Methods and uses of boron compounds for treating nontuberculous mycobacterial infections, and pharmaceutical compositions for treating the same diseases.

Abstract

The present invention provides an organoboron compound of formula I, or a salt thereof, and a pharmaceutical composition thereof, and the use of the organoboron compound and the pharmaceutical composition for treating nontuberculous mycobacterial infections.

Description

Technical Field

[0001] This application provides organoboron compounds for treating nontuberculous mycobacterial infections and pharmaceutical compositions for treating the same diseases. Background Technology

[0002] Nontuberculous mycobacterial (NTM) lung disease (NTM-PD) is a serious, progressive disease caused by certain mycobacteria that may require complex treatment for more than 12 months using multiple antimycobacterial drugs or combinations of such antibiotics (e.g., Daley et al., Clin. Infect. Dis. 2020 Aug 15; 71(4): 905–913). NTM refers to all mycobacterial species except Mycobacterium tuberculosis complex and Mycobacterium leprae. To date, more than 190 NTM bacteria have been identified, most of which are parasitic, but only a few are conditional pathogens that cause human infection. However, in recent years, the incidence and prevalence of NTM disease have increased globally with the increase in patients with acquired immunodeficiency syndrome and immunosuppressed populations. In addition, antibiotic resistance to NTM is increasing. Resistance rates are particularly high in relapsed patients, which can pose challenges to clinical treatment. Due to inadequate treatment and high treatment failure rates, the mortality rate of NTM-PD is higher than that of Mycobacterium tuberculosis (MTB).

[0003] Based on growth temperature, growth rate, colony morphology, and the relationship between pigment production and light response, the NTM flora was divided into four groups using the Runyon classification method. The first three groups are slow-growing mycobacteria, while the fourth group is fast-growing mycobacteria. Group I consists of photochromogenic bacteria, mainly composed of *Mycobacterium kansasense*, *Mycobacterium marineum*, and *Mycobacterium simianum*, while Group II consists of dark-growing mycobacteria, mainly composed of *Mycobacterium scrofula*, *Mycobacterium Gordonum*, and *Mycobacterium surugani*. Group III consists of non-photochromogenic bacteria, including the Mycobacterium avium complex (MAC), *Mycobacterium haemophilus*, *Mycobacterium ulcerans*, *Mycobacterium bufo*, *Mycobacterium marmosetum*, *Mycobacterium terrestrialum*, and *Mycobacterium gasasteri.* Group IV consists of rapidly growing mycobacteria (RGM), including the Mycobacterium abscess complex (MABC), *Mycobacterium occulta*, *Mycobacterium guilloché*, *Mycobacterium margaritiferum*, exogenous mycobacteria, *Mycobacterium smegmatis*, and *Mycobacterium bovis*.

[0004] Because NTMs comprise a group of bacteria that cause serious lung infections, treatment is often complex and requires long-term therapy. Furthermore, the available treatments and regimens are limited because most NTMs are inherently resistant to standard anti-tuberculosis drugs, and different species exhibit different resistance phenotypes.

[0005] For many patients with bacterial infections requiring long-term antibiotic treatment, oral formulations are the most suitable option. Compared to intravenous administration, the advantages of oral administration include the absence of catheter-related infections, lower drug costs, and reduced hospital costs (e.g., the need for healthcare professionals and equipment to administer antibiotics intravenously). Oral therapy is also particularly important for ensuring adherence in patients requiring long-term treatment. For example, treatment for Mycobacterium avium and Mycobacterium abscessis infections typically takes several months.

[0006] Therefore, new therapeutic agents are needed that have novel modes of action, effective activity against drug-resistant isolates, few side effects, and convenient oral administration. Summary of the Invention

[0007] This application provides boron compounds and pharmaceutical compositions thereof for treating nontuberculous mycobacterial infections.

[0008] The boron organic compounds shown below belong to a class of antibiotics with high antibacterial activity, including (anti) Gram-negative and Gram-positive microorganisms, as well as mycobacteria.

[0009]

[0010] As described in U.S. Patent 8,530,452, this tricyclic boron compound is particularly active against Gram-negative bacteria such as *Pseudomonas aeruginosa*, *Acinetobacter baumannii*, *Escherichia coli*, and *Klebsiella pneumoniae*. However, the activity of this compound against mycobacteria has not been reported. In fact, the cell envelope of mycobacteria is very different from that of typical Gram-positive and Gram-negative bacteria, and it cannot be assumed that antibiotics are effective against both Gram-negative bacteria and mycobacteria. As described in this application, the salt form of this boron compound has been found to unexpectedly exhibit activity against mycobacteria. Furthermore, as described below, this compound exhibits only moderate oral bioavailability. In contrast, certain prodrugs described in this application exhibit enhanced oral bioavailability and improved systemic exposure, which is crucial for pathogen eradication. Certain compounds described in this application exhibit an important and advantageous dual therapeutic property: efficacy against mycobacteria and oral bioavailability. This represents a significant advancement compared to most antibiotics, such as cephalosporins, which can only be administered intravenously in hospitals.

