CN114699412A - Sulfonamide compound and application thereof in preparation of medicine for treating autoimmune diseases - Google Patents

Abstract

The invention discloses a sulfonamide compound and its application in preparing a medicine for treating autoimmune diseases, and belongs to the technical field of medicine. The sulfonamide compound is a compound whose structural formula is shown in formula (I)-(VI) or any pharmaceutically acceptable salt thereof, and the compound has glucocorticoid receptor binding activity and can target carbohydrates. The corticosteroid receptor ligand domain can effectively inhibit the activation of downstream pro-inflammatory signaling pathways NF-κB, AP1 and other pathways, and has a significant anti-inflammatory effect, and the compound cannot induce transcriptional activation, and will not cause transcriptional activation. In addition, the compound is not cytotoxic and has no binding activity to other steroid nuclear receptors. Therefore, it is used as a small molecule modulator of glucocorticoid receptors in autoimmune diseases mediated by glucocorticoid receptors, providing new therapeutic strategies and methods for clinical practice.

Description

Sulfonamide compound and its application in preparing medicine for treating autoimmune disease

technical field

The invention relates to the technical field of medicine, in particular to the application of sulfonamide compounds with glucocorticoid receptor binding activity in the preparation of glucocorticoid receptor small molecule regulators.

Background technique

Glucocorticoids (GCs) are widely used in clinical anti-inflammatory drugs for the treatment of asthma, psoriasis and other inflammatory diseases. GCs mainly exert their therapeutic effects through the glucocorticoid receptor (GR). But long-term glucocorticoid use is limited by serious side effects, manifested in hypertension and major metabolic side effects such as glucose intolerance, muscle wasting, skin thinning, and osteoporosis.

Current studies have shown that the anti-inflammatory mechanism of glucocorticoids is: GR that is not activated by GCs binds to binding proteins such as HSP90 in the cytoplasm. When bound to GCs, the conformation of GR LBD changes, GRα releases HSP, enters the nucleus, and acts as a transcription factor Play the role of transcriptional activation or transcriptional repression on downstream genes. Once inside the nucleus, GR binds to the GRE response element (+)GRE in the form of homodimerization to induce gene transcriptional expression, which is called the transcriptional activation pathway of GR. Since the GRE transcriptional activation pathway is involved in human glucose metabolism, bone and endocrine function, it is currently considered to be the main cause of side effects of GCs drugs. Simultaneous GCs binding can also cause direct and indirect transcriptional repression of GR: GCs-induced direct transcriptional repression is the direct binding of ligand-activated GR to evolutionarily conserved (-)GRE [inverted repeat (IR)nGRE]; indirect transcription Inhibition, also known as "tethered transrepression", interferes with downstream promoters by binding to specific factors such as NF-κB (p65), AP1 (c-jun), or STAT3 in a manner that does not bind directly to DNA. Inflammatory signaling pathway, resulting in decreased production of cytokines, chemokines, adhesion factors, matrix metalloproteinases, and cyclooxygenase-2 (COX-2) associated with inflammatory diseases. It is generally believed that the anti-inflammatory effects of GCs are associated with indirect transcriptional repression, while direct transcriptional inhibition and direct transcriptional activation are associated with side effects.

In order to reduce the side effects of GCs, it is an important strategy to research anti-inflammatory drugs to find GR small-molecule regulators that do not have transcriptional activation function and have significant anti-inflammatory effects. Drug design targeting GRɑ has achieved great success. Structurally, GR consists of 777 amino acid residues and is divided into 4 main domains, namely N-terminal domain (NTD), DNA-binding domain (DBD), hinge region and C-terminal domain (ligand-binding domain). , LBD). Reported studies have focused on the development of partial agonists or selective glucocorticoid receptor modulators, compounds that activate inflammatory inhibitory pathways but avoid targeting pathways that cause GC-related side effects.

Several compounds with glucocorticoid receptor modulating activity have been identified. For example, patent document CN112236416A discloses that pyrimidine cyclohexenyl compounds are used as glucocorticoid receptor modulators in the treatment of inflammatory diseases. Patent documents CN111556867A and CN 111491931A disclose that substituted pyrrolidones are useful as glucocorticoid receptor modulators for the treatment and/or prevention of disorders mediated by glucocorticoid receptors. Developing more novel and effective glucocorticoid receptor-targeting compounds with fewer side effects to expand clinical drug options is a problem to be solved by those skilled in the art.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a small molecule compound with glucocorticoid receptor binding activity as a small molecule modulator targeting glucocorticoid receptor for the treatment of inflammation-related diseases such as asthma and rheumatoid joints inflammation, psoriasis and other autoimmune diseases.

To achieve the above object, the present invention adopts the following technical solutions:

The present invention provides the application of any one of the compounds represented by the structural formulas (I)-(VI) or any of their pharmaceutically acceptable salts in the preparation of medicines for treating autoimmune diseases,

in,

R ¹ , R ² and R ³ are each independently hydrogen, halogen, cyano, nitro, SF ₅ , SCN, amino, C ₁ -C ₆ alkylamino, bis(C ₁ -C ₆ )alkylamino , hydroxyl, carboxyl, C ₁ -C ₈ alkyl, C ₃ -C ₆ cycloalkyl, C ₅ -C ₇ cycloalkenyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₃ -C ₆ halocycloalkoxy, C ₁ -C ₆ alkyl-C ₃ -C ₆ halocycloalkoxy, C ₁ -C ₆ alkyl -C ₁ - C ₆ alkoxy, C ₁ -C ₆ alkyl-C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl-cyano base, C ₁ -C ₆ alkyl-C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkenyloxy, C ₂ -C ₆ alkynyl, C ₂ -C ₆ alkyne Oxy, SH, C ₁ -C ₆ thioalkyl, C ₁ -C ₆ sulfinyl alkyl, C ₁ -C ₆ sulfonyl alkyl, C ₁ -C ₆ halosulfonyl alkyl, C ₁ -C ₆ alkyl-C ₁ -C ₆ alkoxyamino, C ₁ -C ₆ alkylcarbonyl, C ₃ -C ₆ cycloalkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, C ₁ -C ₆ alkane Oxycarbonyl, C ₁ -C ₆ alkylaminocarbonyl, bis(C ₁ -C ₆ )alkylaminocarbonyl, five- or six-membered aryl, five- or six-membered heteroaryl, C ₁ -C ₆ alkane base-five- or six-membered aryl, five- or six-membered arylaminocarbonyl, five- or six-membered aryl-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl - five or six-membered Heteroaryl, five- or six-membered heteroaryl-C ₁ -C ₆ alkyl, five- or six-membered arylcarbonyl, five- or six-membered arylamido, five- or six-membered heteroarylcarbonyl, Five- or six-membered heteroarylamido, five- or six-membered heteroarylaminocarbonyl, five- or six-membered heterocycle, C ₁ -C ₆ alkyl-five- or six-membered heterocyclyl, five-membered Or six-membered heterocyclyl-C ₁ -C ₆ alkyl, five- or six-membered heterocyclylcarbonyl, five- or six-membered heterocyclyl amido, five- or six-membered heterocyclylaminocarbonyl, eight-membered to fourteen-membered heteroaromatic bicyclic or tricyclic ring systems, _C1 - _C6 alkyl-eight- to fourteen-membered heteroaromatic bicyclic or tricyclic ring systems, eight- to fourteen-membered heteroaromatic bicyclic or tricyclic ring systems Ring system-C ₁ -C ₆ alkyl, eight- to fourteen-membered heteroaromatic bicyclic or tricyclic ring system carbonyl, eight- to fourteen-membered heteroaromatic bicyclic or tricyclic ring system amido, octa membered to fourteen membered heteroaromatic bicyclic or tricyclic ring system aminocarbonyl;

Or C ₁ -C ₆ alkylamino, bis(C ₁ -C ₆ ) alkylamino, C ₁ -C ₈ alkyl, C ₃ -C ₆ cycloalkyl, C ₅ -C ₇ cycloalkenyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₃ -C ₆ halocycloalkoxy, C ₁ -C ₆ alkyl-C ₃ -C ₆ Halocycloalkoxy, C ₁ -C ₆ alkyl-C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl-C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkoxy - C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl-cyano, C ₁ -C ₆ alkyl-C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ Alkenyloxy, C2 _{- C6alkynyl} , C2 _{- C6alkynyloxy} , _C1 -C6thioalkyl, _{C1 -} C6sulfinylalkyl, _{C1 - C6sulfonylalkane} base, C ₁ -C ₆ halosulfonylalkyl, C ₁ -C ₆ alkyl-C ₁ -C ₆ alkoxyamino, C ₁ -C ₆ alkylcarbonyl, C ₃ -C ₆ cycloalkylcarbonyl , C ₁ -C ₆ haloalkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylaminocarbonyl, bis(C ₁ -C ₆ ) alkylaminocarbonyl, five- or six-membered aryl , five- or six-membered heteroaryl, C ₁ -C ₆ alkyl-five- or six-membered aryl, five- or six-membered arylaminocarbonyl, five- or six-membered aryl-C ₁ -C ₆ Alkyl, C1- _C6alkyl -five- or _six -membered heteroaryl, five- or six-membered heteroaryl- _C1 - _C6 -alkyl, five- or six-membered arylcarbonyl, five- or six-membered Arylamido, five- or six-membered heteroarylcarbonyl, five- or six-membered heteroarylamido, five- or six-membered heteroarylaminocarbonyl, five- or six-membered heterocycle, C ₁ - C ₆ alkyl-five- or six-membered heterocyclyl, five- or six-membered heterocyclyl-C ₁ -C ₆ alkyl, five- or six-membered heterocyclylcarbonyl, five- or six-membered heterocyclylamide base, five- or six-membered heterocyclylaminocarbonyl, eight- to fourteen-membered heteroaromatic bicyclic or tricyclic ring systems, C ₁ -C ₆ alkyl-eight- to fourteen-membered heteroaromatic bicyclic or tricyclic ring systems Ring ring system, 8- to 14-membered heteroaromatic bicyclic or tricyclic ring system -C ₁ -C ₆ alkyl, 8- to 14-membered heteroaromatic bicyclic or tricyclic ring system carbonyl, 8- to ten-membered Four-membered heteroaromatic bicyclic or tricyclic ring system amido, eight- to fourteen-membered heteroaromatic bicyclic or tricyclic ring system amidocarbonyl, by hydrogen, halogen, cyano, nitro, hydroxyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy or C ₁ -C ₆ thioalkyl mono- or polysubstituted;

