Indole compound as well as preparation method and application thereof

Abstract

The invention relates to an indole derivative as well as a preparation method and application thereof. The compound is a compound shown as a formula (I) or pharmaceutically acceptable salt thereof, Ar3-R-Ar1-Ar2 (formula I). A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided. The invention also provides application of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof in preparation of a CYP1A1 inhibitor. The compound provided by the invention has good safety and curative effect, and can be used for treating or preventing bacterial infection, sepsis, inflammation or organ injury.

Description

Technical Field

[0001] This invention relates to the field of chemical pharmaceutical technology, specifically to small molecule drugs, and particularly to a compound or its salt that can be used as a CYP1A1 enzyme activity inhibitor or an antibacterial drug, as well as its preparation method and uses. Background Technology

[0002] The cytochrome P450 superfamily (CYP) is a key monooxygenase system in the human body, widely involved in the metabolism of endogenous substances (such as steroids and fatty acids) and exogenous compounds (such as drugs, toxins, and carcinogens). Among them, CYP1 family members CYP1A1, CYP1A2, and CYP1B1 play a central role in xenobiotic metabolism. In particular, CYP1A1, due to its broad substrate spectrum and unique tissue distribution characteristics, has become an important target for drug metabolism, toxicology, and disease mechanism research.

[0003] CYP1A1 is mainly expressed in extrahepatic tissues such as the lungs, gastrointestinal tract, and skin. Its catalytic activity encompasses various oxidation reactions, including hydroxylation, epoxidation, and O-demethylation, enabling it to metabolize various environmental carcinogens and endogenous bioactive substances, such as polycyclic aromatic hydrocarbons (PAHs), dioxins, and aflatoxins. Some epoxidation intermediates among CYP1A1 metabolites are strongly electrophilic, forming covalent adducts with DNA, inducing gene mutations, and thus participating in the occurrence and progression of various malignant tumors (such as lung cancer, liver cancer, breast cancer, and prostate cancer). Furthermore, high expression of CYP1A1 in tumor cells has been shown to be closely related to cancer cell proliferation, migration, and chemotherapy resistance, suggesting its potential value as a tumor marker and therapeutic target.

[0004] Besides tumorigenesis, CYP1A1 is also involved in the development and progression of various inflammatory and infectious diseases. Studies have shown that CYP1A1 expression is regulated by the aryl hydrocarbon receptor (AhR) signaling pathway, which plays a crucial role in inflammatory responses, oxidative stress, and immune regulation. CYP1A1 inhibits the arginine-guanidine-polyamine / γ-aminobutyric acid (GABA) metabolic axis, thereby suppressing the mobilization capacity of macrophages under infectious conditions and exacerbating sepsis-related organ damage (such as acute kidney injury and intestinal barrier dysfunction). In pathogen infection models such as Mycoplasma and Citrobacter, high expression of CYP1A1 has also been shown to be positively correlated with disease severity. Therefore, CYP1A1 not only participates in the metabolism of exogenous toxins but also regulates host immune responses and inflammatory damage through metabolic reprogramming mechanisms, becoming a potential node for therapeutic intervention in infectious diseases.

[0005] Given the propathogenic effects of CYP1A1 in various major diseases, its inhibitors have been considered a promising pharmacological tool. However, existing CYP1A1 inhibitors generally suffer from poor selectivity, low bioavailability, and high toxicity, and no drugs targeting this target have yet been approved for marketing. Particularly in the field of anti-infective therapy, the increasing resistance to traditional antibiotics has led to a continuous rise in global bacterial infection-related mortality. According to the 2019 Global Burden of Disease Study, bacterial infection-related deaths reached 13.7 million, accounting for 13.6% of all deaths worldwide, making it the second leading cause of death after ischemic heart disease. Traditional antibiotic development is trapped in a vicious cycle of "resistance-new drugs-re-resistance," highlighting the urgent need to develop novel non-antibiotic anti-infective strategies.

[0006] Against this backdrop, intervention strategies targeting the host metabolic enzyme CYP1A1 offer a novel approach to the treatment of infectious diseases. By inhibiting CYP1A1 activity, it is possible to block its mediated pathological metabolic pathways, restore host immune homeostasis, and thus achieve anti-infective therapeutic effects without relying on antibiotics. However, current technologies have not yet disclosed CYP1A1 inhibitors with high activity, high selectivity, and low toxicity, and there is also a lack of structural optimization and drug development studies targeting this target. Therefore, developing novel CYP1A1 inhibitors and establishing patent protection around their chemical structures, preparation methods, and pharmaceutical applications has significant scientific and industrial value.

[0007] Some compounds that inhibit CYP1A1 enzyme activity and are used to treat sepsis have been disclosed in Chinese invention patent ZL 202411096223.2, but it remains very important to find and develop new structural chemical entities with better efficacy or lower toxicity. Summary of the Invention

[0008] The purpose of this invention is to provide a class of indole compounds and a method for synthesizing such compounds. The indole compounds provided by this invention can be used to prevent or treat systemic inflammatory responses and autoimmune disorders, and have been demonstrated to have good safety and efficacy in clinical trials.

[0009] The chemical structure, synthesis method, and pharmacological effects of the indole compounds in this invention have not been reported in any literature or patents.

[0010] This invention first provides a compound of formula I or a pharmaceutically acceptable salt thereof.

[0011] Ar3-R-Ar1-Ar2 (Formula I)

[0012] Where R is Ar1 is a five-membered heteroaryl group containing one or two heteroatoms independently selected from N and O, which is substituted by a halogen group, a C1-6 alkyl group, a C1-6 alkynyl group, or a phenyl group; Ar2 is a phenyl or pyridyl group substituted by a C1-6 alkyl group, an ester group, or a fused group; Ar1 ​​and Ar2 are fused together; Ar3 is an unsubstituted or substituted phenyl, pyridyl, furanyl, thiophene, indolyl, indole, indocyanine, methylenedioxyphenyl, N,N'-dimethylindocyanine, benzofuran, indanyl, or naphthoquinonefuranyl group.

