Compounds and uses thereof

Abstract

The present application provides a compound comprising a structure shown in formula (I), and the present application also provides use of the compound for selectively inhibiting or preventing growth of Helicobacter pylori, and / or preparing a medicament.

Description

Technical Field

[0001] This application relates to the field of biomedicine, specifically to a compound and its uses. Background Technology

[0002] Helicobacter pylori (Hp) commonly resides in the gastric mucosa, primarily causing chronic gastritis and peptic ulcers. It is closely related to gastric cancer and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. 15%–20% of Hp-infected individuals develop peptic ulcers, 5%–10% develop Hp-related dyspepsia, and approximately 1% develop gastric malignancies (gastric cancer, MALT lymphoma). In 1994, the World Health Organization / International Agency for Research on Cancer classified Hp as a Group 1 carcinogen. Hp infection is very prevalent worldwide, especially in developing countries. In China, the infection rate is close to 50% in people over 25 years old, over 60% in people over 35 years old, and around 80% in people over 70 years old. Eradication of Hp is of great practical significance, but in recent years, antibiotic resistance to Hp has become increasingly severe, which is the main reason for the failure of Hp eradication.

[0003] Existing drugs for treating *Helicobacter pylori* infection, such as clarithromycin, amoxicillin, and levofloxacin, are broad-spectrum antibiotics. They not only inhibit *Helicobacter pylori* but also have antibacterial activity against gut microbiota. Therefore, when used clinically for eradication therapy, they often lead to gut microbiota imbalance, causing gastrointestinal dysfunction during medication use. This is especially true for patients with gastrointestinal complications, such as those with IBD, where medication can increase gastrointestinal sensitivity to various stimuli, leading to a worsening of their condition. The compound disclosed in this application has only inhibitory activity against *Helicobacter pylori* and no activity against gut microbiota. Therefore, its use will not cause gastrointestinal dysfunction, reducing gastrointestinal toxicity and side effects. Furthermore, it can reduce the risk of drug resistance. Helicobacter pylori drug resistance is a serious problem. Although resistance rates vary across regions, the overall resistance rates are as follows: clarithromycin resistance rate is 20-50%, metronidazole resistance rate is 40-70%, levofloxacin resistance rate is 20-50%, and amoxicillin resistance rate is also increasing year by year. For patients undergoing retreatment, the resistance rate is even higher, with resistance rates for clarithromycin, metronidazole, and levofloxacin approaching 90%. The compound disclosed in this application maintains high antibacterial activity against clinically resistant strains, including both single-drug and multi-drug resistant strains, without cross-resistance, and with an extremely low resistance frequency.

[0004] Existing H. pylori treatments are limited in their use due to drug resistance, gastrointestinal side effects, and unsatisfactory therapeutic effects. The compounds disclosed in this application can overcome the limitations of existing H. pylori treatments. Summary of the Invention

[0005] This application provides a compound, or its stereoisomers, hydrates, deuterated derivatives, esters, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, and pharmaceutical compositions thereof. The compound provided in this application exhibits strong *Helicobacter pylori* (Hp) inhibitory activity and does not exhibit cross-resistance with existing drugs, thus addressing the drug resistance problem of current therapeutic agents. Furthermore, the compound has a low resistance frequency, potentially slowing or eliminating the development of drug resistance. Additionally, the compound exhibits inhibitory activity only against *Hp* and has no activity against intestinal flora, thus avoiding gastrointestinal dysfunction and reducing gastrointestinal toxicity.

[0006] On one hand, this application provides a compound, or a stereoisomer, hydrate, deuterated product, ester, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein the compound comprises the structure of formula (I):

[0007]

[0008] in,

[0009] X, Y, Z, and V are each independently selected from N or C;

[0010] R 1 Selected from: -H, any substituted C1–C5 alkyl, any substituted C3–C5 alkenyl, any substituted C3–C5 ynyl, any substituted C3–C6 cycloalkyl;

[0011] R 2 It can be any substituted alicyclic hydrocarbon group or alihexacyclic group;

[0012] R 3 Selected from: -H, -CN, any substituted C1-C3 alkoxy, any substituted C1–C6 alkyl, any substituted C2–C6 alkenyl, any substituted C2–C6 alkynyl, any substituted C3–C6 cycloalkyl, any substituted 4-6 heterocyclic alkyl.

[0013] R 4 R 5 R 6 R 7 Whether identical or different, each is independently selected from one of the following: -H, -F, -Cl, -CN, -OR', -SR', -NR'R”, -NO2, -C(=O)R', -C(=O)OR', -OC(=O)R', -C(=O)NHR', -NHC(=O)R', where R' and R” are identical or different, each representing hydrogen, any substituted straight-chain or branched C1–C4 alkyl, any substituted C3–C8 cycloalkyl, any substituted 4-8 membered heterocyclic alkyl, or R' and R” forming a 4-8 membered heterocycle.

[0014] In some implementations, when R 1 When R is methyl, ethyl or cyclopropyl, 2 Selected from one of the following: any substituted saturated C3–C8 cycloalkyl, any substituted saturated 4–8-membered heterocyclic alkyl, any substituted unsaturated C5–C8 cycloalkyl, any substituted unsaturated 5–8-membered heterocyclic alkyl, any substituted C6–C 11 Bicycloalkyl, with arbitrary substitution at C6–C 11 Bicyclic heterocyclic group.

[0015] In some implementations, when R 1 When R is -H, 2 Selected from one of the following: substituted saturated C5–C7 cycloalkyl, substituted saturated C3–C4 or C8 cycloalkyl, substituted saturated 4- to 8-membered heterocyclic alkyl, substituted unsaturated C5–C8 cycloalkyl, substituted unsaturated 5- to 8-membered heterocyclic alkyl, substituted C6–C 11 Bicycloalkyl, with arbitrary substitution at C6–C 11 Bicyclic heterocyclic group.

[0016] In some implementations, R 2 for Where q is an integer between 0 and 3, and 0 represents the base here.

[0017] The group does not exist;

[0018] Ra represents saturated C3–C8 cycloalkyl groups, saturated 4–8-membered heterocyclic alkyl groups, unsaturated C5–C8 cycloalkyl groups, unsaturated 5–8-membered heterocyclic alkyl groups, and C6–C6 cycloalkyl groups. 11 Bicycloalkyl, C6–C 11 Bicyclic heterocyclic groups;

[0019] Each Rb is independently selected from one or more combinations of the following: -H, -F, -CN, -Ra', =CHRa',

[0020] -ORa', -SRa', -NR'Ra", -NO2, -C(=O)-, -C(=O)Ra', -C(=O)ORa', -OC(=O)Ra', -

[0021] C(=O)NHRa', -NHC(=O)Ra', -R”C(=O)Ra', -R”C(=O)ORa', -R”OC(=O)Ra', -

[0022] Ra”C(=O)NHRa’, -Ra”NHC(=O)Ra’,

[0023] Ra' and Ra" may be the same or different, each representing hydrogen, any substituted straight-chain or branched C1-C4 alkyl, any substituted C3-C8 cycloalkyl, any substituted 4-8 heterocyclic alkyl, or Ra' and Ra" forming a 4-8 heterocyclic ring.

[0024] In some implementations, Ra is

[0025]

[0026] Where n1 is an integer from 0 to 5, and 0 represents that the group does not exist here.

[0027] In some implementations, Ra is

[0028]

[0029] Where n2 is an integer between 0 and 3, and 0 represents the absence of the group at this point.

[0030] In some implementations, Ra is

[0031]

[0032] Where n3 is an integer from 1 to 5, and n4 is an integer from 1 to 5.

[0033] In some implementations, Ra is

[0034]

[0035] Where n5 is an integer from 1 to 5, and n6 is an integer from 1 to 5.

[0036] In some implementations, Ra is

[0037]

[0038] Where n7 is an integer between 0 and 2, n8 is an integer between 0 and 2, n9 is an integer between 1 and 2, and 0 represents that the group does not exist here.

[0039] In some implementations, Ra is

[0040]

[0041] Where n10 is an integer between 2 and 4, and X is selected from N, O and S.

[0042] In some implementations, Ra is

[0043]

[0044] Where n11 is an integer between 0 and 2, X is selected from N, O and S, and 0 represents that the group does not exist here.

[0045] In some implementations, Ra is

[0046]

[0047] Where n12 is an integer from 1 to 4, n13 is an integer from 0 to 2, n14 is an integer from 2 to 4, X is selected from N, O and S, and 0 represents that the group does not exist here.

[0048] In some implementations, Ra is

[0049]

[0050] Where n15 is an integer from 1 to 5, n16 is an integer from 0 to 2, n17 is an integer from 2 to 4, X is selected from N, O and S, and 0 represents that the group does not exist here.

[0051] In some implementations, R 2 for Where q is an integer between 0 and 3, and 0 represents that the group does not exist here;

[0052] When Ra is a saturated C5–C7 cycloalkyl group, q is an integer from 1 to 3, and each Rb is independently selected from one or more combinations of the following: -F, -CN, -R', =CHR', -OR', -SR', -NR'R", -NO2, -C(=O)-, -

[0053] C(=O)R', -C(=O)OR', -OC(=O)R', -C(=O)NHR', -NHC(=O)R', -R”C(=O)R',-

[0054] R"C(=O)OR', -R"OC(=O)R', -R"C(=O)NHR', -R"NHC(=O)R';

[0055] When Ra is a saturated C3–C4 or C8 cycloalkyl, a saturated 4-8 membered heterocyclic alkyl, an unsaturated C5–C8 cycloalkyl, an unsaturated 5-8 membered heterocyclic alkyl, or a C6–C 11 When the Rb is a bicyclic alkyl group, or a 6- to 11-membered bicyclic heteroalkyl group, each Rb is independently selected from one or more of the following combinations: -H, -F, -CN, -Ra',

[0056] =CHRa', -ORa', -SRa', -NRa'Ra", -NO2, -C(=O)-, -C(=O)Ra', -C(=O)ORa', -

[0057] OC(=O)Ra', -C(=O)NHRa', -NHC(=O)Ra', -Ra”C(=O)Ra', -Ra”C(=O)ORa', -

[0058] Ra”OC(=O)Ra’, -Ra”C(=O)NHRa’, -Ra”NHC(=O)Ra’;

[0059] Ra' and Ra" may be the same or different, each representing hydrogen, any substituted straight-chain or branched C1–C4 alkyl, any substituted C3–C8 cycloalkyl, any substituted 4-8 membered heterocyclic alkyl, or Ra' and Ra" forming a 4-8 membered heterocycle.

[0060] In some implementations, Ra is

[0061]

[0062] Where n1 is 0-1 or 5, or n is an integer from 2 to 4, and 0 represents that the group does not exist here.

[0063] In some implementations, Ra is

[0064]

[0065] Where n2 is an integer between 0 and 3, and 0 represents the absence of the group at this point.

[0066] In some implementations, Ra is

[0067]

[0068] Where n3 is an integer from 1 to 5, and n4 is an integer from 1 to 5.

[0069] In some implementations, Ra is

[0070]

[0071] Where n5 is an integer from 1 to 5, and n6 is an integer from 1 to 5.

[0072] In some implementations, Ra is

[0073]

[0074] Where n7 is an integer between 0 and 2, n8 is an integer between 0 and 2, n9 is an integer between 1 and 2, and 0 represents that the group does not exist here.

[0075] In some implementations, Ra is

[0076]

[0077] Where n10 is an integer between 2 and 4, and X is selected from N, O and S.

[0078] In some implementations, Ra is

[0079]

[0080] Where n11 is an integer between 0 and 2, X is selected from N, O and S, and 0 represents that the group does not exist here.

[0081] In some implementations, Ra is

[0082]

[0083] Where n12 is an integer from 1 to 4, n13 is an integer from 0 to 2, n14 is an integer from 2 to 4, and X is selected from N, O, and S.

[0084] In some implementations, Ra is

[0085]

[0086] Where n15 is an integer from 1 to 5, n16 is an integer from 0 to 2, n17 is an integer from 2 to 4, and X is selected from N, O, and S.

[0087] In some implementations, Rb is selected from one or a combination of the following:

[0088] -H, -F, -OH, -NH2, -C(=O)-, -NH-, =CH2, =CH2CH3, -CH3, -CF3, -Et, -CH2CF3, -CH(CH3)2, -C(CH3)3, -OMe, -OCF3, -OEt, -OCH2CF3, -OCH(CH3)2, -OBn, -SMe.

[0089] In some implementations, R2 is selected from one of the following:

[0090]

[0091]

[0092] In some implementations, R3 is selected from:

[0093] -H, -Me, -CN, -OMe, -CF3, -OCF 3、

[0094] In some embodiments, R4, R5, R6, and R7 are each independently selected from one of the following: -H, -F, -Cl, -Br, -I, -CN, -NMe2, pyrrole, -OMe, -CF3, -OCF3, -NH2, and -Me.

[0095] In some embodiments, any substitution includes either being unsubstituted or substituted by one or more substituents selected from the following: -F, -Cl, -CN, -OH, -O-, -CH2-, -SH, -NH2, -NO2, =CH-, -NH-, amide, carbonyl, ester, straight-chain or branched C1–C4 alkyl, straight-chain or branched C2–C4 alkenyl, straight-chain or branched C2–C4 alkynyl, C3–C8 cycloalkyl, 4-8 membered heterocyclic alkyl, aryl, heteroaryl.

[0096] In some embodiments, the compound has one of the following structures:

[0097]

[0098]

[0099]

[0100] On the other hand, this application provides a composition comprising the aforementioned compound and optionally a pharmaceutically acceptable carrier.

[0101] In some embodiments, the composition further comprises a second therapeutic agent.

[0102] In some embodiments, the second therapeutic agent is selected from proton pump inhibitors, potassium-competitive acid blockers, acid suppressants, efflux pump inhibitors, antibacterial agents, mucosal protectants, anti-inflammatory drugs, anticoagulants, platelet aggregation inhibitors, antipyretics, lipid-lowering agents, and zinc salts.

[0103] On the other hand, this application provides a kit comprising the compound and / or the composition described herein.

[0104] On the other hand, this application provides a method for inhibiting or preventing bacterial growth, comprising applying an effective amount of the compound and / or the composition, and / or the kit.

[0105] On the other hand, this application provides a treatment method comprising administering an effective amount of the said compound and / or the said composition, and / or the said kit to a subject in need.

[0106] In some implementations, the subject is infected with bacteria.

[0107] In some embodiments, the bacteria is Helicobacter pylori.

[0108] On the other hand, this application provides the use of the compound and / or the composition and / or the kit described herein for inhibiting or preventing bacterial growth.

[0109] On the other hand, this application provides the use of the compound and / or the composition and / or the kit described herein for the preparation of a medicament for the treatment and / or prevention of diseases or conditions caused by bacterial infections.

[0110] In some embodiments, the bacteria is Helicobacter pylori.

[0111] In some embodiments, the disease or condition is selected from: gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis, gastric cancer, and gastric mucosa-associated lymphoid tissue lymphoma.

[0112] On the other hand, a method for preparing the compound.

[0113] Other aspects and advantages of this application will be readily apparent to those skilled in the art from the detailed description below. Only exemplary embodiments of this application are shown and described in the following detailed description. As will be appreciated by those skilled in the art, the content of this application enables them to make modifications to the disclosed specific embodiments without departing from the spirit and scope of the invention to which this application pertains. Detailed Implementation

[0114] The following specific embodiments illustrate the implementation of the invention. Those skilled in the art can easily understand other advantages and effects of the invention from the content disclosed in this specification.

[0115] Terminology Definition

[0116] In this application, the term "compound" refers to the compound of this application, and the term includes various stereoisomers, deuterated products, solvates, metabolites, prodrugs, esters, pharmaceutically acceptable salts, etc. of the compound of this application.

[0117] In this application, the term "stereoisomer" generally refers to tautomers, mesosomes, racemates, enantiomers, and / or diastereomers of the compounds of this application. The term "diastereomer" generally refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers can have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The terms "tautomer" or "tautomer form" are used interchangeably and generally refer to structural isomers of different energies that can be interconverted through a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via the rearrangement of some bonding electrons. The term "meta-form" generally refers to a molecule containing asymmetric atoms, but whose total optical rotation is zero due to symmetry. The terms "racemic form" or "racemic mixture" generally refer to a composition consisting of two enantiomers in equimolar amounts. Unless otherwise specified, all compounds appearing in this application are intended to include all possible optical isomers, such as compounds with a single chirality, or mixtures of various chiral compounds (i.e., racemates). In all compounds of this application, each chiral carbon atom may optionally be in the R configuration or S configuration, or a mixture of R and S configurations.