p is 1, 2 or 3;

Z is O, N or C;

或者所述并环结构Ⅰ被至少一个R¹所取代；A ¹ , A ² are each independently H, C, CR ¹ , O, S or NR ¹ , or form a ring structure I with a benzene ring and continuous atoms

Or the said ring structure I is substituted by at least one R ¹ ;

或者所述并环结构Ⅱ被至少一个R¹所取代。Q ¹ , Q ² are each independently H, C, CR ¹ , O, S or NR ¹ , or together with Z and continuous atoms to form a ring structure II

Alternatively the cyclostructure II is substituted with at least one R ¹ .

Preferably, R ¹ is amino, halogen, C ₁ -C ₈ alkyl, C ₁ -C ₆ alkylcarbonyl, C ₃ -C ₆ cycloalkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylaminocarbonyl, bis(C ₁ -C ₆ ) alkylaminocarbonyl,

Or amino, C ₁ -C ₈ alkyl, C ₁ -C ₆ alkylcarbonyl, C ₃ -C ₆ cycloalkylcarbonyl, C ₁ -C ₆ haloalkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylaminocarbonyl, bis(C ₁ -C ₆ ) alkylaminocarbonyl by hydrogen, halogen, cyano, nitro, hydroxyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy or C ₁ -C ₆ thio Alkyl mono- or polysubstituted.

More preferably, R ¹ is halogen, C ₁ -C ₈ alkyl. Halogen, C ₁ -C ₈ alkyl can be replaced by hydrogen, halogen, cyano, nitro, hydroxyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ - C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy or C ₁ -C ₆ thioalkyl mono- or polysubstituted.

Preferably, Z is C or N.

More preferably, Z is N.

Preferably, p is 2 or 3.

More preferably, p is 3.

Preferably, R ² and R ³ are H and substituted benzo rings.

The substituted benzo ring is

更为优选，A¹，A²为

优选的，Z，Q¹，Q²共同组成取代哌啶、取代吲哚啉、取代哌嗪。Preferably, A ¹ and A ² are

More preferably, A ¹ and A ² are

Preferably, Z, Q ¹ and Q ² together form substituted piperidine, substituted indoline and substituted piperazine.

Preferably, the structural formula of the compound is as follows:

The research of the present invention shows that the above compounds have high selectivity for targeting glucocorticoid receptors, effectively inhibit the activation of downstream pro-inflammatory signaling pathways NF-κB, AP1 and other pathways, have significant anti-inflammatory effects, and can reduce the generation of side effects . That is, the action mechanism of the above compound is: the compound has glucocorticoid receptor binding activity, and by targeting the glucocorticoid receptor, inhibits the NF-κB signaling pathway and/or the AP1 signaling pathway, thereby reducing the expression of inflammatory factors. Thus, the compounds can be used as glucocorticoid receptor modulators in the treatment of disorders mediated by the glucocorticoid receptor.

Further, the autoimmune disease is asthma, rheumatoid arthritis, psoriasis, and inflammation.

The present invention also provides a method for preparing the above-mentioned compound, which can be obtained by the following reaction scheme:

Reaction Route 1:

Wherein, the substituent R= contains methyl or other alkyl substitution, halogen atom substitution (-F, -Cl, -Br), methoxy substitution, nitro, cyano, thiophene ring, trifluoromethyl and other groups Substituted aromatic or aromatic heterocycles.

Reaction Route 2:

萘环，嘧啶以及其他芳香环或含有卤素或烷基等取代基的芳香环等。Wherein, substituent R=cyclopropyl, benzene ring group, pyrrole; benzene ring group containing hydrogen, halogen, cyano, nitro, hydroxyl substituent; C1-C6 haloalkoxy mono- or poly-substituted gene;

Naphthalene ring, pyrimidine and other aromatic rings or aromatic rings containing substituents such as halogen or alkyl, etc.

Substituent R' = aromatic ring substituted with CH3 or other alkyl group, halogen atom substitution (-F, -Cl, -Br), methoxy group, nitro group, thiophene ring, trifluoromethyl group, etc. Aromatic heterocycle.

Reaction Route 3:

Substituent R"=-CH3, halogen atom substitution (-F, -Cl, -Br), -OCH3, nitro, n-butyl, isopropyl and other alkyl substitution, aromatic ring substitution, trifluoromethyl, by Hydrogen, halogen, cyano, nitro, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy or C1-C6 thioalkyl mono- or poly-substituted and other genes.

The present invention uses the compound HP-19 as the lead compound to synthesize a new sulfonamide compound through the above method, and the structural formula is shown in any of the following:

The present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of one or more of the sulfonamide compounds described in any one, or a pharmaceutically acceptable salt thereof, or a deuterated product thereof, and a pharmaceutically acceptable salt thereof. acceptable carrier.

Glossary: "Alkyl" means a straight or branched hydrocarbon chain comprising 1 to 6 carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, and substituted alkyl groups. The alkyl groups of the present invention may be optionally substituted one or more times with halogen or hydroxy. Thus, the term "alkyl" also includes, for example, trifluoromethyl and other haloalkyl groups, hydroxymethyl and other hydroxylated alkyl groups as indicated.

"Alkoxy" means an -O-alkyl group in which alkyl is as defined above. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, and substituted alkoxy. The alkoxy groups of the present invention may be optionally substituted one or more times with halogen.

"Aromatic ring" refers to an all-carbon monocyclic or fused polycyclic group of 5-12 carbon atoms with a fully conjugated pi electron system. Non-limiting examples of aryl groups are: benzene ring, naphthalene ring, anthracene ring.

"Heteroaromatic" refers to a non-all-carbon monocyclic or fused polycyclic group of 5-12 carbon atoms with a fully conjugated pi electron system. Non-limiting examples of aryl groups are: pyridine, imidazole, furan, thiazole, purine, indole, thiophene, azaindole.

"Cycloalkyl" refers to a saturated carbocyclic ring of 3-8 ring atoms, examples including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

"Halogen" means fluorine, chlorine, bromine or iodine.

"Pharmaceutically acceptable salts" include alkali metal salts, alkaline earth metal salts, other metal salts, inorganic base salts, organic base salts, inorganic acid salts, lower alkane sulfonates, aryl sulfonates, organic acid salts, amino acids Salt.

Preferably, the pharmaceutically acceptable salts are hydrochloride, benzenesulfonate, toluenesulfonate, phosphate, maleate, sulfate, acetate, citrate, fumarate acid or tartrate.

The medicament also includes a pharmaceutically acceptable carrier. The "pharmaceutically acceptable carrier" refers to the conventional pharmaceutical carriers in the pharmaceutical field, including conventional diluents in the pharmaceutical field, excipients such as water, etc., fillers such as starch, etc., binders such as cellulose derivatives, gelatin, etc. , wetting agents such as glycerin, disintegrating agents such as agar, calcium carbonate, etc., adsorption carriers such as kaolin and bentonite, surfactants such as cetyl alcohol, absorption accelerators such as quaternary ammonium compounds, lubricants such as talc, etc., if necessary Flavoring agents, sweeteners, etc. may be added.

The pharmaceutical formulations are suitable for administration by any suitable route, such as nasal spray, oral spray (inhalation), oral (including buccal or sublingual), rectal, topical (including buccal, sublingual) or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes. The pharmaceutical formulations of the present invention can be prepared by any method known in pharmacy. For example, by bringing the active ingredient into association with a carrier or excipient.

The beneficial effects that the present invention has:

The compounds provided by the invention have glucocorticoid receptor binding activity, can target the glucocorticoid receptor ligand domain, effectively inhibit the activation of downstream pro-inflammatory signaling pathways NF-κB, AP1 and other pathways, and have significant anti-inflammatory properties. In addition, the compound has no cytotoxicity and has no binding activity to other steroid nuclear receptors, so it is used to prepare anti-inflammatory drugs It has potential application value in the treatment of autoimmune diseases mediated by glucocorticoid receptors.

