Use of a compound for the manufacture of a mycobacterium inhibitor

Abstract

The present application provides a kind of as formula (I) compound or its pharmaceutically acceptable salt in preparation treatment and / or prevention with mycobacterium tuberculosis and / or non-tuberculous mycobacterium related disease of pharmaceutical composition in the use of purposes.The compound of the present application has excellent bactericidal effect to mycobacterium, and its specificity is strong, and there is no cross resistance with existing anti-tuberculosis drugs, provides breakthrough direction for drug-resistant tuberculosis treatment.(I)

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to the use of a compound in the preparation of mycobacterial inhibitors. Background Technology

[0002] Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mycobacterium tuberculosis). Mycobacterium tuberculosis , Mtb Tuberculosis (TB) is a chronic infectious disease that remains one of the deadliest infectious diseases in the world. According to the World Health Organization (WHO) Global Tuberculosis Report 2025, an estimated 10.7 million new cases of TB were diagnosed globally in 2024, with approximately 1.23 million deaths.

[0003] Drug-resistant tuberculosis (TB) also poses a serious public health challenge. In 2024, there were approximately 390,000 cases of multidrug-resistant (MDR / rifampicin-resistant) TB worldwide, with a resistance rate of 3.2% in newly diagnosed patients and as high as 16% in retreatment patients. The treatment period for drug-resistant TB (especially MDR-TB and extensively drug-resistant TB) can last as long as 18-24 months, which not only imposes a heavy economic and lifestyle burden on patients but also further exacerbates the spread of drug-resistant strains due to poor adherence.

[0004] The limitations of existing drugs make it imperative to develop novel anti-tuberculosis drugs with entirely new mechanisms of action, high efficacy, low toxicity, and the ability to overcome existing drug resistance.

[0005] DprE1 (Decaprenylphosphoryl-β-D-ribose 2′-epimerase 1) is a key enzyme in the synthesis of the cell wall of Mycobacterium tuberculosis. DprE1 and its counterpart DprE2 co-catalyze the epimerization of decaprenylphosphoryl-β-D-ribose (DPR) to decaprenylphosphoryl-β-D-arabinose (DPA), the sole arabinose donor precursor for the synthesis of arabinogalactan and lipoarabinomannan. Arabinogalactan is an essential component for the structural integrity of the mycobacterial cell wall; inhibiting DprE1 blocks cell wall synthesis, thereby killing Mycobacterium tuberculosis. Due to its high specificity within the Mycobacterium genus and the absence of homologous enzymes in mammalian cells, DprE1 has become a popular target for anti-tuberculosis drug development.

[0006] Several DprE1 inhibitors have entered clinical trials, including covalent inhibitors BTZ043 and PBTZ169, and non-covalent inhibitors TBA-7371 and OPC-167832. Despite this, no new anti-tuberculosis drugs targeting DprE1 have been officially approved for marketing globally, and with the emergence of resistance to novel drugs such as bedaquiline, drug-resistant tuberculosis is entering a new and dangerous phase. Therefore, developing novel DprE1 inhibitors with novel structures, excellent activity, and good safety profiles has significant clinical and market value.

[0007] In summary, there is an urgent need in this field to develop DprE1 inhibitors with high safety and efficacy to specifically inhibit mycobacteria and thereby treat mycobacterial-related diseases. Summary of the Invention

[0008] The purpose of this invention is to provide a novel mycobacterial inhibitor targeting DprE1, a key enzyme in mycobacterial cell wall synthesis.

[0009] In a first aspect, the present invention provides the use of a compound of formula (I) and a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and / or prevention of diseases associated with Mycobacterium tuberculosis and / or non-tuberculous mycobacteria. (I).

[0010] In another preferred embodiment, the nontuberculous mycobacteria include Mycobacterium abscessus and Mycobacterium smegmatis.