[0011] In one aspect, this application provides a method for treating nontuberculous mycobacterial infections, comprising administering a therapeutically effective amount of a compound of formula (I):

[0012]

[0013] Or its pharmaceutically acceptable salts may be given to mammals in need of treatment;

[0014] in:

[0015] R 1 Selected from H, C 1-24 Alkyl-C(=O)-, C 1-24 Alkoxy-C(=O)-, C 3-7 Cycloalkyl-C(=O)-, heteroalkyl-C(=O)-, aryl-C(=O)-, heteroaryl-C(=O)- and (5-methyl-1,3-dioxacyclopenten-2-one-4-yl)methyl; and R 2 Selected from C 1-24 Alkyl-C(=O)-, C 1-24 Alkoxy-C(=O)-, C 3-7 Cycloalkyl-C(=O)-, heteroalkyl-C(=O)-, aryl-C(=O)-, heteroaryl-C(=O)- and (5-methyl-1,3-dioxacyclopenten-2-one-4-yl)methyl; or R 1 and R 2 Together they form a heterocyclic group, wherein the heterocyclic group is selected from 1,3-dioxane, 2-C 1-6 Alkyl-1,3-dioxane, 2,2-di(C 1-6 alkyl)-1,3-dioxane, 2-methyl-1,3-dioxane, 2-aryl-1,3-dioxane, 2-(2-carboxyphenyl)-1,3-dioxane, 2-(4-carboxyphenyl)-1,3-dioxane and 2-C 1-6 Alkyl OC(=O)-1,3-dioxane; each optionally dilated by one to four R 3 replace;

[0016] R 3 Each time it appears, it is independently selected from groups including halogens, hydroxyl groups, C1-C6 alkyl groups, C3-C6 cycloalkyl groups, C1-C6 alkoxy groups, aryl groups, and heteroaryl groups; or

[0017] When bonded to adjacent carbons, the two Rs 3 The groups together with the carbons they are attached to form fused C3-C6 cycloalkyl groups; or when attached to the same carbon, the two R groups form fused C3-C6 cycloalkyl groups. 3 The groups, together with the carbon atoms they are attached to, form spiroC3-C6 cycloalkyl groups;

[0018] Each R 3 Optionally substituted independently with 1-3 halogens, hydroxyl groups, or C1-C3 alkyl groups; or

[0019] The hydrogen atom is absent in the -OH group bonded to the boron atom, and R in the compound of formula I. 2The oxygen atom bonded to the boron atom forms a compound of formula II. Therefore, in another aspect, this application provides a method for treating nontuberculous mycobacterial infections, comprising administering a therapeutically effective amount of a compound of formula II:

[0020]

[0021] Or its pharmaceutically acceptable salts may be given to mammals in need of treatment;

[0022] in:

[0023] R 1 Selected from H, C 1-24 Alkyl-C(=O)-, C 1-24 Alkoxy-C(=O)-, C 3-7 Cycloalkyl-C(=O)-, heteroalkyl-C(=O)-, aryl-C(=O)-, heteroaryl-C(=O)- and (5-methyl-1,3-dioxacyclopenten-2-one-4-yl)methyl.

[0024] In another aspect, this application provides the use of compounds of formula I or II, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for treating nontuberculous mycobacterial infections.

[0025] In another aspect, this application provides a pharmaceutical composition comprising a compound of formula I or formula II or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier for treating nontuberculous mycobacterial infections.

[0026] Nontuberculous mycobacteria include, but are not limited to: Mycobacterium scrofulaceum, Mycobacterium gordonae, Mycobacterium avium, Mycobacterium abscessus, Mycobacterium intercelleulare, Mycobacterium fortuitum, Mycobacterium peregrinum, Mycobacterium smegmatis, and Mycobacterium massiliense. Attached Figure Description

[0027] Figure 1This is a graph showing the colony-forming unit (CFU) counts in the lungs of mice 14 days after administration of the compound of Example 4 described in Example 7 (10 mg / kg subcutaneously, daily), GSK656 (100 mg / kg subcutaneously, daily), linezolid (100 mg / kg orally, daily), or clarithromycin (200 mg / kg orally, daily).

[0028] Figure 2A These are images of H&E-stained tissue sections from mice that were not infected with Mycobacterium abscessus CIP108297 in the following mouse lung infection model of Mycobacterium abscessus.

[0029] Figure 2B The images are H&E stained tissue sections from mice infected with Mycobacterium abscessus CIP108297 but untreated in the following mouse lung infection model.

[0030] Figure 2C Images are H&E-stained tissue sections of mice infected with Mycobacterium abscessus CIP108297 and treated with the compound of Example 4 14 days after lung infection in the mouse model described below. Detailed Implementation

[0031] Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0032] The terms alkyl, alkenyl, etc., refer to straight-chain and branched groups, but references to a single group such as "propyl" only include the straight-chain group, while references to branched isomers such as "isopropyl" only include the branched isomer. Alkyl, alkenyl, etc., groups can optionally be replaced by one, two, or three groups selected from halogens, aryl groups, and hexyl groups. 1 Or Het 2 Substituents are substituted. Representative examples include, but are not limited to, difluoromethyl, 2-fluoroethyl, trifluoroethyl, -CH=CH-aryl, -CH=CH-Het. 1 , -CH2-phenyl, etc.

[0033] The term "cycloalkyl" refers to a cyclic, saturated, monovalent hydrocarbon group having 3-6 carbon atoms, such as cyclopropyl and cyclohexyl. The cycloalkyl group may optionally be surrounded by one, two, or three groups selected from halogens, aryl groups, and hexyl groups. 1 Or Het 2 Substituents are substituted.