Description of drawings

Figure 1 shows the structure and anti-inflammatory activity of the virtual screening hits.

Figure 2 shows the transcriptional inhibition of NF-kb by compounds HP-19 and dexamethasone (Dex).

Figure 3 shows the results of the binding strength of compounds with obvious anti-inflammatory activity to glucocorticoid receptors under the condition of 10 μM.

Figure 4 is a test of the binding activity of compounds to GR LBD.

Figure 5 is an evaluation of the transcriptional inhibition of AP-1 (A) and the transcriptional activation of GR by compounds HP-19 and dexamethasone (Dex).

Figure 6 is an evaluation of compounds HP-19, mifepristone (RU486) and Azd9567 for GR transcriptional antagonism.

Figure 7 shows the effect of HP-19 on the expression of endogenous target genes of GR detected by qPCR.

Figure 8 shows the safety evaluation of compound HP-19.

Figure 9 shows the selectivity of compound HP-19 for androgen receptor (A) and progesterone receptor (B), respectively.

Detailed ways

The present invention will be further described below in conjunction with specific embodiments.

The experimental methods used in the following examples are conventional methods unless otherwise specified.

The materials, reagents, etc. used in the following examples can be obtained from commercial sources unless otherwise specified.

Example 1

1. Structure-based virtual screening

Experimental principle: Use structure-based virtual screening to predict the binding mode and binding free energy between compounds in the compound database and glucocorticoid receptors, and screen small molecule compounds that can bind to glucocorticoid receptors.

Experimental method: Based on the crystal structure of the glucocorticoid receptor (PDB number: 6EL9), the Glide molecular docking module of the Schrodinger molecular simulation software package was used to conduct a structure-based virtual screening of the chemdiv small molecule database, and the best 3000 compounds were scored. Conformational analysis was performed and 88 compounds were finally purchased for activity screening.

Experimental results: 24 potential glucocorticoid analogs were screened and possessed different chemical backbones (Figure 1).

2. Evaluation experiment of anti-inflammatory ability of glucocorticoid receptor

Detection principle: Because the anti-inflammatory effect of glucocorticoids is mainly through the transcriptional inhibition pathway-that is, the inhibition of NF-κB (p65) and AP1 (c-jun) signaling pathways causes the expression of inflammatory factors to decrease. The dual luciferase reporter assay system is sensitive and used to measure two separate luciferase reporter genes in one system, firefly luciferase and marine Renilla luciferase, marine Renilla luciferase in different types of mammals The expression in animal cells is stable and the expression activity is not sensitive to external drug stimulation, which can be used to correct errors caused by different transfection efficiencies. Therefore, in the dual-luciferase reporter gene test, Renilla luciferase serves as a control reporter gene to provide the normalization of the experimental reporter gene Firefly luciferase test; when the inhibitory activity of the test compound against NF-κB or AP-1 is higher, Firefly The smaller the relative ratio of luciferase/Renillaluciferase, the stronger the anti-inflammatory ability of the tested compound.

Detection step: In the detection method of the present invention, cervical cancer cells (Hela) are seeded into a transparent 96-well plate at a density of 1×10 ⁴ cells/well. After the cells were stably attached, Hela was co-transfected with human full-length GRɑ protein, pNF-κB-luc and Rencilla (pRL-TK) using Lipofectamine 3000. 24 h after transfection, cells were treated with 5 ng/ml of TNFα and 10 μM of test compound, respectively. After 18 hours, the cell culture plate was taken out, washed twice with PBS, and the waste liquid was discarded, and 20 μl of 1ⅹPLB lysis buffer (Passive Lysis Buffer) was added to each well, 30 μl per well. Place the cell culture plate on a shaker to fully lyse for 30 minutes. The relative luciferase content in each cell well was determined using a microplate reader to obtain Fireflyluciferase/Renilla luciferase.

Test results: When 10 μM is administered, the transcriptional inhibitory activity of the compound on NF-kb is shown in Figure 1. HP-21, HP-30, HP-49 and HP-57 with benzenesulfonamide structure had more than 50% transcriptional inhibitory activity on NF-kb at 10 μM concentration. Among them, HP-49 has better transcriptional inhibitory activity of NF-kb, IC ₅₀ =0.256μM. HP-7 with N-phenylsulfonamide also had better transcriptional inhibitory activity against NF-kb, IC ₅₀ =0.17 μM.

Among all 24 compounds, compounds with N-phenylbenzenesulfonamide (such as HP-5, HP-11, HP-12, HP-14, HP-18, HP-19, HP-23, HP-25 , HP-28, HP-29, HP-31, HP-39 and HP-40) had the best anti-inflammatory activity.

As shown in Figure 2, HP-19 had the strongest NF-κB inhibitory activity among the tested compounds, and its IC ₅₀ was 41 nM, which was in the same order of magnitude as the positive compound dexamethasone (IC ₅₀ =12 nM).

Small molecules with transcriptional inhibitory activity greater than 50% were selected to further measure their _IC50 values and used for the next step of target validation.

3. Glucocorticoid receptor competitive binding experiment verification and target binding strength

TR-FRET GR竞争结合测定时，将Fluormone^TMGS1 Green示踪剂添加到配体测试化合物或溶剂对照中，然后添加GR-LBD(GST)和Tb-anti-GST抗体的混合物。在室温下孵育2h后，分别在520nm和495nm的波长下分别读数，计算出TR-FRET比率值(ratio)为520:495，可用于根据化合物的剂量响应曲线确定IC₅₀。如果待测化合物竞争性配体会竞争三元复合物中的配体，使得该比率值下降。并非靶向该位点，则该值保持原水平。利用以上原理，即可定量测定化合物对糖皮质激素受体的靶向结合能力。Detection principle: The time-resolved fluorescence resonance energy transfer (TR-FRET) technique of Invitrogen was used to detect the binding ability of compounds to glucocorticoid receptors. when carried out

For the TR-FRET GR competition binding assay, Fluormone ^™ GS1 Green tracer is added to the ligand test compound or solvent control, followed by a mixture of GR-LBD (GST) and Tb-anti-GST antibody. After 2 h incubation at room temperature, readings were performed at wavelengths of 520 nm and 495 nm, respectively, and the calculated TR-FRET ratio (ratio) was 520:495, which could be used to determine the IC ₅₀ from the dose-response curve of the compound. This ratio decreases if the test compound competes for the ligand in the ternary complex. If this site is not targeted, the value remains at the same level. Using the above principles, the targeted binding ability of the compound to the glucocorticoid receptor can be quantitatively determined.

Detection step: Mix the mixture of glucocorticoid receptor ligand binding domain {GR-LBD(His-GST)} and Tb-anti-GST antibody with the test compound of different concentration gradients, and then add the ligand with fluorescence (Fluormone ^™ GS1 Green) with 10 μM dexamethasone as a positive control. Using a multifunctional microplate reader to detect changes in ratio, quantitatively determine whether compounds with high antagonistic activity accurately target glucocorticoid receptors.

Test results: As shown in Figure 3, at the compound concentration of 10 μM, HP-1, HP-6, HP-19, HP-24, HP-26 and HP-67 all showed higher targeting glucocorticoid receptors Ligand Domain Capability. Further, we selected compounds HP-19, HP-24 and HP-67, which have strong anti-inflammatory effects at the same time, for concentration gradient detection. As shown in Figure 4, compounds HP-19, HP-24 and HP-67 were concentration-dependent, indicating that compounds HP-19, HP-24 and HP-67 correctly targeted the glucocorticoid receptor ligand domain and exert an anti-inflammatory effect.

4. Evaluation experiments of compounds on the inhibition of AP-1 signaling pathway

Detection principle: Because the anti-inflammatory effect of glucocorticoids is mainly through the transcriptional inhibition pathway-that is, the inhibition of NF-κB (p65) and AP1 (c-jun) signaling pathways causes the expression of inflammatory factors to decrease. Therefore, in the dual-luciferase reporter gene test, Renilla luciferase was used as a control reporter gene to provide the normalization of the experimental reporter gene Firefly luciferase test; when the inhibitory activity of the test compound AP-1 was higher, Firefly luciferase/Renilla luciferase relative The smaller the ratio, the stronger the anti-inflammatory ability of the measured compound.

Detection step: In the detection method of the present invention, cervical cancer cells (Hela) are seeded into a transparent 96-well plate at a density of 1×10 ⁴ cells/well. After cells were stably attached, Hela was co-transfected with human full-length GRɑ protein, 5ⅹAp-1-luc and Rencilla (pRL-TK) using Lipofectamine 3000. 24h after transfection, cells were treated with 1 ng/ml of PMA (for AP-1 reporter system) and different concentration gradients of test compounds. After 18 hours, the cell culture plate was taken out, washed twice with PBS, and the waste liquid was discarded. 20 μl of 1ⅹ PLB lysis buffer (Passive Lysis Buffer) was added to each well, 30 μl per well. Place the cell culture plate on a shaker to fully lyse for 30 minutes. The relative luciferase content in each cell well was determined using a microplate reader to obtain Firefly luciferase/Renilla luciferase.