[0013] In one embodiment of the invention, Ar3 is selected from...

[0014] Any group in it.

[0015] In one embodiment of the invention, Ar1-Ar2 are selected from...

[0016] Any group in it.

[0017] In one embodiment of the invention, the compound is selected from...

[0018] and Any one of them.

[0019] The present invention also provides a pharmaceutical composition comprising the above-described compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0020] Another aspect of the present invention provides a method for preparing the above-described compound or a pharmaceutically acceptable salt thereof, characterized in that it comprises:

[0021] Optionally, 5-(2-(triphenyl-λ) 5 -phosphine subunit)acetyl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one and Ar3–CHO are reacted to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0022] Optionally, the corresponding ketone and aldehyde are refluxed under sodium hydroxide / methanol or piperidine / ethanol conditions to obtain the compound of formula (I) or a pharmaceutically acceptable salt thereof;

[0023] Ar3 is a phenyl, pyridyl, furanyl, thiophene, indolyl, indocyanine, methylenedioxyphenyl, N,N'-dimethylindocyanine, benzofuran, indanyl, or naphthoquinonefuranyl that is unsubstituted or substituted by one or more substituents selected independently from halogen, C1-6 alkyl, C1-6 alkynyl, and ester.

[0024] The present invention further provides the use of the above-described compounds or pharmaceutically acceptable salts thereof in the preparation of CYP1A1 inhibitors.

[0025] The present invention provides the use of the above-described compounds or pharmaceutically acceptable salts thereof, or the above-described pharmaceutical compositions, in the preparation of medicaments for treating or preventing tumors, bacterial infections, sepsis, inflammation, or organ damage;

[0026] In one embodiment of the invention, the disease or condition is a bacterial infection or the resulting sepsis, inflammation, or organ damage.

[0027] In one embodiment of the present invention, the inflammation and / or organ damage is one or more of the following: skin, muscle, bone, brain, cerebellum, brainstem, spinal cord, eye, ear, nose, tongue, heart, blood vessels, pharynx, trachea, lung, esophagus, stomach, small intestine, large intestine, liver, gallbladder, pancreas, kidney, bladder, urethra, ovary, uterus, testis, spleen, thymus, lymphatic vessels, or lymph nodes.

[0028] In one embodiment of the invention, the inflammation and / or organ damage is one or more inflammations or damages of the liver, kidney, or heart.

[0029] The beneficial effects of the above-described technical solution of the present invention are as follows:

[0030] The indole compound in this invention exerts a completely different mechanism of action in treating sepsis compared to existing drugs such as glucocorticoids, recombinant human activated protein C, and the traditional Chinese medicine injection "Xuebijing". It exerts its therapeutic effect through host-directed therapy (HDT) via macrophage clearance of pathogens, providing a new approach for treating systemic inflammatory response-related diseases. The indole compound described in this invention can significantly reduce the activity of CYP1A1 enzyme in a concentration-dependent manner in Caco 2 cells; in CYP1A1... hi In RAW cells, the activity of the CYP1A1 enzyme can be significantly reduced in a concentration-dependent manner. Cell-level enzyme activity assays indicate that the indole compound provided in this invention has an antagonistic effect on systemic inflammatory response-related diseases and can be used for the prevention and treatment of such diseases. Attached Figure Description

[0031] Figure 1 The image shows the ¹H NMR spectrum of compound 1.

[0032] Figure 2 The image shows the ¹H NMR spectrum of compound 2.

[0033] Figure 3 The image shows the ¹H NMR spectrum of compound 26.

[0034] Figure 4 The image shows the ¹H NMR spectrum of compound 39.

[0035] Figure 5 The image shows the ¹H NMR spectrum of compound 30.

[0036] Figure 6 The graph shows the EROD enzyme activity results obtained by performing EROD assays on Caco-2 cells for compounds at various concentrations. (a) is compound 12, (b) is compound 16, (c) is compound 17, (d) is compound 28, (e) is compound 30, (f) is compound 31, and (g) is compound 37. The horizontal axis represents the concentration of each compound (µM), and the vertical axis represents the enzyme activity (optical density (OD)).

[0037] Figure 7 CY was used for each concentration of compound (a) 12, (b) 16, (c) 17, (d) 28, (e) 30, (f) 31, and (g) 37. h A graph showing the EROD enzyme activity intensity obtained from the EROD assay in RAW cells. The horizontal axis represents the concentration of each compound (µM), and the vertical axes represent the normalized relative enzyme activity (OD) based on the negative control group. Figure 8 IC50 of compounds 12(a), 16(b), 17(c), 28(d), 30(e), 31(f), 33(g), and 37(h) in Caco 2 cells. 50 value. Figure 9 Compounds 12(a), 16(b), 17(c), 28(d), 30(e), 31(f), 33(g), and 37(h) were subjected to CY... h IC in RAW cells 50 value. Detailed Implementation

[0038] To make the technical problems, technical solutions and advantages of the present invention clearer, a detailed description will be given below in conjunction with the accompanying drawings and specific embodiments.

[0039] Unless otherwise specified, all reagents used in this embodiment are of analytical grade, and the progress of all chemical reactions is detected by thin-layer chromatography.

[0040] Unless otherwise specified, all reagents used in this embodiment are chemically pure, and the progress of all chemical reactions is monitored by thin-layer chromatography (TLC).

[0041] As used herein, the term "substituted" means that one or more hydrogen atoms on a specified group are replaced, where chemically permissible, by a specific group, radical, or moiety, i.e., a substituent. As used herein, the term "substituent" means a chemical group, radical, or moiety covalently attached to or (if appropriate) fused to a parent group or moiety. As used herein, the term "optionally substituted" means optionally substituted by a substituent, which includes parallel embodiments of "substituted" and "unsubstituted," and is equivalent to the term "substituted or unsubstituted." This term may further define the substituent as a specified group; for example, the term "optionally methyl substituted" means optionally substituted by a methyl group, which includes parallel embodiments of "substituted" and "unsubstituted," and is equivalent to the term "substituted or unsubstituted." This term can also be further modified by quantifiers, for example, the term "optionally monosubstituted" means optionally substituted by one substituent, which includes parallel technical solutions of "substituted by one substituent" and "unsubstituted", and can be equivalent to the term "substituted or unsubstituted by one substituent"; the term "optionally methyl monosubstituted" means optionally substituted by one methyl group, which includes parallel technical solutions of "substituted by one methyl group" and "unsubstituted", and can be equivalent to the term "substituted or unsubstituted by one methyl group".