[0034] The term "heteroalkyl" refers to an alkyl or cycloalkyl group as defined above, having a component selected from N, O, or S(O). n Substituents of heteroatoms, where n is an integer from 0 to 2, including hydroxyl (OH), C 1-4 Alkoxy, amino, and thio (-SH) substituents, etc. Representative substituents include -NR.a R b -OR a or -S(O) n -R c , where R a It is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, or -COR (where R is C) 1-4 Alkyl); R b It is H, C 1-4 Alkyl group, -SO2R (where R is C) 1-4 Alkyl or C 1-4 Hydroxyalkyl), -SO2NRR' (where R and R' are independently H or C) 1-4 Alkyl group, -CONR'R" (where R' and R" are independently H or C). 1-4 -alkyl); n is an integer from 0 to 2; and R c It is H, C 1-4 Alkyl, C 3-6 cycloalkyl, optionally substituted aryl or NR a R b , where R a and R b As defined above. Representative examples include, but are not limited to, 2-methoxyethyl (-CH2CH2OCH3), 2-hydroxyethyl (-CH2CH2OH), hydroxymethyl (-CH2OH), 2-aminoethyl (-CH2CH2NH2), 2-dimethylaminoethyl (-CH2CH2NHCH3), benzyloxymethyl, thiophene-2-ylthiomethyl, etc.

[0035] The term aryl refers to phenyl, biphenyl, or naphthyl, optionally substituted with 1 to 3 substituents, said substituents being independently selected from halogens, -C 1-4 Alkyl, -OH, -OC 1-4 Alkyl group, -S(O) n C 1-4 Alkyl (n is 0, 1 or 2), -C 1-4 Alkyl NH2, -NHC 1-4 Alkyl, -C(=O)H or -C=N-OR d (R d H or -C 1-4 alkyl).

[0036] Het 1 Each occurrence is independently a C-linked 5- or 6-membered heterocycle, containing 1 to 4 heteroatoms selected from O, N, and S. 2Each occurrence is independently an N-linked 5- or 6-membered heterocycle having 1-4 N atoms and optionally an O or S atom within the ring. "Optional" or "optionally" means that the event or condition subsequently described may but not necessarily occur, and the description includes instances where the event or condition occurs and instances where it does not occur. For example, "aryl group optionally mono- or di-substituted with an alkyl group" means that an alkyl group may but not necessarily be present, and the description includes cases where the aryl group is mono- or di-substituted with an alkyl group and cases where the aryl group is not substituted with an alkyl group.

[0037] "Pharmaceutically acceptable carrier" refers to a carrier that can be used to prepare a pharmaceutical composition, which is generally safe and non-toxic, and which has neither biological significance nor other undesirable content, including carriers that can be used in veterinary and human medicines. The term "pharmaceutically acceptable carrier" as used in the specification and claims includes one or more such carriers.

[0038] A "pharmaceutically acceptable salt" of a compound refers to a druggable salt that possesses the pharmacological activity required by the parent compound. Such salts include:

[0039] (1) Acid addition salts, forming with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentadienoic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-Hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-en-1-carboxylic acid, glucohepanoic acid, 4,4'-methylenebis(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mucoconic acid, etc.; or

[0040] (2) Salts formed when acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth ions or aluminum ions; or coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, glycerolamine, N-methylglucosamine, etc.

[0041] The term "tautomer" refers to two or more forms or isomers of an organic compound that can interconvert through a common chemical reaction called tautomerization, often similar to that described by Smith et al. in Advanced Organic Chemistry. 2001, 5th Ed. NY: Wiley Interscience., pp. 1218–1223. The concept of tautomerism is called tautomerism. Tautomerism can be accompanied by a change from a ring structure to an open structure, for example, as observed, the interconversion between the cyclic pyran form and the open-chain form of glucose via the formation and cleavage of CO bonds. The extent of tautomerism is often influenced by solvent effects, such as hydration with water and the acidity of the medium. The relevant processes for cyclic boron compounds may involve the formation and cleavage of BO bonds, as follows:

[0042]

[0043] The “treatment” of a disease includes:

[0044] (1) Disease prevention, that is, preventing the development of clinical symptoms of a disease in mammals that may be exposed to or susceptible to the disease but have not yet experienced or exhibited symptoms of the disease.

[0045] (2) Suppressing the disease, that is, preventing or reducing the development of the disease or its clinical symptoms, or

[0046] (3) Relieve disease, that is, cause the disease or its clinical symptoms to subside.

[0047] "Therapeutic effective dose" refers to the amount of a compound that is sufficient to affect the treatment of a disease when administered to a mammal. The "therapeutic effective dose" varies depending on the compound, the disease and its severity, and the age and weight of the mammal being treated.

[0048] "Prodrug" refers to any compound that releases an active parent drug in vivo when taken by a mammalian subject. The prodrugs of the compounds described in this application are prepared by modifying the functional groups present in the compounds described in this application so that the modification can be cleaved in vivo to release the parent compound. Prodrugs include the compounds described in this application, wherein the hydroxyl, thiol, amide, or amino groups in the compound are bound to any group that can be cleaved in vivo to regenerate free hydroxyl, amide, amino, or thiol groups, respectively.

[0049] "Patient" refers to an animal, such as a mammal, including non-primates (e.g., cattle, pigs, horses, cats, dogs, rats, and mice) and primates (e.g., monkeys, such as cynomolgus monkeys, chimpanzees, and humans); and, for example, a human. In some embodiments, the patient is a person.