Test results: As shown in Figure 5(A), the compound HP-19 has good inhibitory activity against AP-1, and its IC ₅₀ is 790 nM, indicating that the compound has a good anti-inflammatory effect.

5. Evaluation experiments of compounds on the transcriptional activity of GR

5.1 Evaluation experiments of compounds for GR transcriptional activation

Detection principle: We constructed the cell line Hela-MMTV-luc based on Hela cells. The activity of firefly luciferase in this cell depends on the promoter MMTV (it has been reported in the literature that the MMTV promoter contains glucocorticoid receptor response elements. , is one of the models to detect transcriptional activation activity). The expression of luciferase in Hela-MMTV-luc directly reflects the strength of GR to exert transcription factor activity. The GR transcriptional activation activity of the compounds at the cellular level can be quantified by detecting the expression intensity of luciferase in Hela-MMTV-luc. For compounds with good transcriptional activating activity, we performed concentration gradient detection and calculated _IC50 values.

Detection steps: First, the Hela-MMTV-luc cells were cultured in hormone-free complete medium for 2 days, and the density of 1×10 ⁴ cells/well was inoculated into an opaque white 96-well plate. After the cells adhered stably, different concentrations of gradient compounds and dexamethasone were given. After 24 hours of incubation, the chemiluminescence was detected by a multi-function microplate reader, and the transcriptional activation activity (IC ₅₀ ) of the compounds was quantitatively calculated. The positive drug dexamethasone was used as the control.

Test results: As shown in Figure 5(B), compound HP-19 could not induce transcriptional activation at any concentration, while dexamethasone had strong transcriptional activation. This result suggests that the compound HP-19 may not cause side effects caused by transcriptional activation.

5.2 Evaluation experiments of compounds for GR transcriptional antagonism

Detection principle: Since transcriptional activation is currently considered to be the main cause of side effects caused by long-term clinical use of steroids, if the compound does not have transcriptional activation activity or has an inhibitory effect on the agonistic activity caused by dexamethasone, it may overcome long-term effects. Side effects caused by medication. Therefore, detecting whether a compound has an antagonistic effect on the transcriptional activation of GR is an important evaluation index for overcoming side effects. The GR transcriptional antagonistic activity of the compound at the cellular level can be quantified by detecting whether the compound can reduce dexamethasone-induced luciferase activity in Hela-MMTV-luc cells. For the compounds with good transcriptional antagonistic activity, we do concentration gradient detection and calculate IC ₅₀ values.

Detection step: Hela-MMTV-luc was seeded into an opaque white 96-well plate at a density of 1×10 ⁴ /well. After the cells adhered stably, 100nM dexamethasone was given to induce compounds with different concentration gradients at the same time. After 24 hours of incubation, the chemiluminescence was detected by a multi-function microplate reader, and the transcriptional antagonistic activity (IC ₅₀ ) of the compounds was quantitatively calculated. Positive drugs Mifepristone served as a control.

Test results: As shown in Figure 6, compound HP-19 could not antagonize the transcriptional activation effect caused by dexamethasone at any concentration, while both GR antagonists and small molecule regulators had strong transcriptional antagonism effects of Azd9567. HP-19 may be a small molecule modulator with novel anti-inflammatory mechanism.

6. Expression of inflammatory factors of glucocorticoid receptor protein target genes

Detection principle: GR negatively regulates target genes through transcriptional repression mechanism. Typical target genes include a large number of inflammatory proteins, such as IL-1β, IL-6, IL-8, IL-12, cyclooxygenase 2 (COX -2), etc., GR positively regulates target genes through transcriptional activation mechanism, and GILZ is one of the earliest reported inducible genes through GCR transcriptional activation. In order to confirm that the activity of the compound HP-19 was not caused by false positives, the anti-inflammatory activity of the compound was evaluated by detecting the effect of the compound on the expression of the endogenous target gene of the glucocorticoid receptor at the mRNA level.

1st cDNA cDNA SuperMix进行qPCR，最后通过qPCRSYBR Green Master Mix进行扩增。Detection steps: Quantitative PCR (qPCR) was used to detect the effects of compounds on the expression of endogenous target genes of glucocorticoid receptors at the mRNA level. RAW264.7 cells were cultured in 6-well plates containing 5% charcoal/dextran-treated fetal calf serum (CSS) medium. After 48 hours of treatment, mRNA was extracted using the EZ-10 DNAaway RNA Mini-Preps kit and reverse transcribed into cDNA. use

1st cDNA cDNA SuperMix was used for qPCR and finally amplified by qPCRSYBR Green Master Mix.

Test results: As shown in Figure 7, the compound HP-19 can significantly reduce the mRNA levels of inflammation-related genes IL-6β and COX-2, but has no effect on the mRNA expression levels of IL-1β, which is consistent with the results of transcriptional activation experiments. , the compound did not affect the mRNA expression level of the transcriptional activation target gene GILZ, and indirectly indicated that the compound might reduce the production of side effects.

Seven, MTT method to detect the safety of compound HP-19

Detection principle: In order to detect whether the compound has cytotoxicity, the present invention uses normal mouse embryonic fibroblasts (NIH-3T3) for toxicity detection to determine its safety.

Experimental procedure: NIH-3T3 cells were seeded in a 96-well plate with complete medium at a density of 5×10 ³ cells/well. After the cells adhered, they were incubated at 37°C for 24 hours, and then treated with different concentrations of compound HP-19 for a further 48 hours. After that, 10 μL of 5 mg/ml MTT was added to each well and incubated for 4 hours. Then, 100 μL of SDS-HCl-PBS triple buffer was added to each well, and incubated overnight at 37°C. Finally, the absorbance value of each well at 570nm was detected under the microplate reader, and converted into the survival rate.

Experimental results: As shown in Figure 8, the safety of compound HP-19 in NIH-3T3 was at the same level as that of the positive drug dexamethasone, and even at a high concentration such as 50uM, it did not inhibit cell proliferation. The above results show that the compound HP-19 of the present invention has high safety.

8. Selectivity of test compounds for other nuclear receptors

Assay principle: To test whether the compound is selective for other steroid nuclear receptors such as androgen receptor (AR) and progesterone receptor (PR), we used the established LNCaP-ARR2PB-EGFP cell model and double The luciferase reporter system was used to detect AR and PR, respectively.

The detection principle of AR: As a transcription factor, androgen receptor (AR) needs to bind to a specific sequence to exert its transcriptional activity. In the detection method of the present invention, the reporter gene enhanced green fluorescent protein (EGFP) controlled by the ARR2PB promoter is introduced into androgen receptor-dependent prostate cancer cells (LNCaP), so that the LNCaP cells express androgen receptor-regulated EGFP prostate cancer Cancer cell line (LNCaP-ARR2PB-EGFP). After being treated with different concentration gradient test compounds, the level of EGPF expression in LNCaP-ARR2PB-EGFP cells was detected, and the strength of the compound's ability to activate androgen receptor transcription could be measured.

Detection steps: First, LNCaP-ARR2PB-EGFP cells were cultured in a complete medium without androgen for several days, and the background fluorescence value was detected. After the fluorescence value dropped to a low level, the cells were seeded into a black bottom transparent 96-well plate at a density of 3.5×10 ⁴ cells/well. After the cells adhered stably, they were induced with dihydrotestosterone (DHT) and compounds. After 24-48 hours of incubation, a multi-function microplate reader was used to detect the fluorescence intensity near the wavelength of 530 nm under excitation light of 485 nm. The positive drug was 10 nM DHT. (DHT) as a control.

The detection principle of PR: As a transcription factor, progesterone receptor (PR) needs to bind to a specific sequence to exert its transcriptional activity. The study found that PR can bind to the ARR3tk promoter and cause transcription of downstream genes. In the detection method for evaluating PR, the prostate cancer cell line PC3 was co-transfected with PR, ARR3tk-luc and Rencilla, and Rencilla was used as an internal reference plasmid for correction, and the data was measured using the principle of dual luciferase reporter gene.

Detection step: In the detection method of the present invention, the prostate cell line PC3 is inoculated into a transparent 96-well plate at a density of 1×10 ⁴ cells/well. After the cells were stably attached, PC3 was co-transfected with human full-length PRɑ protein, 3ⅹAR3tK-luc and Rencilla using Lipofectamine 3000. 24h after transfection, cells were treated with different concentrations of HP-19, and 10ng/ml of progestogen was used as a control. After 18 hours, the cell culture plate was taken out, washed twice with PBS, and the waste liquid was discarded. 20 μl of 1ⅹ PLB lysis buffer (Passive Lysis Buffer) was added to each well, 30 μl per well. Place the cell culture plate on a shaker to fully lyse for 30 minutes. The relative luciferase content in each cell well was determined using a microplate reader to obtain Fireflyluciferase/Renilla luciferase.

Experimental results: As shown in Figure 9, the compound HP-19 did not cause transcriptional activation of AR and PR, while the positive drug dexamethasone had a certain transcriptional activation effect on both AR and PR. Dexamethasone's poor selectivity for other nuclear receptors is also a cause of side effects. Therefore, the above results show that the compound HP-19 of the present invention has good AR and PR nuclear receptor selectivity, and can avoid the side effects caused by off-target to a certain extent.

