-propoxybenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -3-yl) methyl) cyclopropanecarboxamide (A14)

Synthetic method reference example 1, total yield 46.7％.¹H-NMR(400MHz,DMSO-d₆)δ7.82(dd,J＝8.2,4.0Hz,2H),7.76(t,J＝7.4Hz,2H),7.65–7.52(m,2H),7.51–7.35(m,2H),7.30–7.15(m,2H),7.05(d,J＝12.4Hz,1H),6.96–6.87(m,1H),4.84(s,1H),4.65(s,1H),4.57(s,1H),4.47(s,1H),3.90–3.73(m,2H),2.74–2.62(m,2H),2.07–1.83(m,1H),1.66–1.51(m,2H),1.42–1.28(m,2H),0.87–0.64(m,11H).¹³C-NMR(126MHz,DMSO-d₆)δ173.85,155.53,144.02,140.01,139.31,139.04,129.85,128.49,128.33,128.23,128.14,127.96,127.75,127.56,127.04,126.35,126.18,125.92,124.35,113.68,69.93,51.24,46.02,44.84,22.87,22.35,11.59,10.73,8.23.

Example 15: n- (5-chloro-2-propoxybenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -4-yl) methyl) benzofuran-2-carboxamide (A15)

Synthetic method reference example 1, total yield 67.2％.¹H-NMR(400MHz,DMSO-d₆)δ7.97–7.81(m,4H),7.80–7.68(m,3H),7.68–7.56(m,2H),7.50–7.36(m,4H),7.30(dd,J＝16.4,8.6Hz,2H),7.06–6.91(m,1H),5.00(s,1H),4.91(s,1H),4.71(s,1H),4.63(s,1H),3.88(d,J＝16.9Hz,2H),2.82–2.66(m,2H),1.72–1.51(m,2H),1.49–1.34(m,2H),0.94–0.72(m,6H).¹³C-NMR(126MHz,DMSO-d₆)δ161.17,155.81,154.47,139.85,137.96,128.88,128.63,128.37,127.69,127.58,127.21,127.18,127.05,124.43,124.19,123.03,113.85,112.15,111.72,70.04,49.04,44.84,22.89,22.27,11.59,10.74.

Example 16: 2-bromo-N- (5-chloro-2-propoxybenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -4-ylmethyl) acetamide (A16)

Synthetic method reference example 1, total yield 62.3％.¹H-NMR(400MHz,DMSO-d₆)δ7.88–7.77(m,4H),7.70(d,J＝8.0Hz,1H),7.61(t,J＝7.3Hz,2H),7.31–7.19(m,3H),7.13–7.00(m,1H),6.94(d,J＝8.8Hz,1H),4.55(s,1H),4.50(s,1H),4.44(s,1H),4.38(s,1H),3.90–3.81(m,2H),2.73–2.64(m,2H),1.68–1.55(m,2H),1.42–1.30(m,2H),0.90–0.79(m,3H),0.77(t,J＝7.4Hz,3H).¹³C-NMR(126MHz,DMSO-d₆)δ172.86,155.79,143.93,139.88,138.33,137.85,128.71,128.28,127.98,127.82,127.74,127.68,127.56,127.40,126.95,124.49,113.86,70.09,60.72,49.59,44.97,43.95,22.89,22.35,11.60,10.79.

Example 17: n- (5-chloro-2-propoxybenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -2-yl) benzofuran-2-carboxamide (A17)

Synthetic method reference example 1, total yield 52.3％.¹H-NMR(400MHz,DMSO-d₆)δ7.71(d,J＝8.1Hz,2H),7.65(d,J＝5.6Hz,1H),7.56(d,J＝7.8Hz,1H),7.47(d,J＝7.7Hz,3H),7.36(s,3H),7.34–7.28(m,2H),7.28–7.18(m,2H),7.11(d,J＝7.9Hz,1H),6.87(d,J＝8.8Hz,1H),6.44(s,1H),5.01(d,J＝14.8Hz,1H),4.14(d,J＝14.8Hz,1H),3.80–3.61(m,2H),2.75–2.63(m,2H),1.50–1.43(m,2H),1.34(d,J＝7.1Hz,2H),0.83–0.76(m,6H).¹³C-NMR(126MHz,DMSO-d₆)δ159.85,155.77,154.18,148.25,142.41,140.28,139.70,137.93,131.52,129.90,129.77,129.45,129.34,128.97,127.52,127.15,126.93,126.66,124.16,124.10,123.21,113.75,112.53,111.92,69.85,47.54,44.80,26.79,22.83,22.24,11.60,10.77.

Example 18: n- (5-chloro-2-propoxybenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -2-yl) cyclopropanecarboxamide (A18)

Synthetic method reference example 1, total yield 49.6％.¹H-NMR(400MHz,DMSO-d₆)δ7.80(d,J＝8.4Hz,2H),7.65(t,J＝5.8Hz,1H),7.50–7.43(m,4H),7.42–7.37(m,1H),7.18(dd,J＝8.7,2.7Hz,1H),7.11–7.07(m,1H),7.02(d,J＝2.7Hz,1H),6.82(d,J＝8.9Hz,1H),4.78(d,J＝14.9Hz,1H),3.85(d,J＝14.9Hz,1H),3.74–3.66(m,1H),3.65–3.55(m,1H),2.74–2.65(m,2H),1.45–1.31(m,5H),0.84–0.70(m,10H).¹³C-NMR(126MHz,DMSO-d₆)δ173.31,155.63,142.75,140.23,139.90,138.64,131.57,130.42,129.86,129.62,129.60,129.04,128.63,127.45,127.09,126.83,124.04,113.64,69.72,46.32,44.83,22.84,22.26,12.92,11.58,10.75,9.00,8.86.

Example 19: 2-bromo-N- (5-chloro-2-propoxybenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -2-yl) acetamide (A19)

Synthetic method reference example 1, total yield 54.9％.¹H-NMR(400MHz,DMSO-d₆)δ7.82(d,J＝7.9Hz,2H),7.72–7.66(m,1H),7.52–7.46(m,3H),7.44–7.24(m,2H),7.22–7.13(m,3H),6.83(d,J＝8.7Hz,1H),4.73(d,J＝15.1Hz,1H),4.07(d,J＝12.1Hz,1H),3.93(d,J＝12.0Hz,1H),3.75(d,J＝15.1Hz,1H),3.73–3.57(m,2H),2.74–2.66(m,2H),1.48–1.29(m,4H),0.78–0.72(m,6H).¹³C-NMR(126MHz,DMSO-d₆)δ166.68,155.53,142.31,140.53,138.84,137.91,131.83,129.90,129.83,129.70,129.66,129.60,129.38,129.24,128.81,127.24,126.87,126.57,124.14,113.64,69.90,69.76,50.32,46.74,44.83,29.20,22.83,22.22,11.62,11.58,10.76,10.73.

Example 20: n- (5-chloro-2-propoxybenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -2-yl) -2- (thiophen-3-yl) acetamide (A20)

Synthetic method reference example 1, total yield 47.8％.¹H-NMR(400MHz,DMSO-d₆)δ7.82–7.77(m,2H),7.69–7.58(m,1H),7.49–7.45(m,2H),7.45–7.35(m,4H),7.34–7.25(m,1H),7.21–7.14(m,1H),7.11–7.08(m,1H),7.08–7.04(m,1H),6.85–6.79(m,2H),4.76(d,J＝15.2Hz,1H),3.73(d,J＝15.2Hz,1H),3.70–3.54(m,3H),3.47(d,J＝15.7Hz,1H),2.74–2.66(m,2H),1.46–1.28(m,4H),0.80–0.69(m,6H).¹³C-NMR(126MHz,DMSO-d₆)δ170.59,155.53,142.66,140.37,139.69,137.91,135.34,131.71,130.45,129.72,129.54,129.32,129.28,129.25,129.09,128.60,127.25,127.21,126.18,124.12,123.12,113.61,69.73,46.24,44.82,35.75,22.84,22.21,11.58,10.72.