[0050] Illustrative Examples

[0051] In one aspect, this application provides a method for treating nontuberculous mycobacterial infections, comprising administering a therapeutically effective amount of a compound of formula (I):

[0052]

[0053] Or its pharmaceutically acceptable salts may be given to patients in need of treatment;

[0054] in:

[0055] R 1 Selected from H, C 1-24 Alkyl-C(=O)-, C 1-24 Alkoxy-C(=O)-, C 3-7 Cycloalkyl-C(=O)-, heteroalkyl-C(=O)-, aryl-C(=O)-, heteroaryl-C(=O)- and (5-methyl-1,3-dioxacyclopenten-2-one-4-yl)methyl; and R 2 Selected from C 1-24 Alkyl-C(=O)-, C 1-24 Alkoxy-C(=O)-, C 3-7 Cycloalkyl-C(=O)-, heteroalkyl-C(=O)-, aryl-C(=O)-, heteroaryl-C(=O)- and (5-methyl-1,3-dioxacyclopenten-2-one-4-yl)methyl; or R 1 and R 2 Together they form a heterocyclic group, wherein the heterocyclic group is selected from 1,3-dioxane, 2-C 1-6 Alkyl-1,3-dioxane, 2,2-di(C 1-6 -alkyl)-1,3-dioxane, 2-methyl-1,3-dioxane, 2-aryl-1,3-dioxane, 2-(2-carboxyphenyl)-1,3-dioxane, 2-(4-carboxyphenyl)-1,3-dioxane and 2-C 1-6 -alkylOC(=O)-1,3-dioxane; each optionally separated by one to four R 3 replace;

[0056] R3, each time it appears, is independently selected from groups including halogens, hydroxyl groups, C1-C6 alkyl groups, C3-C6 cycloalkyl groups, C1-C6-alkoxy groups, aryl groups, and heteroaryl groups; or

[0057] When bonded to adjacent carbons, the two Rs 3 The groups together with the carbons they are attached to form fused C3-C6 cycloalkyl groups; or when attached to the same carbon, the two R groups form fused C3-C6 cycloalkyl groups. 3 The groups, together with the carbon atoms they are attached to, form spiroC3-C6 cycloalkyl groups;

[0058] Each R 3 Optionally substituted independently with 1-3 halogens, hydroxyl groups, or C1-C3 alkyl groups; or

[0059] The hydrogen atom in the -OH group bonded to the boron atom is absent, and R in the compound of formula I is also absent. 2 Together with oxygen atom bonded to boron, it forms a compound of formula II. Therefore, in another aspect, this application provides a method for treating nontuberculous mycobacterial infections, comprising administering a therapeutically effective amount of a compound of formula II:

[0060]

[0061] Or its pharmaceutically acceptable salts may be given to patients in need of treatment;

[0062] in:

[0063] R 1 Selected from H, C 1-24 Alkyl-C(=O)-, C 1-24 Alkoxy-C(=O)-, C 3-7 Cycloalkyl-C(=O)-, heteroalkyl-C(=O)-, aryl-C(=O)-, heteroaryl-C(=O)- and (5-methyl-1,3-dioxacyclopenten-2-one-4-yl)methyl.

[0064] In some implementations, a method of treating nontuberculous mycobacterial infections includes administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient requiring treatment, wherein R 1 It is C 1-4 Alkyl-C(=O)- and R 2 It is C 1-4 Alkyl-C(=O)-.

[0065] On the other hand, this application provides the use of compounds of formula I or II or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating nontuberculous mycobacterial infections.

[0066] Nontuberculous mycobacteria include, but are not limited to: Mycobacterium scrofula, Mycobacterium Gordon, Mycobacterium avium, Mycobacterium abscessus, intracellular mycobacteria, occasional mycobacteria, exogenous mycobacteria, Mycobacterium smegmatis, and Mycobacterium masei.

[0067] The compounds of Formula I or II may be administered in their free base form, or in the form of salts and / or hydrates. In some embodiments, the compounds of Formula I or II are administered in the form of their hydrochloride salts.

[0068] Compounds of Formula I or II, or pharmaceutically acceptable salts thereof, may be administered via a variety of routes of administration, including but not limited to those selected from oral, parenteral, intraperitoneal, intravenous, intraarterial, percutaneous, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, local, subcutaneous, intradiposally, intra-articular, intraperitoneal, and intrathecal routes. In one embodiment, administration is oral.

[0069] The amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, can be determined based on the severity of the disease, the response to the disease, any treatment-related toxicity, and / or the patient's age and health condition. In some embodiments, the amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is 10-1000 mg. In some embodiments, the amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is 100-600 mg. In some embodiments, the amount of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, is 200-400 mg.

[0070] Compounds of Formula I or II, or pharmaceutically acceptable salts thereof, may be administered once or more daily. In some embodiments, compounds of Formula I or II, or pharmaceutically acceptable salts thereof, are administered once daily in a single dose. In one embodiment, the compound is administered twice daily in a single dose. In one embodiment, the compound is administered twice daily in a single dose suitable for oral solid dosage forms.

[0071] On the other hand, this application provides the use of a compound of formula I or II, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating nontuberculous mycobacterial infections. Nontuberculous mycobacteria include, but are not limited to: Mycobacterium scrofula, Mycobacterium Gordonii, Mycobacterium avium, Mycobacterium abscessum, intracellular mycobacteria, occasional mycobacteria, exogenous mycobacteria, Mycobacterium smegmatis, and Mycobacterium masei.