Example 2

Taking HP-19 as the lead compound, the analogs were obtained in two ways: 1) The analogs containing N-phenylbenzenesulfonamide were selected in the Chemdiv compound library, and the binding mode of the compound and GR was predicted by molecular docking. Anti-inflammatory activity evaluation; 2) According to preliminary structure-activity relationship, order or synthesize compounds. The specific implementation is as follows:

Concrete reaction conditions and synthetic route are as follows:

Reaction Route 1:

Wherein, any position substituents on the benzene ring R=-CH ₃ , -F, -OCH ₃

Obtainment of 6-nitro-1,2,3,4-tetrahydroquinoline:

6-Nitroquinoline (1.74g, 10mmol), Hantatzsch ester (6.33g, 25.0mmol) and B(OH) ₃ (123.6mg, 2.0mmol) were placed in a 250mL single-neck flask, and 100mL of dichloroethane DCE was added as a solvent. The reaction was heated to 60°C overnight. After spotting the disappearance of the reaction starting material, an appropriate amount of silica gel was added, the solvent DCE was removed in vacuo, and the obtained crude product was separated through a column to obtain the target product (1.25 g, yield: 70%). ¹ H NMR (400MHz, CDCl ₃ ) δ 8.04 (s, 1H), 7.87 (d, J=2.8Hz, 1H), 6.93 (d, J=2.8Hz, 1H), 3.69 (t, J=6.4Hz) , 2H), 2.68 (t, J=6.8 Hz, 2H), 1.89 (p, J=6.8 Hz, 2H); MS (ESI): 179.08 [M+H] ⁺ .

Obtainment of N-furoyl-6-nitro-1,2,3,4-tetrahydroquinoline:

6-Nitro-1,2,3,4-tetrahydroquinoline (890.5 mg, 5 mmol) and 60% NaH (800 mg, 20 mmol) were placed in a 100 mL double-necked flask, and argon was replaced for protection. Add 30 mL of anhydrous THF at 0°C, and react at 0°C after the addition. After 0.5 h of reaction, furoyl chloride (783.2 mg, 6 mmol) was added dropwise at 0°C. The reaction was placed at room temperature for 2 h, and 10 mL of water was added to quench the reaction after monitoring the completion of the reaction by spotting. Extracted three times with ethyl acetate EA and water. The combined organics were washed with brine, dried _over anhydrous _Na2SO4 and filtered. The filtrate was evaporated under vacuum to give the crude product, which was purified by column chromatography. The title compound (1.09 g, yield: 80%) was obtained. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.08 (d, J=3.0 Hz, 1H), 7.89 (dd, J ₁ =9.0 Hz, J ₂ =3.0 Hz, 1H), 7.37 (dd, J ₁ =1.8 Hz, J ₂ =0.8Hz,1H),7.11-6.99(m,2H),6.48(dd,J ₁ =3.5Hz,J ₂ =2.0Hz,1H),4.03-3.90(m,2H),2.93( t, J=7.0 Hz, 2H), 2.09 (q, J=6.5 Hz, 2H); MS (ESI): 273.09 [M+H] ⁺ .

Obtainment of N-furoyl-6-amino-1,2,3,4-tetrahydroquinoline:

N-furanoyl-6-nitro-1,2,3,4-tetrahydroquinoline (54.4 mg, 0.2 mmol) was placed in a Schlenk tube, a catalytic amount of 10% Pd/C 5 mg was added, and 1 mL of MeOH was added as a After the solvent, _H2 was replaced and reacted at room temperature overnight, and the dot plate showed that the starting point completely disappeared. The reaction solution was filtered through celite to remove Pd/C, and the equivalent product was obtained after the solvent was spin-dried in vacuo. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (d, J=2.8 Hz, 1H), 7.89 (dd, J ₁ =8.0 Hz, J ₂ =2.0 Hz, 1H), 7.37 (dd, J ₁ =2.0 Hz, J ₂ =1.2Hz,1H),7.11-6.99(m,2H),6.48(dd,J ₁ =3.2Hz,J ₂ =1.2Hz,1H),4.78(s,2H),4.03-3.90( m, 2H), 2.93 (t, J=8.0 Hz, 2H), 2.09 (q, J=6.4 Hz, 2H); MS (ESI): 243.10 [M+H] ⁺ .

N-furanoyl-6-(2-methoxy-4,5-methylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-19):

N-furanoyl-6-amino-1,2,3,4-tetrahydroquinoline (48.4 mg, 0.2 mmol) was placed in a Schlenk tube, protected by argon replacement, 1 mL of anhydrous DCM was added, and the organic base pyridine was added (32 μL, 0.4 mmol). 2-methoxy-4,5-methylbenzenesulfonyl chloride (46.8 mg, 0.2 mmol) dissolved in 1 mL of anhydrous DCM was slowly added dropwise at 0°C. After the addition, the reaction was carried out at room temperature for 2h. After the completion of the reaction, a silica gel sample was added, and the final product (80 mg, 92%) was obtained by column chromatography. ¹ H NMR (500 MHz, Acetone-d6) δ 7.69 (s, 1H), 7.47 (dd, J ₁ =, 2.0 Hz, J ₂ =1.0 Hz, 1H), 7.22 (s, 1H), 7.11 (dt, J ₁ =2.0Hz,J ₂ =1.0Hz,1H),6.91-6.87(m,3H),6.61(dd,J ₁ =3.5Hz,J ₂ =1.0Hz,1H),6.48(dd,J ₁ = 3.5Hz, J ₂ =2.0Hz, 1H), 4.00(s, 3H), 3.81-3.79(m, 2H), 2.74(m, 2H), 2.17(s, 3H), 2.38(s, 3H), 1.96 -1.91 (m, 2H); MS (ESI): 441.12 [M+H] ⁺ .

N-furanoyl-6-(2-methoxy-5-fluorobenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-A15):

The above procedure gave the final product (60.2 mg, 70%). ¹ H NMR (500MHz, Acetone-d6) δ 8.69 (s, 1H), 7.79 (dt, J ₁ =8.0Hz, J ₂ =1.5Hz, 1H), 7.60-7.56 (m, 1H), 7.50-7.37 (m, 1H), 7.10 (dd, J ₁ =2.5 Hz, J ₂ =1.0 Hz, 1H), 7.05 (td, J ₁ =8.0 Hz, J ₂ =1.0 Hz, 1H), 6.89 (dd, J ₁ =9.0Hz,J ₂ =2.5Hz,1H),6.83(d,J=9.0Hz,1H),6.53(t,J=3.0Hz,1H),6.46(dd,J ₁ =3.5Hz,J ₂ = 2.0Hz,1H),4.00(s,3H),3.78(t,J=6.5Hz,2H),2.71(t,J=7.0Hz,2H),1.91(p,J=7.0Hz,2H).MS (ESI): 431.09[M+H] ⁺ .

N-furanoyl-6-(3,4-dimethoxybenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-A16):

The above procedure gave the final product (84 mg, 95%). ¹ H NMR (500MHz, Acetone-d6) δ 8.78 (s, 1H), 7.76-7.69 (m, 1H), 7.53 (dd, J ₁ =2.0Hz, J ₂ =1.0Hz, 1H), 7.10-7.02 (m,3H),6.89–6.82(m,2H),6.64(dd,J1 _{= 3.5Hz} ,J2=1.0Hz,1H),6.50(dd,J1 _{= 3.5Hz} ,J2=2.0Hz, 1H), 3.87(s, 3H), 3.65(s, 3H), 3.83–3.79(m, 2H), 2.75(td, J ₁ =7.0Hz, J ₂ =1.0Hz, 2H), 1.97–1.92(m , 2H). MS (ESI): 444.18 [M+H] ⁺ .

N-furanoyl-6-(4-methylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-A17):

The above procedure gave the final product (72.9 mg, 92%). ¹ H NMR (500MHz, Acetone-d6) δ 9.14 (s, 1H), 8.05-7.99 (m, 3H), 7.94 (d, J=8.5Hz, 2H), 7.53 (dd, J1 ₌ 2.0Hz, J ₂ =1.0Hz,1H),7.09(d,J=2.5Hz,1H),6.91(d,J=9.0Hz,1H),6.85(dd,J ₁ =9.0Hz,J ₂ =2.5Hz,1H ), 6.69(dd, J ₁ =3.5Hz, J ₂ =1.0Hz,1H),6.50(dd,J ₁ =3.5Hz,J ₂ =2.0Hz,1H),3.84–3.80(m,2H),2.76 (t, J=6.5 Hz, 2H), 2.42 (s, 3H) 1.97-1.93 (m, 2H); MS (ESI): 397.11 [M+H] ⁺ .

N-furanoyl-6-(4-fluorobenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-A19):

The above procedure gave the final product (64.2 mg, 80%). ¹ H NMR (400MHz, Acetone-d6)δ8.97(s,1H),7.92-7.84(m,2H),7.58(d,J=1.6Hz,1H),7.37(t,J=8.8Hz,2H ), 7.11 (d, J=2.4Hz, 1H), 6.94–6.86 (m, 2H), 6.70 (d, J=3.2Hz, 1H), 6.54 (dd, J ₁ =3.6Hz, J ₂ =1.6Hz , 1H), 3.85 (t, J=6.4 Hz, 2H), 2.79 (6.8 Hz, 2H), 1.99 (p, J=6.4 Hz, 2H); MS (ESI): 401.12 [M+H] ⁺ .

