HK1210954B - Antibacterial compounds - Google Patents

Description

antibacterial compounds

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The present invention relates to novel substituted benzazole derivatives which are substituted with a urea moiety attached to a bridged cycloalkyl group. The invention also relates to such compounds for use as a medicament and additionally for use in the treatment of bacterial diseases, including but not limited to diseases caused by pathogenic mycobacteria (such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium leprae, Mycobacterium avium and Mycobacterium marinum), or pathogenic Staphylococci or Streptococci.

Background of the Invention

Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a serious and potentially fatal infection with a worldwide distribution. Estimates from the World Health Organization indicate that more than 8 million people are infected with TB each year, and 2 million people die from TB each year. In the last decade, TB cases have increased by 20% worldwide, becoming the heaviest burden on most poor communities. If these trends continue, the incidence of TB will increase by 41% over the next two decades. Fifty years since the introduction of an effective chemotherapy, TB remains the leading infectious cause of death among adults in the world after AIDS. Complicating the TB epidemic is the increasing trend of multidrug-resistant strains and the deadly symbiosis with HIV. HIV-positive people infected with TB are 30 times more likely to develop active TB than HIV-negative people, and TB is the cause of death for one in three people with HIV/AIDS worldwide.

The existing methods for treating tuberculosis all relate to the combination of multiple agents.For example, the scheme recommended by the U.S. Public Health Service is that the combination of isoniazid, rifampicin and pyrazinamide continues for two months, followed by independent isoniazid and rifampicin continuing another four months.In patients infected with HIV, these medicines are continued for another seven months.For patients infected with the multidrug-resistant strain of Mycobacterium tuberculosis, medicaments, such as ethambutol, streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofloxacin and ofloxacin, are added in these combination therapies.In the clinical treatment of tuberculosis, neither effective single agent nor any combination of medicaments that provide the possibility of the therapy less than six months duration are present.

There is a high medical need for new drugs that improve current treatments by achieving regimens that help patients and providers comply. Shorter regimens and those that require less supervision are the best way to achieve this need. When four drugs are given together, most of the benefits from treatment occur in the first two months during the booster or sterilization phase; the bacterial burden is greatly reduced, and the patient becomes no longer contagious. A 4- to 6-month continuation or sterilization phase is needed to eliminate persistent bacilli and minimize the risk of relapse. Shortening treatment to an effective sterilizing drug of 2 months or less would be extremely beneficial. Drugs that help compliance by requiring less centralized supervision are also needed. Obviously, compounds that reduce both the overall length of treatment and the frequency of drug administration will provide the greatest benefit.

What complicates the TB epidemic is the increased incidence of multidrug-resistant strains or MDR-TB. Up to 4 percent of all cases worldwide are considered to be MDR-TB-tolerant to those of the most effective drugs in the four-drug standard, isoniazid and rifampicin. When not treated, MDR-TB is fatal and cannot be fully treated by standard therapy, so treatment requires up to 2 years of "second-line" drugs. These drugs are typically toxic, expensive and somewhat effective. In the absence of effective therapy, infectious MDR-TB patients continue to spread the disease, producing new infections with MDR-TB strains. There is a high medical need for new drugs with new mechanisms of action that are expected to exhibit activity against drug-resistant, particularly MDR strains.

As used hereinabove and hereinafter, the term "drug-resistant" is a term well understood by those of ordinary skill in microbiology. A drug-resistant mycobacterium is a mycobacterium that is no longer susceptible to at least one previously effective drug; the mycobacterium has developed the ability to resist attack by at least one previously effective antibiotic. Resistant strains can pass this resistance on to their progeny. Such resistance can be attributed to random genetic mutations in bacterial cells that alter their sensitivity to a single drug or to different drugs.

MDR tuberculosis is a specific form of drug-resistant tuberculosis due to bacteria that are resistant to at least isoniazid and rifampicin (or resistant or intolerant to other drugs), which are currently the two most powerful anti-TB drugs. Therefore, whenever used above or below, "drug-resistant" includes multidrug-resistant.

