Substituted pyrrole-2,5-dione compounds and preparation methods and uses thereof

Abstract

The present invention belongs to the field of medical technology, discloses substituted pyrrole-2,5-dione compounds and preparation methods and uses thereof, relates to pharmaceutical compositions in which the compounds are active ingredients, and their applications in treating and / or preventing infectious diseases caused by Mycobacterium tuberculosis. Specifically, the present invention relates to a compound shown in formula (I), a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the compound of the present invention, wherein R1, R2, and R3 are as described in the specification. The present invention aims to prepare a new compound having anti-mycobacterium tuberculosis activity, which, as a potential new drug, can be used for infectious diseases caused by bacteria, particularly for the treatment or preventive treatment of pulmonary tuberculosis (TB) diseases caused by Mycobacterium tuberculosis.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and particularly relates to substituted pyrrole-2,5-dione compounds represented by general formula (I), preparation methods thereof, pharmaceutical compositions with the compounds as active ingredients, and their use in treating and / or preventing infectious diseases caused by Mycobacterium tuberculosis. Background Art

[0002] Tuberculosis (TB) is a fatal infectious disease of the lungs caused by Mycobacterium tuberculosis. As one of the top ten fatal diseases, tuberculosis has now surpassed AIDS to become the number one single fatal infectious disease. According to the World Health Organization's 2021 Tuberculosis Research Report, there were approximately 9.9 million new tuberculosis patients worldwide in 2020. In recent years, with the increase in the incidence of drug-resistant tuberculosis and the increase in TB / HIV co-infection, the prevention and control of tuberculosis faces serious challenges, and the development of new anti-tuberculosis drugs with new structures and mechanisms is urgent. Summary of the invention

[0003] The technical problem to be solved by the present invention is to provide a substituted pyrrole-2,5-dione compound with novel structure and anti-mycobacterium tuberculosis activity. The present invention finds that the substituted pyrrole-2,5-dione compound has a strong anti-mycobacterium tuberculosis effect and can be used for the treatment or preventive treatment of infectious diseases caused by bacteria, especially pulmonary tuberculosis caused by mycobacteria, and can also be used to overcome problems related to drug resistance. The present invention is completed based on the above findings. SUMMARY OF THE INVENTION

[0005] To this end, the present invention provides, in a first aspect, a compound represented by general formula (I) and an isomer thereof, or a pharmaceutically acceptable salt thereof,

[0006]

[0007] in,

[0008] R1 is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, or substituted or unsubstituted C2-C9 heteroaryl;

[0009] R2 is C3-C7 cycloalkyl, C3-C6 heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted C2-C9 heteroaryl;

[0010] R3 is H, F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, the number of substitutions of R3 on the phenyl group is 1, 2, 3, 4 or 5, and the substituents may be the same or different;

[0011] The substituents on the phenyl, naphthyl and heteroaryl groups in R1 or R2 are selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, methylthio, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylamino, C3-C6 heterocyclyl;

[0012] The C3-C6 heterocyclic group and C2-C9 heteroaryl group contain at least one heteroatom selected from N, O, and S;

[0013] The compound represented by formula (I) does not include:

[0014]

[0015] In a preferred example:

[0016] in,

[0017] R1 is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl;

[0018] R2 is C3-C7 cycloalkyl, C3-C6 heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, imidazo[1,2-b]pyridazinyl, 4,4-dimethylthiobenzopyranyl;

[0019] R3 is F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, or carboxyl, and the number of substitutions of R3 on the phenyl group is 1, 2, 3, 4, or 5, and the substituents may be the same or different;

[0020] The substituents on the phenyl, naphthyl, pyridyl, quinolyl, pyrimidinyl, pyridazinyl, imidazolyl, thienyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl in R1 or R2 are selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, methylthio, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylamino, C3-C6 heterocyclic group;

[0021] The C3-C6 heterocyclic group contains at least one heteroatom selected from N, O, and S.

[0022] In a further preferred embodiment:

[0023] in,

[0024] R1 is a substituted or unsubstituted pyridyl group;

[0025] R2 is C3-C7 cycloalkyl, C3-C6 heterocyclyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, imidazo[1,2-b]pyridazinyl, 4,4-dimethylthiobenzopyranyl;

[0026] R3 is F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, or carboxyl, and the number of substitutions of R3 on the phenyl group is 1, 2, or 3, and the substituents may be the same or different;

[0027] The substituents on the pyridyl, naphthyl, quinolyl, pyrimidinyl, pyridazinyl, imidazolyl, thienyl, furanyl, pyrrolyl in R1 or R2 are optionally selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, methylthio, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylamino, C3-C6 heterocyclic group;

[0028] The C3-C6 heterocyclic group contains at least one heteroatom selected from N, O, and S.

[0029] In some aspects, the compound of formula (I) is selected from the compound of formula (II):

[0030]

[0031] in,

[0032] R1 is a substituted or unsubstituted pyridyl group;

[0033] R2 is C3-C7 cycloalkyl, C3-C6 heterocyclyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, imidazo[1,2-b]pyridazinyl, 4,4-dimethylthiobenzopyranyl;

[0034] The substituents on the pyridyl, naphthyl, quinolyl, pyrimidinyl, pyridazinyl, imidazolyl, thienyl, furanyl, pyrrolyl in R1 or R2 are optionally selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, methylthio, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylamino, C3-C6 heterocyclic group;

[0035] The C3-C6 heterocyclic group contains at least one heteroatom selected from N, O, and S.

[0036] In another preferred embodiment, the compound has the structural formula as shown in (III):

[0037]

[0038] in,

[0039] R1 is substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl;

[0040] R3 is F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, or carboxyl, and the number of substitutions of R3 on the phenyl group is 1, 2, or 3, and the substituents may be the same or different;

[0041] R4 is F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, methylthio, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxyformyl, C1-C4 alkylamino, C3-C6 heterocyclyl, the number of substitutions of R4 on the phenyl group is 1, 2 or 3, and the substituents may be the same or different;

[0042] The substituents on the pyridyl, quinolyl, pyrimidinyl, pyridazinyl, imidazolyl, thienyl, furanyl, pyrrolyl, oxazolyl and isoxazolyl in R1 are selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, methylthio, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylamino and C3-C6 heterocyclic group;

[0043] The C3-C6 heterocyclic group contains at least one heteroatom selected from N, O, and S.

[0044] In some aspects, the compound of formula (I) is selected from the compound of formula (IV):

[0045]

[0046] in:

[0047] R1 is a substituted or unsubstituted pyridyl group;

[0048] R4 is F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, methylthio, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxyformyl, C1-C4 alkylamino, C3-C6 heterocyclyl, the number of substitutions of R4 on the phenyl group is 1, 2 or 3, and the substituents may be the same or different;

[0049] The substituents on the pyridyl group in R1 are optionally selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, methylthio, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylamino, C3-C6 heterocyclic group;

[0050] The C3-C6 heterocyclic group contains at least one heteroatom selected from N, O, and S.

[0051] The pharmaceutically acceptable salts described in the present invention are salts formed between the compounds of the present invention and an acid selected from the group consisting of hydrochloric acid, p-toluenesulfonic acid, tartaric acid, maleic acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid.

[0052] The compound according to any one of the first aspects of the present invention is the target compound of the present invention prepared in the examples (represented by structural formula or described by systematic nomenclature) and its isomers, and pharmaceutically acceptable salts thereof.

[0053] The compound according to any one of the first aspects of the present invention is a compound selected from the following:

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060] The second aspect of the present invention provides a method for preparing any one of the compounds of the first aspect of the present invention, comprising the following steps: (1)

[0062]

[0063] Compound A is mixed with compound Under the action of diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) (preferably DIAD) and triphenylphosphine, under the protection of air or inert gas (Ar or N2), the reaction is carried out at room temperature for 1-24 hours, preferably at room temperature for 1-3 hours, to obtain a compound shown in formula B;

[0064] The compound represented by formula B is mixed with a compound in a suitable solvent (such as N,N-dimethylformamide, ether, preferably N,N-dimethylformamide). Under the action of cuprous iodide, bistriphenylphosphine palladium dichloride and triethylamine, under the protection of an inert gas (Ar or N2), react at 20-80°C for 0.5-12 hours, preferably at 50°C for 1-5 hours, to obtain a compound of formula (I);

[0065] or (2)

[0066]

[0067] Compound A is mixed with compound Under the action of cuprous iodide, bistriphenylphosphine palladium dichloride and triethylamine, under the protection of an inert gas (Ar or N2), react at 20-80°C for 0.5-12 hours, preferably at 50°C for 1-5 hours, to obtain a compound represented by formula C;

[0068] The compound represented by formula C is mixed with a compound in a suitable solvent (e.g., tetrahydrofuran, ether, preferably tetrahydrofuran) Under the action of DEAD or DIAD (preferably DIAD) and triphenylphosphine, under the protection of air or inert gas (Ar or N2), the reaction is carried out at room temperature for 1-24 hours, preferably at room temperature for 1-3 hours, to obtain the compound of formula (I).