Example 21: n- (5-chloro-2-propoxybenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -3-yl) benzofuran-2-carboxamide (A21)

Synthetic method reference example 1, total yield 55.3％.¹H-NMR(400MHz,DMSO-d₆)δ8.09–7.53(m,9H),7.53–7.06(m,7H),7.06–6.40(m,1H),5.12(s,2H),3.76(s,2H),2.69(s,2H),1.68–1.27(m,4H),0.81(s,6H).¹³C-NMR(126MHz,DMSO-d₆)δ159.66,155.89,154.13,148.44,143.03,142.98,140.24,140.00,130.33,129.90,128.89,128.34,127.78,127.56,127.25,127.17,126.93,126.79,126.74,124.22,124.00,123.08,113.80,112.28,111.91,69.96,48.28,44.82,22.86,22.28,11.58,10.76.

Example 22: n- (5-chloro-2-propoxybenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -3-yl) cyclopropanecarboxamide (A22)

Synthetic method reference example 1, total yield 46.8％.¹H-NMR(400MHz,DMSO-d₆)δ7.87–7.77(m,4H),7.68–7.58(m,3H),7.47(t,J＝7.8Hz,1H),7.26–7.13(m,3H),6.88(d,J＝9.0Hz,1H),4.89(s,2H),3.76–3.66(m,2H),2.73–2.63(m,2H),1.46–1.29(m,5H),0.86–0.71(m,10H).¹³C-NMR(126MHz,DMSO-d₆)δ172.83,155.74,143.40,143.17,140.27,140.21,130.54,129.58,128.56,128.47,128.04,127.87,127.61,127.01,126.46,124.13,113.73,69.86,44.83,22.87,22.27,12.96,11.58,10.75,8.70.

Example 23: 2-bromo-N- (5-chloro-2-propoxybenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -3-yl) acetamide (A23)

Synthetic method reference example 1, total yield 46％.¹H-NMR(400MHz,DMSO-d₆)δ7.83(s,4H),7.70(d,J＝8.7Hz,2H),7.63(t,J＝5.9Hz,1H),7.48(t,J＝7.7Hz,1H),7.30(dd,J＝14.0,5.1Hz,2H),7.21(dd,J＝8.7,2.7Hz,1H),6.89(d,J＝8.9Hz,1H),4.85(s,2H),3.92(s,1H),3.70(t,J＝6.3Hz,2H),2.71–2.64(m,2H),1.50–1.41(m,2H),1.38–1.31(m,2H),0.76(t,J＝7.4Hz,6H).13C-NMR(126MHz,DMSO-d₆)δ171.90,155.72,143.10,140.24,130.54,129.60,128.65,127.89,127.61,127.55,124.22,113.72,69.87,60.73,55.36,47.31,44.83,22.86,22.23,11.58.

Example 24: n- (5-chloro-2-propoxybenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -3-yl) -2- (thiophen-3-yl) acetamide (A24)

Synthetic method reference example 1, total yield 60.5％.¹H-NMR(400MHz,DMSO-d₆)δ7.81(d,J＝8.2Hz,2H),7.76(d,J＝8.2Hz,2H),7.69–7.58(m,2H),7.52(s,1H),7.45(t,J＝7.8Hz,1H),7.39(d,J＝4.2Hz,1H),7.27(s,1H),7.18(t,J＝7.9Hz,2H),7.02(s,1H),6.90–6.80(m,2H),4.86(s,2H),3.69(t,J＝6.6Hz,2H),3.50(s,2H),2.73–2.60(m,2H),1.46–1.30(m,4H),0.79–0.72(m,6H).¹³C-NMR(126MHz,DMSO-d₆)δ170.14,155.69,143.23,143.14,140.23,140.12,135.79,130.48,129.53,129.17,128.56,128.46,127.83,127.52,127.31,126.76,125.98,124.18,122.79,113.69,69.85,44.83,35.89,22.87,22.23,11.59,10.72.

Example 25: n- (5-chloro-2- (2, 2-difluoropropoxy) benzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -2-yl) -2- (thiophen-3-yl) acetamide (A25)

Synthetic method reference example 1, total yield 49.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.79(d,J＝7.9Hz,2H),7.71–7.59(m,1H),7.49–7.25(m,6H),7.21(dd,J＝8.8,2.4Hz,1H),7.15(d,J＝7.8Hz,1H),7.06(t,J＝3.8Hz,2H),6.91(d,J＝8.8Hz,1H),6.85(d,J＝4.9Hz,1H),4.83(d,J＝15.5Hz,1H),4.17–3.88(m,2H),3.75(d,J＝15.4Hz,1H),3.66(d,J＝15.8Hz,1H),3.51(d,J＝15.8Hz,1H),2.74–2.66(m,2H),1.55–1.42(m,3H),1.40–1.31(m,2H),0.76(t,J＝7.3Hz,3H).¹³C-NMR(126MHz,DMSO-d₆)δ170.68,154.37,142.58,140.39,139.46,138.00,135.26,131.83,130.42,129.86,129.52,129.40,129.28,129.09,128.63,127.37,127.20,126.19,125.39,123.19,122.38,114.30,69.60,46.26,44.80,35.77,22.86,20.77,11.57.

Example 26: (S) 2- (2-Aminobutoxy) -5-chlorobenzyl-N- (4-propylaminosulfonyl) -2-thiophen-3-acetamide hydrochloride (A26)

Synthetic method reference example 1, total yield 46.0％.¹H-NMR(400MHz,DMSO-d₆)δ8.15(s,3H),7.83(t,J＝8.2Hz,2H),7.77–7.71(m,1H),7.55–7.50(m,4H),7.47–7.42(m,2H),7.29–7.23(m,1H),7.10–7.00(m,2H),6.98–6.89(m,2H),6.85–6.78(m,1H),5.23–4.92(m,1H),4.22–4.09(m,1H),4.04–3.80(m,2H),3.63–3.56(m,1H),3.41(s,1H),3.34(s,2H),3.20–3.06(m,1H),2.78–2.71(m,2H),1.65–1.46(m,2H),1.44–1.35(m,2H),0.95–0.86(m,3H),0.81(t,J＝7.4Hz,3H).¹³C-NMR(126MHz,DMSO-d₆)δ170.84,170.69,154.77,142.49,140.37,139.87,138.39,135.16,131.84,129.99,129.82,129.76,129.51,129.22,129.15,128.77,127.45,127.20,126.30,124.97,123.26,113.85,67.47,51.73,47.65,44.84,35.84,22.90,22.59,11.62,10.14.

Example 27: 2-aminopropoxy-5-chlorobenzyl-4-propylaminosulfonyl-1, 1-biphenyl-2-yl) -2-thiophen-3-acetamide (A27)

Synthetic method reference example 1, total yield 51.5％.¹H-NMR(400MHz,DMSO-d₆)δ7.79(dd,J＝8.3,3.5Hz,2H),7.46(d,J＝4.3Hz,2H),7.44–7.34(m,4H),7.16(dd,J＝8.7,2.7Hz,1H),7.09–7.03(m,2H),6.99(dd,J＝11.2,2.7Hz,1H),6.86–6.81(m,1H),4.93–4.78(m,1H),3.87–3.70(m,1H),3.65–3.52(m,2H),3.52–3.40(m,3H),2.88–2.79(m,1H),2.71(t,J＝7.1Hz,2H),1.40–1.30(m,2H),0.86(d,J＝6.5Hz,3H),0.76(t,J＝7.4Hz,3H).¹³C-NMR(126MHz,DMSO-d₆)δ170.79,154.78,142.51,140.37,139.74,138.33,135.15,131.83,130.04,129.98,129.78,129.52,129.43,129.27,129.17,128.83,128.71,127.35,127.14,126.29,124.93,123.27,113.66,69.45,49.03,46.40,44.84,35.88,22.89,15.52,11.62.