[0072] In some embodiments, the pharmaceutical composition is a formulation suitable for oral administration, including but not limited to tablets, capsules, powders, granules, drops, pastes, and powders. In a preferred embodiment, tablets and capsules are used. Tablets may be ordinary tablets, dispersible tablets, effervescent tablets, sustained-release tablets, controlled-release tablets, or enteric-coated tablets, and capsules may be ordinary capsules, sustained-release capsules, controlled-release capsules, or enteric-coated capsules. The oral formulation can be prepared using conventional methods with pharmaceutically acceptable carriers known in the art. Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, etc. Fillers include starch, lactose, mannitol, microcrystalline cellulose, etc.; absorbents include calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents include water, ethanol, etc.; binders include hydroxypropyl methylcellulose, povidone, microcrystalline cellulose, etc.; disintegrants include cross-linked sodium carboxymethyl cellulose, cross-linked povidone, surfactants, low-substituted hydroxypropyl cellulose, etc.; lubricants include magnesium stearate, talc, polyethylene glycol, sodium dodecyl sulfate, talc, etc. Pharmaceutical excipients also include colorants, sweeteners, etc.

[0073] In one embodiment, the pharmaceutical composition is a solid dosage form suitable for oral administration. For example, the composition may be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or in a liquid medium), ointments containing, for example, up to 10% by weight of an active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In a particular embodiment, the pharmaceutical composition is a capsule.

[0074] When preparing formulations, it may be necessary to grind the active compound to provide a suitable particle size before combining it with other ingredients. If the active compound is substantially insoluble, it is typically ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size is typically adjusted by grinding to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0075] Examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, astragalus gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. Formulations may also include: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents. The compositions described in this application can be prepared using procedures known in the art to provide a rapid, sustained, or delayed release of the active ingredient after administration to a patient.

[0076] To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compounds described in this application. When these preformulation compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, allowing the composition to be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the types described above.

[0077] In one embodiment, a pharmaceutical composition for treating nontuberculous mycobacterial infections is formulated as a single-dose formulation. In one embodiment, the single-dose formulation comprises 10 mg to 1000 mg of a compound of formula I or II or a pharmaceutically acceptable salt thereof. In some embodiments, the single-dose formulation comprises 100 mg to 600 mg of a compound of formula I or II or a pharmaceutically acceptable salt thereof. In one embodiment, the single-dose formulation comprises 200 mg to 400 mg of a compound of formula I or II or a pharmaceutically acceptable salt thereof, preferably 200 mg to 400 mg of a compound of formula I or II or a pharmaceutically acceptable salt thereof.

[0078] The tablets or pills described in this application may be coated or otherwise compounded to provide the advantage of prolonged action. For example, tablets or pills may include an inner dose component and an outer dose component, the latter being an encapsulated form on top of the former. These two components can be separated by an intestinal layer, which serves to resist disintegration in the stomach and allows the inner component to enter the duodenum intact or with delayed release. A variety of materials can be used for this intestinal layer or coating, including various polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0079] In some embodiments, the drug is administered continuously for 4-18 months, preferably 4-6 months.

[0080] In another embodiment, the pharmaceutical composition is administered in combination with other antibiotics currently used to treat NTM infections, such as amikacin, clarithromycin, azithromycin, or ciprofloxacin.

[0081] Unless otherwise stated, the dosages and ranges provided herein are based on the molecular weight of the free base form of the compound of formula I or II.

[0082] The preferred compound of formula II is:

[0083]

[0084] Or its pharmaceutically acceptable salt.

[0085] Other preferred compounds of formula I include the following structures.

[0086]

[0087] Or its pharmaceutically acceptable salt.

[0088] Preferred compounds of formula II include the following structures:

[0089]

[0090] Or its pharmaceutically acceptable salt.

[0091] In some embodiments, the pharmaceutically acceptable salt form of the compound of formula I or II is a hydrochloride salt.

[0092] Example

[0093] The embodiments described in the following examples are intended to illustrate, and not limit, the scope of this disclosure. Common abbreviations well-known to those skilled in the art are used throughout. Unless otherwise specified, 1 1H NMR spectra were recorded using DMSO-d6 on a 300 MHz instrument. Mass spectrometry data for the positive ionization method are provided. Unless otherwise specified, chromatography was performed using silica gel chromatography. TLC was thin-layer chromatography. HPLC was reversed-phase HPLC. Unless otherwise specified, all reagents were either from commercial sources or prepared using conventional methods described in existing literature.

[0094] Example 1

[0095] (2S)-3-acetoxy-1-{[(3S)-3-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[2,1-c][1,2]oxorborol-7-yl]oxy}propyl-2-ylacetate hydrochloride

[0096]

[0097] Preparation scheme of the compound in Example 1:

[0098]

[0099] Intermediate 2. Ac₂O (32 μL, 0.33 mmol) was added dropwise to a solution of intermediate 1 (60 mg, 0.26 mmol, prepared as described in US application US2013 / 0165411) and pyridine (31 μL, 0.33 mmol) in DCM (2 mL), and the resulting mixture was stirred for 2 hours. After the reaction was complete, the solvent was removed by concentration, and the residue was purified by pre-HPLC to give intermediate 2 (25 mg). MS (m / z): 438 [M+H].

[0100] Example 1. Intermediate 2 was dissolved in a 5M HCl (2 mL) solution of dioxane at room temperature, and the resulting mixture was stirred for 1 hour. The mixture was then lyophilized to give a pale yellow powder of the compound of Example 1 (16.9 mg). MS (m / z): 338 [M+H]. 1 H NMR: (400MHz, D2O): 7.48 (t, J=8.0Hz, 1H); 7.01 (d, J=7.6Hz, 1H); 6.92 (dd, J=12.0, 8.0Hz, 1H); 5.35 (dd, J=7.4, 3 .0Hz, 1H); 4.35~4.17(m, 5H); 3.73~3.60(m, 1H); 3.56~3.51(m, 2H); 3.08~3.01(m, 1H); 1.99(s, 3H), 1.98(s, 3H).