[0042] As used herein, the term "pharmaceutically acceptable salt" may refer to a salt prepared from a pharmaceutically acceptable nontoxic alkali or acid.

[0043] When a compound is basic, its corresponding salt can be prepared from pharmaceutically acceptable, non-toxic acids (including inorganic and organic acids). Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, cuprous, ferric, ferrous, lithium, magnesium, potassium, sodium, and zinc salts, especially ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from organic bases include salts of primary, secondary, and tertiary amines, as well as cyclic and substituted amines (such as naturally occurring and synthetic substituted amines). Salts derived from organic bases include, but are not limited to, salts of arginine, betaine, caffeine, choline, N′,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, heparin, isopropylamine, lysine, methyl reduced glucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0044] When a compound is acidic, its corresponding salt can be prepared from pharmaceutically acceptable non-toxic alkalis (including inorganic and organic bases). Salts derived from organic acids include, but are not limited to, acetates, benzenesulfonates, benzoates, camphorsulfonates, citrates, ethanesulfonates, fumarates, gluconates, glutamates, hydrobromide, hydrochlorides, hydroxyethanesulfonates, lactates, maleates, malates, mandelates, methanesulfonates, mucilages, nitrates, pyrates, pantothenates, phosphates, succinates, sulfates, tartrates, and p-toluenesulfonates.

[0045] As used herein, the term "inhibition" means the complete or partial prevention, reduction, inhibition, or inactivation of the physiological function (i.e., activity) of one or more specific proteins (such as CYP1A1); the term "inhibitor" means a substance (e.g., a small molecule compound, but not limited thereto) capable of completely or partially preventing, reducing, inhibiting, or inactivating the physiological function (i.e., activity) of one or more specific proteins (such as CYP1A1). For example, a "CYP1A1 inhibitor" is a substance that prevents or reduces, inhibits, or inactivates the physiological function (i.e., activity) of CYP1A1. CYP1A1 inhibitors can inhibit the activity of CYP1A1 by binding to or interacting with CYP1A1, but are not limited thereto. CYP1A1 inhibitors can also prevent or reduce the activity of CYP1A1 by preventing or reducing the expression of the CYP1A1 gene. CYP1A1 inhibitors can lead to a decrease in the expression level of CYP1A1, such as a decrease in the level of CYP1A1 mRNA or CYP1A1 protein, further reducing the activity of CYP1A1. Inhibitors of CYP1A1 can include transcriptional repressors that reduce CYP1A1 expression levels. All means and methods that result in reduced CYP1A1 activity (possibly due to lower expression) should be considered as part of the CYP1A1 inhibitors used in this article.

[0046] As used herein, the term “treatment” can refer to the eradication, suppression, reduction, or delay of a disease, disorder, or condition, such as eradicating, suppressing, reducing, or delaying the development of at least one clinical symptom, or reducing or improving at least one bodily parameter, including those that the patient may not be able to identify. “Treatment” can be physical (e.g., stabilization of identifiable symptoms), physiological (e.g., stabilization of bodily parameters), or modulating the disease, disorder, or condition in both. “Treatment” can be slowing the onset or progression rate of a condition, disorder, or disease, reducing or alleviating associated symptoms, producing complete or partial remission of the condition, or a combination thereof. The results obtained by “treatment” include, but are not limited to, reduction or alleviation of symptoms, reduction in disease severity, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or slowing of the disease state, and remission (partial or complete remission), whether detectable or undetectable. “Treatment” can also refer to extended survival relative to the expected survival time without treatment. "Treatment" can also include the suppression or reduction of an increase in the severity of a pathological state or symptoms relative to the absence of treatment, and does not necessarily imply the complete cessation of the disease, symptom, or condition. An individual requiring treatment (e.g., a person) may be an individual who already suffers from the relevant disease, symptom, or condition.

[0047] As used herein, the term "prevention" can refer to the eradication, suppression, reduction, or delay of the risk of developing a disease, condition, or illness, or the eradication, suppression, reduction, or improvement of a potential disease, condition, or illness that is being prevented. An individual requiring prevention (e.g., a person) can be an individual who does not yet have the relevant disease, condition, or illness. "Prevention" includes delaying the onset of a disease relative to when no treatment has been given to the individual, and does not necessarily mean that the relevant disease, condition, or illness is permanently prevented. To obtain the benefit of prevention, a pharmaceutical composition may be administered to a patient at risk of developing a particular disease or to a patient with one or more physiological symptoms of a disease, even if the disease has not yet been diagnosed.

[0048] Unless otherwise stated, methods for evaluating the effectiveness of treatment and / or prevention of disease are generally known in the art.

[0049] R¹ can be an aryl or heteroaryl group that has been optionally substituted.

[0050] The optional substitution can refer to substitution by a substituent, that is, R¹ can be an aryl or heteroaryl group substituted by one or more substituents.