[0118] "Deuterium" usually refers to the hydrogen (H) isotope deuterium.

[0119] "Deuteration" or "deuterated product" refers to the situation where a hydrogen atom on an alkyl, cycloalkyl, alkylene, aryl, heteroaryl, mercapto, heterocycloalkyl, alkenyl, or alkynyl group is replaced by at least one deuterium atom. The upper limit of the number of deuterations is equal to the sum of the number of hydrogen atoms that can be replaced in the substituted group. Unless otherwise specified, the number of deuterations is any integer between 1 and this upper limit, such as 1-20 deuterium atoms, 1-10 deuterium atoms, 1-6 deuterium atoms, 1-3 deuterium atoms, 1-2 deuterium atoms, or 1 deuterium atom.

[0120] The term "solvent" generally refers to an association or complex of one or more solvent molecules with the compound of this application. Non-limiting examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0121] The terms "metabolite" or "metabolic product" generally refer to products generated by the metabolism of a particular compound or its salt in the body. Metabolites of compounds can be identified using conventional techniques known in the art, and their activity can be determined using tests as described in this application. Such products can be generated by, for example, oxidation, hydroxylation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the compound to which the application is administered. Therefore, this application includes metabolites of the compounds of this application, including compounds generated by methods comprising exposing the compound of this application to a mammal for a period of time sufficient to produce its metabolites.

[0122] The term "prodrug" or "prodrug precursor" generally refers to a drug precursor compound that, when administered to a subject, undergoes a chemical transformation through metabolism or a chemical process to yield the compound of this application or its salt. Information regarding prodrugs is well known in the art (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).

[0123] Non-limiting examples of prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties (e.g., propionate esters), lower alkenyl esters, di-lower alkyl-amino lower alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetoxymethyl ester), acyloxy lower alkyl esters (e.g., neopentyloxymethyl ester), aryl esters (phenyl esters), aryl-lower alkyl esters (e.g., benzyl esters), substituted (e.g., substituted with methyl, halogen, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower alkylamides, di-lower alkylamides, and hydroxyamides. Prodrugs that are converted to their active form through other mechanisms in vivo are also included.

[0124] When the term “lower” is used with organic groups or compounds, it usually means that the compound or group can be branched or unbranched and has no more than and includes 7 carbon atoms, for example, 1-6 carbon atoms, 1-5 carbon atoms or 1-4 carbon atoms.

[0125] The term "ester" generally refers to those esters that are hydrolyzed in vivo and include those that readily break down in the human body, leaving behind the parent compound or its salts. Suitable ester groups can include those derived from pharmaceutically acceptable aliphatic carboxylic acids. Representative examples of specific esters include, but are not limited to, formate esters, acetate esters, propionate esters, butyrate esters, acrylate esters, and ethyl succinate.

[0126] The term "pharmaceutically acceptable salt" generally refers to a pharmaceutically acceptable organic or inorganic salt of the compound of this application. Exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, hydrochlorides, hydrobromides, hydroiodates, nitrates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannins, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucurons, glycosides, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, bis(hydroxynaphthyl)ate (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthyl)ate), alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. Pharmaceutically acceptable salts may involve the inclusion of another molecule, such as an acetate ion, a succinate ion, or other counterion. The counterion can be any organic or inorganic component that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. In instances where multiple charged atoms are part of a pharmaceutically acceptable salt, the salt may have multiple counterions. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0127] In this application, the term "alkyl" generally refers to a residue derived from an alkane by removing a hydrogen atom. Alkyl groups can be substituted or unsubstituted, substituted or non-substituted. The term "alkyl" generally refers to a saturated straight-chain or branched aliphatic hydrocarbon group having residues derived from the removal of hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane. It can be a straight-chain or branched group containing 1 to 20 carbon atoms, for example, containing 1 to 12 carbon atoms, such as a chain alkyl containing 1 to 6 carbon atoms. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl, isopentyl, or hexyl, etc. Alkyl groups can be substituted or unsubstituted, alternative or non-alternative. For example, when substituted, the substituent can be substituted at any usable connection point. The substituent can be independently and optionally selected from one or more substituents chosen from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0128] In some cases, the number of carbon atoms in a hydrocarbon substituent (i.e., alkyl, cycloalkyl, etc.) is determined by the prefix "C". x -C y "or "C x-yThe term "C1-C6 alkyl" indicates that x represents the minimum number of carbon atoms in the substituent, and y represents the maximum number. Therefore, "C1-C6 alkyl" or "C 1-6 "Alkyl" refers to an alkyl substituent containing 1 to 6 carbon atoms. In some cases, the number of carbon atoms in a hydrocarbon substituent (i.e., alkyl, cycloalkyl, etc.) is indicated by the prefix "C". z The symbol “c6 alkyl” indicates that “c6 alkyl” refers to an alkyl substituent containing 6 carbon atoms.

[0129] In this application, the term "alkenyl" generally refers to a partially unsaturated branched or straight-chain hydrocarbon having at least one carbon-carbon double bond. The alkenyl group may optionally be substituted. In this application, the terms "C2-C3 alkenyl," "C2-C4 alkenyl," "C2-C5 alkenyl," "C2-C6 alkenyl," "C2-C7 alkenyl," and "C2-C8 alkenyl" generally refer to alkenyl groups containing at least two, and at most three, four, five, six, seven, or eight carbon atoms, respectively. Unless otherwise stated, alkenyl groups generally refer to C2-C6 alkenyl groups. Non-limiting examples of alkenyl groups in this application include vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.

[0130] The term "alkynyl" generally refers to a partially unsaturated branched or straight-chain hydrocarbon having at least one carbon-carbon triple bond. The alkynyl group may optionally be substituted. In this application, the terms "C2-C3 alkynyl," "C2-C4 alkynyl," "C2-C5 alkynyl," "C2-C6 alkynyl," "C2-C7 alkynyl," and "C2-C8 alkynyl" generally refer to alkynyl groups containing at least two, and at most three, four, five, six, seven, or eight carbon atoms, respectively. Unless otherwise stated, alkynyl groups are generally C2-C6 alkynyl. Non-limiting examples of alkynyl groups in this application include ethynyl, propynyl, butynyl, pentyynyl, hexynyl, heptyynyl, octyynyl, nonynyl, and decanynyl, etc.

[0131] Aromaticity is a chemical property. In aromatic molecules, the conjugated system of unsaturated bonds, lone pairs of electrons, and empty orbitals has a unique stabilizing effect that cannot be explained by considering conjugation alone. The presence of aromaticity can be determined using Hückel's rule.

[0132] The term "alicyclic hydrocarbon group" refers to a functional group formed by removing a hydrogen atom from a non-aromatic cyclic hydrocarbon.

[0133] In this application, the term "heterocyclic group" generally refers to a monocyclic, bicyclic, or tricyclic, saturated or partially unsaturated, non-aromatic ring system having 3 to 20 ring atoms, including systems containing fused rings, wherein at least one ring atom is a heteroatom. Examples of heteroatoms include nitrogen, oxygen, and sulfur. In some embodiments, a heterocyclic group refers to a saturated ring system, such as a 3- to 12-membered saturated heterocyclic group ring system, or a 3- to 8-membered saturated heterocyclic group ring system. In some embodiments, a heterocyclic group refers to a 5- to 8-membered saturated heterocyclic group ring system. In some embodiments, a heterocyclic group refers to a 5- to 6-membered saturated heterocyclic group ring system. In some embodiments, a heterocyclic group comprises 1 to 4 heteroatoms. In some embodiments, a heterocyclic group comprises a 3- to 7-membered monocyclic ring having one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocyclic group comprises a 4- to 6-membered monocyclic ring having one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In another example, a heterocyclic group comprises a 3-membered monocyclic ring. In another example, a heterocyclic group comprises a 4-membered monocyclic ring. In another example, the heterocyclic group comprises a 5-6 membered monocyclic ring. In one example, the heterocyclic group comprises 0 to 3 double bonds.

[0134] The term "aliphatic heterocyclic group" refers to a functional group formed by removing a hydrogen atom from a heterocyclic compound that is not aromatic, or a heterocyclic group that is not aromatic.

[0135] The term "cycloalkyl" generally refers to a fully hydrogenated, non-aromatic ring consisting of a single, two, or three rings containing 3 to 10 carbon atoms. Accordingly, a cycloalkyl group can be a single ring, typically containing 3 to 7 ring atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Alternatively, two or three rings may be fused together, for example, bicyclodecyl and naphthyl. The term "cycloalkyl" also includes bridging bicycloalkyl systems, for example, but not limited to, bicyclo[2.2.1]heptane and bicyclo[1.1.1]pentane. As described in this application, depending on the circumstances, a cycloalkyl group may optionally be substituted with 1 to 5 of the above-mentioned suitable substituents, for example, fluorine, chlorine, deuterium, cyano, trifluoromethyl, C1-C6 alkoxy, trifluoromethoxy, difluoromethoxy, or C1-C6 alkyl.

[0136] The term "heterocyclic alkyl" generally refers to a monovalent saturated moiety consisting of one to three rings having one, two, three, or four heteroatoms and 3 to 10 carbon atoms. Heterocyclic alkyl groups can be optionally substituted as defined in this application. Examples of heterocyclic alkyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, homopiperazinyl, and aza-alkyl groups. The heterocyclic alkyl group can be optionally substituted with 1 to 5 suitable substituents as defined in this application, such as fluorine, chlorine, pyrazolyl, imidazolinyl, imidazolinyl, pyridinyl, pyrimidinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolinyl, isothiazolyl, quininecycloyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzoxazolyl, benzoazolylidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. Depending on the application, the heterocyclic alkyl group may be optionally substituted with 1 to 5 suitable substituents as defined herein, such as fluorine, chlorine, deuterium, cyano, trifluoromethyl, C1-C6 alkoxy, C6-C6... 10 Aryloxy, trifluoromethoxy, difluoromethoxy, or C1-C6 alkyl.

[0137] The terms "alkoxy" and "alkyloxy" generally refer to the part of the formula -OR, where R is a straight-chain saturated alkyl or branched saturated alkyl part as defined herein, bonded by an oxygen atom. Alkoxy groups may optionally be substituted as defined herein. Non-limiting examples of such alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, etc.

[0138] The term "haloalkyl" generally refers to an alkyl group that has been substituted with one or more halogen substituents.

[0139] The term "halogen" or "halogenated" usually refers to -F, -Cl, -Br, or -I.

[0140] The term "aryl" generally refers to a monocyclic or bicyclic aromatic ring system of hydrocarbons, wherein such rings can be fused. If the rings are fused, one of the rings must be a completely unsaturated ring, and the fused rings can be completely saturated, partially unsaturated, or completely unsaturated. The term "fused" means that the second ring exists (i.e., shares) two adjacent atoms with the first ring. The term "aryl" includes aromatic groups, such as phenyl, naphthyl, tetrahydronaphthyl, indenyl, biphenyl, 4-(pyridin-3-yl)phenyl, 2,3-dihydro-1H indenyl, and 1,2,3,4-tetrahydronaphthyl. Depending on the circumstances, the aryl group may optionally be substituted by one to five of the above-mentioned suitable substituents.

[0141] In this application, the term "heteroaryl" generally refers to a residue derived from the removal of a hydrogen atom from a carbon atom of a heteroaryl ring. The term "heteroaryl ring" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms may be selected from the group consisting of oxygen, sulfur, and nitrogen. Heteroaryl groups may be 5 to 10-membered, or 5- or 6-membered, and non-limiting examples of heteroaryl groups include pyridinyl, furanyl, thiopheneyl, pyrroleyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridinyl, pyrazinyl, triazinyl, isoquinolinyl, and indazoleyl, etc. Heteroaryl rings may be fused to aryl, heterocyclic, or cycloalkyl rings, wherein the ring attached to the parent structure is a heteroaryl ring.

[0142] In some embodiments, the number of atoms in a cyclic substituent (i.e., a heteroaryl or heterocycloalkyl) containing one or more heteroatoms is indicated by the prefix "x-y", where x is the minimum number of atoms in the ring moiety forming the substituent, and y is the maximum number. Thus, for example, "5-6 heteroaryl" refers to a heteroaryl containing 5 to 6 atoms in the ring moiety of the heteroaryl, including one or more heteroatoms.

[0143] In this application, the term "heteroatom" generally refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of basic nitrogen. The term "nitrogen" may also include substituted nitrogen.

[0144] The term "fused-ring group" generally refers to a saturated or unsaturated fused-ring system involving a non-aromatic bicyclic system, where at least one ring is non-aromatic. Such a system can contain independent or conjugated unsaturated states. Each ring in a fused bicyclic ring is either a carbocyclic or heterocyclic, and examples include, but are not limited to, hexahydro-furan[3,2-b]furanyl, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 7-azabicyclic[2.2.1]heptyl, fused bicyclic[3.3.0]octyl, fused bicyclic[3.1.0]hexyl, 1,2,3,4,4a,5,8,8a-octahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and 2,3-dihydroindenyl, all of which are included within the scope of fused bicyclic systems.

[0145] The term "spirocyclic group" generally refers to a polycyclic group in which two carbon rings share a single carbon atom. "Heterospirocyclic group" generally refers to a polycyclic group in which two monocyclic rings share a single carbon atom, and the two rings may contain one or more heteroatoms.

[0146] The term "bridged ring group" generally refers to a ring group in which any two carbon rings share two non-directly connected carbon atoms. Based on the number of rings, it is classified as a two-ring, three-ring, four-ring, etc. "Hyper-bridged ring group" generally refers to a multi-ring heterocyclic group in which two rings share two non-adjacent carbon atoms or heteroatoms.

[0147] The term "independently" or "independently" generally means that when a substituent has more than one variable, the choice of each instance of the substituent is independent of the other variables listed as suitable variables. Therefore, each substituent may be the same as or different from the other substituents.

[0148] The term "optionally substituted" generally means that the group in question may be substituted or not substituted by one or more additional groups, without limitation, said additional groups may be selected individually and independently from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, alkoxy, mercapto, cyano, acetyl, deuterium, halogen, carbonyl, thiocarbonyl, isocyanate, thiocyanate, isothiocyanate, nitro, amide, sulfonyl, phosphoryl, haloalkyl, fluoroalkyl and amino groups including monosubstituted and disubstituted amino groups, and protected derivatives thereof. Non-limiting examples of optional substituents include deuterium, halogens, -CN, -C(O)-, =O, =N-OH, =N-OR, =NR, OR, -C(O)R, -C(O)OR, -OC(O)R, -OC(O)OR, -C(O)NHR, -C(O)NR2, -OC(O)NHR, -OC(O)NR2, -SR-, -S(O)R, -S(O)2R, -NHR, -N(R)2, -NHC(O)R, -NRC(O)R, -NHC(O)OR, -NRC(O)OR, S(O)2 NHR, -S(O)2N(R)2, -NHS(O)2NR2, -NRS(O)2NR2, -NHS(O)2R, -NRS(O)2R, C1-C8 alkyl, C1-C8 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen-substituted C1-C8 alkyl, and halogen-substituted C1-C8 alkoxy, wherein each R is independently selected from hydrogen, deuterium, halogen, C1-C8 alkyl, C1-C8 alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen-substituted C1-C8 alkyl, and halogen-substituted C1-C8 alkoxy. The position and number of such substituents are determined by well-known valence state constraints for each group; for example, =O is a suitable substitution for alkyl groups.

[0149] In some embodiments, any substitution includes unsubstituted or substituted with one or more substituents selected from the following: -F, -Cl, -CN, -OH, -O-, -CH2-, -SH, -NH2, -NO2, =CH-, -NH-, amide, carbonyl, ester, straight-chain or branched C1–C4 alkyl, straight-chain or branched C2–C4 alkenyl, straight-chain or branched C2–C4 alkynyl, C3–C8 cycloalkyl, 3-8 membered heterocyclic alkyl, aryl, heteroaryl.