[0011] In a preferred embodiment, the disease associated with Mycobacterium tuberculosis is tuberculosis; the disease associated with nontuberculous mycobacteria is nontuberculous mycobacterial disease. Preferably, the tuberculosis is selected from the group consisting of: pulmonary tuberculosis, renal tuberculosis, bladder tuberculosis, reproductive system tuberculosis, intestinal tuberculosis, tuberculous peritonitis, bone and joint tuberculosis, tuberculous meningitis, lymph node tuberculosis, cutaneous tuberculosis, and hematogenous disseminated tuberculosis; The nontuberculous mycobacterial diseases mentioned are selected from the following group: lung infections, skin and soft tissue infections, and lymphadenitis.

[0012] In a preferred embodiment, the compound reduces the viable count of Mycobacterium tuberculosis and / or non-tuberculous mycobacteria by ≥1.5 log within 9 days (e.g., 7, 6, 5, 4, 3, or 2 days) at a concentration of 2-10 × MIC. 10 Preferably ≥2 log 10 More preferably ≥2.5 log 10 .

[0013] In a preferred embodiment, the tuberculous mycobacteria and / or nontuberculous mycobacteria are standard strains.

[0014] In a preferred embodiment, the compound reduces the viable count of standard strains of Mycobacterium tuberculosis and / or non-tuberculous mycobacteria by ≥1.5 log₂ / ₅ within 9 days (e.g., 7, 6, 5, 4, 3, or 2 days) at a concentration of 2-10 × MIC. 10 Preferably ≥2log 10 More preferably ≥2.5 log 10 .

[0015] In another preferred embodiment, the compound reduces the viable count of a standard strain of Mycobacterium tuberculosis by ≥3 log₂ within 9 days (e.g., 7, 6, 5, 4, 3, or 2 days) at a concentration of 2×MIC. 10 Preferably ≥3.5 log 10 More preferably ≥4log 10 .

[0016] In another preferred embodiment, the compound reduces the viable count of a standard strain of Mycobacterium tuberculosis by ≥3 log₂ within 9 days (e.g., 7, 6, 5, 4, 3, or 2 days) at a concentration of 10 × MIC. 10 Preferably ≥3.5 log 10 More preferably ≥4log 10 The optimal choice is ≥5 log 10 The optimal value is ≥5.5 log. 10 .

[0017] In another preferred embodiment, the standard strain of Mycobacterium tuberculosis is H37Rv.

[0018] In another preferred embodiment, the compound reduces the viable count of a standard strain of nontuberculous mycobacteria by ≥3 log within 9 days (e.g., 7, 6, 5, 4, 3, or 2 days) at a concentration of 2-10 × MIC. 10 .

[0019] In another preferred embodiment, the compound reduces the viable count of a standard strain of nontuberculous mycobacteria by ≥3 log at a concentration of 2×MIC for 9 days (e.g., 7, 6, 5, 4, 3, or 2 days). 10 Preferably ≥3.5 log 10 More preferably ≥4log 10 The optimal choice is ≥5 log 10 The optimal value is ≥5.5 log. 10 .

[0020] In another preferred embodiment, the compound reduces the viable count of a standard strain of nontuberculous mycobacteria by ≥3 log at a concentration of 10×MIC for 9 days (e.g., 7, 6, 5, 4, 3, or 2 days). 10 Preferably ≥3.5 log 10 More preferably ≥4log 10 The optimal choice is ≥5 log 10 The optimal value is ≥5.5 log. 10 .

[0021] In another preferred embodiment, the standard strain of the nontuberculous mycobacterium is ATCC 19977.

[0022] In a preferred embodiment, the compound has no antibacterial activity (MIC) against Salmonella, Enterobacter cloacae, and / or Klebsiella pneumoniae. 90 >1000 μM).

[0023] In another preferred embodiment, the compound exhibits an antimicrobial MIC against Mycobacterium tuberculosis and / or non-tuberculous mycobacteria. 90 The range is 30~260 μM, for example 31.25, 62.5, 125 or 250 μM.