[0051] In some embodiments, the substituent may be: halogen (such as fluorine, chlorine, bromine, iodine); alkyl (such as C... 1-6 Alkyl groups, especially C 1-4Alkyl groups, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.; cycloalkyl groups (such as C... 3-8 Cycloalkyl groups, especially cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.; alkenyl groups (such as C... 2-6 Alkenyl groups, especially vinyl, propenyl, propenyl, butenyl, butenyl, butenyl, and butenyl; alkynyl groups (such as C...). 2-6 Alkenyl, especially ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, etc.; aryl (such as phenyl, naphthyl, anthracene, etc.); aralkyl (such as benzyl, phenethyl, etc.); amino; primary amino (such as methylamino, ethylamino, propanyl, butylamino, phenylamino, etc.); secondary amino (such as dimethylamino, diethylamino, diphenylamino, etc.); aminoalkyl (such as aminomethyl, aminoethyl, aminopropyl, aminobutyl, etc.); acylamino (such as formamide, acetylamino, propionylamino, butyrylamino, benzylamino, etc.); cyano; nitro; nitroso; hydroxyl; alkoxy (such as methoxy, ethoxy, propoxy, butoxy, phenoxy, etc.); trifluoromethoxy; hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, etc.); acyl (such as formyl, acetyl, propionyl, butyryl, benzyl, etc.); carbamoyl; carboxyl; alkoxycarbonyl ( Examples include tert-butyloxycarbonyl); aryloxycarbonyl (e.g., benzyloxycarbonyl); phosphonyl; primary phosphonyl (e.g., methylphosphonyl, ethphosphonyl, propionylphosphonyl, butylphosphonyl, phenylphosphonyl, etc.); secondary phosphonyl (e.g., dimethylphosphonyl, diethylphosphonyl, diphenylphosphonyl, etc.); phosphonylalkyl (e.g., phosphonomethyl, phosphonoethyl, phosphonopropyl, phosphonobutyl, etc.); phosphonyl; phosphonoylene; mercapto; alkylthio (e.g., methylthio, ethio, propionyl, butylthio, phenylthio, etc.); mercaptoalkyl (e.g., mercaptomethyl, ... Mercaptoethyl, mercaptopropyl, mercaptobutyl, etc.; sulfonyl groups (such as methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl, benzylsulfonyl, etc.); sulfinyl groups (such as methylsulfinyl, ethanesulfinyl, propanesulfinyl, butanesulfinyl, benzylsulfinyl, etc.); sulfonic acid groups; sulfinyl groups; boronic acid groups; optionally substituted silyl groups (e.g., trimethylsilyl); or optionally substituted siloxy groups (e.g., tert-butyldimethylsiloxy), but not limited thereto. In some embodiments, the substituents are further substituted by one or more additional substituents.

[0052] In some embodiments, R¹ may be an optionally substituted aryl group, particularly an optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted anthracene group. In some embodiments, the optionally substituted aryl group (such as an optionally substituted phenyl, naphthyl, or anthracene group) may be a halogenated and / or alkynylated aryl group (such as a halogenated and / or alkynylated phenyl, naphthyl, or anthracene group), particularly a halogenated aryl group (such as a halogenated phenyl, naphthyl, or anthracene group), or particularly an alkynylated aryl group (such as an alkynylated phenyl, naphthyl, or anthracene group). In some embodiments, the optionally substituted phenyl group (including the optionally substituted phenyl group in an optionally substituted styryl group) may be a halogenated and / or alkynylated phenyl group, particularly a halogenated phenyl group, or particularly an alkynylated phenyl group. In some embodiments, the optionally substituted phenyl group may be... , where: n is 0, 1, 2, 3, 4, or 5, especially 1, 2, 3, 4, or 5, even more especially 1; each X is independently selected from the substituents described above, especially halogens or alkynyl groups (such as fluorine or alkynyl), even more especially halogens (such as fluorine), or especially alkynyl groups.

[0053] In some embodiments, R¹ or the optionally substituted phenyl group may be a fluorophenyl (such as 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl), a difluorophenyl (such as 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, or 3,5-difluorophenyl), a trifluorophenyl (such as 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, or 3,4,5-trifluorophenyl), a tetrafluorophenyl (such as 2,3,4,5-tetrafluorophenyl, 2,3,4,6-tetrafluorophenyl, or 2,3,5,6-tetrafluorophenyl), or a pentafluorophenyl (2,3,4,5,6-pentafluorophenyl).

[0054] In some embodiments, R¹ may be an optionally substituted heteroaryl group. In some embodiments, R¹ or the optionally substituted heteroaryl group may be optionally substituted, particularly optionally methyl-substituted, aza, oxa, thia, azaoxa, or azathia, a five-membered heterocyclic group, a six-membered heterocyclic group, a six-membered cyclopentacyclic group (such as benzo[5] cyclopentacyclic group), or a six-membered cyclopentacyclic group (such as benzo[6] cyclopentacyclic group). In some embodiments, R¹ or the optionally substituted heteroaryl group may be optionally methyl-substituted, aza, oxa, or thia, a five-membered heterocyclic group, a six-membered heterocyclic group, a benzo[5] cyclopentacyclic group, or a benzo[6] cyclopentacyclic group.

[0055] In some embodiments, R¹ may be optionally substituted with pyrroloyl, furanyl, thiopheneyl, pyrazolyl, imidazoleyl, thiazolyl, isothiazolyl, thiazolyl, isothiazolyl, pyridyl, pyranyl, thiazolyl, pyrazinyl, pyrazinyl, thiazolyl, benzopyrroloyl (such as indoleyl or isoyindoleyl), benzofuranyl, benzothiopheneyl, benzopyrazolyl, or benzimidazoleyl (such as indoleyl). ), benzo[azolyl], benzo[iso[azolyl], benzo[thiazolyl], benzo[isothiazolyl], benzo[pyridyl] (such as quinolinyl or isoquinolinyl), benzo[pyranyl] (such as chromenyl or isochromenyl), benzo[thiaranyl], benzo[pyridazinyl] (such as terazinyl or phthalazinyl), benzo[pyrimidinyl] (quinazolinyl), benzo[azolyl], benzo[thiazolyl], purine, naphthidyl, or pteridinyl. In some embodiments, R¹ may be optionally substituted pyridyl, pyrroloyl, quinolinyl, indolyl, furanyl, benzo[furanyl], thiophene, or benzo[thiophene].