[0150] In this application, the term "pharmaceutically acceptable carrier" generally refers to a pharmaceutically acceptable substance, composition, or medium involving the carrying or transport of chemical reagents, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulation materials. Pharmaceutically acceptable carriers include pharmaceutically acceptable salts, wherein the term "pharmaceutically acceptable salt" includes salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, a base-additive salt can be obtained by contacting a neutral form of such compounds with a sufficient amount of the desired base in a net manner or in a suitable inert solvent. Examples of pharmaceutically acceptable base-additive salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, an acid-additive salt can be obtained by contacting a neutral form of such compounds with a sufficient amount of the desired acid in a net manner or in a suitable inert solvent. Examples of pharmaceutically acceptable acid-additive salts include salts derived from inorganic acids and salts derived from relatively non-toxic organic acids. Certain specific compounds of this invention contain basic and acidic functional groups capable of converting the compound into a salt that undergoes base or acid addition.

[0151] In this application, the term "bacteria" generally refers to a class of prokaryotes lacking a distinct nucleus and membranous organelles. The bacteria may be spherical, rod-shaped, or spiral-shaped. The bacteria may include interlike species, such as *Escherichia*, *Salmonella*, *Shigella*, *Klebsiella*, *Vibrio*, *Pasteurella*, *Borrelia*, *Leptospira*, *Campylobacter*, *Clostridium*, *Corynebacterium*, *Yersinia*, *Treponema*, *Rickettsia*, and *Chlamydia*. a) Mycoplasma, Coxiella, Neisseria, Listeria, Haemophilus, Helicobacter, Legionella, Pseudomonas, Bordetella, Brucella, Staphylococcus, Streptococcus, Enterococcus, Bacillus, Mycobacterium, Nocardia, etc. The term "bacterial infection" generally refers to any obstruction caused by the amplification and / or presence of bacteria as described in this application in cells or a subject. Bacterial infection can be caused by the growth and reproduction of bacteria (e.g., pathogenic bacteria), the production of toxins and other metabolites.

[0152] In this application, the term "subject in need" generally refers to any organism to which the compound and / or composition described in this application may be administered, for example for experimental, diagnostic, preventive and / or therapeutic purposes. Typical subjects include animals (e.g. mammals such as mice, rats, rabbits, dogs, non-human primates and humans) and / or plants.

[0153] In this application, the term "comprising" generally means including the explicitly specified features, but does not exclude other elements. The terms "above" and "below" generally refer to situations that include the stated number.

[0154] The term "prevention and / or treatment" includes not only the prevention and / or treatment of disease, but also generally includes preventing the onset of disease, slowing or reversing the progression of disease, preventing or slowing the onset of one or more symptoms associated with the disease, reducing and / or alleviating one or more symptoms associated with the disease, reducing the severity and / or duration of the disease and / or any symptoms associated with it and / or preventing a further increase in the severity of the disease and / or any symptoms associated with it, preventing, reducing or reversing any physiological damage caused by the disease, and any pharmacological effects that are generally beneficial to the patient being treated. The compositions of this application do not need to achieve a complete cure or eradication of any symptom or manifestation of the disease to form a viable therapeutic agent. As recognized in the relevant art, a medicine used as a therapeutic agent may reduce the severity of a given disease state, but does not need to eliminate every manifestation of the disease to be considered a useful therapeutic agent. Similarly, a treatment administered prophylactically constitutes a viable preventive agent without completely and effectively preventing the onset of the condition. It is sufficient to simply reduce the effects of the disease in the subject (e.g., by reducing the number or severity of its symptoms, or by increasing the effectiveness of another treatment, or by producing another beneficial effect), or reduce the likelihood of the disease occurring or worsening.

[0155] The terms “administration” or “application” include the route by which the compound is introduced into a subject to achieve its intended function. Non-limiting examples of possible routes of administration include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

[0156] The term "effective amount" includes the amount that effectively achieves the desired result within the necessary dosage and time period. The effective amount of a compound can vary depending on factors such as the subject's disease state, age, and weight, as well as the compound's ability to elicit the desired response in that subject. Dosing regimens can be adjusted to provide the optimal therapeutic response. "Therapeutic effective amount" refers to the amount of the compound of this application that (i) treats or prevents a specific disease, condition, or symptom, (ii) reduces, improves, or eliminates one or more symptoms of a specific disease, condition, or symptom, or (iii) prevents or delays the onset of one or more symptoms of the specific disease, condition, or symptom described in this application. In the case of cancer, the therapeutically effective amount of the drug can reduce the number of cancer cells; reduce tumor size; inhibit (i.e., to some extent slow down and preferably stop) the infiltration of cancer cells into peripheral organs; inhibit (i.e., to some extent slow down and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more symptoms associated with the cancer to some extent. The drug may be cytotoxic and / or inhibitory to the extent that it can stop and / or kill the growth of existing cancer cells. For cancer treatment, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0157] The term "contact" generally refers to two or more different types of substances coming into contact with each other in any order, in any manner, and for any duration. In some embodiments, the interaction includes one or more hydrogen bonds, covalent bonds, ionic bonds, hydrophobic contacts, and / or van der Waals contacts.

[0158] The terms "subject" or "patient" generally refer to an animal, such as a mammal, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a human. Invention Details

[0160] compound

[0161] On one hand, this application provides a compound, or a stereoisomer, hydrate, deuterated product, ester, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein the compound comprises the structure of formula (I):

[0162]

[0163] in,

[0164] X, Y, Z, and V are each independently selected from N or C;

[0165] R 1 Selected from: -H, any substituted C1–C5 alkyl, any substituted C3–C5 alkenyl, any substituted C3–C5 ynyl, any substituted C3–C6 cycloalkyl;

[0166] R 2 It can be any substituted alicyclic hydrocarbon group or alihexacyclic group;

[0167] R 3 Selected from: -H, -CN, any substituted C1-C3 alkoxy, any substituted C1–C6 alkyl, any substituted C2–C6 alkenyl, any substituted C2–C6 alkynyl, any substituted C3–C6 cycloalkyl, any substituted 4-6 heterocyclic alkyl.

[0168] R 4 R 5 R 6 R 7Whether identical or different, each is independently selected from one of the following: -H, -F, -Cl, -CN, -OR', -SR', -NR'R”, -NO2, -C(=O)R', -C(=O)OR', -OC(=O)R', -C(=O)NHR', -NHC(=O)R', where R' and R” are identical or different, each representing hydrogen, any substituted straight-chain or branched C1–C4 alkyl, any substituted C3–C8 cycloalkyl, any substituted 4-8 membered heterocyclic alkyl, or R' and R” forming a 4-8 membered heterocycle.

[0169] In some implementation schemes, R 1 It can be -H, any substituted C1–C5 alkyl, any substituted C3–C5 alkenyl, any substituted C3–C5 ynyl or any substituted C3–C6 cycloalkyl.

[0170] In some implementation schemes, R 1 It can be -H.

[0171] In some implementation schemes, R 1 It can be any substituted C1–C5 alkyl group.

[0172] In some implementation schemes, R 1 It can be any substituted C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl or C5 alkyl.

[0173] In some implementation schemes, R 1 It can be C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, or C5 alkyl. For example, R 1 It can be n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl, or tert-isopentyl.

[0174] In some implementation schemes, R 1 It can be any substituted C3–C5 alkenyl group.

[0175] In some implementation schemes, R 1 It can be any substituted C3 alkenyl, C4 alkenyl, or C5 alkenyl.

[0176] In some implementation schemes, R 1 It can be C3-alken, C4-alken, or C5-alken. For example, R 1 It can be propenyl, n-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, or 2-methyl-2-butenyl.

[0177] In some implementation schemes, R 1It can be any substituted C3–C5 ynyl group.

[0178] In some implementation schemes, R 1 It can be any substituted C3 ynyl group, C4 ynyl group, or C5 ynyl group.

[0179] In some implementation schemes, R 1 It can be C3-, C4-, or C5-. For example, R 1 It can be propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, or 3-methyl-1-butynyl.

[0180] In some implementation schemes, R 1 It can be any substituted C3–C6 cycloalkyl group.

[0181] In some implementation schemes, R 1 It can be any substituted C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl or C6 cycloalkyl.

[0182] In some implementation schemes, R 1 It can be a C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, or C6 cycloalkyl. For example, R 1 It can be cyclopropyl (a functional group formed by removing a hydrogen atom from cyclopropane), cyclobutyl (a functional group formed by removing a hydrogen atom from cyclobutane), cyclopentyl (a functional group formed by removing a hydrogen atom from cyclopentane), or cyclohexyl (a functional group formed by removing a hydrogen atom from cyclohexane).

[0183] In some implementation schemes, R 1 It can be any substituted methyl, ethyl, or cyclopropyl group.

[0184] In some implementation schemes, R 1 It can be methyl, ethyl, or cyclopropyl.

[0185] In some implementation schemes, R 1 It can be methyl.

[0186] In some implementation schemes, R 1 It can be ethyl.

[0187] In some implementation schemes, R 1 It can be cyclopropyl.

[0188] In some implementation schemes, R 1 It can be -CF3.

[0189] In some implementations, R 3It can be -H, -CN, any substituted C1-C3 alkoxy, any substituted C1–C6 alkyl, any substituted C2–C6 alkenyl, any substituted C2–C6 alkynyl, any substituted C3–C6 cycloalkyl, or any substituted 4- to 6-membered heterocyclic alkyl.

[0190] In some implementation schemes, R 3 It can be -H.

[0191] In some implementation schemes, R 3 It can be any substituted C1–C3 alkoxy group. For example, R 3 It can be any substituted methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, or pentoxy.

[0192] In some implementations, R 3 It can be -OMe or -OCF3

[0193] In some implementation schemes, R 3 It can be -CN.

[0194] In some implementation schemes, R 3 It can be any substituted C1–C6 alkyl group.

[0195] In some implementation schemes, R 3 It can be any substituted C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl.

[0196] In some implementation schemes, R 3 It can be C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl. For example, R 3 It can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl or tert-isopentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,3-dimethylbutyl or 2,2-dimethylbutyl.

[0197] In some implementation schemes, R 3 It can be any substituted C2–C6 alkenyl group.

[0198] In some implementation schemes, R 3 It can be any substituted C2-alkenyl, C3-alkenyl, C4-alkenyl, C5-alkenyl, or C6-alkenyl.

[0199] In some implementation schemes, R 3 It can be C2-alken, C3-alken, C4-alken, C5-alken, or C6-alken. For example, R 3It can be vinyl, 1-propenyl, 2-propenyl, n-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl or 2-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 2,3-dimethyl-1-butenyl, 3,3-dimethyl-1-butenyl.

[0200] In some implementation schemes, R 3 It can be any substituted C2–C6 ynyl group.

[0201] In some implementation schemes, R 3 It can be any substituted C2 ynyl group, C3 ynyl group, C4 ynyl group, C5 ynyl group, or C6 ynyl group.

[0202] In some implementation schemes, R 3 It can be C2-alkynyl, C3-alkynyl, C4-alkynyl, C5-alkynyl, or C6-alkynyl. For example, R 3 It can be ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-methyl-1-pentynyl, 3-methyl-1-pentynyl, 4-methyl-2-pentynyl or 2,2-dimethyl-1-butynyl.

[0203] In some implementation schemes, R 3 It can be any substituted C3–C6 cycloalkyl group.

[0204] In some implementation schemes, R 3 It can be any substituted C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl or C6 cycloalkyl.

[0205] In some implementation schemes, R 3 It can be a C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, or C6 cycloalkyl. For example, R 1 It can be cyclopropyl (a functional group formed by removing a hydrogen atom from cyclopropane), cyclobutyl (a functional group formed by removing a hydrogen atom from cyclobutane), cyclopentyl (a functional group formed by removing a hydrogen atom from cyclopentane), or cyclohexyl (a functional group formed by removing a hydrogen atom from cyclohexane).

[0206] In some implementations, R3 is selected from one of the following:

[0207] -H, -Me, -CN, -OMe, -CF3, -OCF3,

[0208] In some implementations, R3 can be -H, -Me, -CN, -OMe, -CF3, -OCF3,

[0209] R 4 R 5 R 6 R 7 They can be the same or different. R 4 R 5 R 6 R 7 R' and R" can be selected independently from one of the following: -H, -F, -Cl, -CN, -OR', -SR', -NR'R", -NO2, -C(=O)R', -C(=O)OR', -OC(=O)R', -C(=O)NHR', -NHC(=O)R', where R' and R" may be the same or different, each representing hydrogen, any substituted straight-chain or branched C1–C4 alkyl, any substituted C3–C8 cycloalkyl, any substituted 4-8 member heterocyclic alkyl, or R' and R" forming a 4-8 member heterocycle.

[0210] For example, R 4 R 5 R 6 -H, R 7 This is one of the functional groups described in the previous paragraph, such as R. 7 It can be -H, -F, -Cl, -Br, -I, -CN, -NMe2, pyrrole, -OMe, -CF3, -OCF3, -NH2, or -Me.

[0211] For example, R 4 R 5 R 7 -H, R 6 It is one of the functional groups mentioned in the previous paragraph, such as R. 6 It can be -H, -F, -Cl, -Br, -I, -CN, -NMe2, pyrrole, -OMe, -CF3, -OCF3, -NH2, or -Me.

[0212] For example, R 4 R 6 R 7 -H, R 5 It is one of the functional groups mentioned in the previous paragraph, such as R. 5 It can be -H, -F, -Cl, -Br, -I, -CN, -NMe2, pyrrole, -OMe, -CF3, -OCF3, -NH2, or -Me.

[0213] For example, R 5 R 6 R7 -H, R 4 It is one of the functional groups mentioned in the previous paragraph, such as R. 4 It can be -H, -F, -Cl, -Br, -I, -CN, -NMe2, pyrrole, -OMe, -CF3, -OCF3, -NH2, or -Me.

[0214] In some implementations, R4, R5, R6, and R7 can be independently selected from one of the following: -H, -F, -Cl, -Br, -I, -CN, -NMe2, pyrrole, -OMe, -CF3, -OCF3, -NH2, and -Me.

[0215] In some implementations, X, Y, Z, and V are each independently selected from N or C.

[0216] For example, X, Y, Z, and V are all C or all N. Another example: Y, Z, and V are C, and X is N. Another example: X, Z, and V are C, and Y is N. Another example: X, Y, and V are C, and Z is N. Another example: X, Y, and Z are C, and V is N. Another example: Z and V are C, and X and Y are N. Another example: Y and V are C, and X and Z are N. Another example: Y and Z are C, and X and V are N. Another example: X, Z, and V are N, and Y is C. Another example: X, Y, and V are N, and Z is C. Another example: X, Y, and Z are N, and V is C.

[0217] In some implementations, when R 1 When R is methyl, ethyl or cyclopropyl, 2 It can be selected from one of the following: any substituted saturated C3–C8 cycloalkyl, any substituted saturated 4–8-membered heterocycloalkyl, any substituted unsaturated C5–C8 cycloalkyl, any substituted unsaturated 5–8-membered heterocycloalkyl, any substituted C6–C 11 Bicycloalkyl and any substituted C6–C 11 Bicyclic heterocyclic group.

[0218] In some implementations, when R 1 When R is methyl, ethyl or cyclopropyl, 2 It can be any substituted saturated C3–C8 cycloalkyl, any substituted saturated 4–8-membered heterocyclic alkyl, any substituted unsaturated C5–C8 cycloalkyl, any substituted unsaturated 5–8-membered heterocyclic alkyl, any substituted C6–C 11 Bicycloalkyl or any substituted C6–C 11 Bicyclic heterocyclic group.

[0219] In some implementations, when R 1 When R is methyl, ethyl or cyclopropyl, 2 It can be any substituted saturated C3–C8 cycloalkyl group. For example, R 2 It can be any substituted C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl, or C8 cycloalkyl.

[0220] In some implementations, when R 1 When R is methyl, ethyl or cyclopropyl, 2 It can be any substituted unsaturated C5–C8 cycloalkyl group. For example, R 2 It can be any substituted C5, C6, C7, or C8 cyclic alkenyl group. For example, R 2 It can be any substituted cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptenyl, 1,3-cycloheptadienyl, 1,4-cycloheptadienyl, 1,3,5-cycloheptadienyl, cyclooctenyl, 1,3-cyclooctadienyl, 1,5-cyclooctadienyl, 1,3,5,7-cyclooctatetraenyl.