[0024] In another preferred embodiment, the compound exhibits an antimicrobial MIC against Mycobacterium tuberculosis and / or Mycobacterium abscessus. 90 The range is 30~260 μM, for example 31.25, 62.5, 125 or 250 μM.

[0025] In another preferred embodiment, the compound inhibits the activity of DprE1.

[0026] In another preferred embodiment, the compound inhibits the production of mutant drug-resistant mycobacterial strains.

[0027] In a preferred embodiment, the drug is a pharmaceutical composition that further includes other anti-tuberculosis mycobacterial drugs and / or other anti-nontuberculosis mycobacterial drugs.

[0028] In a preferred embodiment, the other anti-tuberculosis mycobacterial drugs are selected from the group consisting of: rifampin, isoniazid, pyrazinamide, ethambutol, streptomycin, ethionamide, para-aminosalicylic acid, capreomycin, kanamycin, ofloxacin, amikacin, cycloserine, bedaquiline, diramani, or combinations thereof; The other anti-nontuberculous mycobacterial drugs mentioned are selected from the group consisting of: amikacin, clofazimine, azithromycin, clarithromycin, cefoxitin, moxifloxacin, ciprofloxacin, imipenem, meropenem, or combinations thereof.

[0029] In a preferred embodiment, the pharmaceutical composition further includes a pharmaceutically acceptable carrier, excipient, or excipient.

[0030] In another preferred embodiment, the carrier is selected from the group consisting of: sustained-release agents, excipients, fillers, diluents, binders, wetting agents, disintegrants, absorption promoters, adsorbent carriers, surfactants, or lubricants.

[0031] In another preferred embodiment, the dosage form of the pharmaceutical composition is selected from the group consisting of tablets, capsules, granules, pills, powders, solutions, suspensions, emulsions, liposomes, transdermal preparations, and suppositories, or combinations thereof.

[0032] In another preferred embodiment, the pharmaceutical composition is administered by a method of administration selected from the group consisting of oral administration, injection administration, cavity administration, or respiratory administration.

[0033] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0034] Figure 1 The compound ARQ-092 was shown to be effective for... Mtb The bactericidal ability, CFU represents the number of live bacteria.

[0035] Figure 2 The compound ARQ-092 was shown to have bactericidal activity against Mycobacterium abscessus.

[0036] Figure 3 The effects of compound ARQ-092 in combination with clinical anti-tuberculosis drugs (RIF, INH, or STR) were demonstrated. Mtb Its bactericidal ability.

[0037] Figure 4 The in vivo bactericidal effect of ARQ-092, used alone or in combination with RIF, was demonstrated. Detailed Implementation

[0038] Through long-term and in-depth research and extensive screening, the inventors have developed a novel mycobacterial inhibitor targeting DprE1, a key enzyme in the mycobacterial cell wall synthesis pathway. Using structure-based virtual screening and drug susceptibility testing with standard and clinical strains, the inventors obtained a compound that specifically targets mycobacteria and exhibits significant antibacterial effects. This compound demonstrates excellent in vitro and in vivo bactericidal activity and shows no cross-resistance with existing anti-tuberculosis drugs. When used in combination with first-line anti-tuberculosis drugs, it can further enhance bactericidal activity and inhibit the emergence of drug-resistant mutants. Based on these findings, the inventors have completed this invention.

[0039] the term To facilitate a clearer understanding of this disclosure, certain terms are first defined. As used herein, unless otherwise expressly specified herein, each of the following terms shall have the meaning given below. Other definitions are set forth throughout the application.

[0040] Active ingredients As used herein, “compound of the present invention” means a compound of formula (I), and also includes its stereoisomers, its optical isomers, its pharmaceutically acceptable salts, its crystal forms, its isotopic derivatives, its prodrugs, its metabolites, its solvates or hydrates thereof.

[0041] Unless otherwise specified, the structural formulas described in this invention are intended to include all stereoisomers (such as cis-trans isomers, enantiomers, diastereomers, and conformational isomers): R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, cis-trans isomers of cycloalkanes, etc. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, or conformational isomers, is within the scope of this invention.