N-furanoyl-6-(4-nitrobenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-A22):

The above procedure gave the final product (61.5 mg, 72%). ¹ H NMR (400MHz, Acetone-d6)δ9.24(s,1H),8.46-8.39(m,2H),8.11-8.03(m,2H),7.57(d,J=1.6Hz,1H),7.12 (d, J=2.4Hz, 1H), 6.98–6.81 (m, 2H), 6.73 (d, J=3.6Hz, 1H), 6.53 (dd, J1 _{= 3.6Hz} , J2=2.0Hz, 1H) , 3.84 (t, J=6.4 Hz, 2H), 2.78 (t, J=6.4 Hz, 2H), 2.00–1.96 (m, 2H). MS(ESI): 428.12 [M+H] ⁺ .

N-furanoyl-6-(2-methoxy-5-fluoro-4-methylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-A23):

The above procedure gave the final product (81.0 mg, 88%). ¹ H NMR (500 MHz, Acetone-d6) δ 7.69 (s, 1H), 7.47 (dd, J ₁ =2.0 Hz, J ₂ =1.0 Hz, 1H), 7.22 (s, 1H), 7.11 (dt, J ₁ =2.0Hz, J2=1.0Hz, 1H), _6.91–6.87 (m, 2H), 6.61 (dd, J1 _{= 3.5Hz} , J2=1.0Hz, 1H), 6.48 (dd, J1 ₌ 3.5 Hz, J ₂ =2.0Hz,1H),4.00(s,3H),3.81–3.79(m,2H),2.74(td,J ₁ =7.0Hz,J ₂ =1.0Hz,2H),2.38(d, J = 0.5 Hz, 3H), 1.96-1.91 (m, 2H). MS (ESI): 461.08 [M+H] ⁺ .

Reaction Route 2:

N-anilinoyl-6-amino-1,2,3,4-tetrahydroquinoline:

Aniline (186.3mg, 2.0mmol), solid triphosgene (148.3mg, 1.0mmol) were added to a 25mL single-neck flask, 5mL anhydrous THF was added to dissolve, and triethylamine (1.2mL, 8.0mmol) was added dropwise at 0°C, A large amount of white solid was precipitated. After the dropwise addition, the reaction was moved to room temperature for 2 h. After the reaction was completed, the solvent was spin-dried in vacuo, 6-nitro-1,2,3,4-tetrahydroquinoline (178.1 mg, 1.0 mmol), N,N-diisopropylethylamine (0.52 mL, 3.0 mmol) were added. mmol) with 5 mL of solvent dichloromethane DCM. React overnight at room temperature. After the reaction, an appropriate amount of silica gel was added, the solvent DCM was removed in vacuo, and the obtained crude product was separated through a column to obtain the target product (124.8 mg, yield: 42%); MS(ESI): 298.08 [M+H ] ⁺ . The resulting product was subjected to reductive hydrogenation with 10% Pd/C (12.5 mg). Obtained equivalent product (112.2 mg); MS (ESI): 268.16 [M+H] ⁺ .

N-anilinoyl-6-(2-methoxy-4,5-dimethylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-A8):

The above procedure gave the final product HP-A8 (48.4 mg, 52%). ¹ H NMR (500 MHz, Acetone-d6) δ 10.20 (s, 1H), 8.78 (s, 1H), 7.76-7.69 (m, 2H), 7.53 (dd, J ₁ =2.0 Hz, J ₂ =1.0 Hz ,1H),7.10–7.02(m,3H),6.89–6.82(m,2H),6.64(dd,J1 _{= 3.5Hz} ,J2=1.0Hz,2H),6.50(dd,J1 ₌ 3.5Hz , J ₂ =2.0Hz, 1H), 3.87(s, 3H), 3.83–3.79(m, 2H), 2.87(s, 3H), 2.80(s, 3H), 2.75(td, J ₁ =7.0Hz, J ₂ =1.0 Hz, 2H), 1.97-1.92 (m, 2H).; MS (ESI): 466.16 [M+H] ⁺ .

N-anilinoyl-6-(4-methylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-A18):

The above procedure gave the final product HP-A18 (37.9 mg, 48%). ¹ H NMR (500 MHz, Acetone-d6) δ 8.69 (s, 1H), 7.79 (dt, J ₁ =8.0 Hz, J ₂ =1.5 Hz, 1H), 7.58 (ddd, J ₁ =8.5 Hz, J ₂ = 7.5 Hz, J ₃ =2.0 Hz, 1H), 7.50–7.37 (m, 1H), 7.19 (dd, J ₁ =8.5, J ₂ =1.0 Hz, 1H), 7.10 (dd, J ₁ =2.5 Hz, J ₂ =1.1Hz,1H),7.05(td,J ₁ =7.5Hz,J ₂ =1.0Hz,1H),6.89(dd,J ₁ =9.0Hz,J ₂ =2.5Hz,1H),6.83(d , J=9.0Hz, 1H), 6.53 (t, J=3.0Hz, 1H), 6.46 (dd, J1 ₌ 3.4Hz, J2=1.8Hz, 2H), 3.78 (t, J=6.4Hz, 2H ₎ ), 2.71 (t, J=6.6 Hz, 2H), 2.40 (s, 1H), 1.91 (p, J=6.5 Hz, 2H) ^. ; MS (ESI): 422.10 [M+H] ⁺ .

Reaction Route 3:

N-substituted benzoyl-6-amino-1,2,3,4-tetrahydroquinoline:

Various substituted carboxylic acid organic compounds (2.0 mmol) were added to a 25 mL single-neck flask, 5 mL of thionyl chloride SOCl ₂ was added, and the reaction was placed at a temperature of 100° C. for a reflux reaction for 4 h. After the reaction, the solvent was spin-dried, and an appropriate amount of anhydrous THF was added to dissolve the product. It was added to 6-nitro-1,2,3,4-tetrahydroquinoline (178.1 mg, 1.0 mmol)/NaH reaction system according to the method described above, and the reaction was carried out at room temperature for 2 h after the addition. The post-treatment method is the same as the above operation, and the obtained product is subjected to 10% Pd/C reductive hydrogenation. Equivalent product can be obtained.

N-pyrroyl-6-(2-methoxy-4,5-methylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-A1):

The above procedure gave the final product (61.5 mg, 70%). ¹ H NMR (500MHz, Acetone-d6) δ 8.71 (s, 1H), 7.68 (s, 1H), 7.57 (dd, J ₁ =5.0Hz, J ₂ =1.5Hz, 1H), 7.21 (s, 1H) ), 7.13(d, J=2.5Hz, 1H), 6.92–6.85(m, 3H), 3.99(s, 3H), 3.81(t, J=6.5Hz, 2H), 2.75–2.73(m, 2H) , 2.39 (s, 3H), 2.25 (s, 3H), 1.97–1.93 (m, 2H); MS (ESI): 440.18 [M+H] ⁺ .

N-Benzoyl-6-(2-methoxy-4,5-methylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-A3):

The above procedure gave the final product (79.2 mg, 88%). ¹ H NMR (400MHz, Acetone-d6)δ8.66(s,1H),7.55(d,J=6.8Hz,2H),7.32(d,J=8.6Hz,2H),7.13-7.07(m,3H) ), 7.01(s, 2H), 3.98(s, 3H), 3.72(t, J=6.4Hz, 2H), 2.68(t, J=6.8Hz, 2H), 2.27(s, 3H), 2.19(s ,3H),1.87( _p ,J=6.8Hz,3H),0.93(dq,J1 ₌ 6.0Hz,J2=3.2Hz,2H),0.76(dt,J1 ₌ 8.0Hz,J2= _3.2Hz , 2H); MS (ESI): 451.12 [M+H] ⁺ .

N-Cyclopropionyl-6-(2-methoxy-4,5-methylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-A4):

The above procedure gave the final product (58.8 mg, 71%). ¹ H NMR (400MHz, Acetone-d6)δ7.46(s,1H),7.24(s,1H),7.10(d,J=2.5Hz,1H),7.07-7.02(m,1H),7.00(s ,1H),3.81(s,3H),3.69(t,J＝6.4Hz,2H),3.32(s,3H),2.86(s,2H),2.68(t,J＝6.8Hz,2H),2.29 (s, 3H), 2.18 (s, 3H), 1.89 (p, J=6.8 Hz, 2H), 1.70 (d, J=8.0 Hz, 2H), 1.45 (dd, J ₁ =13.6 Hz, J ₂ = 10.4 Hz, 2H), 1.18 (d, J=9.2 Hz, 2H); MS (ESI): 415.18 [M+H] ⁺ .