Example 28: n- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -2-yl) -2-thiophen-3-yl-N- (4-trifluoromethyl) benzyl acetamide (A28)

Synthetic method reference example 1, total yield 43.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.84–7.79(m,2H),7.67(t,J＝5.9Hz,1H),7.58(d,J＝8.1Hz,2H),7.52–7.45(m,4H),7.40–7.35(m,2H),7.28(d,J＝8.1Hz,2H),7.06–7.00(m,2H),6.78(dd,J＝4.9,1.3Hz,1H),5.12(d,J＝15.1Hz,1H),3.78(d,J＝15.1Hz,1H),3.63–3.52(m,1H),3.45–3.37(m,1H),2.79–2.67(m,2H),1.44–1.30(m,2H),0.76(t,J＝7.4Hz,3H).¹³C-NMR(126MHz,DMSO-d₆)δ170.53,142.61,142.33,140.40,139.60,138.16,135.18,131.96,130.32,129.93,129.75,129.48,129.25,128.35,128.10,127.21,126.17,126.11,125.74,125.61,125.58,125.55,123.27,123.17,51.96,44.84,35.70,35.62,22.85,11.60.

Example 29: n- (4-Fluorobenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -3-yl) -2- (thiophen-3-yl) acetamide (A29)

Synthetic method reference example 1, total yield 59.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.84–7.74(m,4H),7.69–7.60(m,2H),7.46(dd,J＝15.7,7.9Hz,2H),7.39(d,J＝4.1Hz,1H),7.22(dd,J＝8.3,5.5Hz,2H),7.15–7.00(m,4H),6.86(d,J＝4.8Hz,1H),4.90(s,2H),3.51(s,2H),2.71–2.64(m,2H),1.41–1.30(m,2H),0.76(t,J＝7.4Hz,3H).¹³C-NMR(126MHz,DMSO-d₆)δ170.16,162.75,160.81,143.07,142.98,140.27,140.23,135.81,134.17,134.15,130.59,129.22,128.66,127.92,127.53,127.38,126.88,125.99,122.83,115.63,115.46,51.79,44.84,35.85,22.88,11.59.

Example 30: n- (4-cyanobenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -3-yl) -2- (thiophen-3-yl) acetamide (A30)

Synthetic method reference example 1, total yield 61.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.84–7.77(m,4H),7.77–7.71(m,2H),7.70–7.61(m,2H),7.58(t,J＝2.0Hz,1H),7.50–7.36(m,4H),7.27–7.18(m,1H),7.05(s,1H),6.87(d,J＝5.2Hz,1H),5.00(s,2H),3.55(s,2H),2.71–2.63(m,2H),1.41–1.29(m,2H),0.76(t,J＝7.4Hz,3H).¹³C-NMR(126MHz,DMSO-d₆)δ170.50,143.86,143.04,140.29,135.66,132.77,130.69,129.25,128.48,127.97,127.52,127.23,126.96,126.02,122.93,119.20,110.37,44.83,35.75,22.87,11.60.

Example 31: n- (4-nitrobenzyl) -N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -3-yl) -2- (thiophen-3-yl) acetamide (A31)

Synthetic method reference example 1, total yield 41.0％.¹H-NMR(400MHz,DMSO-d₆)δ8.15–8.11(m,2H),7.83–7.77(m,4H),7.70–7.65(m,1H),7.65–7.59(m,2H),7.51(d,J＝8.7Hz,2H),7.46(d,J＝7.8Hz,1H),7.39(dd,J＝4.9,3.0Hz,1H),7.25–7.22(m,1H),7.06(s,1H),6.87(d,J＝4.7Hz,1H),5.06(s,2H),3.56(s,2H),2.71–2.63(m,2H),1.41–1.28(m,2H),0.81–0.72(m,3H).¹³C-NMR(126MHz,DMSO-d₆)δ170.54,147.11,146.01,143.03,140.39,140.29,135.63,130.72,129.49,129.25,128.47,127.99,127.52,127.20,127.01,126.04,123.98,122.96,52.27,44.83,35.75,22.87,11.59.

Example 32: n- (4 '- (N-methylaminosulfonyl) - [1,1' -biphenyl ] -3-yl) -2-thiophen-3-yl-N- (4-trifluoromethyl) benzyl acetamide (A32)

Synthetic method reference example 1, total yield 45.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.78(d,J＝1.8Hz,4H),7.65(dd,J＝15.7,7.8Hz,3H),7.55–7.37(m,6H),7.22(d,J＝7.9Hz,1H),7.05(s,1H),6.87(d,J＝5.0Hz,1H),5.01(s,2H),3.55(s,2H),2.40(d,J＝5.0Hz,3H).¹³C-NMR(126MHz,DMSO-d₆)δ170.41,143.22,143.04,142.89,140.30,138.91,135.69,130.69,129.41,129.24,129.17,128.57,128.33,128.08,127.99,127.71,127.29,126.98,126.16,126.03,125.71,125.68,123.26,122.92,52.28,35.78,35.72,29.10,22.53.

Example 33: n- (4 '- (N-ethylaminosulfonyl) - [1,1' -biphenyl ] -3-yl) -2-thiophen-3-yl-N- (4-trifluoromethyl) benzyl) acetamide (A33)

Synthetic method reference example 1, total yield 43.9％.¹H-NMR(400MHz,DMSO-d₆)δ7.83–7.73(m,4H),7.69–7.59(m,4H),7.53(t,J＝1.9Hz,1H),7.45(dd,J＝10.3,8.0Hz,3H),7.39(dd,J＝4.9,3.0Hz,1H),7.21(dd,J＝7.7,1.9Hz,1H),7.08–7.01(m,1H),6.87(d,J＝4.9Hz,1H),5.01(s,2H),3.54(s,2H),2.80–2.72(m,2H),1.31–1.16(m,2H),0.95(t,J＝7.2Hz,3H).¹³C-NMR(126MHz,DMSO-d₆)δ170.41,143.09,143.03,142.89,140.31,140.22,135.69,130.69,129.24,129.18,128.54,128.34,128.09,127.95,127.53,127.29,126.97,126.02,125.79,125.71,125.68,125.65,123.63,122.92,38.00,35.78,15.19.

Example 34: 4-fluoro-N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -3-yl) -N- (4-trifluoromethylbenzyl) benzamide (A34)

Synthetic method reference example 1, total yield 47.9％.¹H-NMR(400MHz,DMSO-d₆)δ7.78(d,J＝8.0Hz,2H),7.72–7.59(m,5H),7.55(d,J＝6.2Hz,3H),7.48–7.39(m,3H),7.26(t,J＝7.8Hz,1H),7.11–7.00(m,3H),5.25(s,2H),2.70–2.62(m,2H),1.39–1.29(m,2H),0.76(t,J＝7.4Hz,3H).¹³C-NMR(126MHz,DMSO-d₆)δ169.48,163.88,161.91,143.73,143.02,142.71,140.24,139.79,132.80,132.77,131.56,131.49,130.19,129.08,128.09,127.83,127.49,126.64,125.78,125.75,125.72,125.69,115.42,115.25,52.75,44.81,22.86,11.57.

Example 35: n- (4 '- (N-hexylsulfamoyl) - [1,1' -biphenyl ] -3-yl) -2-thiophen-3-yl-N- (4-trifluoromethyl) benzyl) acetamide (A35)

Synthetic method reference example 1, total yield 46.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.85–7.71(m,4H),7.70–7.57(m,4H),7.53–7.36(m,5H),7.22(d,J＝7.9Hz,1H),7.05(s,1H),6.87(d,J＝5.0Hz,1H),5.01(s,2H),3.55(s,2H),2.76–2.65(m,2H),1.37–1.25(m,2H),1.20–1.09(m,6H),0.75(t,J＝6.8Hz,3H).¹³C-NMR(126MHz,DMSO-d₆)δ170.40,143.03,140.30,135.69,130.70,129.23,128.34,127.92,127.50,127.28,126.95,126.02,125.70,125.63,122.90,52.28,42.97,35.78,31.17,29.34,26.10,22.38,14.26.