[0042] The compounds of this invention may contain cis-trans isomers, one or more chiral carbon atoms, and thus can produce cis-trans isomers, chiral isomers, enantiomers, diastereomers, and other combinations of stereoisomers. Cis-trans isomerism refers to the diastereomeric phenomenon in which different functional groups in a compound molecule are arranged differently in space due to a restrictive factor that allows for free rotation. This restrictive factor is generally caused by non-rotating functional groups in the structure of organic compounds, such as C=C double bonds, C=N double bonds, C=S double bonds, N=N double bonds, heterocycles, or cycloalkanes. Organic molecules containing such isomers, such as alkenes, azo compounds, and cycloalkanes, are considered cis-trans isomers. Cis refers to the same ligands being in adjacent positions, generally denoted by "cis" or "cis-"; trans refers to the same ligands being in diagonal positions, generally denoted by "trans" or "trans-". Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. This invention aims to include all possible isomers, their racemic and optically pure forms. The compounds of this invention can be prepared using racemic, cis-trans, chiral, diastereomer, or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0043] Conventional techniques for preparing / separating individual optical isomers (i.e., cis-trans isomers and chiral isomers) include chiral synthesis from suitable cis-trans precursors or optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography.

[0044] To design the synthesis of a specific stereoisomer of the compound of this invention, it can be prepared asymmetrically or derivatized with a chiral auxiliary. The resulting stereo mixture is then separated, and the chiral auxiliary is removed to obtain pure cis-trans monomers, chiral monomers, or mixed stereoisomers. If the molecule contains a cis-trans isomer center, it can be purified by column chromatography (normal-phase silica gel column or reverse-phase high-performance liquid chromatography) to obtain pure cis or trans products. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomeric salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain pure enantiomers.

[0045] This invention also includes isotopically labeled compounds (i.e., isotopic derivatives), equivalent to the original compounds disclosed herein. However, it is common practice for one or more atoms to be substituted with atoms of different atomic weights or mass numbers. Examples of isotopes in the isotopic derivatives of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2H, 3H, 13C, 11C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Isotopic derivatives of the compounds of this invention are all within the scope of protection of this invention. In this document, 3H-labeled and 14C-labeled compounds are useful in tissue distribution experiments of drugs and substrates. Tritium (i.e., 3H) and carbon-14 (i.e., 14C)-labeled compounds are relatively easy to prepare and detect, and are the preferred isotopes. Furthermore, heavier isotope substitutions, such as deuterium (2H), are preferred in certain cases due to their excellent metabolic stability, which offers advantages in some therapies, such as increasing half-life or reducing dosage in vivo. Isotope-labeled compounds can be prepared using general methods by replacing non-isotopic reagents with readily available isotope-labeling reagents, according to the schemes disclosed in the examples.

[0046] As used herein, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0047] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionates, hexanoates, octanoates, decanoates, undecenoates, glycolates, gluconates, lactates, sebates, adipates, glutarate, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbic acid salts, salicylates, 4-aminosalicylic acid salts, and naphthalene disulfonates. These salts can be prepared using methods known in this field.

[0048] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0049] Metabolites of the compound represented by formula (I) and its pharmaceutically acceptable salts, as well as prodrugs that can be converted in vivo into the compound represented by formula (I) and its pharmaceutically acceptable salts, are also included within the scope of protection of this invention.

[0050] As used herein, the term "solvent" refers to a complex of a compound of formula (I) coordinated with a solvent molecule in a specific ratio.

[0051] As used herein, the term "hydrate" refers to a complex of the compound represented by formula (I) coordinated with water molecules in a specific ratio.