[0069] The third aspect of the present invention provides a pharmaceutical composition, which comprises a therapeutically effective amount of any compound of the first aspect of the present invention or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

[0070] The fourth aspect of the present invention provides use of the compound or pharmaceutically acceptable salt thereof according to any one of the first aspect of the present invention, or the pharmaceutical composition according to any one of the third aspect of the present invention in the preparation of a drug for treating and / or preventing infectious diseases caused by Mycobacterium tuberculosis.

[0071] The foregoing description only summarizes certain aspects of the present invention, but is not limited to these aspects. These aspects and other aspects will be described in more detail and complete below. DETAILED DESCRIPTION OF THE INVENTION

[0073] Various aspects and features of the present invention are further described below.

[0074] The various terms and phrases used in the present invention have the general meanings known to those skilled in the art. Even so, the present invention still hopes to provide a more detailed description and explanation of these terms and phrases. If the terms and phrases mentioned are inconsistent with the known meanings, the meanings expressed in the present invention shall prevail. The following are the definitions of various terms used in the present invention, which apply to the terms used in the entire specification of this application, unless otherwise specified in specific circumstances.

[0075] In general, the term "substituted or unsubstituted" means that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When a given structure always has more than one position that can be substituted by one or more substituents selected from a specific group, the substituents can be substituted the same or differently at each position.

[0076] C i -C jRepresents a moiety having an integer "i" (including i) to an integer "j" (including j) of carbon atoms. Thus, for example, C1-C4 alkyl refers to an alkyl group having 1, 2, 3, or 4 carbon atoms, and C1-C3 alkyl refers to an alkyl group having 1, 2, or 3 carbon atoms. For example, C3-C6 heterocyclyl refers to a heterocyclyl group having 3 to 6 (including 3 and 6) carbon atoms, including but not limited to morpholinyl, thiomorpholinyl, piperazinyl, and piperidinyl.

[0077] As used herein, the term "alkyl" refers to an alkyl group having a specified number of carbon atoms, which is a linear or branched alkyl group, and which may include its subgroups, for example, when referring to "C1-C3 alkyl", it may also include sub-range groups represented by C1-C2 alkyl, as well as specific groups such as methyl, ethyl, n-propyl, isopropyl.

[0078] As used herein, the terms "alkoxy" and "alkylamino" are conventional expressions and refer to an alkyl group attached to the remainder of the molecule through an oxygen atom or an amine group, respectively, wherein the alkyl group is as described herein.

[0079] As used herein, the term "haloalkyl" means that the hydrogen on the alkyl group is replaced by one or more halogen atoms, such examples include, but are not limited to, monochloromethyl, monofluoromethoxy and the like.

[0080] As described herein, the term "cycloalkyl" refers to a cyclic alkyl group having a specified number of ring carbon atoms, and it may include its subgroups, for example, when referring to "C3-C6 cycloalkyl", it may also include sub-range groups represented by C3-C5 cycloalkyl, C4-C6 cycloalkyl, etc., as well as specific groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0081] As described herein, the term "C2-C9 heteroaryl" refers herein to an aromatic group having 1 to 4 heteroatoms as ring atoms, the remaining ring atoms being carbon, and the heteroatoms include oxygen, sulfur and nitrogen. Examples of heteroaryl include, but are not limited to, pyridyl, pyridazinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, imidazolyl, pyrrolyl, furanyl, thienyl, pyrazinyl, etc.

[0082] As described herein, the term "ring" means a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl. The so-called ring includes a condensed ring. The number of atoms in the ring is usually defined as the number of ring members, for example, "C3-C6 ring" means 3-6 atoms arranged around.

[0083] As used herein, the term "heteroatom" refers to O, S, N, including any oxidation state of N and S; primary, secondary, tertiary amines and quaternary ammonium salts; or a hydrogen atom on a nitrogen atom in a heterocyclic ring is substituted.

[0084] As used herein, the terms "halogen," "halo," and the like refer to fluorine (F), chlorine (Cl), or bromine (Br).

[0085] In the present invention, "room temperature" refers to a temperature from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature from 20°C to 30°C; in other embodiments, room temperature refers to 25°C.

[0086] As used herein, the term "effective amount" refers to the amount of a drug that can achieve the desired treatment of a disease or condition described herein in a subject.

[0087] As used herein, the term "pharmaceutically acceptable" when describing, for example, a "pharmaceutically acceptable salt" means that the salt is not only physiologically acceptable to a subject, but also refers to a synthetic substance having pharmaceutical use value.

[0088] As described herein, the term "pharmaceutical composition", which may also refer to a "composition", can be used to achieve the treatment of the diseases or disorders described herein in a subject, especially a mammal.

[0089] "Treatment" for illness includes:

[0090] (1) preventing the disease, that is, preventing the clinical symptoms of the disease from occurring in a mammal that is exposed to or susceptible to the disease but does not experience or show symptoms of the disease,

[0091] (2) inhibiting the disease, i.e., arresting or reducing the progression of the disease or its clinical symptoms,

[0092] (3) Alleviate the disease, that is, cause recovery of the disease or its clinical symptoms.

[0093] "Therapeutically effective amount" refers to the amount of a compound that is sufficient to achieve treatment of a disease when administered to a mammal for the treatment of the disease. The therapeutically effective amount will vary depending on the compound, the disease to be treated and its severity, and the age, weight, sex, and other factors of the mammal. The therapeutically effective amount may also refer to any amount of the compound that is sufficient to achieve the desired beneficial effect, including preventing, inhibiting, or alleviating the disease as described in (1)-(3) above. For example, the amount of the compound may be between 0.1-250 mg / kg, or preferably, 0.5-100 mg / kg, or more preferably, 1-50 mg / kg, or even more preferably, 2-20 mg / kg. Preferably, the amount of the compound is administered to the mammal twice a day. More preferably, the amount of the compound is administered to the mammal once a day.

[0094] As described herein, the term "disease and / or condition" refers to a physical state of the subject, which is related to the disease and / or condition described in the present invention. For example, the disease and / or condition described in the present invention refers to a tuberculosis infectious disease.

[0095] As described herein, the term "subject" may refer to a patient or other animal, particularly a mammal, such as a human, dog, monkey, cow, horse, etc., that receives the compound of formula (I) or its pharmaceutical composition for treating the disease or condition described in the present invention.

[0096] Another aspect of the present invention also relates to a pharmaceutical composition having the compound of the present invention as an active ingredient. The pharmaceutical composition can be prepared according to methods known in the art. The compound of the present invention can be combined with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants to prepare any dosage form suitable for human or animal use.

[0097] The compounds of the present invention or pharmaceutical compositions containing the same can be administered in unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc.

[0098] The dosage form can be a liquid dosage form, a solid dosage form or a semisolid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o / w types, w / o types and multiple emulsions), suspensions, injections (including water injections, powder injections and infusions), eye drops, nasal drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, micropills, dropping pills, suppositories, films, patches, aerosols (powders), sprays, etc.; semisolid dosage forms can be ointments, gels, pastes, etc.

[0099] The compound of the present invention can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

[0100] In order to prepare the compound of the present invention into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and solubilizers. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent may be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and solubilizing agent may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0101] The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0102] In order to prepare the dosing unit into a capsule, the active ingredient compound of the present invention can be mixed with a diluent and a cosolvent, and the mixture can be directly placed in a hard capsule or a soft capsule. The active ingredient compound of the present invention can also be first prepared into granules or pellets with a diluent, a binder, and a disintegrant, and then placed in a hard capsule or a soft capsule. The diluents, binders, wetting agents, disintegrants, and cosolvents used to prepare tablets of the compound of the present invention can also be used to prepare capsules of the compound of the present invention.