[0221] In some implementations, when R 1 When R is methyl, ethyl or cyclopropyl, 2 It can be any substituted saturated 4- to 8-membered heterocyclic alkyl group. For example, R 2 It can be a saturated 4-membered heterocyclic group, a saturated 5-membered heterocyclic group, a saturated 6-membered heterocyclic group, a saturated 7-membered heterocyclic group, or a saturated 8-membered heterocyclic group. For example, R 2 Self-acetidine that can be arbitrarily substituted, Butane, thiobutane, azircyclopentane, oxacyclopentane, thiocyclopentane, azircyclohexane, oxacyclohexane, thiocyclohexane, azircycloheptane, oxacycloheptane, thiocycloheptane, azircyclooctane, oxacyclooctane or thiocyclooctane.

[0222] In some implementations, when R 1 When R is methyl, ethyl or cyclopropyl, 2 It can be any substituted unsaturated 5- to 8-membered heterocyclic alkyl group. For example, R 2 It can be an unsaturated 5-membered heterocyclic group, an unsaturated 6-membered heterocyclic group, an unsaturated 7-membered heterocyclic group, or an unsaturated 8-membered heterocyclic group.

[0223] In some implementations, when R 1 When R is methyl, ethyl or cyclopropyl, 2 C6–C can be arbitrarily substituted 11 Bicycloalkyl or any substituted C6–C 11A bicyclic heterocyclic group. R 2 It can be any substituted C6 bicycloalkyl, C7 bicycloalkyl, C8 bicycloalkyl, C9 bicycloalkyl, C 10 Bicycloalkyl, C 11 Bicycloalkyl, C6 bicycloheteroalkyl, C7 bicycloheteroalkyl, C8 bicycloheteroalkyl, C9 bicycloheteroalkyl, C 10 Bicyclic heteroalkyl, C 11 Bicyclic heteroalkyl groups.

[0224] In some implementations, when R 1 When R is methyl, ethyl or cyclopropyl, 2 It can be Where q is an integer between 0 and 3, with 0 representing the absence of the group. For example, q can be 0, 1, 2, or 3. (Ra represents different alicyclic hydrocarbon groups or alicyclic heterocyclic groups. Rb represents the substitution of alicyclic hydrocarbon groups or alicyclic heterocyclic groups.)

[0225] In some implementations, when R 1 When Ra is methyl, ethyl, or cyclopropyl, it can be a saturated C3–C8 cycloalkyl, a saturated 4–8-membered heterocycloalkyl, an unsaturated C5–C8 cycloalkyl, an unsaturated 5–8-membered heterocycloalkyl, or a C6–C 11 Bicycloalkyl, C6–C 11 Bicyclic heterocyclic group.

[0226] In some implementations, when R 1 When Rb is methyl, ethyl, or cyclopropyl, it can be independently selected from one or more of the following combinations: -H, -F, -CN, -Ra', =CHRa', -ORa', -SRa', -NR'Ra”, -NO2, -C(=O)-, -C(=O)Ra', -C(=O)ORa', -OC(=O)Ra', -C(=O)NHRa', -NHC(=O)Ra', -Ra”C(=O)Ra', -Ra”C(=O)ORa', -R”OC(=O)Ra', -Ra”C(=O)NHRa', -Ra”NHC(=O)Ra', where Ra' and Ra” may be the same or different, each representing hydrogen, any substituted straight-chain or branched C1-C4 alkyl, any substituted C3-C8 cycloalkyl, any substituted 4-8 membered heterocyclic alkyl, or Ra' and Ra” forming a 4-8 membered heterocycle. Rb can be a single functional group or a combination of functional groups.

[0227] In some implementations, when R 1When Rb is methyl, ethyl, or cyclopropyl, it may include: -H, -F, -CN, -Ra', =CHRa', -ORa', -SRa', -NR'Ra”, -NO2, -C(=O)Ra', -C(=O)ORa', -OC(=O)Ra', -C(=O)NHRa', -NHC(=O)Ra', -Ra”C(=O)Ra', -Ra”C(=O)ORa', -R”OC(=O)Ra', -Ra”C(=O)NHRa', -Ra”NHC(=O)Ra', where Ra' and Ra” may be the same or different, each representing hydrogen, any substituted straight-chain or branched C1-C4 alkyl, any substituted C3-C8 cycloalkyl, any substituted 4-8 membered heterocyclic alkyl, or Ra' and Ra” forming a 4-8 membered heterocycle.

[0228] In some implementations, when R 1 When Rb is methyl, ethyl, or cyclopropyl, it can be independently selected from one or a combination of the following: -H, -F, -OH, -NH2, -C(=O)-, -NH-, =CH2, =CH2CH3, -CH3, -CF3, -Et, -CH2CF3, -Boc, -CH(CH3)2, -C(CH3)3, -OMe, -OCF3, -OEt, -OCH2CF3, -OCH(CH3)2, -OBn, -SMe, -NHBoc, -NHC(=O)CH3, -NHC(=O)CF3, -NHC(=O)CH(CH3) 2、 -NHC(=O)C(CH3)3, -NHC(=O)OCH3, -NHC(=O)OCH2CH3, -NHC(=O)NHCH2CH3, -NHC(=O)N(CH3)2, -NHC(=O)NHCH2CF3, -NHC(=O)NHCH(CH3)2, Rb can be a single functional group or a combination of functional groups.

[0229] In some implementations, when R 1When Rb is methyl, ethyl, or cyclopropyl, it can be -H, -F, -OH, -NH2, -NHMe, -NCH(CH3)2, =CH2, =CH2CH3, -CH3, -CF3, -Et, -CH2CF3, -CH(CH3)2, -C(CH3)3, -OMe, -OCF3, -OEt, -OCH2CF3, -OCH(CH3)2, -OBn, -SMe, -NHBoc, -NHC(=O)CH3, -NHC(=O)CF3, -NHC(=O)CH(CH3)2, -NHC(=O)C(CH3)3, -NHC(=O)OCH3, -NHC(=O)OCH2CF3, -NHC(=O)OCH2CH3. -NHC(=O)NHCH2CH3, -NHC(=O)N(CH3)2, -NHC(=O)NHCH2CF3, -NHC(=O)NHCH(CH3)2 or

[0230] There can be multiple Rb, such as two or three. Each Rb can be the same or different. For example, when there are two Rb, one Rb can be -F, and the other Rb can be -NH2, -OH, -OCH3, or -NHBoc. Multiple Rb can substitute on the same atom or on different atoms.

[0231] In some implementations, when R 1 When Ra is methyl, ethyl, or cyclopropyl, it is...

[0232]

[0233] Where n1 is an integer from 0 to 5, with 0 representing the absence of the group. In some implementations, n1 can be 0, 1, 2, 3, 4, or 5. For example, Ra can be... The above functional groups can be connected to any carbon atom on any ring to form an atom of formula (I) to form formula (I).

[0234] Furthermore, the compound described in formula (I) may have the following structure:

[0235]

[0236] In some implementations, when R 1 When Ra is methyl, ethyl, or cyclopropyl, it is...

[0237]

[0238] Where n2 is an integer from 0 to 3, with 0 representing the absence of the functional group. In some implementations, n2 can be 0, 1, 2, or 3. The dashed lines represent any number of unsaturated bonds at any position. For example, Ra can be...

[0239] The above functional groups can be connected to any carbon atom on any ring to form an atom of formula (I) to form formula (I).

[0240] Furthermore, the compound described in formula (I) may have the following structure:

[0241]

[0242] In some implementations, when R 1 When Ra is methyl, ethyl, or cyclopropyl, it is...

[0243]

[0244] Where n3 is an integer from 1 to 5, and n4 is an integer from 1 to 5. In some implementations, n3 can be 1, 2, 3, 4, or 5. n4 can be 1, 2, 3, 4, or 5. For example, Ra can be... The above functional groups can be connected to any carbon atom on any ring to form an atom of formula (I) to form formula (I).

[0245] Furthermore, the compound described in formula (I) may have the following structure:

[0246]

[0247] In some implementations, when R 1 When Ra is methyl, ethyl, or cyclopropyl, it is...

[0248]

[0249] Where n5 is an integer from 1 to 5, and n6 is an integer from 1 to 5. In some implementations, n5 can be 0, 1, 2, 3, 4, or 5, and n6 can be 0, 1, 2, 3, 4, or 5. For example, Ra can be... or The above functional groups can be connected to any carbon atom on any ring to form an atom of formula (I) to form formula (I).

[0250] Furthermore, the compound described in formula (I) may have the following structure:

[0251]

[0252] In some implementations, when R 1 When Ra is methyl, ethyl, or cyclopropyl, it is...

[0253]

[0254] Where n7 is an integer between 0 and 2, n8 is an integer between 0 and 2, n9 is an integer between 1 and 2, and 0 represents the absence of the group. In some embodiments, n7 can be 0, 1, or 2. In some embodiments, n8 can be 0, 1, or 2. n9 can be 1 or 2. For example, Ra can be...

[0255] The above functional groups can be connected to any carbon atom on any ring to form an atom of formula (I) to form formula (I).

[0256] Furthermore, the compound described in formula (I) may have the following structure:

[0257]

[0258] In some implementations, when R 1 When Ra is methyl, ethyl, or cyclopropyl, it is...

[0259]

[0260] Where n10 is an integer between 2 and 4, and X is selected from N, 0, and S. In some implementations, n10 can be 2, 3, or 4. X can be N, 0, or S. For example, Ra can be...

[0261] The above functional groups can be connected to any carbon atom on any ring to form an atom of formula (I) to form formula (I).

[0262] Furthermore, the compound described in formula (I) may have the following structure:

[0263]

[0264] In some implementations, when R 1 When Ra is methyl, ethyl, or cyclopropyl, it is... Where n11 is an integer between 0 and 2, X is selected from N, O, and S, and 0 represents the absence of a functional group. The dashed lines represent any number of unsaturated bonds at any position. In some embodiments, n11 can be 0, 1, or 2. X can be N, O, or S. For example, Ra can be...

[0265] , The above functional groups can be connected to any carbon atom on any ring to form an atom of formula (I) to form formula (I).

[0266] Furthermore, the compound described in formula (I) may have the following structure:

[0267]

[0268] In some implementations, when R 1 When Ra is methyl, ethyl, or cyclopropyl, it is...

[0269]

[0270] Where n12 is an integer from 1 to 4, n13 is an integer from 0 to 2, n14 is an integer from 2 to 4, X is selected from N, O, and S, and 0 represents the absence of the functional group. In some embodiments, n12 can be 1, 2, 3, or 4. In some embodiments, n13 can be 0, 1, or 2. In some embodiments, n14 can be 2, 3, or 4. In some embodiments, X can be N, O, or S. For example, Ra is... The above functional groups can be connected to any carbon atom on any ring to form an atom of formula (I) to form formula (I).

[0271] Furthermore, the compound described in formula (I) may have the following structure:

[0272]

[0273] In some implementations, when R 1 When Ra is methyl, ethyl, or cyclopropyl, it is...

[0274]

[0275] Where n15 is an integer from 1 to 5, n16 is an integer from 0 to 2, n17 is an integer from 2 to 4, and X is selected from N, O, and S, with 0 representing the absence of the functional group. In some embodiments, n15 can be 1, 2, 3, 4, or 5. In some embodiments, n16 can be 0, 1, or 2. In some embodiments, n17 can be 2, 3, or 4. In some embodiments, X can be N, O, or S. For example, Ra can be... The above functional groups can be connected to any carbon atom on any ring to form an atom of formula (I) to form formula (I).

[0276] Furthermore, the compound described in formula (I) may have the following structure:

[0277]

[0278] In some implementations, when R 1 When R is -H, 2 You can choose from one of the following: R 2 It can be a substituted saturated C5–C7 cycloalkyl, an substituted saturated C3–C4 or C8 cycloalkyl, an substituted saturated 4-8 heterocyclic alkyl, an substituted unsaturated C5–C8 cycloalkyl, an substituted unsaturated 5-8 heterocyclic alkyl, or an substituted C6–C 11 Bicycloalkyl or any substituted C6–C 11 Bicyclic heterocyclic group.

[0279] In some implementations, when R 1 When R is -H, 2 It can be a substituted saturated C5–C7 cycloalkyl, an substituted saturated C3–C4 or C8 cycloalkyl, an substituted saturated 4-8 heterocyclic alkyl, an substituted unsaturated C5–C8 cycloalkyl, an substituted unsaturated 5-8 heterocyclic alkyl, or an substituted C6–C 11 Bicycloalkyl or any substituted C6–C 11 Bicyclic heterocyclic group.

[0280] In some implementations, when R 1 When R is -H, 2 It can be a substituted saturated C5–C7 cycloalkyl group. For example, R 2 It can be a substituted C5-cycloalkyl, C6-cycloalkyl, or C7-cycloalkyl. When R... 1 When R is -H, 2 When R is a substituted saturated C5–C7 cycloalkyl group, 2 The group has a non-hydrogen substitution.

[0281] In some implementations, when R 1 When R is -H, 2 It can be any substituted saturated C3–C4 or C8 cycloalkyl group. For example, R 2 It can be any substituted C3 cycloalkyl, C4 cycloalkyl, or C8 cycloalkyl.

[0282] In some implementations, when R 1 When R is -H, 2 It can be any substituted unsaturated C5–C8 cycloalkyl group. For example, R 2 It can be any substituted C5, C6, C7, or C8 cyclic alkenyl group. For example, R 2It can be any substituted cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptenyl, 1,3-cycloheptadienyl, 1,4-cycloheptadienyl, 1,3,5-cycloheptadienyl, cyclooctenyl, 1,3-cyclooctadienyl, 1,5-cyclooctadienyl, 1,3,5,7-cyclooctatetraenyl.

[0283] In some implementations, when R 1 When R is -H, 2 It can be any substituted saturated 4- to 8-membered heterocyclic alkyl group. For example, R 2 It can be a saturated 4-membered heterocyclic group, a saturated 5-membered heterocyclic group, a saturated 6-membered heterocyclic group, a saturated 7-membered heterocyclic group, or a saturated 8-membered heterocyclic group. For example, R 2 Self-acetidine that can be arbitrarily substituted, Butane, thiobutane, azircyclopentane, oxacyclopentane, thiocyclopentane, azircyclohexane, oxacyclohexane, thiocyclohexane, azircycloheptane, oxacycloheptane, thiocycloheptane, azircyclooctane, oxacyclooctane or thiocyclooctane.

[0284] In some implementations, when R 1 When R is -H, 2 It can be any substituted unsaturated 5- to 8-membered heterocyclic alkyl group. For example, R 2 It can be an unsaturated 5-membered heterocyclic group, an unsaturated 6-membered heterocyclic group, an unsaturated 7-membered heterocyclic group, or an unsaturated 8-membered heterocyclic group.

[0285] In some implementations, when R 1 -H, R 2 C6–C can be arbitrarily substituted 11 Bicycloalkyl or any substituted C6–C 11 A bicyclic heterocyclic group. R 2 It can be any substituted C6 bicycloalkyl, C7 bicycloalkyl, C8 bicycloalkyl, C9 bicycloalkyl, C 10 Bicycloalkyl, C 11 Bicycloalkyl, C6 bicycloheteroalkyl, C7 bicycloheteroalkyl, C8 bicycloheteroalkyl, C9 bicycloheteroalkyl, C 10 Bicyclic heteroalkyl, C 11 Bicyclic heteroalkyl groups.

[0286] In some implementations, when R 1 When R is -H, 2 It can be Where q is an integer between 0 and 3, with 0 representing the absence of the group. For example, q can be 0, 1, 2, or 3. (Ra represents different alicyclic hydrocarbon groups or alicyclic heterocyclic groups. Rb represents the substitution of alicyclic hydrocarbon groups or alicyclic heterocyclic groups.)

[0287] In some implementations, when R 1 When -H is present, Ra can be a substituted saturated C5–C7 cycloalkyl, an substituted saturated C3–C4 or C8 cycloalkyl, an substituted saturated 4- to 8-membered heterocyclic alkyl, an substituted unsaturated C5–C8 cycloalkyl, an substituted unsaturated 5- to 8-membered heterocyclic alkyl, or an substituted C6–C 11 Bicycloalkyl or any substituted C6–C 11 Bicyclic heterocyclic group.

[0288] There can be multiple Rb, such as 2 or 3. Each Rb can be the same or different.