Example 36: 2-bromo-N- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -2-yl) -N- (4-trifluoromethyl) benzyl) acetamide (A36)

Synthetic method reference example 1, total yield 51.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.83(d,J＝7.9Hz,2H),7.69(t,J＝5.8Hz,1H),7.64–7.52(m,4H),7.52–7.45(m,2H),7.44–7.37(m,1H),7.31(dd,J＝8.2,2.6Hz,2H),7.22–7.08(m,1H),5.08(dd,J＝15.2,4.5Hz,1H),4.33–4.12(m,2H),4.09–3.92(m,1H),3.88–3.67(m,1H),2.76–2.67(m,2H),1.41–1.28(m,2H),0.76(t,J＝7.4Hz,3H).¹³C-NMR(126MHz,DMSO-d₆)δ172.27,166.62,142.54,142.09,141.63,140.53,138.22,138.09,131.98,130.31,130.14,129.90,129.82,129.70,129.62,129.34,129.31,127.22,125.63,125.58,61.07,51.79,44.84,22.86,11.58.

Example 37: n- (4 '- (N-propylaminosulfonyl) - [1,1' -biphenyl ] -2-yl) -N- (4- (trifluoromethyl) benzyl) cyclopropanecarboxamide (A37)

Synthetic method reference example 1, total yield 49.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.81(d,J＝8.1Hz,2H),7.65(t,J＝5.9Hz,1H),7.59(d,J＝8.1Hz,2H),7.53(d,J＝8.2Hz,2H),7.50–7.44(m,2H),7.44–7.37(m,1H),7.27(d,J＝8.0Hz,2H),7.09(d,J＝7.8Hz,1H),5.14–5.05(m,1H),3.94–3.86(m,1H),2.75–2.67(m,2H),1.41–1.29(m,3H),0.76(t,J＝7.4Hz,4H),0.70–0.48(m,3H).¹³C-NMR(126MHz,DMSO-d₆)δ170.16,155.71,143.32,143.27,140.12,138.87,135.81,130.50,129.53,129.18,128.57,128.50,127.90,127.82,127.75,127.33,126.80,125.99,124.20,122.80,113.69,69.86,47.30,35.89,29.12,22.24,10.72.

Example 38: n- (4 '- (10H-phenothiazin-10-yl) sulfonyl) - [1,1' -biphenyl ] -2-ylmethyl) -N- (5-chloro-2-propoxybenzyl) cyclopropanecarboxamide (A38)

Synthetic method reference example 1, total yield 49.8％.¹H-NMR(400MHz,DMSO-d₆)δ7.66(t,J＝7.1Hz,2H),7.51–7.40(m,3H),7.40–7.29(m,5H),7.29–7.17(m,3H),7.14–7.06(m,4H),7.00–6.87(m,2H),4.64(s,1H),4.54(s,1H),4.43(d,J＝5.9Hz,2H),3.88(t,J＝6.4Hz,1H),3.83(t,J＝6.3Hz,1H),1.96–1.76(m,1H),1.68–1.50(m,2H),0.87–0.78(m,5H),0.76–0.66(m,2H).¹³C-NMR(126MHz,DMSO-d₆)δ174.01,155.68,146.14,139.26,137.01,135.34,135.12,132.84,130.22,130.17,129.99,129.13,128.87,128.67,128.32,128.05,127.99,127.96,127.73,127.59,127.52,127.38,127.33,127.18,126.21,124.37,113.80,70.01,49.27,46.92,44.88,22.28,11.33,10.71,8.12.

Example 39: n- (5-chloro-2-propoxybenzyl) -N- (4, 4-dihydroisoquinoline-2 (1H) -sulfonyl) - [1,1' -biphenyl ] -3-yl) methyl) -2-thiophen-3-ylacetamide (A39)

Synthetic method reference example 1, total yield 44.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.84(d,J＝7.9Hz,2H),7.48–7.34(m,6H),7.17–7.01(m,9H),6.82(d,J＝5.0Hz,1H),6.78(d,J＝8.8Hz,1H),4.73(d,J＝15.1Hz,1H),4.20(d,J＝7.1Hz,2H),3.75–3.41(m,5H),3.29(d,J＝6.2Hz,3H),2.83(t,J＝6.0Hz,2H),1.39–1.28(m,2H),0.68(t,J＝7.4Hz,3H).¹³C-NMR(126MHz,DMSO-d₆)δ170.58,155.48,143.52,139.73,137.58,135.56,135.31,133.36,131.95,131.69,130.48,129.86,129.74,129.38,129.28,129.13,128.56,128.18,127.23,127.14,126.87,126.59,126.12,124.08,123.15,113.54,69.68,47.76,46.32,44.10,35.78,28.31,22.38,10.78.

Example 40: n- (5-chloro-2-propoxybenzyl) -N- (3, 4-dihydroisoquinoline-2 (1H) -sulfonyl) - [1,1' -biphenyl ] -2-yl) benzofuran-2-carboxamide (A40)

Synthetic method reference example 1, total yield 55.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.87–7.78(m,2H),7.75(t,J＝5.2Hz,2H),7.64(d,J＝7.9Hz,1H),7.60(s,1H),7.50(d,J＝7.8Hz,1H),7.43–7.25(m,4H),7.24–7.11(m,3H),7.10–6.97(m,4H),6.89(dd,J＝8.8,3.0Hz,1H),6.54(s,1H),5.06(s,2H),4.15(s,2H),3.25(t,J＝5.7Hz,2H),2.79(t,J＝5.9Hz,2H),2.64(s,1H),2.29(s,1H),1.50–1.36(m,2H),0.76–0.66(m,3H).¹³C-NMR(126MHz,DMSO-d₆)δ159.65,155.88,154.14,148.43,143.87,143.03,139.78,135.50,133.42,132.00,130.39,129.88,129.10,128.90,128.55,127.98,127.26,127.16,127.08,126.92,126.88,126.86,126.81,126.55,124.23,124.00,123.08,113.79,112.31,111.92,69.95,55.35,47.65,43.98,28.43,22.27,10.76.

Example 41: n- (5-chloro-2-propoxybenzyl) -N- (3, 4-dihydroisoquinoline-2 (1H) -sulfonyl) - [1,1' -biphenyl ] -2-yl) cyclopropanecarboxamide (A41)

Synthetic method reference example 1, total yield 54.9％.¹H-NMR(400MHz,DMSO-d₆)δ7.90–7.80(m,4H),7.64(d,J＝7.9Hz,1H),7.60(d,J＝1.9Hz,1H),7.47(t,J＝7.9Hz,1H),7.25–7.16(m,3H),7.13–7.04(m,4H),6.89–6.83(m,1H),4.88(s,2H),4.20(s,2H),3.70(t,J＝6.4Hz,2H),3.29(d,J＝5.9Hz,2H),2.82(t,J＝6.0Hz,2H),1.49–1.29(m,3H),0.85–0.79(m,2H),0.75(t,J＝7.4Hz,3H),0.68–0.58(m,2H).¹³C-NMR(126MHz,DMSO-d₆)δ172.81,155.73,143.99,143.43,139.96,135.57,133.44,132.02,130.59,129.56,129.12,128.59,128.56,128.05,128.02,127.10,127.06,126.87,126.57,124.12,113.73,69.85,49.04,47.67,44.01,28.42,22.26,12.96,10.75,8.69,8.12.

Example 42: n- (5-chloro-2-propoxybenzyl) -N- (3, 4-dihydroisoquinoline-2 (1H) -sulfonyl) - [1,1' -biphenyl ] -2-yl) -2-thiophen-3-acetamide (A42)

Synthetic method reference example 1, total yield 62.3％.¹H-NMR(400MHz,DMSO-d₆)δ7.86(d,J＝8.5Hz,2H),7.79(d,J＝8.5Hz,2H),7.65(d,J＝7.8Hz,1H),7.52(d,J＝2.0Hz,1H),7.45(t,J＝7.9Hz,1H),7.38(dd,J＝4.9,3.0Hz,1H),7.26(d,J＝2.7Hz,1H),7.18(dd,J＝8.7,2.6Hz,2H),7.14–7.04(m,4H),7.02–6.97(m,1H),6.85(dd,J＝12.3,6.8Hz,2H),4.85(s,2H),4.20(s,2H),3.68(t,J＝6.4Hz,2H),3.49(s,2H),3.29(d,J＝5.9Hz,2H),2.83(t,J＝6.0Hz,2H),1.49–1.32(m,2H),0.72(t,J＝7.4Hz,3H).¹³C-NMR(126MHz,DMSO-d₆)δ170.15,155.69,143.98,143.29,135.78,135.54,133.43,132.01,130.53,129.53,129.15,129.12,128.57,128.51,128.04,127.79,127.36,127.10,126.86,126.58,125.99,124.20,122.79,113.68,69.84,47.66,47.29,44.00,35.89,28.42,22.23,10.71.