N-Phenylacetyl-6-(2-methoxy-4,5-methylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-A7):

The above procedure gave the final product (64.1 mg, 69%). ¹ H NMR (400MHz, Acetone-d6) δ 7.62(s, 1H), 7.55(s, 1H), 7.43(d, J=8.0Hz, 2H), 7.32(d, J=8.6Hz, 2H), 7.13–7.07(m, 3H), 7.01(t, J=6.4Hz, 1H), 3.98(s, 3H), 3.72(t, J=6.4Hz, 2H), 2.74(s, 2H), 2.68(t , J=6.8Hz, 2H), 2.27(s, 3H), 2.19(s, 3H), 1.87( _p , J=6.8Hz, 2H), 0.93(dq, J1 ₌ 6.0Hz, J2=3.2Hz , 2H), 0.76 (dt, J ₁ =8.0 Hz, J ₂ =3.2 Hz, 2H); MS (ESI): 465.13 [M+H] ⁺ .

N-cyclohexanoyl-6-(2-methoxy-4,5-methylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-A13):

The above procedure gave the final product (71.2 mg, 78%). ¹ H NMR (400 MHz, Acetone-d6) δ 7.51 (s, 1H), 7.40 (tt, J ₁ =6.4 Hz, J ₂ =2.4 Hz, 1H), 7.32-7.25 (m, 4H), 7.10 (d , J=2.0Hz, 1H), 7.00(s, 1H), 6.78(dd, J1 ₌ 8.6Hz, J2=2.4Hz, 2H ₎ , 3.94(s, 3H), 3.75(t, J=6.4Hz , 2H), 2.79 (t, J=6.4Hz, 2H), 2.31 (s, 3H), 2.22 (s, 3H), 1.94 (q, J=6.4Hz, 2H) ^. ; MS (ESI): 457.23 [ M+H] ⁺ .

N-Thienyl-6-(2-methoxy-5-fluoro-4-methylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-B24):

The above procedure gave the final product (78.1 mg, 82%). ¹ H NMR (500MHz, Acetone-d6) δ 8.71 (s, 1H), 7.68 (s, 1H), 7.57 (dd, J ₁ =5.0Hz, J ₂ =1.5Hz, 1H), 7.21 (s, 1H) ), 7.13 (d, J=2.5Hz, 1H), 6.92–6.85 (m, 4H), 3.99 (s, 3H), 3.81 (t, J=6.5Hz, 2H), 2.75–2.73 (m, 2H) , 2.39 (s, 3H), 1.97–1.93 (m, 2H). MS (ESI): 477.09 [M+H]+.

N-Acetyl-6-(2-methoxy-5-fluoro-4-methylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-B25):

The above procedure gave the final product (79.2 mg, 88%). ¹ H NMR (500MHz, Acetone-d6)δ8.71(s,1H),7.65(s,1H),7.40-7.35(m,1H),7.26(d,J=6.5Hz,4H),7.21(s ,1H),7.09(dt,J1 ₌ 2.0Hz,J2=1.0Hz,1H ₎ ,6.73(s,2H),3.97(s,3H),3.74(t,J=6.5Hz,2H),2.78 (dd, J ₁ =7.0 Hz, J ₂ =1.0 Hz, 2H), 2.41-2.40 (m, 3H), 1.97-1.92 (m, 2H). MS (ESI): 409.12 [M+H] ⁺ .

N-Benzoyl-6-(2-methoxy-5-fluoro-4-methylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-B26):

The above procedure gave the final product (86.5 mg, 92%). ¹ H NMR (500MHz, Acetone-d6) δ 8.79 (s, 1H), 7.69 (s, 1H), 7.20 (s, 1H), 7.04 (dd, J ₁ =17.0 Hz, J ₂ =6.0 Hz, 2H ), 4.00(s, 3H), 3.66(t, J=6.5Hz, 2H), 2.66(t, J=7.0Hz, 2H), 2.13–2.02(m, 6H), 1.87(q, J ₁ =6.0 Hz, J ₂ =5.0 Hz, 2H). MS (ESI): 471.12 [M+H] ⁺ .

N-Cyclopropionyl-6-(2-methoxy-5-fluoro-4-methylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-B27):

The above procedure gave the final product (66.0 mg, 76%). ¹ H NMR (500MHz, Acetone-d6)δ8.81(s,1H),7.69(s,1H),7.33(d,J=9.0Hz,1H),7.20(s,1H),7.09-7.04(m ,2H),4.00(s,3H),3.71(t,J=6.5Hz,2H),2.67(t,J=7.0Hz,2H),2.36(s,3H),1.86(dd,J ₁ =9.0 Hz, J ₂ =4.5 Hz, 3H), 0.93-0.90 (m, 2H), 0.75-0.72 (m, 2H) ^. MS (ESI): 435.19 [M+H] ⁺ .

N-Cyclohexanoyl-6-(2-methoxy-5-fluoro-4-methylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-B28):

The above procedure gave the final product (74.2 mg, 78%). ¹ H NMR (600MHz, Acetone-d6)δ8.78(s,1H),7.69(d,J=1.2Hz,1H),7.20(s,1H),7.09-7.03(m,2H),4.00(s ,3H),3.66(t,J＝6.4Hz,2H),2.73–2.62(m,3H),2.36(s,3H),1.85(p,J＝6.6Hz,2H),1.64(dd,J ₁ =36.0Hz,J ₂ =12.0Hz,5H),1.42(td,J ₁ =12.6Hz,J ₂ =12.0Hz,J ₃ =3.6Hz,2H),1.22-1.05(m,3H).MS(ESI ): 477.18[M+H] ⁺ .

N-Pyridinyl-6-(2-methoxy-5-fluoro-4-methylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-B29):

The above procedure gave the final product (86.7 mg, 92%). ¹ H NMR (600MHz, DMSO-d6) δ9.93(s,1H), 7.73(s,1H), 7.62(s,1H), 7.29–7.22(m,2H), 7.14(s,1H), 6.87 –6.80(m, 2H), 3.89(s, 3H), 3.65 – 3.58(m, 2H), 3.35(s, 6H), 3.20(s, 3H), 2.54 – 2.50(m, 3H), 2.35(d , J=8.4 Hz, 6H), 1.55 (p, J=6.4 Hz, 2H). MS(ESI): 472.15 [M+H] ⁺ .

N-4-tert-Butylbenzoyl-6-(2-methoxy-5-fluoro-4-methylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-B30) :

The above procedure gave the final product (100.0 mg, 95%). ¹ H NMR (600MHz, Acetone-d6)δ8.72(s,1H),7.66(s,1H),7.36-7.31(m,2H),7.20(s,1H),7.11(d,J=2.4Hz ,1H),7.03–6.98(m,2H),6.75(dd,J ₁ =8.4Hz,J ₂ =2.4Hz,1H),6.67(s,1H),3.98(s,3H),3.75(t, J=6.4 Hz, 2H), 2.78 (t, J=6.4 Hz, 2H), 2.40 (s, 3H), 1.97-1.93 (m, 2H). MS (ESI): 527.20 [M+H] ⁺ .

N-4-Methoxybenzoyl-6-(2-methoxy-5-fluoro-4-methylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP-B31) :

The above procedure gave the final product (88.3 mg, 94%). ¹ H NMR (600MHz, Acetone-d6)δ8.69(s,1H),7.66(s,1H),7.21-7.20(m,1H),7.17(d,J=8.4Hz,2H),7.10-7.06 (m, 3H), 6.77–6.69 (m, 2H), 3.98 (s, 3H), 3.75–3.72 (m, 2H), 2.79–2.76 (m, 2H), 2.40 (d, J=0.6Hz, 3H ), 2.33 (s, 3H), 1.93 (q, J=6.6 Hz, 2H). MS (ESI): 501.17 [M+H] ⁺ .

N-3,4-Dimethoxybenzoyl-6-(2-methoxy-5-fluoro-4-methylbenzenesulfonamido)-1,2,3,4-tetrahydroquinoline (HP -B32):

The above procedure gave the final product (103.9 mg, 98%). ¹ H NMR(600MHz,DMSO-d6)δ9.94(s,1H),7.62(s,1H),7.24(s,1H),6.92(d,J＝2.4Hz,1H),6.86(d,1H) =1.8Hz,2H),6.83(d,J=1.6Hz,1H),6.72(d,J=8.4Hz,1H),6.65(dd,J ₁ =8.4Hz,J ₂ =2.4Hz,1H), 3.87(s, 3H), 3.76(s, 3H), 3.66(t, J=6.0Hz, 2H), 3.56(s, 3H), 2.70(t, J=6.6Hz, 2H), 2.35(s, 3H ), 2.09 (s, 2H), 1.84 (q, J=6.6 Hz, 2H); MS (ESI): 531.18 [M+H] ⁺ .

Example 3: Evaluation of HP-19 Based Analog Activity

Taking HP-19 as the lead compound, we obtained a total of 24 compounds. As shown in Tables 1 and 2, the transcriptional inhibitory activity of most compounds against NF-kb was greater than 50% when administered at 10 μM. For N-phenylsulfonamide compounds, only one HP-26 (ChemDiv ID: V016-8573) was purchased due to fewer skeleton types in the compound library. The activity evaluation is as follows:

Table 1 Inhibitory activity of N-phenylsulfonamide compounds (1) on NF-κB transcription level

Table 2 Inhibitory activity of N-phenylsulfonamide compounds (2) on NF-κB transcription level

The description of the embodiments is intended to explain the principles of the present invention and exemplify its practical application, so that others skilled in the art can utilize the present invention for implementation and modification. The scope of the invention is defined by the claims and their equivalents.