[0289] In some implementations, when R 1 When Ra is -H, and Ra is a saturated C5–C7 cycloalkyl group, each Rb is independently selected from one or more combinations of the following: -F, -CN, -Ra', =CHRa', -ORa', -SRa', -NR'Ra", -NO2, -C(=O)-, -C(=O)Ra', -C(=O)ORa', -OC(=O)Ra', -C(=O)NHRa', -NHC(=O)Ra', -R a”C(=O)Ra', -Ra”C(=O)ORa', -Ra”OC(=O)Ra', -Ra”C(=O)NHRa', -Ra”NHC(=O)Ra', where Ra' and Ra” may be the same or different, each representing hydrogen, any substituted straight-chain or branched C1-C4 alkyl, any substituted C3-C8 cycloalkyl, any substituted 4-8 membered heterocyclic alkyl, or Ra' and Ra” forming a 4-8 membered heterocycle. Rb can be a single functional group among the above functional groups, or Rb can be a combination of the above functional groups.

[0290] In some implementations, when R 1When Ra is -H, and Ra is a saturated C5–C7 cycloalkyl group, Rb can include: -F, -CN, -Ra', =CHRa', -ORa', -SRa', -NR'Ra”, -NO2, -C(=O)-, -C(=O)Ra', -C(=O)ORa', -OC(=O)Ra', -C(=O)NHRa', -NHC(=O)Ra', -Ra”C(=O)Ra', -Ra”C(=O)ORa', -Ra”OC(=O)Ra', -Ra”C(=O)NHRa', -Ra”NHC(=O)Ra', where Ra' and Ra” may be the same or different, each representing hydrogen, any substituted straight-chain or branched C1–C4 alkyl group, any substituted C3–C8 cycloalkyl group, any substituted 4–8 member heterocyclic alkyl group, or Ra' and Ra” forming a 4–8 member heterocyclic ring.

[0291] In some implementations, when R 1 When Ra is -H, and Ra is a saturated C5–C7 cycloalkyl group, Rb can be independently selected from one or a combination of the following: -F, -OH, -NH2, -C(=O)-, -NH-, =CH2, =CH2CH3, -CH3, -CF3, -Et, -CH2CF3, -Boc, -CH(CH3)2, -C(CH3)3, -OMe, -OCF3, -OEt, -OCH2CF3, -OCH(CH3)2, -OBn, -SMe, -NHBoc, -NHC(=O)CH3, -NHC(=O)CF3, -NHC(=O)CH(CH3) 2、 -NHC(=O)C(CH3)3, -NHC(=O)OCH3, -NHC(=O)OCH2CH3, -NHC(=O)NHCH2CH3, -NHC(=O)N(CH3)2, -NHC(=O)NHCH2CF3, -NHC(=O)NHCH(CH3)2, Rb can be a single functional group or a combination of functional groups.

[0292] In some implementations, when R 1When Ra is a saturated C5–C7 cycloalkyl group, Rb can include: -F, -OH, -NH2, -NHMe, -NCH(CH3)2, =CH2, =CH2CH3, -CH3, -CF3, -Et, -CH2CF3, -CH(CH3)2, -C(CH3)3, -OMe, -OCF3, -OEt, -OCH2CF3, -OCH(CH3)2, -OBn, -SMe, -NHBoc, -NHC(=O)CH3, -NHC(=O)CF3, -NHC(=O)CH(CH3)2, -NHC(=O)C(CH3)3, -NHC(=O)OCH3, -NHC(=O)OCH2CF3, -NHC(=O)OCH2CH3, -NHC(=O)NHCH2CH3, -NHC(=O)N(CH3)2, -NHC(=O)NHCH2CF3, -NHC(=O)NHCH(CH3)2 or

[0293] In some implementations, when R 1 When Ra is -H, it refers to any substituted saturated C3–C4 or C8 cycloalkyl, any substituted saturated 4- to 8-membered heterocyclic alkyl, any substituted unsaturated C5–C8 cycloalkyl, any substituted unsaturated 5- to 8-membered heterocyclic alkyl, or any substituted C6–C 11 Bicycloalkyl or any substituted C6–C 11 When the bicyclic heterocyclic group is used, each Rb is independently selected from one or more combinations of the following: -H, -F, -CN, -Ra', =CHRa', -ORa', -SRa', -NR'Ra”, -NO2, -C(=O)-, -C(=O)Ra', -C(=O)ORa', -OC(=O)Ra', -C(=O)NHRa', -NHC(=O)Ra', -Ra”C(=O)Ra', -Ra”C(=O)ORa', -Ra”OC(=O)Ra', -Ra”C(=O)NHRa', -Ra”NHC(=O)Ra'.

[0294] In some implementations, when R 1 When Ra is -H, it refers to any substituted saturated C3–C4 or C8 cycloalkyl, any substituted saturated 4- to 8-membered heterocyclic alkyl, any substituted unsaturated C5–C8 cycloalkyl, any substituted unsaturated 5- to 8-membered heterocyclic alkyl, or any substituted C6–C 11 Bicycloalkyl or any substituted C6–C 11When the bicyclic heterocyclic group is used, Rb can include: -H, -F, -CN, -Ra', =CHRa', -ORa', -SRa', -NR'Ra”, -NO2, -C(=O)-, -C(=O)Ra', -C(=O)ORa', -OC(=O)Ra', -C(=O)NHRa', -NHC(=O)Ra', -Ra”C(=O)Ra', -Ra”C(=O)ORa', -Ra”OC(=O)Ra', -Ra”C(=O)NHRa', -Ra”NHC(=O)Ra', where Ra' and Ra” may be the same or different, each representing hydrogen, any substituted straight-chain or branched C1-C4 alkyl, any substituted C3-C8 cycloalkyl, any substituted 4-8 membered heterocyclic alkyl, or Ra' and Ra” forming a 4-8 membered heterocycle.

[0295] In some implementations, when R 1 When Ra is -H, it refers to any substituted saturated C3–C4 or C8 cycloalkyl, any substituted saturated 4- to 8-membered heterocyclic alkyl, any substituted unsaturated C5–C8 cycloalkyl, any substituted unsaturated 5- to 8-membered heterocyclic alkyl, or any substituted C6–C 11 Bicycloalkyl or any substituted C6–C 11 When the bicyclic heterocyclic group is used, Rb can be independently selected from one or more of the following combinations: -H, -F, -OH, -NH2, -C(=O)-, -NH-, =CH2, =CH2CH3, -CH3, -CF3, -Et, -CH2CF3, -Boc, -CH(CH3)2, -C(CH3)3, -OMe, -OCF3, -OEt, -OCH2CF3, -OCH(CH3)2, -OBn, -SMe, -NHBoc, -NHC (=O)CH3, -NHC(=O)CF3, -NHC(=O)CH(CH3)2, -NHC(=O)C(CH3)3, -NHC(=O)OCH3, -NHC(=O)OCH2CH3, -NHC(=O)NHCH2CH3, -NHC(=O)N(CH3)2, -NHC(=O)NHCH2CF3, -NHC(=O)NHCH(CH3)2, Rb can be a single functional group or a combination of functional groups.

[0296] In some implementations, when R 1When Ra is -H, it refers to any substituted saturated C3–C4 or C8 cycloalkyl, any substituted saturated 4- to 8-membered heterocyclic alkyl, any substituted unsaturated C5–C8 cycloalkyl, any substituted unsaturated 5- to 8-membered heterocyclic alkyl, or any substituted C6–C 11 Bicycloalkyl or any substituted C6–C 11 When the bicyclic heterocyclic group is used, Rb can be: -H, -F, -OH, -NH2, -NHMe, -NCH(CH3)2, =CH2, =CH2CH3, -CH3, -CF3, -Et, -CH2CF3, -CH(CH3)2, -C(CH3)3, -OMe, -OCF3, -OEt, -OCH2CF3, -OCH(CH3)2, -OBn, -SMe, -NHBoc, -NHC(=O)CH3, -NHC(=O)CF3, -NHC(=O)CH(CH3)2, -NHC(=O)C(CH3)3, -NHC(=O)OCH3, -NHC(=O)OCH2CF3, -NHC(=O)OCH2CH3. -NHC(=O)NHCH2CH3, -NHC(=O)N(CH3)2, -NHC(=O)NHCH2CF3, -NHC(=O)NHCH(CH3)2 or

[0297] In some implementations, when R 1 When it is -H, where Ra is

[0298]

[0299] Where n1 is 0-1 or 5, and 0 represents the absence of the group. For example, Ra can be... The above functional groups can be connected to any carbon atom on any ring to form an atom of formula (I) to form formula (I).

[0300] Furthermore, the compound described in formula (I) may have the following structure:

[0301]

[0302] In some implementations, when R 1 When it is -H, where Ra is

[0303]

[0304] Where n2 is an integer from 0 to 3, with 0 representing the absence of the functional group. In some implementations, n2 can be 0, 1, 2, or 3. The dashed lines represent any number of unsaturated bonds at any position. For example, Ra can be... The above functional groups can be connected to any carbon atom on any ring to form an atom of formula (I) to form formula (I).

[0305] Furthermore, the compound described in formula (I) may have the following structure:

[0306]

[0307]

[0308] In some implementations, when R 1 When it is -H, where Ra is

[0309]

[0310] Where n3 is an integer from 1 to 5, and n4 is an integer from 1 to 5. In some implementations, n3 can be 1, 2, 3, 4, or 5. n4 can be 1, 2, 3, 4, or 5. For example, Ra can be... The above functional groups can be connected to any carbon atom on any ring to form an atom of formula (I) to form formula (I).

[0311] Furthermore, the compound described in formula (I) may have the following structure:

[0312]

[0313] In some implementations, when R 1 When it is -H, where Ra is

[0314]

[0315] Where n5 is an integer from 1 to 5, and n6 is an integer from 1 to 5. In some implementations, n5 can be 0, 1, 2, 3, 4, or 5, and n6 can be 0, 1, 2, 3, 4, or 5. For example, Ra can be... or The above functional groups can be connected to any carbon atom on any ring to form an atom of formula (I) to form formula (I).

[0316] Furthermore, the compound described in formula (I) may have the following structure:

[0317]

[0318] In some implementations, when R 1 When it is -H, where Ra is

[0319]

[0320] Where n7 is an integer between 0 and 2, n8 is an integer between 0 and 2, n9 is an integer between 1 and 2, and 0 represents the absence of the group. In some embodiments, n7 can be 0, 1, or 2. In some embodiments, n8 can be 0, 1, or 2. n9 can be 1 or 2. For example, Ra can be...

[0321] The above functional groups can be connected to any carbon atom on any ring to form an atom of formula (I) to form formula (I).

[0322] Furthermore, the compound described in formula (I) may have the following structure:

[0323]

[0324] In some implementations, when R 1 When it is -H, where Ra is

[0325]

[0326] Where n10 is an integer between 2 and 4, and X is selected from N, 0, and S. In some implementations, n10 can be 2, 3, or 4. X can be N, 0, or S. For example, Ra can be...

[0327] The above functional groups can be connected to any carbon atom on any ring to form an atom of formula (I) to form formula (I).

[0328] Furthermore, the compound described in formula (I) may have the following structure:

[0329]

[0330] In some implementations, when R 1 When it is -H, where Ra is

[0331]

[0332] Where n11 is an integer between 0 and 2, X is selected from N, O, and S, and 0 represents the absence of a functional group. The dashed lines represent any number of unsaturated bonds at any position. In some embodiments, n11 can be 0, 1, or 2. X can be N, O, or S. For example, Ra can be...

[0333] , The above functional groups can be connected to any carbon atom on any ring to form an atom of formula (I) to form formula (I).

[0334] Furthermore, the compound described in formula (I) may have the following structure:

[0335]

[0336] In some implementations, when R 1 When it is -H, where Ra is

[0337]

[0338] Where n12 is an integer from 1 to 4, n13 is an integer from 0 to 2, n14 is an integer from 2 to 4, X is selected from N, O, and S, and 0 represents the absence of the functional group. In some embodiments, n12 can be 1, 2, 3, or 4. In some embodiments, n13 can be 0, 1, or 2. In some embodiments, n14 can be 2, 3, or 4. In some embodiments, X can be N, O, or S. For example, Ra is... The above functional groups can be connected to any carbon atom on any ring to form an atom of formula (I) to form formula (I).

[0339] Furthermore, the compound described in formula (I) may have the following structure:

[0340]

[0341] In some implementations, when R 1 When it is -H, where Ra is

[0342]

[0343] Where n15 is an integer from 1 to 5, n16 is an integer from 0 to 2, n17 is an integer from 2 to 4, and X is selected from N, O, and S, with 0 representing the absence of the functional group. In some embodiments, n15 can be 1, 2, 3, 4, or 5. In some embodiments, n16 can be 0, 1, or 2. In some embodiments, n17 can be 2, 3, or 4. In some embodiments, X can be N, O, or S. For example, Ra can be... The above functional groups can be connected to any carbon atom on any ring to form an atom of formula (I) to form formula (I).

[0344] Furthermore, the compound described in formula (I) may have the following structure:

[0345]

[0346] In some implementations, R2 may be selected from the following:

[0347]

[0348]

[0349] In some implementations, R2 may be selected from the following:

[0350]

[0351] In some implementations, R2 may be selected from the following:

[0352]

[0353] In some embodiments, the compound represented by formula (I) can be one of the following structures:

[0354]

[0355]

[0356]

[0357] This application discloses the following implementation methods:

[0358] 1. A compound, or a stereoisomer, hydrate, deuterated derivative, ester, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein the compound comprises the structure of formula (I):

[0359]

[0360] in,

[0361] X, Y, Z, and V are each independently selected from N or C;

[0362] R 1 Selected from: -H, any substituted C1–C5 alkyl, any substituted C3–C5 alkenyl, any substituted C3–C5 ynyl, any substituted C3–C6 cycloalkyl;

[0363] R 2 It can be any substituted alicyclic hydrocarbon group or alihexacyclic group;

[0364] R 3 Selected from: -H, -CN, any substituted C1-C3 alkoxy, any substituted C1–C6 alkyl, any substituted C2–C6 alkenyl, any substituted C2–C6 alkynyl, any substituted C3–C6 cycloalkyl, any substituted 4-6 heterocyclic alkyl.

[0365] R 4 R 5 R 6 R 7Whether identical or different, each can be independently selected from one of the following: -H, -F, -Cl, -CN, -

[0366] OR', -SR', -NR'R", -NO2, -C(=O)R', -C(=O)OR', -OC(=O)R', -C(=O)NHR', -

[0367] NHC(=O)R', where R' and R" may be the same or different, each representing hydrogen, any substituted straight-chain or branched C1–C4 alkyl, any substituted C3–C8 cycloalkyl, any substituted 4-8 heterocyclic alkyl, or R' and R" forming a 4-8 heterocyclic ring.

[0368] 2. The compound according to embodiment 1,

[0369] Where R 1 Methyl, ethyl, or cyclopropyl can be substituted in any way.

[0370] R 2 Selected from one of the following: any substituted saturated C3–C8 cycloalkyl, any substituted saturated 4–8-membered heterocyclic alkyl, any substituted unsaturated C5–C8 cycloalkyl, any substituted unsaturated 5–8-membered heterocyclic alkyl, any substituted C6–C 11 Bicycloalkyl, with arbitrary substitution at C6–C 11 Bicyclic heterocyclic group.

[0371] 3. The compound according to embodiment 1,

[0372] Where R 1 -H;

[0373] R 2 Selected from one of the following: substituted saturated C5–C7 cycloalkyl, substituted saturated C3–C4 or C8 cycloalkyl, substituted saturated 4- to 8-membered heterocyclic alkyl, substituted unsaturated C5–C8 cycloalkyl, substituted unsaturated 5- to 8-membered heterocyclic alkyl, substituted C6–C 11 Bicycloalkyl, with arbitrary substitution at C6–C 11 Bicyclic heterocyclic group.