[0056] In some embodiments, R¹ may be an optionally substituted pyridyl group (such as optionally substituted pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl), a pyrroloyl group (such as optionally substituted 1H-pyrrolo-2-yl or 1H-pyrrolo-3-yl), a quinolinyl group (such as optionally substituted quinolin-2-yl, quinolin-3-yl, or quinolin-4-yl), an indoleyl group (such as optionally substituted 1H-indole-2-yl or 1H-indole-3-yl), or a thiophenyl group (such as optionally substituted thiophene-2-yl or thiophene-3-yl), particularly pyridyl, pyrroloyl, quinolinyl, indoleyl, or thiophenylyl groups with optional methyl monosubstituted pyridyl, pyrroloyl, quinolinyl, indoleyl, or thiophenyl groups. In some embodiments, R¹ may be an optionally substituted pyridyl group, particularly methylpyridyl, and more particularly 6-methylpyridin-3-yl. In some embodiments, R¹ may be an optionally substituted pyrrole group, particularly methylpyrrole, and more particularly 1-methyl-1H-pyrrole-2-yl. In some embodiments, R¹ may be an optionally substituted quinolinyl group, particularly quinolinyl, and more particularly quinolin-2-yl or quinolin-3-yl. In some embodiments, R¹ may be an optionally substituted indole group, particularly methylindole, and more particularly 1-methyl-1H-indole-3-yl. In some embodiments, R¹ may be an optionally substituted thiophenyl group, particularly thiophenyl, and more particularly thiophen-2-yl or thiophen-3-yl.

[0057] In some embodiments, R¹ may be phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 2,4,5-trifluorophenyl, 2,3,4,5,6-pentafluorophenyl, 4-borate-2-fluorophenyl, 2-chloro-4-fluorophenyl, 2-ethynylphenyl, 3-ethynylphenyl, 4-ethynylphenyl, 4-tert-butylphenyl, 4-phenylphenyl, 4-cyanophenyl, 4-(dimethylamino)phenyl, 4-nitrophenyl, 4-butoxyphenyl, 3-(trifluoromethoxy)phenyl, 4-(tert-butyldimethylsiloxy)phenyl, 2-(diphenylphosphino)phenyl, 4-methylthiophenyl, 1-naphthyl, 9-anthrayl, 1-(tert-butoxycarbonyl)-1H-pyrrole-2-yl, 1-methyl-1H-pyrrole -2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 6-methylpyridin-3-yl, 2-bromopyridin-3-yl, pyrimidin-2-yl, quinoline-2-yl, quinoline-3-yl, 1-acetyl-1H-indole-3-yl, 1-methyl-1H-indole-3-yl, 1-benzyl-1H-indole-3-yl, 1-benzyl-5-methoxy-1H-indole -3-yl, furan-3-yl, furan-2-yl, benzo[b]furan-3-yl, benzo[b]furan-2-yl, 5-nitrofuran-2-yl, 5-iodofuran-2-yl, thiophene-2-yl, thiophene-3-yl, benzo[b]thiophene-2-yl, cyclopropane, (E)-styryl, (E)-4-fluorostyryl, phenylethynyl, or trimethylsilylethynyl.

[0058] In some embodiments, R¹ may be fluorophenyl, trifluorophenyl, or ethynylphenyl, or optionally methyl monosubstituted pyridyl, pyrroleyl, quinolinyl, indolyl, or thiophenyl; particularly fluorophenyl or ethynylphenyl.

[0059] In some embodiments, R¹ may be 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4,5-trifluorophenyl, 2-ethynylphenyl, 3-ethynylphenyl, 4-ethynylphenyl, 6-methylpyridin-3-yl, 1-methyl-1H-pyrrolo-2-yl, 1-methyl-1H-indol-3-yl, quinolin-2-yl, quinolin-3-yl, thiophen-2-yl, or thiophen-3-yl; particularly 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4,5-trifluorophenyl, 2-ethynylphenyl, 3-ethynylphenyl, 4-ethynylphenyl, 6-methylpyridinol-3-yl, 1-methyl-1H-pyrrolo-2-yl, 1-methyl-1H-indol-3-yl, quinolin-2-yl, quinolin-3-yl, thiophen-2-yl, or thiophen-3-yl; The following are quinoline-3-yl, 1-methyl-1H-pyrrolo-2-yl, 1-methyl-1H-indol-3-yl, quinoline-2-yl, or thiophen-3-yl; more particularly 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4,5-trifluorophenyl, 2-ethynylphenyl, 3-ethynylphenyl, 4-ethynylphenyl, 6-methylpyridin-3-yl, 1-methyl-1H-pyrrolo-2-yl, or 1-methyl-1H-indol-3-yl; even more particularly 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-ethynylphenyl, 3-ethynylphenyl, or 4-ethynylphenyl.

[0060] R2 can be an aryl or heteroaryl group that can be substituted.

[0061] The present invention provides compounds as shown in compounds 1 to 37.

[0062] The following examples illustrate the preparation steps of some representative compounds of this application. Those skilled in the art, based on the specific preparation methods of the compounds disclosed in Examples 1-5 below, and in conjunction with conventional preparation and purification methods in the art, should be able to deduce the preparation methods of other compounds of formula (I).

[0063] Example 1 Synthesis of indole compound 1 (Structural formula of the indole compound (I) synthesized in this example)

[0064] 1.1 Experimental Methods: The synthesis method is as follows:

[0065] Weigh 0.2 mmol (1 equiv.) of 1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxaldehyde, 0.2 mmol (1 equiv.) of 1-methyl-3-acetylindole, and 0.6 mmol (3 equiv.) of sodium hydroxide into a 10 mL reaction tube. Add a magnetic stir bar, then add 2 mL of methanol and seal the reaction tube. Reflux for 24 h. After the reaction is complete, a large amount of pale yellow solid precipitates. Filter the solid and wash it with petroleum ether to obtain the product.

[0066] The chemical reaction equation is as follows:

[0067]

[0068] 1.2 Experimental Results: A total of 45.5 mg of indole compound 1 was obtained. High-resolution mass spectrometry analysis showed an ESI-MS m / z of 346.1552 ([M+H]). + The result indicates a molecular weight of 345.1477; and nuclear magnetic resonance spectroscopy confirmed its chemical structure as follows:

[0069]

[0070] The proton NMR spectrum of indole compound 1 is shown below. Figure 1 As shown.