Example 43: 5-chloro-2-propoxybenzyl-N-methylaminosulfonyl-1, 1-biphenyl-3-yl) -2-thiophen-3-acetamide (A43)

Synthetic method reference example 1, total yield 46.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.79(q,J＝8.3Hz,4H),7.66(d,J＝7.7Hz,1H),7.56–7.42(m,3H),7.39(s,1H),7.27(s,1H),7.18(d,J＝8.2Hz,2H),7.02(s,1H),6.87(d,J＝9.5Hz,2H),4.86(s,2H),3.70(d,J＝6.9Hz,2H),3.51(s,2H),2.41(d,J＝4.6Hz,3H),1.50–1.36(m,2H),0.76(d,J＝7.9Hz,3H).¹³C-NMR(126MHz,DMSO-d₆)δ170.16,155.71,143.32,143.27,140.12,138.87,135.81,130.50,129.53,129.18,128.57,128.50,127.90,127.82,127.75,127.33,126.80,125.99,124.20,122.80,113.69,69.86,47.30,35.89,29.12,22.24,10.72.

Example 44: n- (5-chloro-2-propoxybenzyl) -N- (4 '- (N-ethylaminosulfonyl) - [1,1' -biphenyl ] -3-yl) -2- (thiophen-3-yl) acetamide (A44)

Synthetic method reference example 1, total yield 40.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.82(d,J＝8.3Hz,2H),7.76(d,J＝8.3Hz,2H),7.66(d,J＝7.9Hz,1H),7.61(t,J＝5.7Hz,1H),7.52(s,1H),7.45(t,J＝7.9Hz,1H),7.41–7.36(m,1H),7.27(s,1H),7.18(dd,J＝6.2,2.8Hz,2H),7.02(s,1H),6.86(t,J＝7.3Hz,2H),4.86(s,2H),3.74–3.64(m,2H),3.50(s,2H),2.82–2.72(m,2H),1.49–1.35(m,2H),0.95(t,J＝7.2Hz,3H),0.74(t,J＝7.4Hz,3H).¹³C-NMR(126MHz,DMSO-d₆)δ170.16,155.71,143.25,143.20,140.17,135.81,130.49,129.54,129.17,128.57,128.48,127.86,127.82,127.57,127.33,126.79,125.99,124.20,122.80,113.69,69.86,55.35,38.01,35.89,22.24,15.20,10.72.

Example 45: n- (5-chloro-2-propoxybenzyl) -N- (4 '- (N-hexylsulfamoyl) - [1,1' -biphenyl ] -3-yl) -2- (thiophen-3-yl) acetamide (A45)

Synthetic method reference example 1, total yield 45.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.86–7.72(m,4H),7.70–7.56(m,2H),7.52(s,1H),7.49–7.36(m,2H),7.27(s,1H),7.22–7.13(m,2H),7.06–6.91(m,1H),6.86(t,J＝7.6Hz,2H),4.86(s,2H),3.75–3.58(m,2H),3.50(s,2H),2.76–2.66(m,2H),1.49–1.36(m,2H),1.36–1.25(m,2H),1.23–1.09(m,6H),0.76(t,J＝6.5Hz,6H).¹³C-NMR(126MHz,DMSO-d₆)δ170.15,155.71,143.26,140.27,135.80,130.49,129.53,129.13,128.57,127.82,127.55,127.30,126.77,125.98,124.20,122.79,113.69,69.85,47.29,42.98,35.89,31.17,29.34,26.11,22.38,14.27,10.71.

Example 46: n- (5-chloro-2-propoxybenzyl) -N- (3 ' -fluoro-4 ' - (N-propylaminosulfonyl) - [1,1' -biphenyl ] -2-yl) -2- (thiophen-3-yl) acetamide (A46)

Synthetic method reference example 1, total yield 57.8％.¹H-NMR(400MHz,DMSO-d₆)δ7.96(t,J＝5.8Hz,1H),7.76(t,J＝7.9Hz,1H),7.50–7.46(m,2H),7.43–7.39(m,2H),7.18–7.14(m,2H),7.13–7.12(m,1H),7.10(dd,J＝5.1,1.5Hz,1H),7.08(d,J＝2.7Hz,1H),7.04–7.01(m,1H),6.82(dd,J＝4.9,1.3Hz,1H),6.79(d,J＝8.8Hz,1H),4.75(d,J＝15.1Hz,1H),3.85(d,J＝15.1Hz,1H),3.73–3.55(m,3H),3.52–3.46(m,1H),2.85–2.77(m,2H),1.45–1.30(m,4H),0.77–0.71(m,6H).¹³C-NMR(126MHz,DMSO-d₆)δ170.63,157.32,155.54,145.42,139.63,136.76,135.23,131.66,130.56,130.23,129.38,129.32,129.18,129.02,128.64,128.46,128.34,128.23,127.08,126.51,126.24,125.19,124.14,123.15,117.53,113.54,69.84,69.70,46.38,44.72,44.69,35.81,22.93,22.21,11.48,10.68.

Example 47: n- (5-chloro-2-propoxybenzyl) -N- (2 ' -fluoro-4 ' - (N-propylaminosulfonyl) - [1,1' -biphenyl ] -2-yl) -2- (thiophen-3-yl) acetamide (A47)

Synthetic method reference example 1, total yield 48.0％.¹H-NMR(400MHz,DMSO-d₆)δ7.78(t,J＝5.8Hz,1H),7.68(dd,J＝4.1,1.6Hz,1H),7.67–7.64(m,1H),7.50–7.46(m,2H),7.45(d,J＝2.4Hz,1H),7.44–7.40(m,2H),7.15(dd,J＝8.7,2.7Hz,1H),7.09(dd,J＝2.5,1.3Hz,1H),7.04(d,J＝2.7Hz,1H),6.87(dd,J＝4.9,1.2Hz,1H),6.82(d,J＝8.8Hz,1H),4.75(d,J＝15.3Hz,1H),3.74–3.70(m,1H),3.68(t,J＝3.3Hz,1H),3.64(s,1H),3.37(d,J＝15.6Hz,1H),2.78–2.71(m,2H),1.47–1.38(m,2H),1.39–1.30(m,2H),0.78–0.76(m,3H),0.76–0.72(m,3H).¹³C-NMR(126MHz,DMSO-d₆)δ170.70,160.06,158.08,155.41,143.13,140.70,135.62,132.86,132.50,132.34,130.43,130.35,129.29,129.02,128.96,128.50,127.23,126.07,124.13,123.06,114.50,113.53,69.74,46.07,44.86,35.56,22.86,22.19,11.55,10.68.

Example 48:3- (5-chloro-2-propoxybenzyl) -2-thiophen-3-ylacetylamino) -N-propyl-1, 1' -biphenyl-4-carboxamide (A48)

A. Synthesis of intermediate 4-bromo-n-propyl benzamide (21):

4-Bromobenzoic acid (3 g,14.92 mmol) was placed in a 100mL eggplant-shaped bottle, 20mL DCM was added for dissolution, O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroboric acid (TBTU, 5.7g,17.91 mmol) and triethylamine (3.1 mL,22.38 mmol) were added after cooling in ice bath, N-propylamine (1.47 mL,17.91 mmol) was added after 30min of reaction, and the reaction was carried out overnight at room temperature. The reaction was detected to be complete by thin layer chromatography. The reaction mixture was washed 3 times with saturated sodium bicarbonate (NaHCO ₃, 8 mL), 1mol/L hydrochloric acid (HCl, 8 mL), and saturated sodium chloride (NaCl, 8 mL) in this order. Then adding proper amount of anhydrous sodium sulfate (Na ₂SO₄) into the organic phase, drying, concentrating after 15-20min, separating by column chromatography to obtain intermediate 21 for the next synthesis (white solid, 2.8g, yield) 78.0％).¹H-NMR(400MHz,DMSO-d₆)δ8.51(t,J＝5.7Hz,1H),7.77–7.72(m,2H),7.63(d,J＝8.6Hz,2H),3.20–3.13(m,2H),1.53–1.43(m,2H),0.84(t,J＝7.4Hz,3H).