[0052] As described herein, the compounds of the present invention can be substituted with any number of substituents or functional groups to broaden their scope. Generally, the term "substitution" refers to replacing a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are substituted by multiple specific substituents, each position of the substituent can be the same or different. The term "substitution" as used herein includes all permissible organic group substitutions. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic groups. As described herein, heteroatomic nitrogen may be supplemented with a hydrogen substituent or any permissible organic group described above to complete its valence state. Furthermore, the present invention is not intended to limit permissible substituted organic groups in any way. The present invention considers the combination of substituents and variable groups to be beneficial in the treatment of diseases in the form of stable compounds. The term "stable" here means having a stable compound that, when tested over a sufficiently long period, maintains sufficient integrity of the compound structure, preferably remaining effective for a sufficiently long period, and is used herein for the purposes described above.

[0053] Pharmaceutical Compositions and Administration Because the compounds of this invention can kill both Mycobacterium tuberculosis and non-tuberculous mycobacteria, and are used to treat diseases such as pulmonary tuberculosis, renal tuberculosis, bladder tuberculosis, and lung infections, the compounds of this invention, their pharmaceutically acceptable salts, crystal forms, solvates, or hydrates thereof, as well as pharmaceutical compositions containing the compounds of this invention as the main active ingredient, can be used to prevent and / or treat (stabilize, alleviate, or cure) diseases associated with Mycobacterium tuberculosis and / or non-tuberculous mycobacteria (pulmonary tuberculosis, renal tuberculosis, bladder tuberculosis, lung infections, etc.).

[0054] The pharmaceutical compositions of the present invention comprise the compound of the present invention within a safe and effective range and a pharmaceutically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0055] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0056] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include, but are not limited to, oral administration and parenteral administration (intravenous, intramuscular, or subcutaneous).

[0057] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0058] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0059] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0060] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0061] In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0062] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0063] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as needed.

[0064] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0065] When administered in combination, the pharmaceutical composition further comprises one or more (two, three, four, or more) other pharmaceutically acceptable compounds. One or more (two, three, four, or more) of these other pharmaceutically acceptable compounds may be used simultaneously, separately, or sequentially with the compounds of the present invention for the prevention and / or treatment of diseases associated with Mycobacterium tuberculosis.

[0066] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to the mammal (such as a human) requiring treatment. The dosage at the time of administration is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1-2000 mg, preferably 20-500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0067] The main advantages of this invention include: (1) This invention has discovered a novel mycobacterial (including tuberculous mycobacterium and non-tuberculous mycobacteria) inhibitor, providing a theoretical basis for drug development based on the mycobacterial cell wall synthesis pathway.

[0068] (2) The compounds of the present invention have excellent in vitro and in vivo bactericidal effects against mycobacteria, and are highly specific.

[0069] (3) The compounds of the present invention can inhibit the production of mutant drug-resistant mycobacteria, providing a breakthrough direction for the treatment of drug-resistant tuberculosis.

[0070] (4) The compounds of the present invention can be used in combination with clinical anti-tuberculosis drugs to further improve the bactericidal effect, which provides a new strategy for the treatment of mycobacterial-related diseases.

[0071] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0072] Example 1: 1. Screening of DprE1 inhibitors Targeting DprE1, a key enzyme in the mycolic acid synthesis pathway of mycobacteria, a number of novel mycobacterial inhibitors were identified through structural virtual screening from drugs already approved by the US FDA for the treatment of other diseases and compounds undergoing preclinical research. Mtb Drug susceptibility testing was performed on the relevant compounds in H37Rv. The results are shown in Table 1.

[0073] Table 1. Screening of DprE1 inhibitors As shown in Table 1, among the 10 DprE1 inhibitors screened virtually, compound 3... (ARQ-092), 8 9 For Mycobacterium tuberculosis ( Mtb Minimum inhibitory concentration (MIC) of H37Rv 90 The concentrations were relatively low, ranging from 31.25 to 62.5 μM, with compound 3 being the most abundant. Minimum inhibitory concentration (MIC) of (ARQ-092) 90The lowest concentration was 31.25 μM, which is close to the minimum inhibitory concentration range (0.1-10 μM) of first-line drugs for tuberculosis treatment.