[0071] Example 2: Synthesis of indole compound 2 (Structural formula of indole compound (I) synthesized in this example)

[0072] 2.1 Experimental Methods: The synthesis method is as follows:

[0073] Weigh out 5-(2-(triphenyl-λ) 5 (-phosphine-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (0.2 mmol, 1 equiv.)

[0074] 1-Methyl-1H-indazole-3-carboxaldehyde (0.2 mmol, 1 equiv.) was added to a 10 mL reaction tube, a magnetic stir bar was added, and the mixture was purged three times. Toluene (2 mL) was added as the reaction solvent under argon atmosphere. The system was then sealed with a polytetrafluoroethylene stopcock and heated to 120 °C for 24 h. The reaction was monitored by TLC. After the reaction was complete, the toluene was removed by concentration, and the residue was purified by column chromatography.

[0075] The chemical reaction equation is as follows:

[0076]

[0077] 2.2 Experimental Results: A total of 50 mg of indole compound 2 was obtained. High-resolution mass spectrometry (ESI-MS) analysis showed an ESI-MS m / z of 347.1505 ([M+H]). + The result indicates a molecular weight of 346.1430; and nuclear magnetic resonance spectroscopy confirmed its chemical structure as follows:

[0078]

[0079] The proton NMR spectrum of indole compound 2 is shown below. Figure 2 As shown.

[0080] Example 3: Synthesis of indole compound 26

[0081] 3.1 Experimental Methods: The synthesis method is as follows:

[0082] 0.2 mmol (1 equiv.) of 3,4-methylenedioxyacetophenone, 0.2 mmol (1 equiv.) of 1-methyl-1H-5-azaindole-3-carboxaldehyde, and 0.6 mmol (3 equiv.) of sodium hydroxide were weighed into a 10 mL reaction tube. A magnetic stir bar was added, followed by 2 mL of methanol as the reaction solvent. The system was sealed with a polytetrafluoroethylene stopcock and heated to 65 °C for 24 h. The reaction was monitored by TLC. After the reaction was complete, the methanol was removed by concentration, and the residue was purified by column chromatography.

[0083] The chemical reaction equation is as follows:

[0084]

[0085] 3.2 Experimental Results: A total of 42 mg of indole compound 26 was obtained. High-resolution mass spectrometry analysis showed an ESI-MS m / z of 306.1125 ([M+H]). + The result indicates a molecular weight of 305.1052; and nuclear magnetic resonance spectroscopy confirmed its chemical structure as follows:

[0086]

[0087] The proton NMR spectrum of indole compound 26 is shown below. Figure 3 As shown.

[0088] Example 4: Synthesis of indole compound 29

[0089] 4.1 Experimental Methods: The synthesis method is as follows:

[0090] 0.2 mmol (1 equiv.) of 5-acetyl-2,2-difluoro-1,3-benzodioxane, methyl 1-methyl-1H-3-carboxaldehyde-5-indolecarboxylate, and 0.6 mmol (3 equiv.) of piperidine were weighed into a 10 mL reaction tube. A magnetic stir bar was added, followed by 2 mL of ethanol as the reaction solvent. The system was sealed with a polytetrafluoroethylene stopcock and heated to 80 °C for 24 h. The reaction was monitored by TLC. After the reaction was complete, methanol was removed by concentration, and the residue was purified by column chromatography.

[0091] The chemical reaction equation is as follows:

[0092]

[0093] 4.2 Experimental Results: A total of 20 mg of indole compound 29 was obtained. High-resolution mass spectrometry analysis showed an ESI-MS m / z of 343.0889 ([M+H]). + The result indicates a molecular weight of 342.0816; and nuclear magnetic resonance spectroscopy confirmed its chemical structure as follows:

[0094]

[0095] The proton NMR spectrum of indole compound 29 is shown below. Figure 4 As shown.

[0096] Example 5: Synthesis of indole compound 30

[0097] 5.1 Experimental Methods: The synthesis method is as follows:

[0098] 0.2 mmol (1 equiv.) of 6-acetyl-1,4-benzodioxane, 0.2 mmol (1 equiv.) of 1-methyl-1H-5-azaindole-3-carboxaldehyde, and 0.6 mmol (3 equiv.) of sodium hydroxide were weighed into a 10 mL reaction tube. A magnetic stir bar was added, followed by 2 mL of methanol as the reaction solvent. The system was sealed with a polytetrafluoroethylene stopcock and heated to 65 °C for 24 h. The reaction was monitored by TLC. After the reaction was complete, the methanol was removed by concentration, and the residue was purified by column chromatography.

[0099] The chemical reaction equation is as follows:

[0100]

[0101] 5.2 Experimental Results: A total of 42 mg of indole compound 30 was obtained. High-resolution mass spectrometry analysis showed an ESI-MS m / z of 306.1125 ([M+H]). + The result indicates a molecular weight of 305.1052; and nuclear magnetic resonance spectroscopy confirmed its chemical structure as follows:

[0102]

[0103] The proton NMR spectrum of indole compound 30 is shown below. Figure 5 As shown.

[0104] Uses of compounds

[0105] In one aspect, use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a CYP1A1 inhibitor is provided. In another aspect, use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the inhibition of CYP1A1 is provided. In another aspect, a pharmaceutical composition (CYP1A1 inhibitor) for inhibiting CYP1A1 is provided, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof for inhibiting CYP1A1 is provided. In another aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof for inhibiting CYP1A1 is provided. In another aspect, a method for inhibiting CYP1A1 is provided, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0106] In one aspect, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing a disease or condition is provided. In another aspect, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment or prevention of a disease or condition is provided. In another aspect, a pharmaceutical composition for treating or preventing a disease or condition is provided, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating or preventing a disease or condition is provided. In another aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for treating or preventing a disease or condition. In another aspect, a method of treating or preventing a disease or condition is provided, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof. The disease or condition may be a tumor, bacterial infection, sepsis, inflammation, or organ damage, particularly a tumor, or particularly a bacterial infection or sepsis, inflammation, or organ damage resulting therefrom.