[0374] 4. The compound according to embodiment 2,

[0375] Where R 2 for Where q is an integer between 0 and 3, and 0 represents that the group does not exist here;

[0376] Ra represents saturated C3–C8 cycloalkyl groups, saturated 4–8-membered heterocyclic alkyl groups, unsaturated C5–C8 cycloalkyl groups, unsaturated 5–8-membered heterocyclic alkyl groups, and C6–C6 cycloalkyl groups. 11 Bicycloalkyl, C6–C 11 Bicyclic heterocyclic groups;

[0377] Each Rb is independently selected from one or more combinations of the following: -H, -F, -CN, -Ra', =CHRa', -ORa', -SRa', -NR'Ra”, -NO2, -C(=O)-, -C(=O)Ra', -C(=O)ORa', -OC(=O)Ra', -C(=O)NHRa', -NHC(=O)Ra', -R”C(=O)Ra', -R”C(=O)ORa', -R”OC(=O)Ra', -Ra”C(=O)NHRa', -Ra”NHC(=O)Ra',

[0378] Ra' and Ra" may be the same or different, each representing hydrogen, any substituted straight-chain or branched C1-C4 alkyl, any substituted C3-C8 cycloalkyl, any substituted 4-8 heterocyclic alkyl, or Ra' and Ra" forming a 4-8 heterocyclic ring.

[0379] 5. The compound according to embodiment 4, wherein Ra is

[0380]

[0381] Where n1 is an integer from 0 to 5, and 0 represents that the group does not exist here.

[0382] 6. The compound according to embodiment 4, wherein Ra is

[0383]

[0384] Where n2 is an integer between 0 and 3, and 0 represents the absence of the group at this point.

[0385] 7. The compound according to embodiment 4, wherein Ra is

[0386]

[0387] Where n3 is an integer from 1 to 5, and n4 is an integer from 1 to 5.

[0388] 8. The compound according to embodiment 4, wherein Ra is

[0389]

[0390] Where n5 is an integer from 1 to 5, and n6 is an integer from 1 to 5.

[0391] 9. The compound according to embodiment 4, wherein Ra is

[0392]

[0393] Where n7 is an integer between 0 and 2, n8 is an integer between 0 and 2, n9 is an integer between 1 and 2, and 0 represents that the group does not exist here.

[0394] 10. The compound according to embodiment 4, wherein Ra is

[0395]

[0396] Where n10 is an integer between 2 and 4, and X is selected from N, O and S.

[0397] 11. The compound according to embodiment 4, wherein Ra is

[0398]

[0399] Where n11 is an integer between 0 and 2, X is selected from N, O and S, and 0 represents that the group does not exist here.

[0400] 12. The compound according to embodiment 4, wherein Ra is

[0401]

[0402] Where n12 is an integer from 1 to 4, n13 is an integer from 0 to 2, n14 is an integer from 2 to 4, X is selected from N, O and S, and 0 represents that the group does not exist here.

[0403] 13. The compound according to embodiment 4, wherein Ra is

[0404]

[0405] Where n15 is an integer from 1 to 5, n16 is an integer from 0 to 2, n17 is an integer from 2 to 4, X is selected from N, O and S, and 0 represents that the group does not exist here.

[0406] 14. The compound according to embodiment 3, wherein R 2 for Where q is an integer between 0 and 3, and 0 represents that the group does not exist here;

[0407] When Ra is a saturated C5–C7 cycloalkyl group, q is an integer from 1 to 3, and each Rb is independently selected from one or more combinations of the following: -F, -CN, -R', =CHR', -OR', -SR', -NR'R”, -NO2, -C(=O)-, -C(=O)R', -C(=O)OR', -OC(=O)R', -C(=O)NHR', -NHC(=O)R', -R”C(=O)R', -R”C(=O)OR', -R”OC(=O)R', -R”C(=O)NHR', -R”NHC(=O)R';

[0408] When Ra is a saturated C3–C4 or C8 cycloalkyl, a saturated 4-8 membered heterocyclic alkyl, an unsaturated C5–C8 cycloalkyl, an unsaturated 5-8 membered heterocyclic alkyl, or a C6–C 11 When the Rb is a bicyclic alkyl group, or a 6- to 11-membered bicyclic heteroalkyl group, each Rb is independently selected from one or more of the following combinations: -H, -F, -CN, -Ra',

[0409] =CHRa', -ORa', -SRa', -NRa'Ra", -NO2, -C(=O)-, -C(=O)Ra', -C(=O)ORa', -OC(=O)Ra', -C(=O)NHRa' , -NHC(=O)Ra', -Ra"C(=O)Ra', -Ra"C(=O)ORa', -Ra"OC(=O)Ra', -Ra"C(=O)NHRa', -Ra"NHC(=O)Ra';

[0410] Ra' and Ra" may be the same or different, each representing hydrogen, any substituted straight-chain or branched C1–C4 alkyl, any substituted C3–C8 cycloalkyl, any substituted 4-8 membered heterocyclic alkyl, or Ra' and Ra" forming a 4-8 membered heterocycle.

[0411] 15. The compound according to embodiment 14, wherein Ra is

[0412]

[0413] Where n1 is 0-1 or 5, or n is an integer from 2 to 4, and 0 represents that the group does not exist here.

[0414] 16. The compound according to embodiment 14, wherein Ra is

[0415]

[0416] Where n2 is an integer between 0 and 3, and 0 represents the absence of the group at this point.

[0417] 17. The compound according to embodiment 14, wherein Ra is

[0418]

[0419] Where n3 is an integer from 1 to 5, and n4 is an integer from 1 to 5.

[0420] 18. The compound according to embodiment 14, wherein Ra is

[0421]

[0422] Where n5 is an integer from 1 to 5, and n6 is an integer from 1 to 5.

[0423] 19. The compound according to embodiment 14, wherein Ra is

[0424]

[0425] Where n7 is an integer between 0 and 2, n8 is an integer between 0 and 2, n9 is an integer between 1 and 2, and 0 represents that the group does not exist here.

[0426] 20. The compound according to embodiment 14, wherein Ra is

[0427]

[0428] Where n10 is an integer between 2 and 4, and X is selected from N, O and S.

[0429] 21. The compound according to embodiment 14, wherein Ra is

[0430]

[0431] Where n11 is an integer between 0 and 2, X is selected from N, O and S, and 0 represents that the group does not exist here.

[0432] 22. The compound according to embodiment 14, wherein Ra is

[0433]

[0434] Where n12 is an integer from 1 to 4, n13 is an integer from 0 to 2, n14 is an integer from 2 to 4, and X is selected from N, O, and S.

[0435] 23. The compound according to embodiment 14, wherein Ra is

[0436]

[0437] Where n15 is an integer from 1 to 5, n16 is an integer from 0 to 2, n17 is an integer from 2 to 4, and X is selected from N, O, and S.

[0438] 24. The compound according to any one of embodiments 4-13 or 14-23, wherein Rb is selected from one or a combination of the following:

[0439] -H, -F, -OH, -NH2, -C(=O)-, -NH-, =CH2, =CH2CH3, -CH3, -CF3, -Et, -CH2CF3, -CH(CH3)2, -C(CH3)3, -OMe, -OCF3, -OEt, -OCH2CF3, -OCH(CH3)2, -OBn, -SMe.

[0440] 25. The compound as described in any one of embodiments 1-24, wherein R2 is selected from one of the following:

[0441]

[0442] 26. The compound as described in any one of embodiments 1-25, wherein R3 is selected from:

[0443] -H, -Me, -CN, -OMe, -CF3, -OCF 3、

[0444] 27. The compound as described in any one of embodiments 1-26, wherein R4, R5, R6, and R7 are each independently selected from one of the following: -H, -F, -Cl, -Br, -I, -CN, -NMe2, pyrrole, -OMe, -CF3, -OCF3, -NH2, and -Me.

[0445] 28. The compound as described in any one of embodiments 1-27, wherein any substitution includes being unsubstituted or substituted by one or more substituents selected from: -F, -Cl, -CN, -OH, -O-, -CH2-, -SH, -NH2, -NO2, =CH-, -NH-, amide, carbonyl, ester, straight-chain or branched C1–C4 alkyl, straight-chain or branched C2–C4 alkenyl, straight-chain or branched C2–C4 alkynyl, C3–C8 cycloalkyl, 4-8 membered heterocyclic alkyl, aryl, heteroaryl.

[0446] 29. A compound, said compound having one of the following structures:

[0447]

[0448]

[0449]

[0450] 30. A composition comprising the compound of any one of embodiments 1-29 and optionally a pharmaceutically acceptable carrier.

[0451] 31. The composition according to embodiment 30, further comprising a second therapeutic agent.

[0452] 32. The composition according to embodiment 31, wherein the second therapeutic agent is selected from proton pump inhibitors, potassium-competitive acid blockers, acid suppressants, efflux pump inhibitors, antibacterial agents, mucosal protectants, anti-inflammatory drugs, anticoagulants, platelet aggregation inhibitors, antipyretics, lipid-lowering agents, and zinc salts.

[0453] 33. A kit comprising a compound according to any one of embodiments 1-29 and / or a composition according to any one of embodiments 30-32.

[0454] 34. A method for inhibiting or preventing bacterial growth, comprising applying an effective amount of the compound of any one of embodiments 1-29 and / or the composition of any one of embodiments 30-32, and / or the kit described in embodiment 33.

[0455] 35. A treatment method comprising administering to a subject in need an effective amount of the compound of any one of embodiments 1-29 and / or the composition of any one of embodiments 30-32, and / or the kit of embodiment 33.

[0456] 36. The subject is infected with bacteria according to the method of implementation scheme 35.

[0457] 37. The method according to any one of embodiments 35-36, wherein the bacteria is Helicobacter pylori.

[0458] 38. Use of the compound of any one of embodiments 1-29 and / or the composition of any one of embodiments 30-32, and / or the kit of embodiment 33 for inhibiting or preventing bacterial growth.

[0459] 39. Use of the compound of any one of embodiments 1-29 and / or the composition of any one of embodiments 30-32, and / or the kit of embodiment 33 for the preparation of a medicament for the treatment and / or prevention of diseases or conditions caused by bacterial infections.

[0460] 40. The use according to any one of embodiments 38-39, wherein the bacteria is Helicobacter pylori.

[0461] 41. The use according to any one of embodiments 38-40, wherein the disease or condition is selected from: gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis, gastric cancer, and gastric mucosa-associated lymphoid tissue lymphoma.

[0462] 42. A method for preparing the compound according to any one of embodiments 1-29.

[0463] Compound preparation methods

[0464] On the other hand, this application provides a method for preparing the structure shown in synthetic formula (I).

[0465] Option 1: Reactant IV can be prepared by the following reaction to obtain the structure shown in formula (I):

[0466]

[0467] Specifically, Option 1 includes the following steps:

[0468] S1: Compound IV and compound IX undergo a substitution reaction to give compound III, where W is a halogen or a leaving group, such as p-toluenesulfonate or trifluoromethanesulfonate.

[0469] S2: Compound III reacts with compound II to give compound I.

[0470] Option 2: Reactant VII can be prepared by the following reaction to obtain the structure shown in formula (I):

[0471]

[0472] Specifically, Option 2 includes the following steps:

[0473] S1: Compound VII and compound X undergo a nucleophilic reaction to give compound VI.

[0474] S2: Compound VI and compound XI undergo a condensation reaction to give compound V.

[0475] S3: Compound V undergoes a condensation reaction to give compound I.

[0476] Option 3: Reactant VII can be prepared by the following reaction to obtain the structure shown in formula (I):

[0477]

[0478] Specifically, Option 2 includes the following steps:

[0479] S1: Compound VII reacts with compound XII to give compound VIII.

[0480] S2: Compound VIII reacts with compound II to give compound I.

[0481] Composition

[0482] On the other hand, this application provides a kit comprising the compounds described herein and an optional pharmaceutically acceptable carrier. For example, the composition may be in the form of a solution, aerosol, gel, ointment, spray, or suspension, and can be prepared using methods known and conventional in the art. For example, the pharmaceutically acceptable carrier may be selected from excipients for increasing solubility, auxiliaries for enhancing viscosity, and auxiliaries for enhancing penetration.

[0483] In some embodiments, the composition may further comprise a second therapeutic agent. For example, the second therapeutic agent may be selected from proton pump inhibitors, potassium-competitive acid blockers, acid suppressants, efflux pump inhibitors, antibacterial agents, mucosal protectants, anti-inflammatory drugs, anticoagulants, platelet aggregation inhibitors, antipyretics, lipid-lowering agents, and zinc salts. In some embodiments, the mucosal protectant may be a bismuth agent. Bismuth agents may include bismuth citrate, bismuth aluminate, colloidal bismuth pectin, etc.

[0484] All therapeutic agents used in the compositions of the present invention may be used within the dosage range currently known and used in these formulations.

[0485] Reagent test kit

[0486] On the other hand, this application provides a kit containing the compounds and / or compositions described in this application. For example, the kit may further include at least one container for holding the compounds and / or compositions. For example, the kit may contain more than one component and may also include second, third, and / or other containers besides the container, in which the more than one component may be separately placed. For example, the kit may also hold various combinations of the compounds and / or compositions in the containers. For example, the kit may further include buffer reagents, mixing devices, measuring devices, sorting devices, and / or labeling devices. For example, the kit may also include packaging for accommodating various containers. For example, the kit may also include instructions for using the kit components. For example, the instructions may include a physical paper form and / or a machine-readable electronic form.

[0487] method

[0488] On the other hand, this application provides a method for inhibiting or preventing bacterial growth, comprising applying an effective amount of the compound described in this application, the composition described in this application, and / or the kit described in this application. In some embodiments, the method comprises contacting the compound described in this application, the composition described in this application, and / or the kit described in this application with a site infected by bacteria. For example, the site of infection may be inside an animal, on the surface of an animal, inside a plant, or on the surface of a plant.

[0489] On the other hand, this application provides a treatment method comprising administering an effective amount of the compound, composition, and / or kit described in this application to a subject in need. In some embodiments, the treatment method may further comprise mixing the compound, composition, and / or kit described in this application with a therapeutic agent. In some embodiments, the treatment method comprises systemic delivery of the compound, composition, and / or kit described in this application to a subject in need, exposing them extensively to a large portion of the body; this step may be performed by any means known in the art, including but not limited to intravenous, intra-arterial, subcutaneous, and intraperitoneal delivery. In other embodiments, the treatment method comprises local delivery of the compound, composition, and / or kit described in this application to a subject in need, allowing them to directly reach a target site within the organism or to reach a bacterially infected site on the body surface, or through direct contact with a bacterially infected body surface. For example, such local delivery does not exclude systemic pharmacological effects. In some embodiments, the treatment method may comprise administering an effective amount of the compound, composition, and / or kit described herein to a subject in need by means of intramuscular injection, subcutaneous or intradermal injection, intravenous injection, intrathecal injection, inhalation, oral administration, or topical application.

[0490] In the above method, the bacteria are Helicobacter pylori. In this application, the bacteria may also include drug-resistant strains. For example, the drug-resistant strains may be resistant to other antibiotics, including rifamycins such as rifabutin, rifampin, and rifaximin; macrolides such as clarithromycin, azithromycin, and roxithromycin; nitroimidazoles such as metronidazole and ornidazole; fluoroquinolones such as ciprofloxacin, levofloxacin, and moxifloxacin; aminoglycosides such as streptomycin and amikacin; β-lactams such as amoxicillin and ampicillin; tetracyclines such as tetracycline, tigecycline, and minocycline; and nitrofurans such as furazolidone.

[0491] In the above method, the subject is infected with the bacteria, or the subject has a disease or condition caused by the bacterial infection. For example, the disease may be selected from gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis, gastric cancer, or gastric mucosa-associated lymphoid tissue lymphoma.

[0492] use

[0493] On the other hand, this application provides the use of the compounds, compositions, and / or kits described in this application for inhibiting or preventing bacterial growth.

[0494] On the other hand, this application provides the use of the compounds, compositions, and / or kits described in this application for the preparation of medicaments for the treatment and / or prevention of diseases or conditions caused by bacterial infections.

[0495] In the above-described uses, the bacteria are Helicobacter pylori. In this application, the bacteria may also include drug-resistant strains. For example, the drug-resistant strains may be resistant to other antibiotics, including rifamycins such as rifabutin, rifampin, and rifaximin; macrolides such as clarithromycin, azithromycin, and roxithromycin; nitroimidazoles such as metronidazole and ornidazole; fluoroquinolones such as ciprofloxacin, levofloxacin, and moxifloxacin; aminoglycosides such as streptomycin and amikacin; β-lactams such as amoxicillin and ampicillin; tetracyclines such as tetracycline, tigecycline, and minocycline; and nitrofurans such as furazolidone.

[0496] In the above-mentioned uses, the diseases may be selected from gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis, gastric cancer, and gastric mucosa-associated lymphoid tissue lymphoma.