[0074] Example 2: ARQ-092 specifically targets mycobacteria To determine whether ARQ-092 specifically targets mycobacteria, based on Example 1, the activity of the compound ARQ-092, which has a good antibacterial effect against mycobacteria, in Mycobacterium abscessus (… M. abscessus ATCC 19977 ), Mycobacterium smegmatis ( M. smegmatis mc 2 155 ), in Salmonella ( Salmonella Typhimurium, Enterobacter cloacae ( Enterobacter cloacae ) and Klebsiella pneumoniae ( Klebsiella pneumoniae The minimum inhibitory concentration (MIC) in ) 90 The results are shown in Table 2.

[0075] Table 2. Inhibitory effects of ARQ-092 on other strains Table 2 shows that compound ARQ-092 is effective against Mycobacterium abscessus (… M. abscessus ATCC 19977 ) and Mycobacterium smegma ( M. smegmatis mc 2 155 It has a significant inhibitory effect, with a minimum inhibitory concentration (MIC). 90 The concentrations were 80 μM and 45 μM, respectively. Compound ARQ-092 was effective against Salmonella (…). Salmonella Typhimurium, Enterobacter cloacae ( Enterobacter cloacae ) and Klebsiella pneumoniae ( Klebsiella pneumoniae None of them showed any inhibitory effect. This result further confirms that compound ARQ-092 can specifically target mycobacteria.

[0076] Example 3: ARQ-092 has in vitro bactericidal activity To determine whether compound ARQ-092 possesses in vitro bactericidal activity, i.e., whether it is a bactericide (reduced viable bacterial count) rather than a bacteriostatic agent (virulent bacterial count remains essentially unchanged), the effects of ARQ-092 on laboratory standard strains of Mycobacterium tuberculosis were measured at compound concentrations of 2×MIC and 10×MIC. Mtb The effects of H37Rv and the standard strain of Mycobacterium abscessus (ATCC 19977) on the viable count (CFU) of Mycobacterium tuberculosis (H37Rv) and Mycobacterium abscessus (ATCC 19977) are shown below. Figure 1 and Figure 2 As shown.

[0077] Figure 1 The results showed that compound ARQ-092 significantly reduced the number of viable Mycobacterium tuberculosis bacteria at both 2×MIC and 10×MIC concentrations, indicating that compound ARQ-092 is a bactericidal agent capable of effectively eliminating Mycobacterium tuberculosis in vitro, and its bactericidal effect at 10×MIC concentration is superior to that of the first-line anti-tuberculosis drug isoniazid (INH). Furthermore, with increasing experimental time, the number of viable Mycobacterium tuberculosis bacteria continuously decreased until a plateau was reached when using compound ARQ-092, while the number of viable Mycobacterium tuberculosis bacteria showed a trend of first decreasing and then increasing when using isoniazid (INH). This indicates that compound ARQ-092 not only has good bactericidal properties but also a low risk of drug resistance.

[0078] Figure 2 The results showed that compound ARQ-092 significantly reduced the number of viable Mycobacterium abscessus at both 2×MIC and 10×MIC concentrations, indicating that compound ARQ-092 is a bactericide that can effectively eliminate Mycobacterium abscessus in vitro, and its bactericidal effect is superior to that of amikacin (AMK), a commonly used anti-abscessus drug in clinical practice.

[0079] Example 4: ARQ-092 can enhance the bactericidal activity of clinical anti-tuberculosis drugs. To investigate the efficacy of compound ARQ-092 in combination with the clinical anti-tuberculosis drugs INH, RIF, and streptomycin (STR), the effects of compound ARQ-092 on standard strains of Mycobacterium tuberculosis when used in combination with first-line anti-tuberculosis drugs INH, RIF, and streptomycin (STR) were determined. Mtb The bactericidal ability of H37Rv was as follows: Figure 3 As shown.