[0107] In some embodiments, the disease or symptom is a tumor. In some embodiments, the tumor is cancer or precancerous adenoma. In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is a hematologic malignancy. In some embodiments, the tumor (or the cancer) is liver cancer (e.g., hepatocellular carcinoma or bile duct cancer), gastric cancer (e.g., gastric adenocarcinoma, gastric lymphoma, gastric leiomyoma, gastrointestinal stromal tumor, or neuroendocrine carcinoid), ovarian cancer, endometrial cancer, cervical cancer, colorectal cancer (e.g., cecal cancer, appendix cancer, ascending colon cancer, transverse colon cancer, descending colon cancer, sigmoid colon cancer, rectal cancer, or anal cancer), lung cancer (e.g., squamous cell carcinoma of the lung, non-small cell lung cancer, or small cell lung cancer), soft tissue sarcoma, osteosarcoma, fibrosarcoma, skin cancer (e.g., malignant melanoma), testicular cancer, breast cancer, fibrosarcoma, neuroblastoma, etc. Cell tumors, brain cancers (such as gliomas, ependymoma, astrocytoma, oligodendroglioma, brainstem glioma, or oligoastrocytoma), bladder cancer, colorectal cancer, prostate cancer, kidney cancer (such as renal cell carcinoma or renal pelvis carcinoma), pancreatic cancer (such as pancreatic adenocarcinoma, pancreatic acinar cell carcinoma, pancreatic cystic adenocarcinoma, pancreatoblastoma, pancreatic squamous cell carcinoma, pancreatic signet ring cell carcinoma, pancreatic hepatoid cell carcinoma, pancreatic colloid carcinoma, or undifferentiated pancreatic carcinoma), pleural mesothelioma, head and neck squamous cell carcinoma, nasopharyngeal carcinoma, oropharyngeal carcinoma, or blood cancers (such as acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphoblastic leukemia, or lymphoma).

[0108] In some embodiments, the disease or condition is a bacterial infection. In some embodiments, the disease or condition is sepsis, particularly sepsis caused by a bacterial infection. In some embodiments, the disease or condition is inflammation, particularly inflammation caused by a bacterial infection. In some embodiments, the disease or condition is organ damage, particularly organ damage caused by a bacterial infection or sepsis thereof. In some embodiments, the organ damage includes oxidative stress damage.

[0109] In some embodiments, the bacteria may be: Gram-positive bacteria, including but not limited to Staphylococcus aureus (such as methicillin-resistant Staphylococcus aureus), Streptococcus pneumoniae, Enterococcus faecalis, Enterococcus faecium, Enterococcus avians, or Mycobacterium tuberculosis; or Gram-negative bacteria, including but not limited to Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Klebsiella pneumoniae, Enterobacter cloacae, Enterobacter aerogenes, Mycobacterium tuberculosis, Morganella morganii, Providencia schlegelii, or Pseudomonas aeruginosa. In some embodiments, the bacteria are Staphylococcus aureus (especially methicillin-resistant Staphylococcus aureus) or Acinetobacter baumannii.

[0110] In some embodiments, the inflammation and / or organ damage is, but is not limited to, one or more of the following: skin, muscles, bones, brain, cerebellum, brainstem, spinal cord, eyes, ears, nose, tongue, heart, blood vessels, pharynx, trachea, lungs, esophagus, stomach, small intestine, large intestine, liver, gallbladder, pancreas, kidneys, bladder, urethra, ovaries, uterus, testes, spleen, thymus, lymphatic vessels, or lymph nodes, particularly one or more of the liver, kidneys, or heart.

[0111] Example 6 Evaluation of bioactivity (CYP1A1 activity inhibition efficiency)

[0112] 6.1 Experimental Method: The experiment was conducted according to the method described in the inventor's Chinese patent "A Preparation Method of a Benzimidazole-2-one Derivative and Its Use" (Chinese Patent No. ZL202411096223.2), mainly including the following steps:

[0113] Cell culture

[0114] Human Caco-2 cells and mouse CYP1A1-overexpressing RAW264.7 cells (CYP1A1hiRAW264.7 cells, hereinafter referred to as CYhRAW cells) were used for cell culture and the following experiments. Following the method disclosed in CN117925529A, CYP1A1-overexpressing RAW264.7 cells were obtained by transfecting them with a CYP1A1-overexpressing virus.

[0115] Cell passage

[0116] Passage the cells when the cell density reaches 80%. Discard the cell culture supernatant and wash twice with sterile PBS for 2 minutes each time. Add 2 mL of trypsin to the cell culture flask and digest at 37°C for 2 minutes. Add twice the volume of complete culture medium to stop the digestion. Centrifuge at 1200 rpm for 3 minutes, discard the supernatant, and resuspend the cells in 2 mL of culture medium. Add the cell suspension to a new cell culture flask at a ratio of 1:3, add 4 mL of complete culture medium, and incubate at 37°C with 5% CO2.

[0117] Cell cryopreservation

[0118] Discard the cell culture supernatant, wash twice with sterile PBS for 2 minutes each time. After trypsin digestion and centrifugation, resuspend the cells in serum-free cell cryopreservation medium at a concentration of 1×10⁶ cells / mL. 6 –1×10 7 Live cells were cryopreserved and stored in a -80 °C freezer for 24 hours before being transferred to liquid nitrogen for storage.

[0119] Cell resuscitation

[0120] Remove the cryovial from liquid nitrogen, thaw it in a 37 °C water bath, add it to a centrifuge tube containing 2 mL of complete culture medium, mix well, centrifuge at 1200 rpm for 3 minutes, discard the supernatant, resuspend the cells in 5 mL of complete culture medium, add it to a cell culture flask, and culture at 37 °C and 5% CO2.