[0103] To prepare the compound of the present invention into an injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent and an appropriate amount of a solubilizer, cosolvent, pH adjuster, and osmotic pressure regulator commonly used in the art can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjuster can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. If a lyophilized powder injection is prepared, mannitol, glucose, etc. can also be added as a support agent.

[0104] Furthermore, if necessary, colorants, preservatives, perfumes, flavoring agents or other additives may be added to the pharmaceutical preparations.

[0105] In order to achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

[0106] The compound or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0107] Beneficial technical effects

[0108] The inventors of the present application have conducted extensive research and synthesized a series of compounds, and used MABA (Microplate alamar blue assay) to detect the presence of M. tuberculosis H 37 The minimum inhibitory concentration (MIC) of the Rv strain was determined, and the tested compounds showed strong anti-tuberculosis activity. The minimum inhibitory concentration (MIC) of some compounds reached the micromolar level, showing strong anti-tuberculosis activity. In addition, the compounds had low toxicity to Vero cells (IC 50 The present invention provides a substituted pyrrole-2,5-dione compound with novel structure, strong anti-tuberculosis activity and good pharmacokinetic properties, which can be used for the treatment or preventive treatment of infectious diseases caused by bacteria, especially tuberculosis caused by Mycobacterium tuberculosis. DETAILED DESCRIPTION

[0109] The present invention can be described in detail by the following examples, but it is not intended to limit the present invention in any way. The present invention has been described in detail herein, and specific embodiments thereof are disclosed therein, and it is apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0110] For all the following examples, standard manipulations and purification methods known to those skilled in the art can be used.The structures of the compounds were confirmed by nuclear magnetic resonance spectroscopy (NMR).

[0111] Preparation Examples Section

[0112] The structures of the compounds were determined by nuclear magnetic resonance spectroscopy (NMR). The H NMR shift (δ) is given in parts per million (ppm). The coupling constant (J) is given in Hertz (Hz). The NMR spectra were measured using a Mercury-400 or Mercury-500 NMR instrument, with deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-d6) as solvent and tetramethylsilane (TMS) as internal standard.

[0113] Column chromatography generally uses 200-300 mesh silica gel as a carrier.

[0114] All reagents were commercially available of analytical grade.

[0115] Example

[0116] Example 1

[0117] Preparation of 1-benzyl-3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 1)

[0118]

[0119] Synthesis route:

[0120]

[0121] Experimental steps:

[0122] Step 1 Preparation of 3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Intermediate C-1)

[0123] In a 10mL reaction bottle, dissolve phenylacetylene (41mg, 0.4mmol) and 3-iodo-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (73mg, 0.2mmol) in 5mL N,N-dimethylformamide, add cuprous iodide (8mg, 0.04mmol), bistriphenylphosphine palladium dichloride (7mg, 0.01mmol), triethylamine (40mg, 0.4mmol), and react at 50℃ for 3 hours under argon. Concentrate, separate by silica gel (200-300 mesh) column chromatography, and use ethyl acetate-petroleum ether (V:V=1~20:100) mixed solution as eluent. Obtain intermediate C-1 as yellow solid 205mg, 1 H NMR (400MHz, DMSO-d6) δ11.52(brs,1H),8.32(d,J=7.9Hz,2H),7.98(d,J=8.3Hz,2H),7.69–7.64(m,2H),7.58–7.48(m,3H).

[0124] Step 2 Preparation of 1-benzyl-3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 1)

[0125] In a 10mL reaction bottle, benzyl alcohol (33mg, 0.3mmol) and 3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (68mg, 0.2mmol) were dissolved in 5mL of dehydrated tetrahydrofuran, triphenylphosphine (79mg, 0.3mmol) and DIAD (60mg, 0.3mmol) were added, and the mixture was reacted at room temperature under argon for 2 hours. Concentration and separation by silica gel (200-300 mesh) column chromatography were performed, and a mixture of ethyl acetate-petroleum ether (V:V=1~20:100) was used as the eluent. Compound 1 was obtained as a yellow solid of 50mg, 1 H NMR (400MHz, CDCl3) δ8.38 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.63–7.56 (m, 2H), 7.50–7.38 (m, 5H), 7.38–7.28 (m, 3H), 4.80 (s, 2H).

[0126] Example 2

[0127] Preparation of 1-(4-chlorobenzyl)-3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 2)

[0128]

[0129] Using 4-chlorophenylmethanol (42 mg, 0.3 mmol) as the starting material, similar operation steps as in the second step of Example 1 were used to obtain compound 2 as a yellow solid (59 mg). 1 H NMR (400MHz, CDCl3) δ8.37(d,J=8.1Hz,2H),7.75(d,J=8.3Hz,2H),7.62–7.58(m,2H),7.50–7.35(m,5H),7.35–7.28(m,2H),4.76(s,2H).

[0130] Example 3

[0131] Preparation of 1-((1-methyl-1H-imidazol-2-yl)methyl)-3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 3)

[0132]

[0133] Using (1-methyl-1H-imidazol-2-yl)methanol (34 mg, 0.3 mmol) as the starting material, similar operation steps as in the second step of Example 1 were used to obtain compound 3 as a yellow solid (58 mg). 1H NMR (400MHz, CDCl3) δ8.40(d,J=8.2Hz,2H),7.75(d,J=8.2Hz,2H),7.59(d,J=6. 6Hz,2H),7.49–7.39(m,3H),7.00(s,1H),6.84(s,1H),4.88(s,2H),3.81(s,3H).

[0134] Example 4

[0135] Preparation of 1-(pyrimidin-5-ylmethyl)-3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 4)

[0136]

[0137] Using pyrimidin-5-ylmethanol (33 mg, 0.3 mmol) as the starting material, similar operation steps as in the second step of Example 1 were used to obtain compound 4 as a yellow solid (62 mg). 1 H NMR (400MHz, CDCl3) δ9.19 (s, 1H), 8.86 (s, 2H), 8.37 (d, J = 8.1Hz, 2H), 7.77 (d, J = 8.2Hz, 2H), 7.63–7.59 (m, 2H), 7.51–7.40 (m, 3H), 4.82 (s, 2H).

[0138] Example 5

[0139] Preparation of 1-((2-methylpyrimidin-5-yl)methyl)-3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 5)

[0140]

[0141] Using (2-methylpyrimidin-5-yl)methanol (37 mg, 0.3 mmol) as raw material, similar operation steps as in the second step of Example 1 were used to obtain compound 5 as a yellow solid (76 mg). 1 H NMR (400MHz, CDCl3) δ8.75(s,2H),8.37(d,J=8.2Hz,2H),7.76(d,J=8.3Hz,2H),7.63–7.58(m,2H),7.51–7.39(m,3H),4.78(s,2H),2.74(s,3H).

[0142] Example 6

[0143] Preparation of 1-((2-(methylthio)pyrimidin-4-yl)methyl)-3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 6)

[0144]

[0145] Using (2-(methylthio)pyrimidin-4-yl)methanol (47 mg, 0.3 mmol) as raw material, similar operation steps as in the second step of Example 1 were used to obtain compound 6 as a yellow solid (85 mg). 1 H NMR (400MHz, CDCl3) δ8.47(d,J=5.1Hz,1H),8.42(d,J=8.2Hz,2H),7.78(d,J=8.3Hz,2H) ,7.65–7.60(m,2H),7.51–7.40(m,3H),6.92(d,J=5.1Hz,1H),4.89(s,2H),2.44(s,3H).

[0146] Example 7

[0147] Preparation of 1-(pyridazin-3-ylmethyl)-3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 7)

[0148]

[0149] Using pyridazine-3-ylmethanol (33 mg, 0.3 mmol) as raw material, similar operation steps as in the second step of Example 1 were used to obtain compound 7 as a yellow solid (58 mg). 1 H NMR (400MHz, CDCl3) δ9.15 (d, J = 2.9 Hz, 1H), 8.41 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 7.63–7.58 (m, 2H), 7.55–7.39 (m, 5H), 5.17 (s, 2H).

[0150] Example 8

[0151] Preparation of 1-(quinolin-2-ylmethyl)-3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 8)

[0152]

[0153] Using quinolin-2-ylmethanol (48 mg, 0.3 mmol) as the starting material, similar operation steps as in the second step of Example 1 were used to obtain compound 8 as a yellow solid (72 mg).1 H NMR (400MHz, CDCl3) δ9.02(s,1H),8.37(d,J=8.1Hz,2H),8.25(s,1H),8.12(d,J=8.5Hz,1H),7.83(d,J =7.9Hz,1H),7.78–7.74(m,2H),7.74–7.69(m,1H),7.62–7.53(m,3H),7.49–7.39(m,3H),5.01(s,2H).