[0080] Figure 3 The results showed that ARQ-092, when used in combination with INH, RIF, and streptomycin (STR), could more rapidly reduce the number of viable Mycobacterium tuberculosis, improve the bactericidal activity of clinical anti-tuberculosis drugs, and effectively eliminate [the bacteria]. Mtb No drug-resistant mutants were subsequently observed. These results suggest that compound ARQ-092 can be used as a combination drug with first-line anti-tuberculosis drugs in clinical practice, which may help improve clinical efficacy and reduce the emergence of drug-resistant mutant strains.

[0081] Example 5: In vivo efficacy detection of ARQ-092 ARQ-092, which exhibits good in vitro antibacterial activity, was further investigated in mice. Mtb The therapeutic effect was evaluated using an infection treatment model. MtbThe mice used as an infection treatment model were divided into four groups: control group, ARQ-092 monotherapy group, RIF monotherapy group, and ARQ-092+RIF combination therapy group. Each experimental group was administered the drugs by gavage for 2 weeks. The dosages of ARQ-092 and RIF were 100 mg / kg and 10 mg / kg, respectively.

[0082] The results are as follows Figure 4 As shown, compared with the untreated control group, ARQ-092 effectively reduced Mycobacterium tuberculosis in mice, and the therapeutic level was comparable to that of RIF. Furthermore, the combined use of ARQ-092 and RIF resulted in better therapeutic effects, with significantly lower viable bacterial counts compared to either ARQ-092 or RIF alone.

[0083] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, characterized in that, Used to prepare medicines for the treatment and / or prevention of diseases associated with Mycobacterium tuberculosis and / or non-tuberculous mycobacteria; (I)。 2. The use as described in claim 1, characterized in that, The diseases associated with Mycobacterium tuberculosis are tuberculosis; the diseases associated with nontuberculous mycobacteria are nontuberculous mycobacterial diseases. The tuberculosis mentioned therein is selected from the following group: pulmonary tuberculosis, renal tuberculosis, bladder tuberculosis, reproductive system tuberculosis, intestinal tuberculosis, tuberculous peritonitis, bone and joint tuberculosis, tuberculous meningitis, lymph node tuberculosis, cutaneous tuberculosis, and hematogenous disseminated tuberculosis; The nontuberculous mycobacterial diseases mentioned are selected from the following group: lung infections, skin and soft tissue infections, and lymphadenitis.

3. The use as described in claim 1, characterized in that, The compound reduces the viable count of Mycobacterium tuberculosis and / or non-tuberculous mycobacteria by ≥1.5 log within 9 days at a concentration of 2-10×MIC. 10 .

4. The use as described in claim 1, characterized in that, The compound described above has no antibacterial activity against Salmonella, Enterobacter cloacae, and / or Klebsiella pneumoniae, and its antibacterial MIC is [not specified]. 90 >1000 μM.

5. The use as described in claim 1, characterized in that, The compound has an antimicrobial MIC against Mycobacterium tuberculosis and / or non-tuberculous mycobacteria. 90 The range is 30~260 μM.

6. The use as described in claim 1, characterized in that, The tuberculous mycobacteria and / or non-tuberculous mycobacteria mentioned are standard strains.

7. The use as described in claim 1, characterized in that, The compound inhibits the activity of the DprE1 enzyme.

8. The use as described in claim 1, characterized in that, The compound inhibits the production of mutant drug-resistant mycobacterial strains.

9. The use as described in claim 1, characterized in that, The drug is a pharmaceutical composition, which further includes other anti-tuberculosis mycobacterial drugs and / or other anti-nontuberculosis mycobacterial drugs.

10. The use as described in claim 9, characterized in that, The other anti-tuberculosis drugs mentioned are selected from the group consisting of: rifampin, isoniazid, pyrazinamide, ethambutol, streptomycin, ethionamide, para-aminosalicylic acid, capreomycin, kanamycin, ofloxacin, amikacin, cycloserine, bedaquiline, diramani, or combinations thereof; The other anti-nontuberculous mycobacterial drugs mentioned are selected from the group consisting of: amikacin, clofazimine, azithromycin, clarithromycin, cefoxitin, moxifloxacin, ciprofloxacin, imipenem, meropenem, or combinations thereof.

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