B. synthesis of intermediate 2 '-amino-N-propyl- [1,1' -biphenyl ] -4-carboxamide (22):

Intermediate 21 (840 mg,3.49 mmol), (2-aminophenyl) boronic acid (618 mg,4.53 mmol) and tetrakis (triphenylphosphine) palladium (403 mg,0.349 mmol) were placed in a 100mL three-necked flask, 1, 4-dioxane (15 mL) was added to dissolve, and then 2mol/L aqueous potassium carbonate solution (K ₂CO₃, 3 mL) was added to the reaction solution, and the mixture was refluxed for 4 hours at 105℃under nitrogen. The reaction was detected to be complete by thin layer chromatography. The organic solvent in the reaction solution was evaporated to dryness. Ethyl acetate was added to dissolve, and the mixture was washed 3 times with saturated sodium bicarbonate (NaHCO ₃, 10 mL), 1mol/L hydrochloric acid (HCl, 10 mL), and saturated sodium chloride (NaCl, 10 mL) in this order. Then adding appropriate amount of anhydrous sodium sulfate (Na ₂SO₄) into the organic phase, drying for 15-20min, concentrating, and separating by column chromatography to obtain intermediate 22 (light yellow oily substance, 600mg, yield) 67.6％,PE/EA＝7/1).¹H-NMR(400MHz,DMSO-d₆)δ8.46(t,J＝5.7Hz,1H),7.92–7.86(m,2H),7.49–7.45(m,2H),7.06–7.00(m,1H),6.97(dd,J＝7.6,1.6Hz,1H),6.74(d,J＝8.0Hz,1H),6.61(t,J＝7.2Hz,1H),4.83(s,2H),3.24–3.17(m,2H),1.58–1.45(m,2H),0.86(t,J＝7.4Hz,3H).

C. synthesis of intermediate 2- (5-chloro-2-propoxybenzyl) amino-N-propyl-1, 1-biphenyl-4-carboxamide (23):

Intermediate 22 (345 mg,1.36 mmol) and 5-chloro-2-propoxybenzaldehyde (323 mg,1.63 mmol) were placed in a 50mL eggplant-shaped bottle and dissolved in methanol (MeOH, 5 mL). The reaction was carried out at room temperature for 2 hours. Then, methyl orange and sodium cyanoborohydride (NaBH ₃ CN,513mg,8.16 mmol) are added after the reaction liquid is cooled in an ice bath, and hydrochloric acid methanol solution (1:1) is added dropwise to adjust the PH to 3-5. The reaction is carried out for 1 to 2 hours at room temperature. The reaction was detected to be complete by thin layer chromatography. The reaction mixture was evaporated to dryness, saturated NaHCO ₃ (5 mL) was added to adjust pH to 8-9, and then EA was added to extract (5 mL. Times.3). The organic phase was then washed 3 times with saturated NaCl (5 mL). Then adding appropriate amount of anhydrous sodium sulfate (Na ₂SO₄) into the organic phase, drying, concentrating after 15-20min, and separating by column chromatography to obtain intermediate 23 (pale yellow solid, 400mg, yield) 67.5％,PE/EA＝10：1).¹H-NMR(400MHz,DMSO-d₆)δ8.47(t,J＝5.7Hz,1H),7.95–7.89(m,2H),7.47–7.42(m,2H),7.22–7.15(m,2H),7.08(ddd,J＝8.5,7.4,1.6Hz,1H),6.99–6.93(m,2H),6.64(td,J＝7.4,1.0Hz,1H),6.53(dd,J＝8.3,1.1Hz,1H),4.19(dd,J＝13.1,6.3Hz,2H),3.87(t,J＝6.5Hz,2H),3.24–3.18(m,2H),1.63–1.45(m,4H),0.87(td,J＝7.4,4.2Hz,6H).

D. Synthesis of the target Compound 3- (5-chloro-2-propoxybenzyl) -2-thiophen-3-ylacetylamino) -N-propyl-1, 1' -biphenyl-4-carboxamide (A48):

23 (100 mg,0.23 mmol) was placed in a 25mL eggplant-shaped bottle, DCM (2 mL) was added for dissolution, triethylamine (48. Mu.L, 0.344 mmol) and N ₂ were added for protection, thiophene acetic acid (30. Mu.L, 0.344 mmol) was added after cooling at-5℃for 2h. The reaction was detected to be complete by thin layer chromatography. Washing the reaction solution with saturated NaCl (5 mL) for 1 time, adding appropriate amount of anhydrous sodium sulfate (Na ₂SO₄) into the organic phase, drying for 15-20min, concentrating, and separating by column chromatography to obtain target compound A48 (white solid, 80mg, yield) 62.5％,PE/EA＝6/1).¹H-NMR(400MHz,DMSO-d₆)δ8.53(t,J＝5.7Hz,1H),7.95–7.89(m,2H),7.71–7.61(m,3H),7.52–7.40(m,3H),7.33–7.27(m,1H),7.25–7.16(m,2H),7.06(s,1H),6.90(t,J＝7.2Hz,2H),4.90(s,2H),3.72(t,J＝6.7Hz,2H),3.54(s,2H),3.27–3.20(m,2H),1.60–1.51(m,2H),1.51–1.40(m,2H),0.90(t,J＝7.4Hz,3H),0.79(t,J＝7.4Hz,3H).¹³C-NMR(126MHz,DMSO-d₆)δ170.16,166.06,155.71,143.19,141.90,140.80,135.84,134.29,130.40,129.50,129.17,128.54,128.24,127.99,127.86,127.07,126.90,126.60,125.98,124.21,122.77,113.69,69.86,41.46,35.87,22.86,22.24,11.93,10.73.

Example 49:2- (2-bromo-N- (5-chloro-2-propoxybenzyl) acetamido) -N-propyl-1, 1-biphenyl-4-carboxamide (a 49).

Specific synthetic methods reference example 48, total yield 53.0％.¹H-NMR(400MHz,DMSO-d₆)δ8.59–8.41(m,1H),8.00–7.77(m,2H),7.53–7.26(m,5H),7.23–7.08(m,3H),6.90–6.77(m,1H),4.83–4.69(m,1H),4.16–3.87(m,2H),3.86–3.54(m,3H),3.27–3.13(m,2H),1.63–1.37(m,4H),0.94–0.84(m,4H),0.82–0.68(m,3H).¹³C-NMR(126MHz,DMSO-d₆)δ172.29,166.01,155.53,141.37,138.50,138.10,134.29,131.67,130.23,129.45,129.32,128.59,128.55,127.93,127.26,124.13,113.60,69.71,61.06,46.14,41.46,22.84,22.22,11.91,10.68.

Example 50: n- (3 '- (N- (5-chloro-2-propoxybenzyl) -2- (thiophen-3-yl) acetamido) - [1,1' -biphenyl ] -4-yl) sulfonylpropionamide (A50)

A. synthesis of intermediate 4-bromobenzenesulfonamide (24):

4-Bromobenzenesulfonyl chloride (2 g,7.83 mmol) was placed in a 100mL eggplant-shaped bottle and dissolved by adding tetrahydrofuran (20 mL). Ammonia water (3.6 mL,93.96 mmol) was added after cooling in ice bath, and the reaction was carried out at room temperature for 1-1.5h. The reaction was detected to be complete by thin layer chromatography. The reaction was dried by spinning, then DCM and water were added, filtered off with suction, and the cake was dried in vacuo to give intermediate 24, which was directly added to the next step (white solid, 1.5g, 81.5% yield) without purification. ¹H-NMR(400MHz,DMSO-d₆ ) Delta 7.75 (d, j=12.7hz, 1H), 7.45 (s, 1H).