[0154] Example 9

[0155] Preparation of 1-(quinolin-6-ylmethyl)-3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 9)

[0156]

[0157] Using quinolin-6-ylmethanol (48 mg, 0.3 mmol) as the starting material, similar operation steps as in the second step of Example 1 were used to obtain compound 9 as a yellow solid (63 mg). 1 H NMR (400MHz, CDCl3) δ8.91(dd,J=4.3,1.8Hz,1H),8.39(d,J=7.9Hz,2H),8.17(d,J=7.4Hz,1H),8.10(d,J=8.7Hz,1H),7.8 9(d,J=2.0Hz,1H),7.79(dd,J=8.7,2.0Hz,1H),7.75(d,J=8.2Hz,2H),7.63–7.57(m,2H),7.50–7.39(m,4H),4.99(s,2H).

[0158] Example 10

[0159] Preparation of 1-(pyridin-2-ylmethyl)-3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 10)

[0160]

[0161] Using pyridin-2-ylmethanol (33 mg, 0.3 mmol) as the starting material, similar operation steps as in the second step of Example 1 were used to obtain compound 10 as a yellow solid (57 mg). 1H NMR (400MHz, CDCl3) δ8.56(d,J=5.8Hz,1H),8.43(d,J=8.1Hz,2H),7.76(d,J=8.2Hz,2H),7.69(td,J=7.7,1.8Hz,1H),7.62 (t,J=1.6Hz,1H),7.60(d,J=1.8Hz,1H),7.47–7.39(m,3H),7.32(d,J=7.9Hz,1H),7.21(dd,J=7.1,5.4Hz,1H),4.99(s,2H).

[0162] Embodiment 11

[0163] Preparation of 1-(pyridin-3-ylmethyl)-3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 11)

[0164]

[0165] Using pyridin-3-ylmethanol (33 mg, 0.3 mmol) as the starting material, similar operation steps as in the second step of Example 1 were used to obtain compound 11 as a yellow solid (62 mg). 1 H NMR (400MHz, CDCl3) δ8.72(d,J=1.7Hz,1H),8.57(dd,J=4.9,1.7Hz,1H),8.38(d,J=8.1Hz,2H),7.81–7. 78(m,1H),7.76(d,J=8.1Hz,2H),7.62–7.58(m,2H),7.50–7.39(m,3H),7.32–7.27(m,1H),4.82(s,2H).

[0166] Example 12

[0167] Preparation of 1-(pyridin-4-ylmethyl)-3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 12)

[0168]

[0169] Using pyridin-4-ylmethanol (33 mg, 0.3 mmol) as the starting material, similar operation steps as in the second step of Example 1 were used to obtain compound 12 as a yellow solid (59 mg). 1H NMR (400MHz, CDCl3) δ8.61–8.58(m,2H),8.39(d,J=8.0Hz,2H),7.77(d,J=8.4 Hz,2H),7.63–7.59(m,2H),7.50–7.40(m,3H),7.33–7.29(m,2H),4.81(s,2H).

[0170] Example 13

[0171] Preparation of 1-((2-methylpyridin-5-yl)methyl)-3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 13)

[0172]

[0173] Using 2-methylpyridin-5-ylmethanol (37 mg, 0.3 mmol) as the starting material, similar operation steps as in the second step of Example 1 were used to obtain compound 13 as a yellow solid (58 mg). 1 H NMR (400MHz, CDCl3) δ8.59(d,J=2.4Hz,1H),8.37(d,J=8.2Hz,2H),7.75(d,J=8.2Hz,2H),7.67(dd,J=8 .0,2.3Hz,1H),7.62–7.58(m,2H),7.49–7.39(m,3H),7.14(d,J=8.0Hz,1H),4.78(s,2H),2.55(s,3H).

[0174] Embodiment 14

[0175] Preparation of 1-((2-aminopyridin-4-yl)methyl)-3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 14)

[0176]

[0177] Using 2-aminopyridin-4-ylmethanol (37 mg, 0.3 mmol) as the starting material, similar operation steps as in the second step of Example 1 were used to obtain compound 14 as a yellow solid (60 mg). 1H NMR (400MHz, DMSO-d6) δ8.38(d,J=7.9Hz,2H),8.01(d,J=8.1Hz,2H),7.85(d,J=5.3Hz,1H),7.71–7.67(m,2 H),7.60–7.50(m,3H),6.46(dd,J=5.3,1.5Hz,1H),6.34(dd,J=1.6,0.8Hz,1H),5.91(brs,2H),4.59(s,2H).

[0178] Embodiment 15

[0179] Preparation of 1-(furan-2-ylmethyl)-3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 15)

[0180]

[0181] Using 2-furanmethanol (29 mg, 0.3 mmol) as the starting material, similar operation steps as in the second step of Example 1 were used to obtain compound 15 as a yellow solid (55 mg). 1 H NMR(400MHz, CDCl3)δ8.40(d,J=8.1Hz,2H),7.76(d,J=8.2Hz,2H),7.63–7.57(m,2H),7 .49–7.39(m,3H),7.37–7.35(m,1H),6.40–6.38(m,1H),6.34–6.32(m,1H),4.82(s,2H).

[0182] Example 16

[0183] Preparation of 1-(thiophen-2-ylmethyl)-3-(phenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 16)

[0184]

[0185] Using 2-thiophene methanol (34 mg, 0.3 mmol) as the starting material, similar operation steps as in the second step of Example 1 were used to obtain compound 16 as a yellow solid (37 mg). 1H NMR (400MHz, CDCl3) δ8.38(d,J=7.9Hz,2H),7.75(d,J=8.2Hz,2H),7.63–7.57(m,2H),7.49–7.38(m,3 H), 7.25 (dd, J = 5.2, 1.3Hz, 1H), 7.15 (dd, J = 3.5, 1.1Hz, 1H), 6.96 (dd, J = 5.1, 3.5Hz, 1H), 4.98 (s, 2H).

[0186] Embodiment 17

[0187] Preparation of 1-(pyridin-2-ylmethyl)-3-(cyclopropylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 17)

[0188]

[0189] Synthesis route:

[0190]

[0191] Experimental steps:

[0192] The first step is the preparation of 1-(pyridin-2-ylmethyl)-3-iodo-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Intermediate B-1)

[0193] In a 25 mL reaction bottle, pyridine-2-ylmethanol (164 mg, 1.5 mmol) and 3-iodo-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (367 mg, 1.0 mmol) were dissolved in 10 mL of dehydrated tetrahydrofuran, triphenylphosphine (393 mg, 1.5 mmol) and DIAD (303 mg, 1.5 mmol) were added, and the mixture was reacted at room temperature under argon for 2 hours. Concentration and separation by silica gel (200-300 mesh) column chromatography were performed, and a mixture of ethyl acetate-petroleum ether (V:V=1-20:100) was used as the eluent. Intermediate B-1 was obtained as a brown solid (400 mg). 1 H NMR (400MHz, CDCl3) δ8.54(d,J=5.7Hz,1H),8.01(d,J=8.1Hz,2H),7.76(d,J=8.3Hz,2 H),7.67(td,J=7.7,1.8Hz,1H),7.29(d,J=7.9Hz,1H),7.22–7.18(m,1H),4.98(s,2H).

[0194] Step 2 Preparation of 1-(pyridin-2-ylmethyl)-3-(cyclopropylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 17)

[0195] In a 10 mL reaction bottle, cyclopropylacetylene (26 mg, 0.4 mmol) and 1-(pyridin-2-ylmethyl)-3-iodo-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (92 mg, 0.2 mmol) were dissolved in 5 mL N,N-dimethylformamide, and cuprous iodide (8 mg, 0.04 mmol), bistriphenylphosphine palladium dichloride (7 mg, 0.01 mmol), triethylamine (40 mg, 0.4 mmol) were added, and the mixture was reacted at 50 ° C for 3 hours under argon. Concentration, silica gel (200-300 mesh) column chromatography, ethyl acetate-petroleum ether (V: V = 1 to 20: 100) mixed solution as eluent. Compound 17 was obtained as a brown solid 62 mg, 1 H NMR (400MHz, CDCl3) δ8.53(d,J=4.9Hz,1H),8.33(d,J=8.1Hz,2H),7.71(d,J=8.2Hz,2H),7.68–7.62(m,1H),7.26( d,J=7.8Hz,1H),7.18(dd,J=7.5,4.8Hz,1H),4.92(s,2H),1.69–1.60(m,1H),1.11–1.04(m,2H),1.04–0.95(m,2H).