[0101] The following compounds were synthesized according to the steps described in Example 1.

[0102]

[0103] Example 4

[0104] [(2S,6R)-2-(aminomethyl)-4-boron-3,5,8-trioxane[7.3.1.04,13]tetane-1(12),10-dien-6-yl]methanol hydrochloride

[0105]

[0106] The compound of Example 4 was prepared according to the method described in US application US2013 / 0165411.

[0107] Example 5

[0108] [(2S,6S)-2-(aminomethyl)-4-boron-3,5,8-trioxane[7.3.1.04,13]tetane-1(12),9(13),10-trien-6-yl]methyl-2-methylpropionate hydrochloride

[0109]

[0110] The compound of Example 5 was prepared according to the method described in US application US2013 / 0165411.

[0111] Example 7

[0112] [(2S,6S)-2-(aminomethyl)-4-boron-3,5,8-trioxane[7.3.1.04,13]tetane-1(12),9(13),10-trien-6-yl]methyl acetate hydrochloride

[0113]

[0114] The compound of Example 7 was prepared according to the method described in US application US2013 / 0165411.

[0115] Example 8

[0116] [(2S,6S)-2-(aminomethyl)-4-boron-3,5,8-trioxane[7.3.1.04,13]tetadeca-1(12),9(13),10-trien-6-yl]methyl propionate hydrogen chloride

[0117]

[0118] The compound of Example 8 was prepared according to the method described in US application US2013 / 0165411.

[0119] Utility and Testing

[0120] The compounds described in this application are boron compounds and their prodrugs. The prodrugs are converted into parent boron compounds in vivo to exert antibacterial effects. Therefore, the antibacterial activity of the prodrug compounds described in this application is tested using the parent boron compounds.

[0121] In vitro activity of representative compounds against mycobacteria

[0122] The in vitro activity of the parent boron compounds described in this application was assessed using standard testing procedures, such as the determination of the minimum inhibitory concentration (MIC) as described in Clinical and Laboratory Standards Institute (CLSI) document M24-A2. A lower MIC value indicates higher antibacterial activity, while a higher MIC value indicates lower antibacterial activity. Generally, an MIC value of approximately <2 mg / L indicates good therapeutic (i.e., suitable for treatment) efficacy of the antibacterial drug, while an MIC value >8 mg / L indicates a lack of therapeutically useful activity in the test compound.

[0123] The in vitro activity (potency) of the representative compounds described in this application against mycobacteria is illustrated by the MIC data in Table 1 below. It is evident from the data in Table 1 that the compounds of Example 4 exhibit high activity against many mycobacterial pathogens, including *Mycobacterium scrofula*, *Mycobacterium Gordon*, *Mycobacterium avium*, *Mycobacterium abscessum*, intracellular mycobacteria, occasional mycobacteria, exogenous mycobacteria, *Mycobacterium smegmatis*, and *Mycobacterium masei* (MIC range 0.063-2 mg / L). In particular, the compounds of Example 4 demonstrate surprising potency against rapidly growing mycobacteria (RGM), including *Mycobacterium abscessum*, intracellular mycobacteria, occasional mycobacteria, exogenous mycobacteria, *Mycobacterium smegmatis*, and *Mycobacterium masei* (MIC range 0.063-0.125 mg / L).

[0124] Compound GSK656 is a different boron compound disclosed in PCT application WO / 2012 / 033858, which is generally related to the compositions provided in this application. Surprisingly, despite some structural similarities, the compound of Example 4 and GSK656 exhibit very different antibacterial spectra against nontuberculous mycobacteria. Crucially, Example 4 showed strong potency against occasional mycobacteria, exogenous mycobacteria, and Mycobacterium smegmaecum, with a MIC of 0.125 mg / L, while GSK656 had a MIC ≥ 8 mg / L. Based on these values, the activity of compound GSK656 is more than 64 times lower than that of the representative compound of Example 4 provided in this invention.

[0125] Equally surprising is that the compound of Example 4 is also 4 times more potent than GSK656 against NTM pathogens Mycobacterium avium and Mycobacterium intracellulare. Such a significant difference in antibacterial spectrum activity and potency is entirely unexpected. In fact, the compound of Example 4 exhibits a significantly and surprisingly improved activity compared to the reference compound GSK656, and provides antibacterial coverage against NTM pathogens that far exceeds the possible coverage of GSK656. Another boron compound, AN2690, disclosed in US Patent Application US2006 / 0234981, also exhibits moderate or no activity against all tested NTM species. Due to the complexity of NTM infections, compounds with broad-spectrum antibacterial activity covering multiple mycobacteria are most beneficial and convenient for clinical use. Therefore, the compositions provided in this application offer the best option for treating such NTM infections.