Claims (10)

1. The application of any one of the compounds with the structural formulas (I) - (VI) or the pharmaceutically acceptable salts thereof in preparing the medicine for treating the autoimmune disease,

wherein,

R¹、R²and R³Each independently of the others is hydrogen, halogen, cyano, nitro, SF₅SCN, amino, C₁-C₆Alkylamino radical, bis (C)₁-C₆) Alkylamino, hydroxy, carboxy, C₁-C₈Alkyl radical, C₃-C₆Cycloalkyl, C₅-C₇Cycloalkenyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₃-C₆Halogenocycloalkoxy, C₁-C₆alkyl-C₃-C₆Halogenocycloalkoxy, C₁-C₆alkyl-C₁-C₆Alkoxy radical, C₁-C₆alkyl-C₁-C₆Haloalkoxy, C₁-C₆alkoxy-C₁-C₆Alkoxy radical, C₁-C₆Alkyl-cyano, C₁-C₆alkyl-C₃-C₆Cycloalkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkenyloxy radical, C₂-C₆Alkynyl, C₂-C₆Alkynyloxy, SH, C₁-C₆Thioalkyl, C₁-C₆Sulfinylalkyl radical, C₁-C₆Sulfonylalkyl, C₁-C₆Halogenated sulfonylalkyl, C₁-C₆alkyl-C₁-C₆Alkoxyamino group, C₁-C₆Alkylcarbonyl group, C₃-C₆Cycloalkyl carbonyl group, C₁-C₆Halogenoalkylcarbonyl group, C₁-C₆Alkoxycarbonyl, C₁-C₆Alkylaminocarbonyl, bis (C)₁-C₆) Alkylaminocarbonyl, five-or six-membered aryl, five-or six-membered heteroaryl, C₁-C₆Alkyl-five-or six-membered aryl, five-or six-membered arylaminocarbonyl, five-or six-membered aryl-C₁-C₆Alkyl radical, C₁-C₆Alkyl-five-or six-membered heteroaryl, five-or six-membered heteroaryl-C₁-C₆Alkyl, five-or six-membered arylcarbonyl, five-or six-membered arylamido, five-or six-membered heteroarylcarbonyl, five-or six-membered heteroarylamido, five-or six-membered heteroarylaminocarbonyl, five-or six-membered heterocycle, C₁-C₆Alkyl-five-or six-membered heterocyclic group, five-or six-membered heterocyclic group-C₁-C₆Alkyl, five-or six-membered heterocyclylcarbonyl, five-or six-membered heterocyclylaminocarbonyl, an octato fourteen-membered heteroaromatic bicyclic or tricyclic ring system, C₁-C₆Alkyl-octa-to-deca-quaternary heteroaromatic bicyclic or tricyclic ring systems, octa-to-deca-quaternary heteroaromatic bicyclic or tricyclic ring systems-C₁-C₆Alkyl, octa-to deca-quaternary hetero-aryl bi-or tricyclic ring system based carbonyl, octa-to deca-quaternary hetero-aryl bi-or tricyclic ring system based amido, octa-to deca-quaternary hetero-aryl bi-or tricyclic ring system based aminocarbonyl;

or C₁-C₆Alkylamino, bis (C)₁-C₆) Alkylamino radical, C₁-C₈Alkyl radical, C₃-C₆Cycloalkyl radical, C₅-C₇Cycloalkenyl radical, C₁-C₆Haloalkyl, C₁-C₆Alkoxy radical, C₁-C₆Haloalkoxy, C₃-C₆Halogenocycloalkoxy, C₁-C₆alkyl-C₃-C₆Halogenocycloalkoxy, C₁-C₆alkyl-C₁-C₆Alkoxy radical, C₁-C₆alkyl-C₁-C₆Haloalkoxy, C₁-C₆alkoxy-C₁-C₆Alkoxy radical, C₁-C₆Alkyl-cyano, C₁-C₆alkyl-C₃-C₆Cycloalkyl, C₂-C₆Alkenyl radical, C₂-C₆Alkenyloxy radical, C₂-C₆Alkynyl, C₂-C₆Alkynyloxy, C₁-C₆Thioalkyl, C₁-C₆Sulfinylalkyl radical, C₁-C₆Sulfonylalkyl, C₁-C₆Halogenated sulfonyl alkyl, C₁-C₆alkyl-C₁-C₆Alkoxyamino group, C₁-C₆Alkylcarbonyl group, C₃-C₆Cycloalkyl carbonyl group, C₁-C₆Halogenoalkylcarbonyl group, C₁-C₆Alkoxycarbonyl, C₁-C₆Alkylaminocarbonyl, bis (C)₁-C₆) Alkylaminocarbonyl, five-or six-membered aryl, five-or six-membered heteroaryl, C₁-C₆Alkyl-five-or six-membered aryl, five-or six-membered arylaminocarbonyl, five-or six-membered aryl-C₁-C₆Alkyl radical, C₁-C₆Alkyl-five-or six-membered heteroaryl, five-or six-membered heteroaryl-C₁-C₆Alkyl, five-or six-membered arylcarbonyl, five-or six-membered arylamido, five-or six-membered heteroarylcarbonyl, five-or six-membered heteroarylamido, five-or six-membered heteroarylaminocarbonyl, five-or six-membered heterocycle, C₁-C₆Alkyl-five-or six-membered heterocyclic group, five-or six-membered heterocyclic group-C₁-C₆Alkyl, five-or six-membered heterocyclylcarbonyl, five-or six-membered heterocyclylaminocarbonyl, an eight-to ten-membered heteroaromatic bicyclic or tricyclic ring system, C₁-C₆Alkyl-octa-to-deca-quaternary heteroaromatic bicyclic or tricyclic ring systems, octa-to-deca-quaternary heteroaromatic bicyclic or tricyclic ring systems-C₁-C₆Alkyl, octa-to deca-quaternary heteroaromatic bicyclic or tricyclic ringIs selected from the group consisting of aminocarbonyl, amide of an eight-to fourteen-heteroaromatic bicyclic or tricyclic ring system, aminocarbonyl of an eight-to fourteen-heteroaromatic bicyclic or tricyclic ring system, substituted with hydrogen, halogen, cyano, nitro, hydroxy, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆Haloalkoxy or C₁-C₆Thioalkyl mono-or polysubstituted;

p is 1,2 or 3;

z is O, N or C;

A¹，A²each independently is H, C, CR¹O, S or NR¹Or form a ring-merged structure I with a benzene ring and consecutive atoms

Or the fused ring structure I is substituted by at least one R¹Substituted;

Q¹，Q²each independently is H, C, CR¹O, S or NR¹Or form a ring-merged structure with Z and the successive atoms II

Or the said fused ring structure II is substituted by at least one R¹And (4) substituting.

2. The use of claim 1, wherein R is¹Is amino, halogen, C₁-C₈Alkyl radical, C₁-C₆Alkylcarbonyl group, C₃-C₆Cycloalkyl carbonyl group, C₁-C₆Halogenoalkylcarbonyl group, C₁-C₆Alkoxycarbonyl group, C₁-C₆Alkylaminocarbonyl, bis (C)₁-C₆) An alkyl amino carbonyl group,

or amino, C₁-C₈Alkyl radical, C₁-C₆Alkylcarbonyl group, C₃-C₆Cycloalkyl carbonyl group, C₁-C₆Halogenoalkylcarbonyl group, C₁-C₆Alkoxycarbonyl group, C₁-C₆Alkylaminocarbonyl, bis (C)₁-C₆) By hydrogen, halogen, cyano, nitro, hydroxy, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₆Haloalkoxy or C₁-C₆Thioalkyl groups are mono-or polysubstituted.

3. The use of claim 1, wherein R is²And R³Is a combination of H and a substituted benzo ring,

said substituted benzo ring is

4. The use of claim 1, wherein Z, Q¹，Q²The substituted piperidine, the substituted indoline and the substituted piperazine are formed together.

5. The use of claim 1, wherein the compound has the formula:

6. the use of any one of claims 1 to 5, wherein the compound has glucocorticoid receptor binding activity, and wherein inhibition of inflammatory factor expression is modulated by targeting the glucocorticoid receptor, inhibiting the NF- κ B signaling pathway and/or the AP1 signaling pathway.

7. The use according to any one of claims 1 to 5, wherein the autoimmune disease is asthma, rheumatoid arthritis, psoriasis, inflammation.

8. Sulfonamide compounds of the formula shown in any one of the following,

9. a pharmaceutical composition comprising a therapeutically effective amount of one or more sulfonamide compounds of claim 8, or a pharmaceutically acceptable salt or deuterate thereof, and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition of claim 9, wherein the pharmaceutically acceptable salt is a hydrochloride, benzenesulfonate, methylbenzenesulfonate, phosphate, maleate, sulfate, acetate, citrate, fumarate, or tartrate salt.

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