[0196] Embodiment 18

[0197] Preparation of 1-(pyridin-2-ylmethyl)-3-(cyclohexylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 18)

[0198]

[0199] Cyclohexyl acetylene (43 mg, 0.4 mmol) was used as the starting material, and the same operation steps as those in the second step of Example 17 were used to obtain compound 18 as a yellow solid (71 mg). 1H NMR (400MHz, CDCl3) δ8.54(d,J=4.9Hz,1H),8.39(d,J=8.2Hz,2H),7.71(d,J=8.2Hz,2H),7.66(td,J=7.7,1.8Hz,1H),7.28(d,J=7.8H z,1H),7.23–7.14(m,1H),4.94(s,2H),2.85–2.76(m,1H),1.98–1.88(m,2H),1.81–1.70(m,2H),1.68–1.53(m,3H),1.46–1.36(m,3H).

[0200] Embodiment 19

[0201] Preparation of 1-(pyridin-2-ylmethyl)-3-(cyclohex-1-enylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 19)

[0202]

[0203] Using 1-ethynylcyclohexene (43 mg, 0.4 mmol) as the starting material, similar operation steps as in the second step of Example 17 were used to obtain compound 19 as a yellow solid (71 mg). 1 H NMR (400MHz, CDCl3) δ8.54(d,J=4.8Hz,1H),8.38(d,J=8.1Hz,2H),7.71(d,J=8.2Hz,2H),7.66(td,J=7.7,1.8Hz,1H),7 .28(d,J=7.9Hz,1H),7.19(dd,J=7.6,4.9Hz,1H),6.51–6.46(m,1H),4.95(s,2H),2.31–2.18(m,4H),1.75–1.60(m,4H).

[0204] Embodiment 20

[0205] Preparation of 1-(pyridin-2-ylmethyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 20)

[0206]

[0207] Using 3-alkynyl imidazole [1,2-b] pyridazine (56 mg, 0.4 mmol) as raw material, similar operation steps as the second step in Example 17 were used to obtain compound 20 as an orange-red solid (51 mg). 1H NMR (400MHz, DMSO-d6) δ8.89(d,J=4.4Hz,1H),8.60(d,J=8.2Hz,2H),8.50(d,J=4.9Hz,2H),8.35(d,J=9.1Hz,1H),8.01(d,J=8.3 Hz,2H),7.80(td,J=7.7,1.8Hz,1H),7.52(dd,J=9.1,4.5Hz,1H),7.48(d,J=7.9Hz,1H),7.31(dd,J=7.5,4.8Hz,1H),4.90(s,2H).

[0208] Embodiment 21

[0209] Preparation of 1-(pyridin-2-ylmethyl)-3-(thiophen-2-ylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 21)

[0210]

[0211] Using 2-ethynylthiophene (43 mg, 0.4 mmol) as the starting material, similar operation steps as in the second step of Example 17 were used to obtain compound 21 as an orange solid (72 mg). 1 H NMR (400MHz, CDCl3) δ8.55(d,J=4.9Hz,1H),8.40(d,J=8.2Hz,2H),7.75(d,J=8.2Hz,2H),7.70–7.64(m,1 H),7.52–7.47(m,2H),7.30(d,J=7.9Hz,1H),7.24–7.17(m,1H),7.10(dd,J=5.1,3.7Hz,1H),4.97(s,2H).

[0212] Embodiment 22

[0213] Preparation of 1-(pyridin-2-ylmethyl)-3-(thiophen-3-ylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 22)

[0214]

[0215] Using 3-ethynylthiophene (43 mg, 0.4 mmol) as the starting material, similar operation steps as in the second step of Example 17 were used to obtain compound 22 as a yellow solid (71 mg). 1H NMR (400MHz, CDCl3) δ8.55(d,J=5.9Hz,1H),8.41(d,J=8.1Hz,2H),7.77–7.72(m,3H),7.70–7.64(m,1H),7.3 7(dd,J=5.0,3.0Hz,1H),7.30(d,J=7.9Hz,1H),7.26(dd,J=5.0,1.2Hz,1H),7.22–7.17(m,1H),4.97(s,2H).

[0216] Embodiment 23

[0217] Preparation of 1-(pyridin-2-ylmethyl)-3-((5-(piperidin-1-yl)pyridin-3-yl)ethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 23)

[0218]

[0219] Using 3-ethynyl-5-(piperidin-1-yl)pyridine (74 mg, 0.4 mmol) as raw material, similar operation steps as the second step in Example 17 were adopted to obtain compound 23 as an orange-red solid (66 mg). 1 H NMR (400MHz, CDCl3) δ8.55(d,J=4.1Hz,1H),8.40(d,J=8.1Hz,2H),8.34(s,1H),8.21(s,1H),7.76(d,J=8.4Hz,2H),7.71– 7.63(m,1H),7.32–7.29(m,2H),7.21–7.17(m,1H),4.97(s,2H),3.28–3.22(m,4H),1.73–1.69(m,4H),1.66–1.61(m,2H).

[0220] Embodiment 24

[0221] Preparation of 1-(pyridin-2-ylmethyl)-3-((4,4-dimethylthiochroman-6-yl)ethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 24)

[0222]

[0223] Using 6-ethynyl-4,4-dimethylthiochroman (80 mg, 0.4 mmol) as the starting material, similar operation steps as in the second step of Example 17 were used to obtain compound 24 as an orange solid (72 mg). 1H NMR (400MHz, CDCl3) δ8.55(d,J=4.3Hz,1H),8.43(d,J=8.2Hz,2H),7.75(d,J=8.3Hz,2H),7.67(td,J=7.7,1.8Hz,1H),7.57(d,J=1.8Hz ,1H),7.30(d,J=7.9Hz,1H),7.25–7.17(m,2H),7.12(d,J=8.2Hz,1H),4.97(s,2H),3.10–3.03(m,2H),1.99–1.92(m,2H),1.34(s,6H).

[0224] Embodiment 25

[0225] Preparation of 1-(pyridin-2-ylmethyl)-3-(naphthalen-1-ylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 25)

[0226]

[0227] Using 1-naphthylacetylene (61 mg, 0.4 mmol) as the starting material, similar operation steps as in the second step of Example 17 were used to obtain compound 25 as an orange solid (80 mg). 1 H NMR (400MHz, CDCl3) δ8.58(d,J=4.9Hz,1H),8.51(d,J=8.1Hz,2H),8.46(d,J=8.6Hz,1H),7.97(d,J=8.4Hz,1H),7.92–7.84(m,2H),7.79(d,J= 8.2Hz,2H),7.70(td,J=7.7,1.8Hz,1H),7.65–7.55(m,2H),7.51(dd,J=8.4,7.1Hz,1H),7.35(d,J=7.8Hz,1H),7.25–7.20(m,1H),5.03(s,2H).

[0228] Embodiment 26

[0229] Preparation of 1-(pyridin-2-ylmethyl)-3-(naphthalen-2-ylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 26)

[0230]

[0231] Using 2-naphthylacetylene (61 mg, 0.4 mmol) as the starting material, similar operation steps as in the second step of Example 17 were used to obtain compound 26 as an orange solid (67 mg). 1H NMR (400MHz, CDCl3) δ8.56(d,J=4.8Hz,1H),8.47(d,J=8.1Hz,2H),8.16(s,1H),7.90–7.83(m,3H),7.79(d,J=8.2Hz,2H),7.68(td, J=7.7,1.8Hz,1H),7.60(dd,J=8.5,1.5Hz,1H),7.58–7.54(m,2H),7.32(d,J=7.8Hz,1H),7.20(dd,J=7.5,3.7Hz,1H),4.99(s,2H).

[0232] Embodiment 27

[0233] Preparation of 1-(pyridin-2-ylmethyl)-3-((4-methylphenyl)ethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 27)

[0234]

[0235] Using p-methylphenylacetylene (46 mg, 0.4 mmol) as the starting material, similar operation steps as in the second step of Example 17 were used to obtain compound 27 as a yellow solid (60 mg). 1 H NMR (400MHz, CDCl3) δ8.55(d,J=4.0Hz,1H),8.44(d,J=8.1Hz,2H),7.75(d,J=8.2Hz,2H),7.66(td,J=7.7,1.8Hz,1H ),7.50(d,J=8.2Hz,2H),7.30(d,J=8.1Hz,1H),7.22(d,J=7.7Hz,2H),7.21–7.16(m,1H),4.97(s,2H),2.41(s,3H).