[0497] Example

[0498] Example 1 The compound preparation method of this application

[0499] General Synthesis Method 1: Taking the synthesis of compound 1 as an example

[0500] Compound 1: 2-(4-Methoxycyclohexyl)-1,3-Dimethylquinoline-4(1H)-one

[0501]

[0502] Step 1: N,4-Dimethoxy-N-methylcyclohexane-1-formamide

[0503] In a 250 mL reaction flask, EDCI (1.725 g, 9 mmol, 1.5 eq), HOBt (810 mg, 6 mmol, 1.0 eq), DMAP (74 mg, 0.6 mmol, 0.1 eq), and triethylamine (1.818 g, 18 mmol, 3.0 eq) were added to a 20 mL DMF solution of 4-methoxycyclohexane-1-carboxylic acid (948 mg, 6 mmol, 1.0 eq). The mixture was stirred for 30 min, and then dimethyl hydroxylamine hydrochloride (588 mg, 6 mmol, 1.0 eq) was added. The mixture was stirred at room temperature. Quenching with water (100 mL), extraction with dichloromethane (3 x 100 mL), combining the organic phases, washing successively with water (100 mL) and saturated brine (150 mL), drying the organic phase with anhydrous sodium sulfate, filtering, removing the solvent by vacuum distillation, and purifying the crude product by silica gel column chromatography (dichloromethane:methanol 30:1, v / v) to give 980 mg of the title compound, in 81% yield. LCMS: [M+H] + 202.1

[0504] Step 2: 1-(4-methoxycyclohexyl)prop-1-one

[0505] In a 100 mL reaction flask, 1 N-ethyl magnesium bromide (14.6 mL) was added to an anhydrous tetrahydrofuran (20 mL) solution of N,4-dimethoxy-N-methylcyclohexane-1-carboxamide (980 mg, 4.85 mmol, 1.0 eq) and the reaction was stirred at room temperature. The reaction was quenched with saturated ammonium chloride solution (50 mL), extracted with dichloromethane (2 x 100 mL), and the organic phases were combined and washed successively with water (100 mL) and saturated brine (100 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1, v / v) to give 400 mg of the title compound, in a yield of 48.5%.

[0506] Step 3: 2-(4-methoxycyclohexyl)-1,3-dimethylquinoline-4(1H)-one

[0507] In a 100 mL reaction flask, 20 mL of anhydrous tetrahydrofuran was added, and the mixture was cooled to -70 °C. 1 mL of 2N LDA in n-hexane was added, followed by dropwise addition of 1-(4-methoxycyclohexyl)prop-1-one (170 mg, 1 mmol, 1.0 eq) and 1-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (177 mg, 1 mmol, 1.0 eq) in anhydrous tetrahydrofuran (10 mL). The reaction was stirred under controlled temperature. The mixture was quenched with 50 mL of saturated ammonium chloride solution, extracted with dichloromethane (2 x 100 mL), and the organic phases were combined. The samples were washed successively with 100 mL of water and 150 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (dichloromethane:methanol 20:1, v / v) to give 24 mg of the title compound, with a yield of 8.4%. LCMS: [M+H] + 286.1

[0508] General Synthesis Method 2: Taking Compound 2 as an Example

[0509] Compound 2: 2-(4-methoxycyclohexyl)-3-methylquinoline-4(1H)-one

[0510]

[0511] Step 1: 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)aniline

[0512] In a 250 mL reaction flask, a solution of 2-aminobenzonitrile (10 g, 84.75 mmol, 1.0 eq) in chlorobenzene (100 mL) was added, along with 2-amino-2-methyl-1-propanol (15 g, 169.5 mmol, 2.0 eq) and anhydrous zinc chloride (2.3 g, 16.95 mmol, 0.2 eq). The mixture was stirred at 130 °C. The mixture was cooled, and the solvent was removed by vacuum distillation. The mixture was then extracted with water (100 mL) and dichloromethane (2 x 200 mL). The combined organic phases were washed successively with water (100 mL) and saturated brine (100 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to give 6.6 g of the crude compound, with a yield of 40.7%. LCMS: [M+H] + 191.1.

[0513] Step 2: 2-(4-methoxycyclohexyl)-3-methylquinoline-4(1H)-one

[0514] In a 100 mL reaction flask, 1-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)aniline (192 mg, 1 mmol, 1.0 eq) in n-butanol (10 mL) was added, along with 1-(4-methoxycyclohexyl)prop-1- (177 mg, 1 mmol, 1 eq) and trifluoromethanesulfonic acid (15 mg, 0.1 mmol, 0.1 eq). The mixture was stirred at 130 °C. The mixture was cooled, and the solvent was removed by vacuum distillation. The pH was adjusted to 9 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed successively with water (100 mL) and saturated brine (100 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (dichloromethane:methanol 20:1, v / v) to give 20 mg of the title compound, in a yield of 7.3%. LCMS: [M+H]+272.1

[0515] General Synthesis Method 3, taking compound 3 as an example

[0516] Compound 3: (3-(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)cyclopentyl)tert-butyl carbamate

[0517]

[0518] Step 1: 2-Aminophenylacetone

[0519] In a 100 mL reaction flask, a solution of 2N-ethyl magnesium bromide (47 mL, 94.06 mmol, 3.0 mmol) in tetrahydrofuran was added dropwise to a 20 mL solution of anhydrous tetrahydrofuran containing 3.7 g of 2-aminobenzonitrile (3.7 g, 31.36 mmol, 1.0 eq). The reaction was stirred. The reaction was quenched with 100 mL of saturated ammonium chloride solution and extracted with ethyl acetate (3 x 100 mL). The organic phases were combined and washed successively with 2 x 100 mL of water and 100 mL of saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1, v / v) to give 1.4 g of the title compound, in 29.9% yield.

[0520] Step 2: (3-((2-propionylphenyl)carbamoyl)cyclopentyl)tert-butyl carbamate

[0521] In a 250 mL reaction flask, HATU (5.7 g, 15 mmol, 1.5 eq), DIPEA (3.87 g, 30 mmol, 3.0 eq), and DMAP (122 mg, 1 mmol, 0.1 eq) were added to a 20 mL DCM solution of 2-aminophenylacetone (2.3 g, 10 mmol, 1.0 eq) and stirred for 30 min. Then, 3-(tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid (1.49 g, 10 mmol, 1.0 eq) was added and the mixture was stirred at room temperature. Quenching with water (100 mL), extraction with dichloromethane (3 x 100 mL), combining the organic phases, washing successively with water (100 mL) and saturated brine (150 mL), drying the organic phase with anhydrous sodium sulfate, filtering, removing the solvent by vacuum distillation, and purifying the crude product by silica gel column chromatography (ethyl acetate: petroleum ether 10:1, v / v) to give 1.3 g of the title compound, in a yield of 36%. LCMS: [M+H]+361.4.

[0522] Step 3: (3-(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)cyclopentyl)tert-butyl carbamate

[0523] In a 100 mL reaction flask, sodium hydroxide (217 mg, 5.44 mmol, 2.0 eq) was added to a 20 mL solution of SM-4 (980 mg, 2.72 mmol, 1.0 eq) in 1,4-dioxane. The mixture was heated to 110 °C and stirred. The solution was concentrated under reduced pressure, and the pH was adjusted to approximately 7 by adding 1 N aqueous hydrogen chloride solution. Extraction was performed using dichloromethane (2 x 100 mL). The combined organic phases were washed successively with water (100 mL) and saturated brine (100 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (dichloromethane:methanol 20:1, v / v) to give 600 mg of the title compound, in 64% yield. LCMS: [M+H] + 343.2.

[0524] The compounds listed in Table 1 below were prepared using the general preparation method described above.

[0525] Table 1

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536] Compound 131: 2-(cyclopent-1-en-1-yl)-1,3-dimethylquinoline-4(1H)-one

[0537]

[0538] In a 50 mL reaction flask, a solution of compound 22 (30 mg, 0.13 mmol, 1.0 eq) in N,N-dimethylformamide (5 mL) was added, along with potassium carbonate (54 mg, 0.39 mmol, 3.0 eq) and methyl iodoforme (41 mg, 0.26 mmol, 2 eq). The mixture was stirred at room temperature. The solvent was removed by vacuum distillation. The mixture was extracted with water (10 mL) and dichloromethane (2 x 20 mL). The combined organic phases were washed successively with water (10 mL) and saturated brine (10 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 3:1, v / v) to give 28 mg of the title compound, in 83% yield. LCMS: [M+H] + 240.1

[0539] The compounds in Table 2-1 below were synthesized using the same synthetic method as compound 131:

[0540] Table 2-1

[0541]

[0542]

[0543] Compound 140: 2-(3-aminocyclopentyl)-1,3-dimethylquinoline-4(1H)-one

[0544]

[0545] In a 50 mL reaction flask, a solution of dioxane (3.6 mL, 7.3 mmol, 5.0 eq) of 2N hydrogen chloride was added to a 5 mL DCM solution of compound 3 (520 mg, 1.46 mmol, 1.0 eq), and the mixture was stirred at room temperature. The mixture was filtered to give 330 mg of the title compound in 88% yield. LCMS: [M+H] + 257.2.

[0546] The compounds listed in Table 2-2 were synthesized using the same synthetic method as compound 140:

[0547] Table 2-2

[0548]

[0549]

[0550] Compound 148: N-(3-(1,3-dimethyl-4-oxo-1,4-dihydroquinolin-2-yl)cyclopentyl)acetamide

[0551]

[0552] In a 100 mL reaction flask, a solution of compound 140 (65 mg, 0.25 mmol, 1.0 eq) in DCM (5 mL) was added, along with TEA (77 mg, 0.76 mmol, 3.0 eq) and DMAP (5 mg, 0.05 mmol, 0.2 eq). The mixture was stirred for 30 min, then acetic anhydride (32 mg, 0.30 mmol, 1.2 eq) was added, and the reaction was stirred at room temperature. The reaction was quenched with water (50 mL), extracted with dichloromethane (2 x 50 mL), and the organic phases were combined. The mixture was washed successively with water (50 mL) and saturated brine (50 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (dichloromethane:methanol 20:1, v / v) to give 16 mg of the title compound, in a yield of 21%. LCMS: [M+H] + 299.2.

[0553] The compounds listed in Table 3 below were synthesized using the same synthetic method as compound 148:

[0554] Table 3

[0555]

[0556]

[0557] Compound 161: 2-(3-(methylamino)cyclopentyl)-1,3-dimethylquinoline-4(1H)-one

[0558]

[0559] In a 100 mL reaction flask, a methanol solution (5 mL) of compound 140 (50 mg, 0.1953 mmol, 1.0 eq) was added to a 37% formaldehyde solution (14 mg, 0.1758 mmol, 1.0 eq) and sodium borohydride acetate (62 mg, 0.2930 mmol, 1.5 eq). The reaction was stirred at room temperature. The mixture was quenched with saturated ammonium chloride solution (20 mL), extracted with dichloromethane (2 x 50 mL), and the organic phases were combined and washed successively with water (50 mL) and saturated brine (50 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (dichloromethane:methanol 15:1, v / v) to give 5 mg of the title compound, with a yield of 9%.

[0560] The compounds listed in Table 4 below were synthesized using the same synthetic method as compound 161:

[0561] Table 4

[0562]

[0563]

[0564] Compound 168: (3-(1,3-dimethyl-4-oxo-1,4-dihydroquinolin-2-yl)cyclopentyl)carbamate

[0565]

[0566] In a 100 mL reaction flask, a 5 mL solution of compound 140 (50 mg, 0.1953 mmol, 1.0 eq) in DCM was added, along with TEA (80 mg, 0.7812 mmol, 4.0 eq) and CDI (47 mg, 0.2930 mmol, 1.5 eq), and the mixture was stirred. An ethanol solution of 2N sodium ethoxide (0.15 mL, 0.2930 mmol, 1.5 eq) was added, and the mixture was stirred at room temperature. A 50 mL solution of saturated ammonium chloride was added, followed by extraction with 2 x 50 mL dichloromethane. The organic phases were combined and washed successively with 50 mL of water and 50 mL of saturated brine. The organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (dichloromethane:methanol 20:1, v / v) to give 5 mg of the title compound, in a yield of 7%. LCMS: [M+H] + 329.2.

[0567] The compounds listed in Table 5 below were synthesized using the same synthetic method as compound 168:

[0568] Table 5

[0569]

[0570]

[0571] Compound 177: (1-(3-(1,3-dimethyl-4-oxo-1,4-dihydroquinolin-2-yl)cyclopentyl)-3-ethylurea

[0572]

[0573] In a 100 mL reaction flask, a solution of compound 140 (50 mg, 0.20 mmol, 1.0 eq) in DCM (5 mL) was added, along with TEA (80 mg, 0.78 mmol, 4.0 eq) and CDI (47 mg, 0.29 mmol, 1.5 eq), and the mixture was stirred. A 2N tetrahydrofuran solution of ethylamine (0.3 mL, 0.59 mmol, 3.0 eq) was added, and the mixture was stirred at room temperature. A saturated ammonium chloride solution (50 mL) was added, followed by extraction with dichloromethane (2 x 50 mL). The organic phases were combined and washed successively with water (50 mL) and saturated brine (50 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (dichloromethane:methanol 20:1, v / v) to give 8 mg of the title compound, in a yield of 12%. LCMS: [M+H] + 328.2.

[0574] The compounds listed in Table 6 below were synthesized using the same synthetic method as compound 177:

[0575] Table 6

[0576]

[0577]

[0578] Compound 187: 2-Cyclopentyl-1-methyl-3-vinylquinoline-4(1H)-one

[0579]

[0580] Step 1: 2-Cyclopentyl-1-methylquinoline-4(1H)-one

[0581] The title compound was synthesized using step 3 of method one. LCMS: [M+H] + 228.1

[0582] Step 2: 2-Cyclopentyl-3-iodo-1-methylquinoline-4(1H)-one

[0583] In a 100 mL reaction flask, 2-cyclopentyl-1-methylquinoline-4(1H)-one (750 mg, 3 mmol, 1.0 eq) was dissolved in 20 mL of acetonitrile, and NIS (675 mg, 3 mmol, 1.0 eq) was added. The reaction was stirred at room temperature. The mixture was quenched with 50 mL of saturated ammonium chloride solution, extracted with dichloromethane (2 x 100 mL), and the organic phases were combined. The mixture was washed successively with 50 mL of sodium thiosulfate aqueous solution and 2 x 100 mL of water. The organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (dichloromethane:methanol 30:1, v / v) to give 1.02 g of the title compound, in 88% yield. LCMS: [M+H] + 354.0.

[0584] Step 3: 2-Cyclopentyl-1-methyl-3-vinylquinoline-4(1H)-one

[0585] In a 100 mL reaction flask, a solution of 2-cyclopentyl-3-iodo-1-methylquinoline-4(1H)-one (280 mg, 0.74 mmol, 1.0 eq) in dioxane (5 mL) was added, along with vinylboronic acid pinacol ester (342 mg, 2.22 mmol, 3.0 eq), anhydrous potassium carbonate (306 mg, 2.22 mmol, 3 mmol), and Pd(dppf)Cl2 (110 mg, 0.15 mmol, 0.2 eq). The mixture was purged with nitrogen for protection and heated to 100 °C with stirring. Quenching with saturated ammonium chloride solution (50 mL), extraction with dichloromethane (2 x 50 mL), combining the organic phases, washing successively with water (100 mL) and saturated brine (100 mL), drying the organic phase with anhydrous sodium sulfate, filtering, removing the solvent by vacuum distillation, and purifying the crude product by silica gel column chromatography (dichloromethane:methanol 30:1, v / v) to give 20 mg of the title compound, in 9.7% yield. LCMS: [M+H] + 254.2.