B. Synthesis of intermediate (4 '-aminosulfonyl- [1,1' -biphenyl ] -3-yl) carbamic acid tert-butyl ester (25):

Intermediate 24 (900 mg,3.83 mmol), (3- ((t-butoxycarbonyl) amino) phenyl) boronic acid (1.36 g,5.75 mmol) and tetrakis (triphenylphosphine) palladium (442 mg,0.383 mmol) were placed in a three-necked flask, 1, 4-dioxane was added to dissolve (15 mL), and 2mol/L K ₂CO₃ aqueous solution (3 mL) was added, nitrogen blanketed, and refluxed at 105℃for 4h. The reaction was detected to be complete by thin layer chromatography. The organic solvent in the reaction solution was evaporated to dryness. Ethyl acetate was added to dissolve, and the mixture was washed 3 times with saturated sodium bicarbonate (NaHCO ₃, 8 mL), 1mol/L hydrochloric acid (HCl, 8 mL), and saturated sodium chloride (NaCl, 8 mL) in this order. Then adding appropriate amount of anhydrous sodium sulfate (Na ₂SO₄) into the organic phase, drying for 15-20min, concentrating, and separating by column chromatography to obtain intermediate 25 (yellow solid, 900mg, yield) 69.2％,PE/EA＝15/1).¹H NMR(400MHz,DMSO-d₆)δ9.46(s,1H),7.90–7.85(m,2H),7.83(t,J＝1.9Hz,1H),7.76–7.71(m,2H),7.44(dd,J＝2.6,1.3Hz,1H),7.37(d,J＝5.4Hz,2H),7.33(d,J＝7.9Hz,1H),7.29–7.25(m,1H),1.45(s,9H).

C. Synthesis of intermediate tert-butyl 4'- (N-propionylsulfamoyl) - [1,1' -biphenyl ] -3-yl) carbamate (26):

N-propionic acid (139. Mu.L, 1.867 mmol) was dissolved in tetrahydrofuran (15 mL), N-carbonyldiimidazole (CDI, 303mg,1.867 mmol) was added, and the mixture was refluxed at 70℃for 1h under nitrogen. The reaction solution was then cooled to room temperature, and intermediate 25 (500 mg, 1.433 mmol) and 1, 8-diazabicyclo undec-7-ene (DBU, 536. Mu.L, 3.59 mmol) were added to the reaction solution and reacted at room temperature for 4 hours. The reaction was detected to be complete by thin layer chromatography. Tetrahydrofuran was dried by spin-drying, dissolved in DCM, and washed 1 time with water (5 mL), saturated sodium chloride (NaCl, 8 mL) in sequence. Then adding appropriate amount of anhydrous sodium sulfate (Na ₂SO₄) into the organic phase, drying for 15-20min, concentrating, and separating by column chromatography to obtain intermediate 26 (white solid, 500mg, yield) 66.0％,PE/EA＝5/1).¹H NMR(400MHz,DMSO-d₆)δ12.06(s,1H),9.49(s,1H),7.96(ddd,J＝8.5,4.3,2.4Hz,4H),7.88–7.52(m,7H),7.45(d,J＝7.9Hz,2H),7.40–7.32(m,2H),7.29(tt,J＝6.2,2.4Hz,2H),2.21(dd,J＝9.0,5.8Hz,4H),1.46(dd,J＝4.4,2.7Hz,18H),0.95–0.79(m,6H).

D. Synthesis of intermediate N- (3 '-amino- [1,1' -biphenyl ] -4-sulfonyl) propanamide (27)

Intermediate 26 (400 mg) was placed in a 50mL eggplant-shaped bottle, 3mL of DCM was added for dissolution, and 1mL of ethyl acetate hydrochloride was added dropwise for reaction at room temperature for 2h. The reaction was detected to be complete by thin layer chromatography. Adding saturated sodium bicarbonate to the reaction solution to adjust pH to 8-9, adding DCM (5 mL) for extraction for 1 time, washing the organic phase with saturated sodium chloride (5 mL) for 1 time, adding appropriate amount of anhydrous sodium sulfate (Na ₂SO₄) to the organic phase, drying for 15-20min, concentrating, and separating by column chromatography to obtain intermediate 27 (pale yellow solid, 250mg, yield) 83.3％).¹H-NMR(400MHz,DMSO-d₆)δ7.91–7.86(m,2H),7.73–7.67(m,2H),7.09(t,J＝7.8Hz,1H),6.84(t,J＝1.9Hz,1H),6.80–6.77(m,1H),6.61–6.57(m,1H),2.21–2.12(m,2H),0.85(t,J＝7.5Hz,3H).

E. synthesis of intermediate N- (3 '- ((5-chloro-2-propoxybenzyl) amino) - [1,1' -biphenyl ] -4-yl) sulfonyl) propanamide (28)

Intermediate 27 (300 mg,0.99 mmol) and 5-chloro-2-propoxybenzaldehyde (196 mg,0.99 mmol) were placed in a50 mL eggplant-shaped bottle and dissolved in methanol (MeOH, 10 mL). The reaction was carried out at room temperature for 2 hours. Then, methyl orange and cyano sodium borohydride (NaBH ₃ CN,186mg,2.96 mmol) were added to the reaction solution after the temperature was lowered in an ice bath, and a hydrochloric acid methanol solution (1:1) was added dropwise to adjust the pH to 3-5. The reaction is carried out for 1 to 2 hours at room temperature. The reaction was detected to be complete by thin layer chromatography. The reaction mixture was evaporated to dryness, saturated NaHCO ₃ (10 mL) was added to adjust pH to 8-9, and then EA was added to extract (8 mL. Times.3). The organic phase was then washed 3 times with saturated NaCl. Then adding proper amount of anhydrous sodium sulfate (Na ₂SO₄) into the organic phase, drying for 15-20min, concentrating, separating by column chromatography to obtain intermediate 28 (pale yellow solid, 400mg, yield 83.6％,PE/EA＝8：1).¹H-NMR(400MHz,DMSO-d₆)δ12.02(s,1H),7.93–7.88(m,2H),7.75–7.69(m,2H),7.26–7.12(m,3H),6.98(d,J＝8.8Hz,1H),6.86–6.81(m,2H),6.60–6.54(m,1H),6.34(t,J＝6.2Hz,1H),4.26(d,J＝6.0Hz,2H),3.96(t,J＝6.4Hz,2H),2.24–2.15(m,2H),1.79–1.66(m,2H),0.95(t,J＝7.4Hz,3H),0.86(t,J＝7.4Hz,3H).f. synthesis of target compound N- (3 '- (N- (5-chloro-2-propoxybenzyl) -2- (thiophen-3-yl) acetamido) - [1,1' -biphenyl ] -4-yl) sulfonyl propionamide (A50)

2- (Thiophen-3-yl) acetic acid (78 mg,0.617 mmol) was placed in a 25mL eggplant-shaped bottle, DCM (5 mL) was added for dissolution, triethylamine (86. Mu.L, 0.617 mmol) and bis (2-oxo-3-oxazolidinyl) hypophosphorous acid chloride (Bop-Cl, 157mg,0.617 mmol) were added after cooling in ice bath, intermediate 28 (100 mg,0.21 mmol) was added after 30min of reaction, and the reaction was carried out overnight at room temperature. The reaction was detected to be complete by thin layer chromatography. To the reaction solution were successively added saturated sodium bicarbonate (NaHCO ₃, 8 mL), 1mol/L hydrochloric acid (HCl, 8 mL), and saturated sodium chloride (NaCl, 8 mL), each washed 3 times. Then adding appropriate amount of anhydrous sodium sulfate (Na ₂SO₄) into the organic phase, drying for 15-20min, concentrating, and separating by column chromatography to obtain final product A50 (white solid, 80mg, yield) 62.5％).¹H-NMR(400MHz,DMSO-d₆)δ12.07(s,1H),7.93(d,J＝8.3Hz,2H),7.82–7.76(m,2H),7.66(d,J＝7.8Hz,1H),7.53(s,1H),7.46(t,J＝7.8Hz,1H),7.39(d,J＝3.6Hz,1H),7.26(s,1H),7.19(s,2H),7.02(s,1H),6.88(d,J＝8.8Hz,1H),6.84(s,1H),4.86(s,2H),3.70(t,J＝6.5Hz,2H),3.50(s,2H),2.26–2.16(m,2H),0.86(t,J＝7.4Hz,3H),0.74(t,J＝7.4Hz,3H).¹³C-NMR(126MHz,DMSO-d₆)δ172.77,170.15,155.71,144.45,143.29,139.94,138.96,135.79,130.52,129.55,129.18,128.71,128.58,127.79,127.45,126.90,125.98,124.20,122.82,113.68,69.85,47.32,35.90,29.15,22.24,10.71,8.68.