[0236] Embodiment 28

[0237] Preparation of 1-(pyridin-2-ylmethyl)-3-((3-fluorophenyl)ethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 28)

[0238]

[0239] Using 3-fluorophenylacetylene (48 mg, 0.4 mmol) as raw material, similar operation steps as in the second step of Example 17 were used to obtain compound 28 as a yellow solid (57 mg). 1H NMR (400MHz, CDCl3) δ8.54(d,J=4.4Hz,1H),8.40(d,J=8.1Hz,2H),7.77(d,J=8.3Hz,2H),7.67 (td,J=7.7,1.8Hz,1H),7.41–7.37(m,2H),7.33–7.27(m,2H),7.23–7.13(m,2H),4.97(s,2H).

[0240] Embodiment 29

[0241] Preparation of 1-(pyridin-2-ylmethyl)-3-((4-chlorophenyl)ethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 29)

[0242]

[0243] Using 4-chlorophenylacetylene (55 mg, 0.4 mmol) as raw material, similar operation steps as the second step in Example 17 were used to obtain compound 29 as a yellow solid (71 mg). 1 H NMR (400MHz, CDCl3) δ8.54(d,J=4.9Hz,1H),8.40(d,J=8.2Hz,2H),7.76(d,J=8.3Hz,2H),7.66(td,J=7.7,1.8Hz, 1H), 7.53 (d, J = 8.5Hz, 2H), 7.39 (d, J = 8.5Hz, 2H), 7.30 (d, J = 7.8Hz, 1H), 7.19 (dd, J = 8.1, 5.5Hz, 1H), 4.97 (s, 2H).

[0244] Embodiment 30

[0245] Preparation of 1-(pyridin-2-ylmethyl)-3-((4-trifluoromethylphenyl)ethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 30)

[0246]

[0247] Using 4-trifluoromethylphenylacetylene (68 mg, 0.4 mmol) as the starting material, similar operation steps as in the second step of Example 17 were used to obtain compound 30 as a yellow solid (79 mg). 1H NMR (400MHz, CDCl3) δ8.55(d,J=4.1Hz,1H),8.40(d,J=7.9Hz,2H),7.77(d,J=8.4Hz,2 H),7.73–7.64(m,5H),7.31(d,J=7.9Hz,1H),7.20(dd,J=7.1,5.4Hz,1H),4.98(s,2H).

[0248] Embodiment 31

[0249] Preparation of 1-(pyridin-2-ylmethyl)-3-((4-cyanophenyl)ethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 31)

[0250]

[0251] Using 4-cyanophenylacetylene (51 mg, 0.4 mmol) as the starting material, similar operation steps as in the second step of Example 17 were used to obtain compound 31 as a yellow solid (54 mg). 1 H NMR (400MHz, CDCl3) δ8.54(d,J=4.0Hz,1H),8.37(d,J=8.2Hz,2H),7.77(d,J=8.2Hz,2H),7.70(d,J =2.8Hz, 4H), 7.64 (d, J = 6.0Hz, 1H), 7.31 (d, J = 7.8Hz, 1H), 7.20 (dd, J = 6.4, 4.9Hz, 1H), 4.98 (s, 2H).

[0252] Embodiment 32

[0253] Preparation of 1-(pyridin-2-ylmethyl)-3-((4-methoxyphenyl)ethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 32)

[0254]

[0255] Using 4-methoxyphenylacetylene (52 mg, 0.4 mmol) as raw material, similar operation steps as the second step in Example 17 were adopted to obtain compound 32 as an orange-red solid (68 mg). 1H NMR (400MHz, CDCl3) δ8.56(d,J=4.9Hz,1H),8.43(d,J=8.2Hz,2H),7.75(d,J=8.1Hz,2H),7.69(t,J=7.7Hz,1H),7. 55(d,J=8.9Hz,2H),7.31(d,J=7.9Hz,1H),7.21(t,J=6.6Hz,1H),6.93(d,J=8.8Hz,2H),4.99(s,2H),3.86(s,3H).

[0256] Embodiment 33

[0257] Preparation of 1-(pyridin-2-ylmethyl)-3-((4-trifluoromethoxyphenyl)ethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 33)

[0258]

[0259] Using 4-trifluoromethoxyphenylacetylene (74 mg, 0.4 mmol) as the starting material, similar operation steps as in the second step of Example 17 were used to obtain compound 33 as a yellow solid (94 mg). 1 H NMR (400MHz, CDCl3) δ8.55(d,J=5.1Hz,1H),8.39(d,J=8.2Hz,2H),7.76(d,J=8.3Hz,2H),7 .70–7.61(m,3H),7.31(d,J=7.8Hz,1H),7.29–7.24(m,2H),7.23–7.17(m,1H),4.97(s,2H).

[0260] Embodiment 34

[0261] Preparation of 1-(pyridin-2-ylmethyl)-3-((3,5-dimethoxyphenyl)ethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 34)

[0262]

[0263] Using 3,5-dimethoxyphenylacetylene (65 mg, 0.4 mmol) as raw material, similar operation steps as the second step in Example 17 were adopted to obtain compound 34 as a yellow solid (74 mg). 1H NMR (400MHz, CDCl3) δ8.54(d,J=4.7Hz,1H),8.42(d,J=8.2Hz,2H),7.75(d,J=8.2Hz,2H),7.67(td,J=7.7,1.7Hz,1H) ,7.30(d,J=7.9Hz,1H),7.19(t,J=6.3Hz,1H),6.73(d,J=2.3Hz,2H),6.56(t,J=2.3Hz,1H),4.97(s,2H),3.81(s,6H).

[0264] Embodiment 35

[0265] Preparation of 1-(pyridin-2-ylmethyl)-3-((4-ethylphenyl)ethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 35)

[0266]

[0267] Using 4-ethylphenylacetylene (52 mg, 0.4 mmol) as the starting material, similar operation steps as in the second step of Example 17 were used to obtain compound 35 as a yellow solid (54 mg). 1 H NMR (400MHz, CDCl3) δ8.55(d,J=4.1Hz,1H),8.44(d,J=7.9Hz,2H),7.75(d,J=8.2Hz,2H),7.67(td,J=7.7,1.8Hz,1H),7.53(d,J=8. 4Hz, 2H), 7.30 (d, J = 7.9Hz, 1H), 7.25 (d, J = 8.6Hz, 2H), 7.22–7.17 (m, 1H), 4.97 (s, 2H), 2.70 (q, J = 7.6Hz, 2H), 1.26 (t, J = 7.6Hz, 3H).

[0268] Embodiment 36

[0269] Preparation of 1-(pyridin-2-ylmethyl)-3-((4-butylphenyl)ethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 36)

[0270]

[0271] Using 4-butylphenylacetylene (63 mg, 0.4 mmol) as raw material, similar operation steps as in the second step of Example 17 were used to obtain compound 36 as a yellow solid (82 mg). 1H NMR (400MHz, CDCl3) δ8.55(s,1H),8.44(d,J=8.1Hz,2H),7.75(d,J=8.1Hz,2H),7.67(t,J=7.7Hz,1H),7.52(d,J=8.4Hz,2H),7.30(s, 1H),7.23(d,J=8.5Hz,2H),7.19(s,1H),4.97(s,2H),2.73–2.58(m,2H),1.63–1.56(m,2H),1.42–1.30(m,2H),0.93(t,J=7.3Hz,3H).

[0272] Embodiment 37

[0273] Preparation of 1-(pyridin-2-ylmethyl)-3-((4-tert-butylphenyl)ethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 37)

[0274]

[0275] Using 4-tert-butylphenylacetylene (63 mg, 0.4 mmol) as raw material, similar operation steps as the second step in Example 17 were adopted to obtain compound 37 as a yellow solid (87 mg). 1 H NMR (400MHz, CDCl3) δ8.55(d,J=5.8Hz,1H),8.44(d,J=8.1Hz,2H),7.75(d,J=8.2Hz,2H),7.67(td,J=7.7,1.8Hz,1H ),7.54(d,J=8.6Hz,2H),7.44(d,J=8.8Hz,2H),7.30(d,J=7.8Hz,1H),7.21–7.17(m,1H),4.97(s,2H),1.34(s,9H).