[0126] Table 1. In vitro antibacterial activity against mycobacterial pathogens

[0127]

[0128] To further characterize the antibacterial properties of the compounds described in this application, the minimum bactericidal concentration (MBC) was determined according to Clinical and Laboratory Standards Institute (CLSI) document M24-A2. Both GSK656 and the compound of Example 4 were tested for MIC and MBC against 20 clinical isolates of the Mycobacterium abscessus complex, including Mycobacterium abscessus and Mycobacterium masei. As shown in Table 2, GSK656 and the compound of Example 4 had similar MICs in the clinical isolates. However, quite surprisingly, the compound of Example 4 had a lower MBC against all tested isolates. An MBC / MIC ratio < 4 is considered bactericidal, and a ratio > 4 is considered bacteriostatic. Therefore, the compound of Example 4 was bactericidal against half of the isolates, while GSK656 was bacteriostatic against all isolates. This differentiation, which is beneficial to the compound of Example 4, is quite surprising given their largely similar structures and MIC distributions. Indeed, bactericidal properties are crucial for more effective and efficient eradication of bacterial infections. Specifically, bactericidal compounds can kill or completely eradicate pathogens, while bacteriostatic compounds can only inhibit bacterial growth. In the latter case, residual bacteria may develop resistance to the drug, rendering treatment ineffective, or leading to reinfection after cessation of initial antimicrobial therapy. Therefore, bactericidal agents are preferred over bacteriostatic agents, especially for eradicating persistent mycobacterial infections.

[0129] Table 2. MICs and MBCs of clinical isolates of Mycobacterium abscessus complex.

[0130]

[0131]

[0132] Activities of representative compounds in a mouse model of Mycobacterium abscessus lung infection

[0133] To establish the in vivo efficacy of the compounds described in this application, a mouse model of Mycobacterium abscessus lung infection was established. BALB / c mice (randomized to group 6 mice per group) were administered cyclophosphamide one week prior to infection, followed by intranasal inoculation with Mycobacterium abscessus CIP108297 (10... 7 CFU / mouse). Three days after infection, mice were subsequently treated with 10 mg / kg of the compound of Example 4 or GSK656 subcutaneously daily, or 100 mg / kg of linezolid (an approved antibiotic) or 200 mg / kg of clarithromycin (an approved antibiotic) orally by gavage daily. Figure 1As shown, CFU of *Mycobacterium abscessus* in the lungs was quantified 2 weeks post-infection. Results showed that the compound of Example 4 resulted in a significant reduction in bacteria (~7.8 log10 CFU) compared to the untreated group. Furthermore, mice treated with the compound of Example 4 showed a significant reduction in lung organisms compared to animals treated with GSK656. This significantly enhanced efficacy is unexpected given the similar structure and MIC distribution between GSK656 and the compound of Example 4. This can be attributed to the surprisingly low MBC found in the compound of Example 4. In addition, the compound of Example 4 also showed a higher clearance potential against *Mycobacterium abscessus* compared to linezolid or clarithromycin, which were administered at very high doses.

[0134] H&E-stained tissue sections showed that, two weeks post-infection, control mice exhibited severe alveolar wall thickening, inflammatory cell infiltration, and erythrocyte exudation in their lungs. Conversely, as... Figure 2A-2C As shown, pathological changes were rare and lung injury was negligible in the groups treated with the compound of Example 4. These findings demonstrate the efficacy of the compound of Example 4 in inhibiting the replication of Mycobacterium abscessus in a mouse model of pneumonia.

[0135] Pharmacokinetic data of representative oral-administered prodrugs

[0136] To further elucidate the therapeutic potential of drug compounds, pharmacokinetic (PK) data are typically used to establish key parameters for predicting treatment outcomes, such as the area under the curve (AUC) monitoring systemic drug concentration over time. A higher AUC value indicates greater drug exposure and is generally associated with greater therapeutic potential because a higher amount of drug is available to combat infection. Conversely, a lower AUC value indicates reduced drug exposure, resulting in a smaller amount of antibiotic available to combat bacterial infection. Therefore, the compounds described in this application were tested in an orally administered rat PK model, using a method similar to that described in the monograph *Current Protocols in Pharmacology*, 2005, 7.1.1-71.26, John Wiley & Sons, Inc.

[0137] All compounds were administered to SD rats via intravenous or oral gavage (rats were randomly assigned to groups of 3). The prodrug was converted to the parent drug molecule in vivo. Therefore, only the parent compound of Example 4 was analyzed and quantified in all test samples. As shown in Table 3, the parent compound in Example 4 has a moderate oral bioavailability of 15%. Pharmacokinetic data of the prodrug described in this application showed that at the same dose of 5 mg / kg, systemic exposure and C max Significant improvement. For example, the compound in Example 2 showed significant improvements in exposure levels (AUC) and C.max The values ​​were 2906 hr*ng / ml and 870 ng / ml, respectively. This unexpected result indicates that the in vivo drug exposure and Cmax of the compound of Example 2 were significantly increased by 3.4-fold and 3-fold, respectively, compared to the compound of Example 4. The AUC data obtained in the context of the good efficacy of the compound of Example 4, demonstrated in a mouse model of Mycobacterium abscessus lung infection (see above), strongly suggest that the corresponding prodrug with higher exposure (AUC) has further enhanced therapeutic potential. Importantly, the data indicate that this can be achieved via oral administration. Furthermore, based on known comparisons between rodent tests and human data (such as known interspecies PK scaling), treatment in humans at lower doses is possible.

[0138] Table 3. Pharmacokinetic data of representative prodrugs in rats.