Example 51: activity studies of target Compounds to inhibit LPS/ATP-induced release of IL-1β by mouse macrophages J774A.1 cells were plated onto 96-well plates with 1X 10 ⁵ cells per well. After 12h bacterial Lipopolysaccharide (LPS) (1. Mu.g/mL) was added and incubated for 4.5h at 37 ℃; various concentrations of the target compound were added and incubated at 37℃for 0.5h, followed by the addition of adenine nucleoside triphosphate (ATP). After 0.5h, cell supernatant was collected, and IL-1β content was measured using IL-1β Elisa kit, to calculate the inhibitory activity of the target compound against NLRP3 inflammatory corpuscles. The experimental results are shown in the following table:

Table 1 target Compounds inhibit the activity of LPS/ATP-induced mouse macrophages J774A.1 to release IL-1β (IC) ₅₀：μM)^a

^a IC ₅₀ values in table: the++ is less than or equal to 0.5. Mu.M; ++ is less than or equal to 1. Mu.M; ++ is less than or equal to 10 mu M; + is less than or equal to 30 mu M. The data in the tables are three independent experiments.

The designed compounds all have obvious activity of inhibiting the generation of IL-1 beta by LPS/ATP induced mouse macrophage J774 A.1. Most of these activities have an inhibition IC ₅₀ of less than 1. Mu.M, which is superior to the reported similar compounds glibenclamide and JC-124. Furthermore, the inhibitory activity of representative compounds a18, a20, a23, a28, a49 was prominent, IC ₅₀ reached below 0.5 μm.

Example 52: inhibition experiment of LPS-induced mouse peritonitis by target Compounds A20 and A28

The experimental method comprises the following steps:

(1) Male C57BL/6 mice from 4 to 8 weeks were randomly divided into 5 groups of 5 mice each, and the specific grouping treatment was as follows:

Group 1: blank 5; group 2: injecting blank vector into the abdominal cavity, injecting LPS (35 mg/kg) into the abdominal cavity after 1h, and 5; groups 3-5: the target compounds A20 (10 mg/kg), A28 (10 mg/kg) and the positive drug MCC950 (10 mg/kg) were intraperitoneally injected with LPS (35 mg/kg) after 1 hour, 5 each.

(2) After LPS was intraperitoneally injected for 2.5 hours, blood was collected from the eyeball, and the collected blood was allowed to stand for 1 hour, followed by centrifugation at 3500r/min for 20 minutes.

(3) And (3) measuring the IL-1 beta and TNF-alpha content of the blood supernatant obtained in the step (2) by using an ELISA method.

Experimental results (as shown in fig. 1 and 2): in vivo anti-inflammatory experiments, representative compounds A20 and A28 can remarkably inhibit the release of IL-1 beta in acute peritonitis of mice induced by LPS (figure 1) without affecting the release of another inflammatory factor TNF-alpha (figure 2), which shows that the compounds can specifically inhibit NLRP3 inflammatory corpuscles and have certain selectivity.

The above description is only of the preferred embodiments of the present invention and is not intended to limit the scope of the present invention, and various modifications and variations will be apparent to those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A compound of formula (I), or an optical isomer, diastereomer, racemate or a pharmaceutically acceptable salt, deuterate thereof:

Wherein, Selected from/>N=0-1; the R ₁ substituent is selected from/>Wherein A is selected from C1-C8 aliphatic alkane, C2-C8 aliphatic alkyne, C2-C8 aliphatic alkene, C3-C12 cycloalkane, five-membered aromatic heterocycle or benzene ring or six-membered aromatic heterocycle;

r ₂ and R ₃ are optionally substituted on the benzene ring or on the aromatic heterocyclic skeleton, wherein R ₂ is selected from H, Wherein X ₁ is selected from O, S, n=0-1, r ₄ substituents are selected from H, halogen, hydroxy, methoxy;

r ₃ is selected from H, Wherein R ₅ is selected from H, OH,/> Halogen, C1-C6 alkyl, wherein n=0-6; r ₆ is selected from H, halogen; r ₇ is selected from H, CF ₃、CN、NO₂, OH, halogen.

2. A compound of the general formula (I) according to claim 1, or an optical isomer, diastereoisomer, racemate or a pharmaceutically acceptable salt or deuteride thereof,Selected from/>N=0; r ₁ is selected from/>R ₂ and R ₃ are ortho or meta to the biphenyl nucleus, wherein R ₂ is selected from/>R ₃ is selected from

3. The compound of claim 1, or an optical isomer, diastereomer, racemate, or pharmaceutically acceptable salt, deuterate thereof, wherein the compound of formula (I) is selected from the group consisting of:

4. A process for the preparation of a compound as claimed in any one of claims 1 to 3, or an optical isomer, diastereoisomer, racemate or a pharmaceutically acceptable salt, deuterate thereof, characterized by comprising the steps of:

(1) When R ₁ is The steps are as follows:

Taking the compound 1 as a starting material, and reacting with an amino compound to obtain an intermediate 2; the intermediate 2 reacts with a substituted or unsubstituted boric acid aromatic ring or aromatic heterocyclic analogue under the catalysis of tetra (triphenylphosphine) palladium to obtain an intermediate 3; further carrying out reductive amination reaction on the intermediate 3 and a substituted aldehyde compound to generate an intermediate 4; finally, the intermediate 4 and the substituted carboxylic acid undergo condensation reaction to obtain a target compound 5;

(2) When R ₁ is The steps are as follows:

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 or an optical isomer, diastereomer, racemate or a pharmaceutically acceptable salt, deuterate thereof and a pharmaceutically acceptable diluent or carrier thereof.

6. The pharmaceutical composition of claim 5, wherein the compound or optical isomer thereof, or pharmaceutically acceptable salt or deuterate thereof is present in an amount of 0.1 to 99.9wt%.

7. Use of a compound as defined in any one of claims 1-3, or an optical isomer, diastereomer, racemate or a pharmaceutically acceptable salt thereof, deuterated in the preparation of an NLRP3 inflammation small inhibitor.

8. Use of a compound as defined in any one of claims 1 to 3, or an optical isomer, diastereomer, racemate or a pharmaceutically acceptable salt thereof, deuterated in the preparation of a medicament for the treatment of a disease associated with aberrant activation of NLRP3 inflammatory small body activity.

9. The use according to claim 8, wherein the disease associated with abnormal activation of NLRP3 inflammasome comprises alzheimer's disease, parkinson's disease, multiple sclerosis, traumatic brain injury, huntington's disease, inflammatory bowel disease, acute pneumonia, atypical pneumonia, rheumatoid arthritis, gouty arthritis, osteoarthritis, non-alcoholic hepatitis, acute and chronic gastritis, acute and chronic nephritis, peritonitis, autoimmune encephalitis, sepsis, septic shock, gout, non-alcoholic fatty liver, type II diabetes, heart failure, atherosclerosis, acute myocardial infarction, coronary artery disease, liver fibrosis, pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, depression, cold-imidacloprid-related periodic syndrome, or systemic lupus erythematosus.