[0276] Embodiment 38

[0277] Preparation of 1-(pyridin-2-ylmethyl)-3-((4-bromophenyl)ethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 38)

[0278]

[0279] Using 4-bromophenylacetylene (72 mg, 0.4 mmol) as the starting material, similar operation steps as in the second step of Example 17 were used to obtain compound 38 as a yellow solid (47 mg). 1H NMR (400MHz, CDCl3) δ8.55(d,J=4.8Hz,1H),8.40(d,J=8.1Hz,2H),7.76(d,J=8.2Hz,2H),7.69(td,J=7.7,1. 8Hz,1H),7.56(d,J=8.6Hz,2H),7.46(d,J=8.8Hz,2H),7.31(d,J=7.8Hz,1H),7.24–7.19(m,1H),4.99(s,2H).

[0280] Embodiment 39

[0281] Preparation of 1-(pyridin-2-ylmethyl)-3-((4-acetylphenyl)ethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 39)

[0282]

[0283] Using 4-acetylphenylacetylene (56 mg, 0.4 mmol) as raw material, similar operation steps as the second step in Example 17 were used to obtain compound 39 as a yellow solid (52 mg). 1 H NMR (400MHz, CDCl3) δ8.55(s,1H),8.41(d,J=8.2Hz,2H),7.99(d,J=8.4Hz,2H),7.77(d,J=8.3 Hz,2H),7.72–7.65(m,3H),7.32(d,J=7.8Hz,1H),7.24–7.18(m,1H),4.99(s,2H),2.63(s,3H).

[0284] Embodiment 40

[0285] Preparation of 1-(pyridin-2-ylmethyl)-3-((4-methoxycarbonylphenyl)ethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 40)

[0286]

[0287] Using 4-methoxycarbonylphenylacetylene (64 mg, 0.4 mmol) as the starting material, similar operation steps as in the second step of Example 17 were used to obtain compound 40 as a yellow solid (70 mg). 1H NMR (400MHz, CDCl3) δ8.54(d,J=4.6Hz,1H),8.41(d,J=8.2Hz,2H),8.08(d,J=8.4Hz,2H),7.77(d,J=8.3 Hz,2H),7.70–7.63(m,3H),7.31(d,J=7.8Hz,1H),7.20(dd,J=7.3,5.2Hz,1H),4.98(s,2H),3.95(s,3H).

[0288] Embodiment 41

[0289] Preparation of 1-(pyridin-2-ylmethyl)-3-((4-dimethylaminophenyl)ethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 41)

[0290]

[0291] Using 4-dimethylaminophenylacetylene (58 mg, 0.4 mmol) as the starting material, similar operation steps as in the second step of Example 17 were used to obtain compound 41 as a purple solid (87 mg). 1 H NMR (500MHz, CDCl3) δ8.54(d,J=4.8Hz,1H),8.46(d,J=8.2Hz,2H),7.73(d,J=8.2Hz,2H),7.65(t,J=7.7Hz,1H),7. 48(d,J=9.0Hz,2H),7.28(d,J=7.9Hz,1H),7.17(t,J=6.3Hz,1H),6.67(d,J=9.1Hz,2H),4.96(s,2H),3.05(s,6H).

[0292] Embodiment 42

[0293] Preparation of 1-(pyridin-2-ylmethyl)-3-((4-piperidin-1-yl-phenyl)ethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 42)

[0294]

[0295] Using 1-(4-ethynylphenyl)piperidine (74 mg, 0.4 mmol) as the starting material, similar operation steps as in the second step of Example 17 were used to obtain compound 42 as a red solid (60 mg). 1H NMR (400MHz, CDCl3) δ8.55(d,J=4.3Hz,1H),7.65(td,J=7.7,1.8Hz,1H),7.45(d,J=8.1Hz,2H),7.33(t,J =9.4Hz,2H),7.21–7.09(m,4H),6.83(d,J=8.0Hz,2H),4.85(s,2H),3.18–3.07(m,4H),1.67–1.55(m,6H).

[0296] Embodiment 43

[0297] Preparation of 1-(pyridin-2-ylmethyl)-3-(phenylethynyl)-4-(3-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 43)

[0298]

[0299] Using 3-iodo-4-(3-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (367 mg, 1.0 mmol) as the starting material, the similar operation steps as in the first step of Example 17 were adopted to obtain the intermediate 1-(pyridin-2-ylmethyl)-3-iodo-4-(3-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione, 320 mg of brown solid, and then using phenylacetylene (41 mg, 0.4 mmol) as the starting material, the similar operation steps as in the second step of Example 17 were adopted to obtain compound 43, 52 mg of yellow solid, 1 H NMR (400MHz, CDCl3) δ8.72(s,1H),8.56(d,J=4.9Hz,1H),8.52(d,J=7.9Hz,1H),7.74(d,J=8.2Hz,1H),7.73–7.6 7(m,1H),7.67–7.60(m,3H),7.49–7.39(m,3H),7.32(d,J=7.9Hz,1H),7.23(dd,J=7.4,5.2Hz,1H),5.00(s,2H).

[0300] Embodiment 44

[0301] Preparation of 1-(pyridin-2-ylmethyl)-3-(3-methylphenylethynyl)-4-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (Compound 44)

[0302]

[0303] Using p-methylphenylacetylene (46 mg, 0.4 mmol) as the starting material, similar operation steps as in the second step of Example 43 were used to obtain compound 44 as a yellow solid (60 mg). 1 H NMR (400MHz, CDCl3) δ8.73(s,1H),8.52(d,J=7.8Hz,1H),7.73(d,J=7.9Hz,2H),7.68–7.59(m,1H),7. 51(d,J=7.7Hz,2H),7.36–7.25(m,2H),7.22(d,J=7.8Hz,2H),6.34(s,1H),4.99(s,2H),2.40(s,3H).

[0304] Biological activity test

[0305] 1. In vitro anti-tuberculosis activity test

[0306] Determination method: Microplate Alamar Blue Assay (MABA) was used to determine the in vitro anti-tuberculosis activity.

[0307] Experimental principle: Alamar Blue added to the culture medium can be used as a redox indicator. The color changes from blue to red, reflecting the consumption of oxygen molecules by the studied microorganisms. The color change of Alamar Blue can be measured by a photometer, and its emission wavelength is 590nm.

[0308] Experimental method: A sterile 96-well plate (Falcon3072; Becton Dickinson, Lincoln Park, NJ) was used. The experimental compound was dissolved in DMSO to prepare a 5 mg / mL initial solution. 199 μL 7H9 medium and 1 μL compound initial solution were added to the highest concentration well. After mixing, the solution was diluted 2-fold to the remaining wells. The final concentrations of the compound were: 25, 12.5, 6.25, 3.125, 1.56, 0.78, 0.39, 0.2, 0.1, and 0.05 μg / mL. 37 R v The culture was cultured for 2 to 3 weeks to prepare a bacterial suspension, which was inoculated into 7H9 medium containing 0.05% Tween 80 and 10% ADC and cultured at 37°C for 1 to 2 weeks until the turbidity reached McFarland 1 (equivalent to 10 7 CFU / mL), 100 μL of the bacterial solution was added to each well after dilution of 1:20, and the final concentration of the bacterial solution was 10 6CFU / mL. Two growth control wells without antibiotics were set up on each plate, and the 96-well plate was incubated at 37°C. After 7 days, 20 μL of 10× Alamar Blue and 50 μL of 5% Tween80 were added to the growth control wells and incubated at 37°C for 24 hours. If the color changes from blue to pink, the above amount of Alamar Blue and Tween 80 mixture was added to the wells of each experimental drug, and incubated at 37°C for 24 hours. The color of each well was recorded, and the fluorescence value at 590 nm was measured using an enzyme reader to calculate the MIC. 90 .

[0309] Table 1. In vitro anti-Mycobacterium tuberculosis activity of some compounds of the present invention

[0310]

[0311] It can be seen from the data in Table 1 that the compounds of the present invention have good in vitro anti-Mycobacterium tuberculosis activity.

[0312] 2. Cytotoxicity test

[0313] Determination method: MTT method

[0314] Experimental principle: Cell activity is determined by the reduction of oxidized 3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyl tetrazolium bromide (trade name: Thiazole Blue) / MTT [3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyl tetrazolium bromide] to an insoluble blue formazan compound through mitochondrial dehydrogenase (such as succinate dehydrogenase). The color development after dissolution with DMSO is used for determination. The conversion amount is positively correlated with the number of living cells.