[0139]

[0140]

[0141] Furthermore, in a lung distribution study conducted in Balb / C mice (three mice at each time point), the lung exposure of Example 2 was significantly higher than the plasma exposure (assessed by the area under the lung / plasma concentration-time curve (AUC)). As shown in Table 4, the compounds of Examples 4 and 2 were administered intravenously and orally at 10 mg / kg, respectively. In the analysis of Example 2, the concentrations of the parent compound (Example 4) and the prodrug (Example 2) in plasma and lung were determined. The prodrug (Example 2) was rapidly converted to Example 4, and the prodrug was almost undetectable in plasma. The oral bioavailability of Example 4 generated by Example 2 was 83.95% in mice compared to the AUC of Example 4 administered intravenously. Despite the rapid conversion of the prodrug, surprisingly, more Example 4 was detected in the lung, with a lung / plasma AUC ratio of 5.24, almost 2.2 times that of Example 4 administered intravenously.

[0142] Table 4. Lung and plasma distribution in mice in Examples 4 and 2

[0143]

[0144] The complete and representative data above reveal the surprisingly superior therapeutic potential of the compounds of this application, exhibiting beneficial and unexpected advantages in terms of potency, efficacy, and exposure that were not anticipated in any previous patents or publications concerning boron anti-infective agents. The significant and surprising improvements in markedly different key parameters of the antibacterial compounds provided by this application offer significant benefits for the treatment of humans or mammals, including but not limited to improved bactericidal activity, superior in vivo efficacy, convenient oral administration for extended treatment duration, and reduced potential adverse reactions.

[0145] Every patent, patent application, and publication (e.g., journals, articles, and / or textbooks) disclosure cited in this application is incorporated herein by reference in its entirety. Furthermore, as used in this application and the appended claims, singular articles such as “a,” “an,” and “one” are intended to refer to either the singular or the plural. Although embodiments have been described in conjunction with preferred aspects, changes, equivalent substitutions, and other types of alterations to the embodiments described herein can be made by those skilled in the art upon reading the foregoing specification. Each aspect described above may also include or incorporate such variations or aspects disclosed with respect to any or all other aspects. The description of this application is not limited to the specific aspects described herein, but is intended as a single illustration of the various aspects provided herein. Many modifications and variations can be made to this disclosure without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of this specification, in addition to those listed in this application, will be apparent to those skilled in the art from the foregoing description. It should be understood that this specification is not limited to specific methods, reagents, process conditions, materials, etc., although these methods, reagents, and materials can certainly vary. It should also be understood that the terminology used in this application is for describing certain aspects only and is not intended to be limiting. Therefore, this specification is to be considered exemplary.

Claims

1. Use of a compound of formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of a medicament for treating nontuberculous mycobacterial infections: ； in: R 1 C 1-4 Alkyl-C(=O)-; and R 2 C 1-4 Alkyl-C(=O)-; Furthermore, the nontuberculous mycobacteria mentioned therein are selected from Mycobacterium scrofula, Mycobacterium Gordon, Mycobacterium avium, Mycobacterium abscessus, intracellular mycobacteria, occasional mycobacteria, exogenous mycobacteria, Mycobacterium smegmatis, and Mycobacterium masei.

2. Use of a compound of formula II or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of a medicament for treating nontuberculous mycobacterial infections: ； in: R 1 For H or C 1-4 Alkyl-C(=O)-; Furthermore, the nontuberculous mycobacteria mentioned therein are selected from Mycobacterium scrofula, Mycobacterium Gordon, Mycobacterium abscessus, Mycobacterium sporadicum, Mycobacterium exogenum, Mycobacterium smegmatis, and Mycobacterium masei.

3. The use according to claim 1, characterized in that, The compound is selected from: ； Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

4. The use according to claim 2, characterized in that, The compound is selected from: ； Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

5. The use according to any one of claims 1-4, characterized in that, The pharmaceutically acceptable salt is a hydrochloride salt.

6. The use according to any one of claims 1-4, characterized in that, The compound or a pharmaceutically acceptable salt thereof may be administered orally, intraperitoneally, intravenously, intraarterially, percutaneously, sublingually, intramuscularly, rectally, buccally, intranasally, vaginally, intraocularly, subcutaneously, intra-fatally, intra-articularly, or intrathecally.

7. The use according to any one of claims 1-4, characterized in that, The compound or a pharmaceutically acceptable salt thereof is administered orally via the external route.

8. The use according to any one of claims 1-4, characterized in that, The compound or a pharmaceutically acceptable salt thereof is administered by inhalation.

9. The use according to any one of claims 1-4, characterized in that, The compound or a pharmaceutically acceptable salt thereof is administered topically.

10. The use according to claim 6, characterized in that, The compound or a pharmaceutically acceptable salt thereof is administered in a single dose ranging from 10 to 1000 mg.

11. The use according to claim 10, characterized in that, The compound or a pharmaceutically acceptable salt thereof is administered in a single dose ranging from 100 to 400 mg.

12. The use according to claim 6, characterized in that, The compound or a pharmaceutically acceptable salt thereof is administered once or twice daily in a single dose.

13. The use according to claim 6, characterized in that, The compound or a pharmaceutically acceptable salt thereof shall be administered twice daily in a single dose suitable for oral solid dosage forms.

14. The use according to any one of claims 1-4, characterized in that, The infection can be a skin, respiratory, blood, abdominal, urinary, bone, or eye infection.

15. The use according to any one of claims 1-4, characterized in that, The infection is a soft tissue infection.

16. The use according to claim 6, characterized in that, The compound or pharmaceutical composition is administered for 4-12 months.

17. The use according to claim 6, characterized in that, The compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof shall be administered in a dosage form suitable for oral administration.

18. The use according to claim 6, characterized in that, The compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered in a dosage form suitable for oral administration, and the compound exhibits oral bioavailability of about 50% to 100%.

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