[0586] The compounds listed in Table 7 below were synthesized using the same synthetic method as compound 187:

[0587] Table 7

[0588]

[0589] Example 2

[0590] Cytotoxicity assays of the compounds in this application

[0591] This embodiment provides the in vitro toxicity half-maximal inhibitory concentration (IC50) of the representative compound of this application on HepG2 cells. 50 This test uses the IC50 of the positive compound staphylococcus aureus. 50As a quality control measure, the experimental method is as follows:

[0592] 1) Once the HepG2 cell density is suitable, collect the HepG2 cell suspension, centrifuge at 1000 rpm for 5 min to collect the cells, and discard the supernatant;

[0593] 2) After resuspending and counting, HepG2 cells were seeded evenly in 96-well plates at a density of 195 μL per well;

[0594] 3) The test compound stock solution was first serially diluted 2-fold with DMSO, and then diluted a second time with culture medium, so that the final concentration added to the cell well plate was the initial test concentration of 300 μM (300000 nM, 150000 nM, 75000 nM, 37500 nM, 18750 nM, 9375 nM, 4687.5 nM, 2343.75 nM, 1171.88 nM, 585.94 nM, 0 nM); the positive compound was diluted in the same way, and the final concentration of DMSO was 0.3% for all cases.

[0595] 4) Add the diluted compound to the cell culture plate at a final DMSO concentration of 0.1% and incubate at 37°C with a carbon dioxide concentration of 5%.

[0596] 5) Aspirate 100 μL of HepG2 cell supernatant from each well, add 60 μL of CellCounting-Lite 2.0 Luminescent Cell Viability Assay reagent to each well of the cell culture plate, shake at 350 rpm for 2 min at room temperature, incubate for 30 min, and then detect the ATP level by reading the BMG.

[0597] 6) Data processing was performed using wells containing cells and DMSO solvent as negative controls (High control) and wells containing only culture medium as positive controls (Low control).

[0598] 4. Data Analysis: Set the reading of the negative control to 0% inhibition rate and the reading of the positive control to 100% inhibition rate, and calculate the inhibition rate of each test solution.

[0599]

[0600] Average value of positive control well readings

[0601] Average value of negative control well readings

[0602] IC of the compound is obtained using a nonlinear fitting formula. 50 (Half-maximal inhibitory concentration):

[0603] The test results are shown in Table 8:

[0604] Table 8. In vitro toxicity half-maximal inhibitory concentration (IC50) of representative compounds on HepG2 cells 50 )

[0605]

[0606] The results showed that the test compound had significantly lower in vitro toxicity to HepG2 cells than the control compound, indicating higher safety.

[0607] Example 3

[0608] Antibacterial activity experiments of the compounds in this application

[0609] This embodiment provides the in vitro antibacterial activity of representative compounds of this application against various bacteria. The experimental method is as follows:

[0610] 1. Materials:

[0611] Strains: As shown in Table 9. Store frozen at -80℃; thaw 8 days in advance before use. Use a sterile inoculation loop to scrape a small amount of the frozen bacteria onto a suitable solid culture medium plate and incubate at 35±2℃ for 20-48 hours in a suitable gaseous environment.

[0612] Table 9

[0613] Bacterial species Gram staining classification strain number Enterococcus faecalis G+ ATCC 700221 Staphylococcus aureus G+ ATCC 29213 Klebsiella pneumoniae G- ATCC 43816 Acinetobacter baumannii G- ATCC 19606 Pseudomonas aeruginosa G- ATCC 27853 E. coli G- ATCC 25922 Helicobacter pylori G- ATCC43504

[0614] Compounds: All test compounds were dissolved and diluted with DMSO.

[0615] Culture medium: Trypticase soy agar (TSA), TSA + 5% sheep blood (TSAII), ion-adjusted Mueller Hinton broth (CAMHB), and sheep blood.

[0616] 2. In this embodiment, the in vitro antibacterial activity test determines the minimum inhibitory concentration (MIC) of the compound. The method is as follows:

[0617] 2.1 Bacterial resuscitation

[0618] Two days in advance, use a sterile inoculating loop to scrape a small amount of frozen bacteria and streak it onto a suitable solid culture medium plate. Incubate in a suitable gaseous environment (Enterococcus faecalis ATCC 700221: TSAII, normal atmospheric environment; Staphylococcus aureus / Klebsiella pneumoniae / Acinetobacter baumannii / Pseudomonas aeruginosa / Escherichia coli: TSA, normal atmospheric environment) at 35±2℃ for 20-48 hours. Incubate Helicobacter pylori ATCC43504 in a microaerophilic environment for 72 hours. Using a sterile inoculating loop, pick 5-10 morphologically similar colonies from the above culture plates and streak them again onto a suitable solid culture medium plate. Except for Helicobacter pylori ATCC43504, incubate the culture medium in an incubator at 35±2℃ for 20-48 hours. Incubate Helicobacter pylori ATCC43504 in a microaerophilic environment for 72 hours.

[0619] 2.2 Bacterial Inoculation and Transfer

[0620] Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli: Remove CAMHB from the 4°C freezer and allow it to reach room temperature. Pick 5-10 single bacterial colonies from a solid culture dish and resuspend them in 500 μL of CAMHB. Adjust the turbidity to McFarland 0.5 using a spectrophotometer. Then, dilute the bacteria 200-fold with CAMHB (stepwise dilution, first 10-fold, then 20-fold). Add 90 μL of the corresponding bacterial inoculum to the test plate (except for the sterile control wells).

[0621] Helicobacter pylori: Fresh, pure colonies were picked from solid agar medium after 48-72 hours of culture, diluted with Brucella broth, and prepared into a 2.0 μL McLeod suspension (containing 1 x 10⁻⁶ cells / mL). 7 -1x10 8 (CFU / mL)

[0622] 2.3 Compound dilution and sample loading

[0623] Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli: All test compounds were dissolved in DMSO and diluted with PBS. Transfer 2 mL of 1280 μg / mL compound to the starting wells (A1-H1) of a 96-well deep-dilution plate, then transfer 1 mL of PBS to the remaining wells. Perform 2-fold serial dilutions of each compound sequentially from column 1 to column 11. Transfer 10 μL of the compound from each plate to the corresponding well of the test plate, and simultaneously transfer 10 μL of PBS to the compound-free wells. Add 90 μL of CAMHB medium to the sterile control wells of the test plate.

[0624] Helicobacter pylori: All compounds were dissolved in DMSO and diluted with PBS. Using a serial dilution method, solid agar media containing different drug concentrations were prepared. 3 μL of each medium was inoculated onto the surface of agar plates containing different drug concentrations and blank control plates, and incubated at 37°C for microaerophilic purposes. The lowest drug concentration at which no colonies grew after 72 hours was taken as the MIC value.

[0625] 2.4. Culture and MIC determination

[0626] Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli: After centrifugation and shaking, the culture plates were incubated at 35±2℃ for 20 hours in a standard incubator. The plates were placed on a plate reader, and the reflector was adjusted to observe and record bacterial growth in each well. The minimum inhibitory concentration (MIC) of each compound was recorded according to the Clinical and Laboratory Standards Institute Guidelines (CLSIM 100).

[0627] Helicobacter pylori: The inoculated solid agar medium was placed in a microaerophilic environment at 37°C and cultured. The lowest drug concentration at which no colonies grew after 72 hours was taken as the MIC value.

[0628] The test results are shown in Table 10 below:

[0629] Table 10 shows the minimum inhibitory concentrations (μg / mL) of the tested compounds against representative gut microbiota.

[0630]

[0631]

[0632] The results showed that all tested compounds had a MIC > 128 μg / mL against representative gut microbiota and had no activity, but exhibited strong antibacterial activity against Helicobacter pylori with a selectivity of several thousand times. It is expected that they will not cause gut microbiota dysbiosis and can reduce gastrointestinal side effects.

[0633] Example 4

[0634] The compounds in this application exhibit antibacterial effects against wild-type and clinically isolated drug-resistant Helicobacter pylori.

[0635] The experimental method is as follows:

[0636] 1. Materials:

[0637] Strain revival and passage: as shown in Table 11. Store frozen at -80°C; revive 2 days in advance before use.

[0638] Table 11

[0639] strain number strain source Drug resistance types ATCC43504 ATCC MTZ R ]]> ATCC700392 ATCC / HP6724 Clinical isolates CLA R ]] HP6749 Clinical isolates <![CDATA[AML R ,BET R ,CLA R ,MTZ R ]]> HP6204 Clinical isolates <![CDATA[AML R ,CLA R ,MTZ R ]]> HP6755 Clinical isolates <![CDATA[LVE R ]]> HP6224 Clinical isolates <![CDATA[AML R ,LVE R ,BET R ,CLA R ,MTZ R ]]>

[0640] Using a sterile inoculating loop, scrape a small amount of frozen Helicobacter pylori and streak it onto solid agar medium (MH + 5% sheep blood). Incubate in a microaerophilic environment at 35±1℃ for 72 hours (strain revival). Using a sterile inoculating loop, pick 5-10 morphologically similar colonies from the revival dish and streak them again onto solid agar medium (MH + 5% sheep blood). Incubate in a microaerophilic environment for 72 hours (strain subculturing).

[0641] Preparation of bacterial suspension: Pick fresh, pure colonies from solid agar medium after 72 hours of incubation, dilute with Brucella broth, and prepare a 2.0 g McBurney suspension (containing 1 x 10⁻⁶ cells / mL). 7 -1x10 8 (CFU / mL)

[0642] 2.3 Preparation and inoculation of drug-containing solid agar culture medium

[0643] All compounds were dissolved in DMSO and diluted with PBS. Serial dilutions were used to prepare solid agar media containing various drug concentrations. 3 μL of the prepared bacterial suspension was pipetted onto the surfaces of the agar plates containing different drug concentrations and a blank control plate. The plates were incubated at 35±1℃ in a microaerophilic environment. The lowest drug concentration at which no colonies grew after 72 hours was defined as the MIC (micro-micronization) value.

[0644] The test results are shown in Table 12:

[0645] Table 12: Minimum inhibitory concentrations (μg / mL) of the tested compounds against wild-type and clinically isolated drug-resistant Helicobacter pylori

[0646]

[0647]

[0648] The results showed that all tested compounds exhibited strong inhibitory activity against both wild-type and clinically isolated Helicobacter pylori strains, demonstrating superior in vitro antibacterial activity compared to control compound a. No cross-resistance was observed with existing therapeutic agents such as amoxicillin, clarithromycin, tetracycline, levofloxacin, and metronidazole. These compounds also showed high inhibitory activity against clinically resistant single-drug and multidrug-resistant strains, and no cross-resistance was found with existing Hp treatments, thus addressing the resistance issue of current therapeutic agents.

[0649] Example 5

[0650] Experiments on the spontaneous resistance frequency of the compounds in this application against Helicobacter pylori-induced antibiotics.

[0651] The experimental method is as follows:

[0652] After thawing Helicobacter pylori ATCC43504 from -80℃ cryopreserved tubes, it was inoculated onto fresh Columbia blood agar plates. The plates were placed in a closed incubator with a microaerophilic oxygen supply bag to create a stable microaerophilic environment, and incubated at 37℃ for 72 hours. Colonies were picked to prepare a 2 McFarland suspension. 1 mL of the suspension was inoculated into 5 mL of Brucella broth containing 10% fetal bovine serum (FCS) and incubated at 37℃ for 24 hours at 120 rpm under microaerophilic conditions. The next day, 5 mL of the culture was inoculated into 100 mL of Brucella broth containing 10% FCS and incubated at 37℃ for another 24 hours at 120 rpm under microaerophilic conditions. Then, the suspension was centrifuged at 4000 rpm for 10 minutes, the supernatant was discarded, and 2 mL of physiological saline was added to prepare a 50-fold concentrated suspension. 100 μL of concentrated bacterial suspension was serially diluted tenfold for counting, and the counting plates were incubated at 37°C under microaerophilic conditions for five days. Then, 100 μL each of undiluted, 10-fold diluted, and 100-fold diluted bacterial suspensions were spread onto two Columbus blood agar plates containing different concentrations of Compound 9 (MIC, 2-fold MIC, 4-fold MIC, and 8-fold MIC). All plates were incubated at 37°C under microaerophilic conditions for five days, and the presence or absence of colonies was determined. The colonies that grew were counted. The resistance frequency was defined as the ratio of the number of colonies on the drug-containing plate to the inoculum size.

[0653] The results showed that no drug-resistant bacteria were observed at any concentration (MIC - 8 times MIC) of compound 9, and the resistance frequency was <1.4*10^6. -11 .

[0654] Example 6

[0655] Pharmacokinetic analysis of the compound in rats according to this application

[0656] In this embodiment, rats were used to evaluate the pharmacokinetic behavior of a single intravenous (IV) or oral (PO) administration of the compound, with three rats in each group. Plasma samples were collected from the IV group animals before administration (0 h) and at 0.083 (5 min), 0.25, 0.5, 1, 2, 4, 8, 12, and 24 h after administration. Plasma samples were collected from the PO group before administration (0 h) and at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 h. The concentrations of the test compounds in plasma were determined using high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0657] Table 13 Pharmacokinetic parameters of the tested compounds in rats

[0658]

[0659] Note: (1) C0: Theoretical initial concentration (the drug concentration when the extrapolated line intersects the vertical axis), AUC 0-lastThe area under the plasma concentration-time curve from time 0 to the last quantifiable time point, T 1 / 2 Elimination half-life, CL: total clearance rate, V dss : Apparent volume of distribution in veins at steady state, C max Peak concentration, T max Time to peak concentration; F%: bioavailability.

[0660] According to the test results shown in Table 13, compared with control compound a, compound PO of this application has higher exposure and bioavailability after administration. Combined with in vitro cytotoxicity data and in vitro antibacterial activity data, the compound of this application is expected to have better in vivo efficacy and safety.

Claims

1. A compound, or a stereoisomer, hydrate, deuterated derivative, ester, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof, wherein the compound comprises the structure of formula (I): in, X, Y, Z, and V are each independently selected from N or C; R 1 Selected from: -H, any substituted C1–C5 alkyl, any substituted C3–C5 alkenyl, any substituted C3–C5 ynyl, any substituted C3–C6 cycloalkyl; R 2 It can be any substituted alicyclic hydrocarbon group or alihexacyclic group; R 3 Selected from: -H, -CN, any substituted C1-C3 alkoxy, any substituted C1–C6 alkyl, any substituted C2–C6 alkenyl, any substituted C2–C6 alkynyl, any substituted C3–C6 cycloalkyl, any substituted 4-6 heterocyclic alkyl. R 4 R 5 R 6 R 7 Whether the two are the same or different, each can be independently selected from the following: -H, -F, -Cl, -CN, -OR', - SR', -NR'R", -NO2, -C(=O)R', -C(=O)OR', -OC(=O)R', -C(=O)NHR', - NHC(=O)R', where R' and R" may be the same or different, each representing hydrogen, any substituted straight-chain or branched C1–C4 alkyl, any substituted C3–C8 cycloalkyl, any substituted 4-8 heterocyclic alkyl, or R' and R" forming a 4-8 heterocyclic ring.

2. The compound according to claim 1, Where R 1 It is methyl, ethyl, or cyclopropyl; R 2 Selected from one of the following: any substituted saturated C3–C8 cycloalkyl, any substituted saturated 4–8-membered heterocyclic alkyl, any substituted unsaturated C5–C8 cycloalkyl, any substituted unsaturated 5–8-membered heterocyclic alkyl, any substituted C6–C 11 Bicycloalkyl, with arbitrary substitution at C6–C 11 Bicyclic heterocyclic group.

3. The compound according to claim 1, Where R 1 -H; R 2 Selected from one of the following: substituted saturated C5–C7 cycloalkyl, substituted saturated C3–C4 or C8 cycloalkyl, substituted saturated 4- to 8-membered heterocyclic alkyl, substituted unsaturated C5–C8 cycloalkyl, substituted unsaturated 5- to 8-membered heterocyclic alkyl, substituted C6–C 11 Bicycloalkyl, with arbitrary substitution at C6–C 11 Bicyclic heterocyclic group.

4. A compound, wherein the compound has one of the following structures:

5. A composition comprising the compound of any one of claims 1-4 and optionally a pharmaceutically acceptable carrier.

6. A kit comprising the compound of any one of claims 1-4 and / or the composition of claim 5.

7. A method for inhibiting or preventing bacterial growth, comprising applying an effective amount of the compound of any one of claims 1-4 and / or the composition of claim 5, and / or the kit of claim 6.

8. Use of the compound of any one of claims 1-4 and / or the composition of claim 5, and / or the kit of claim 6 for inhibiting or preventing bacterial growth.

9. Use of the compound of any one of claims 1-4 and / or the composition of any one of claims 5, and / or the kit of claim 6 for the preparation of a medicament for the treatment and / or prevention of diseases or conditions caused by bacterial infections.

10. A method for preparing the compound according to any one of claims 1-4.

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