[0315] Experimental methods: 1. Preparation of cell suspension. Digest the Vero cells that have been cultured to the logarithmic growth phase with 0.25% trypsin for 2 to 3 minutes, discard the digestion solution, add an appropriate amount of culture medium, mix well, take 20μL and count under a microscope with a hemacytometer to prepare a cell suspension of appropriate concentration for later use. At the same time, prepare 5g / L MTT solution with PBS (phosphate buffered solution), filter and sterilize, and set aside. 2. Drug preparation and cytotoxicity detection. Dissolve the test drug in DMSO and dilute it 50 times with culture medium to make the highest test concentration, then use culture medium to make a series of dilutions on a 96-well plate at 1:3. Set 6 concentrations for each compound, with the highest concentration of 64μg / mL, and set 6 parallel wells for each concentration, 50μL / well. Inoculate the prepared cell suspension in a 96-well plate, 50μL / well, with a cell concentration of 4×10 5 / mL. At the same time, set up a cell control well without drug and a blank control well with culture medium. After 48 hours of culture, add MTT 10μL / well and continue to culture for 4 hours. Take out the culture plate, carefully discard the culture medium in the well, add DMSO 100μL to each well, shake until the formazan particles are completely dissolved, and use an enzyme-linked immunosorbent assay to measure its optical density (OD) at a wavelength of 570nm. 570 3. Data processing. Cell inhibition percentage (%) = [(cell control OD 570 Value - OD of drug-added group 570 value) / (cell control OD 570 Value - Blank OD 570 The dose-response curve was fitted using Origin 7.0 software to calculate the concentration of each compound at which the cell inhibition rate was 50% (IC 50 ).

[0316] Table 2. Cytotoxicity of some compounds of the present invention

[0317]

[0318] It can be seen from the data in Table 2 that the compounds of the present invention have low cytotoxicity and exhibit good safety.

[0319] Experimental Example 3: Hepatocyte metabolic stability test

[0320] Experimental Methods: Assays were performed using hepatocytes from male mice (Bioreclamation IVT) and pooled humans (Bioreclamation IVT). Compounds were tested at 1 μM concentration, with a final hepatocyte concentration of 1 million cells / mL. The reaction was initiated by adding 400 μL of preheated hepatocyte solution (2 million cells / mL) to 400 μL of compound solution (2 μM). The reaction mixture was incubated at 37°C in a CO2 incubator at 100 rpm for 120 minutes. At predetermined time points (0, 15, 30, 60, 90, and 120 minutes), 30 μL of the reaction mixture was removed and the reaction was terminated by adding 300 μL of quenching solution containing an internal standard. The samples were mixed thoroughly, centrifuged at 4°C for 15 minutes (4,000 rpm), and the supernatant was analyzed by LC-MS / MS. Chromatographic conditions: Chromatographic column: Kinetex C18 100A (30 mm×3.0 mm, 2.6 μm); Column temperature: room temperature, Mobile phase: acetonitrile-water (containing 0.1% formic acid) gradient; Flow rate: 0.7 mL / min. The metabolic stability of the compound in hepatocytes was evaluated by measuring the residual amount of the compound.

[0321] Table 3 Metabolic stability of some compounds in mouse / human hepatocytes

[0322]

[0323] It can be seen from the data in Table 3 that compounds 10 and 27 of the present invention have good metabolic stability in mouse hepatocytes, and have higher metabolic stability in human hepatocytes.

[0324] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in, R1 is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, or substituted or unsubstituted C2-C9 heteroaryl; R2 is C3-C7 cycloalkyl, C3-C6 heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted C2-C9 heteroaryl; R3 is H, F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, the number of substitutions of R3 on the phenyl group is 1, 2, 3, 4 or 5, and the substituents may be the same or different; The substituents on the phenyl, naphthyl and heteroaryl groups in R1 or R2 are selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, methylthio, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylamino, C3-C6 heterocyclyl; The C3-C6 heterocyclic group and C2-C9 heteroaryl group contain at least one heteroatom selected from N, O, and S; The compound represented by formula (I) does not include:

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof: in, R1 is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl; R2 is C3-C7 cycloalkyl, C3-C6 heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, imidazo[1,2-b]pyridazinyl, 4,4-dimethylthiobenzopyranyl; R3 is F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, or carboxyl, and the number of substitutions of R3 on the phenyl group is 1, 2, 3, 4, or 5, and the substituents may be the same or different; The substituents on the phenyl, naphthyl, pyridyl, quinolyl, pyrimidinyl, pyridazinyl, imidazolyl, thienyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl in R1 or R2 are selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, methylthio, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylamino, C3-C6 heterocyclic group; The C3-C6 heterocyclic group contains at least one heteroatom selected from N, O, and S.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof: in, R1 is a substituted or unsubstituted pyridyl group; R2 is C3-C7 cycloalkyl, C3-C6 heterocyclyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, imidazo[1,2-b]pyridazinyl, 4,4-dimethylthiobenzopyranyl; R3 is F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, or carboxyl, and the number of substitutions of R3 on the phenyl group is 1, 2, or 3, and the substituents may be the same or different; The substituents on the pyridyl, naphthyl, quinolyl, pyrimidinyl, pyridazinyl, imidazolyl, thienyl, furanyl, pyrrolyl in R1 or R2 are optionally selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, methylthio, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylamino, C3-C6 heterocyclic group; The C3-C6 heterocyclic group contains at least one heteroatom selected from N, O, and S.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the general formula (II): in, R1 is a substituted or unsubstituted pyridyl group; R2 is C3-C7 cycloalkyl, C3-C6 heterocyclyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, imidazo[1,2-b]pyridazinyl, 4,4-dimethylthiobenzopyranyl; The substituents on the pyridyl, naphthyl, quinolyl, pyrimidinyl, pyridazinyl, imidazolyl, thienyl, furanyl, pyrrolyl in R1 or R2 are optionally selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, methylthio, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylamino, C3-C6 heterocyclic group; The C3-C6 heterocyclic group contains at least one heteroatom selected from N, O, and S.

5. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the general formula (III): in: R1 is substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl; R3 is F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, or carboxyl, and the number of substitutions of R3 on the phenyl group is 1, 2, or 3, and the substituents may be the same or different; R4 is F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, methylthio, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxyformyl, C1-C4 alkylamino, C3-C6 heterocyclyl, the number of substitutions of R4 on the phenyl group is 1, 2 or 3, and the substituents may be the same or different; The substituents on the pyridyl, quinolyl, pyrimidinyl, pyridazinyl, imidazolyl, thienyl, furanyl, pyrrole, oxazolyl, isoxazolyl in R1 are optionally selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, methylthio, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylamino, C3-C6 heterocyclic group; The C3-C6 heterocyclic group contains at least one heteroatom selected from N, O, and S.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the general formula (IV): in, R1 is a substituted or unsubstituted pyridyl group; R4 is F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, methylthio, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxyformyl, C1-C4 alkylamino, C3-C6 heterocyclyl, the number of substitutions of R4 on the phenyl group is 1, 2 or 3, and the substituents may be the same or different; The substituents on the pyridyl group in R1 are optionally selected from the following groups: F, Cl, Br, hydroxyl, amino, nitro, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, carboxyl, methylthio, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylamino, C3-C6 heterocyclic group; The C3-C6 heterocyclic group contains at least one heteroatom selected from N, O, and S.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

8. A method for preparing a compound according to any one of claims 1 to 7, comprising the following steps: (1) Compound A and Compound The compound of formula B is obtained by Mitsunobu reaction, and then A sonchitoku coupling reaction occurs to obtain a compound represented by formula (I); or (2) Compound A and Compound Sonogaoka coupling reaction occurs to obtain a compound shown in formula C, which is then reacted with the compound The Mitsunobu reaction occurs to obtain a compound represented by formula (I), Wherein, R1, R2, and R3 are defined as described in any one of claims 1 to 7.

9. A pharmaceutical composition, characterized in that The composition comprises a therapeutically and / or preventively effective amount of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients.

10. The pharmaceutical composition according to claim 9, characterized in that The auxiliary material is selected from carriers, excipients, diluents or vehicles.

11. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or the composition according to claim 9 or 10 in the preparation of a medicament for treating and / or preventing infectious diseases caused by Mycobacterium tuberculosis.

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