[0121] EROD test

[0122] 7-Ethoxy-3H-phenazine-3-one-O-deethylase (EROD) is an expression product of CYP1A1. CYP1A1 inhibitors inhibit CYP1A1 activity, thereby inhibiting EROD activity; therefore, detecting the degree of inhibition of EROD activity can detect the extent to which CYP1A1 inhibitors inhibit CYP1A1 activity.

[0123] Seed 500 µL of Caco-2 cell suspension or CYhRAW cell suspension into 48-well plates, with 5 × 10⁶ cells per well. 4 One cell adhered for 4 hours.

[0124] Prepare DMSO solutions of each drug at various concentrations (the compounds prepared in each manufacturing example, or bergamot (bergamot) as a positive control, or no compound added as a negative control), and dilute them 10 times with DMEM medium to obtain solutions of each drug at various concentrations.

[0125] Add 5 µL of each drug solution of each concentration to a 48-well plate seeded with cells, so that the final concentration of each drug is 5 µM, 500 nM, or 50 nM, to pretreat the cells for 12 hours; set 3 replicates for each drug concentration.

[0126] After pretreatment, discard the supernatant, wash cells twice with lukewarm PBS, and add 100 µL of sterile PBS containing 5 µM 7-ethoxy-3H-phenazine-3-one and 10 µM dicumarol to each well. Incubate at 37°C and 5% CO2 for 30 minutes. Transfer 75 µL of culture supernatant to a black-bottomed 96-well plate, and add 125 µL of anhydrous methanol to each well to terminate the reaction.

[0127] Detected using a fluorescent microplate reader (excitation light 530 nm, emission light 590 nm).

[0128] 6.2 Test Results

[0129] EROD tests were performed using compounds 1 to 36 of this application, and the results are shown in Table 1.

[0130] Table 1

[0131]

[0132]

[0133] 1.3IC 50 Value determination

[0134] The EROD test was performed as described above, but the final concentrations of each drug were changed to 10 pM, 100 pM, 1 nM, 10 nM, 100 nM, 1 µM, 10 µM, and 20 µM to determine the IC50. 50 value.

[0135] Please refer to Figure 8 and Figure 9 Table 1 shows the EROD enzyme activity obtained by performing EROD assays on Caco-2 and CYHRAW cells at various concentrations of compounds 12, 16, 17, 28, 30, 31, 33, and 37. Table 2 shows the calculated IC50 values ​​of each compound in Caco-2 and CYHRAW cells. 50 value.

[0136] Table 2

[0137]

[0138] 1.4 Activity comparison between the compound described in this invention and the compound with patent number ZL202411096223.2

[0139] Compared to patent number ZL202411096223.2, the compound described in this invention exhibits significantly enhanced activity. At a concentration of 50 nM, the compound demonstrates significant inhibitory activity, while patent number ZL202411096223.2 shows almost no inhibitory activity at the same concentration. Furthermore, the inhibitory activity at high concentrations is also improved compared to patent number ZL202411096223.2. The following section selects two patents for IC analysis. 50 The compounds measured are described.

[0140] Table 3 (Compounds described in this invention)

[0141]

[0142] Table 4 (Compounds described in patent number ZL202411096223.2)

[0143]

[0144] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A class of indole compounds, wherein the compound is a compound of formula I or a pharmaceutically acceptable salt thereof. Ar3-R-Ar1-Ar2 (Formula I); in, R is Ar1 is a five-membered heteroaryl group containing one or two heteroatoms independently selected from N and O, which is substituted by a halogen group, a C1-6 alkyl group, a C1-6 alkynyl group, or a phenyl group; Ar2 is a phenyl or pyridyl group substituted by a C1-6 alkyl group, an ester group, or a fused group; Ar1 ​​and Ar2 are fused together; Ar3 is an unsubstituted or substituted phenyl, pyridyl, furanyl, thiophene, indolyl, indole, indocyanine, methylenedioxyphenyl, N,N'-dimethylindocyanine, benzofuran, indanyl, or naphthoquinonefuranyl group.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, Ar3 is selected from Any group in it.

3. The compound or pharmaceutically acceptable salt of claim 1 or 2, wherein, Ar1-Ar2 are selected from Any group in it.

4. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, selected from... ; ； ; ； and Any one of them.

5. A pharmaceutical composition comprising the compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

6. A method for preparing the compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-4, characterized in that, include: Optionally, 5-(2-(triphenyl-λ) 5 -phosphine subunit)acetyl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one and Ar3–CHO are reacted to obtain a compound of formula (I) or a pharmaceutically acceptable salt thereof; Optionally, the corresponding ketone and aldehyde are refluxed under sodium hydroxide / methanol or piperidine / ethanol conditions to obtain the compound of formula (I) or a pharmaceutically acceptable salt thereof; Ar3 is a phenyl, pyridyl, furanyl, thiophene, indolyl, indocyanine, methylenedioxyphenyl, N,N'-dimethylindocyanine, benzofuran, indanyl, or naphthoquinonefuranyl that is unsubstituted or substituted by one or more substituents selected independently from halogen, C1-6 alkyl, C1-6 alkynyl, and ester.

7. Use of the compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof in the preparation of a CYP1A1 inhibitor.

8. Use of the compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 5, in the preparation of a medicament for treating or preventing tumors, bacterial infections, sepsis, inflammation, or organ damage; Preferably, the disease or symptom is a bacterial infection or the resulting sepsis, inflammation, or organ damage.

9. The use as described in claim 8, characterized in that, The inflammation and / or organ damage refers to one or more of the following: skin, muscles, bones, brain, cerebellum, brainstem, spinal cord, eyes, ears, nose, tongue, heart, blood vessels, pharynx, trachea, lungs, esophagus, stomach, small intestine, large intestine, liver, gallbladder, pancreas, kidney, bladder, urethra, ovary, uterus, testis, spleen, thymus, lymphatic vessels, or lymph nodes. Preferably, the inflammation and / or organ damage is one or more inflammations or damages of the liver, kidney, or heart.

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