Another factor in controlling the TB epidemic is the problem of latent TB. Despite decades of tuberculosis (TB) prevention and control programs, there are still about 2 billion people who are asymptomatically infected with Mycobacterium tuberculosis. About 10% of these individuals are at risk of developing active TB during their lifetime. The global epidemic of TB is exacerbated by the infection of HIV patients with TB and the emergence of multidrug-resistant TB strains (MDR-TB). The reactivation of latent TB is a high risk factor for disease progression and causes 32% of HIV-infected individuals to die. In order to control the TB epidemic, it is necessary to discover new drugs that can kill dormant or latent bacilli. Dormant TB can be reactivated to cause disease through several factors, such as suppressing host immunity through the use of immunosuppressants, such as antibodies to tumor necrosis factor α or interferon-γ. In the case of HIV-positive patients, the only preventive treatment available for latent TB is a two- to three-month regimen of rifampicin and pyrazinamide. The efficacy of this treatment regimen is still unclear and, in addition, the length of treatment is a major constraint in resource-constrained environments. Therefore, there is a strong need to identify new drugs that can serve as chemopreventive agents for individuals harboring latent TB bacilli.

Mycobacterium tuberculosis enters healthy individuals via inhalation; they are phagocytosed by alveolar macrophages in the lungs. This leads to an effective immune response and the formation of granulomas, which consist of macrophages infected with M. tuberculosis surrounded by T cells. After a period of 6-8 weeks, the host immune response leads to the death of infected cells through the following: necrosis of some extracellular bacilli surrounded by macrophages, necrosis of epithelial cells and surrounding lymphoid tissue layers, and accumulation of caseous material. In healthy individuals, most mycobacteria are killed in these environments, but a small fraction survives and is believed to exist in a non-replicating, hypometabolic state and is resistant to killing by anti-TB drugs such as isoniazid. These bacilli can persist in this altered physiological environment, even for the lifetime of an individual, without showing any clinical symptoms of disease. However, in 10% of these cases, these latent bacilli can reactivate and cause disease. One hypothesis for the development of these recalcitrant bacteria is the pathophysiological environment of human lesions, namely, reduced oxygen tension, nutrient limitation, and acidic pH. These factors have been hypothesized to render these bacteria phenotypically resistant to the major antimycobacterial drugs.

In addition to managing the TB epidemic, there is also the emerging problem of resistance to first-line antibiotics. Some important examples include penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococci, methicillin-resistant Staphylococcus aureus, and multidrug-resistant Salmonella.

The consequences of antibiotic resistance are severe. Infections caused by resistant microorganisms fail to respond to treatment, resulting in prolonged illness and a greater risk of death. Treatment failure also leads to longer-term infectivity, which increases the number of infected people circulating in the community and, therefore, exposes the general population to the risk of contracting infections with resistant strains.

Hospitals are a key component of the antimicrobial resistance problem worldwide. A combination of highly susceptible patients, intensive and prolonged antimicrobial use, and cross-infection has resulted in infections with highly resistant bacterial pathogens.

Self-medication with antimicrobials is another major factor in the development of tolerance. Self-medicated antimicrobials may be unnecessary, are often inappropriately administered, or may not contain the appropriate amount of active drug.

Patient compliance with recommended treatments is another major issue. Patients forget to take their medications, interrupt their treatment when they start to feel better, or may not be able to afford the full course of treatment, thereby creating an ideal environment for microbes to adapt rather than be killed.

As resistance to multiple antibiotics emerges, physicians are faced with infections for which no effective treatment exists. The morbidity, mortality, and financial costs of such infections impose an increasing burden on healthcare systems worldwide.

Therefore, there is a high need for new compounds for the treatment of bacterial infections, especially mycobacterial infections (including drug-resistant and latent mycobacterial infections), as well as other bacterial infections, especially those caused by resistant bacterial strains.

International patent application WO 2007/140439 discloses various compounds that can be used as cannabinoid receptor ligands. However, this document only discloses fused bicyclic rings in which the "azole" part is non-aromatic.

International patent application WO 2005/037845 discloses various benzothiazoles which are substituted with urea attached to an adamantyl group. However, this document only discloses compounds which are ubiquitin ligase inhibitors.

International Patent Application WO 2004/105755 discloses various benzothiazoles, but such compounds are only disclosed as being useful for treating diseases associated with adenosine A2A receptors. International Patent Application WO 2000/056725 discloses various benzothiazoles, but such compounds are only disclosed for use as anti-inflammatory agents and radiosensitizers. International Patent Application WO 99/24035 discloses benzothiazoles, but such compounds are only disclosed as protein tyrosine kinase inhibitors. German Patent Application DE 1970-2003841 (and equivalents) discloses certain benzimidazoles and tricyclics, however, such compounds are only disclosed in the context of antiviral and immunosuppressive properties.

The journal articles "Farmaco" (1995), 50(5), 321-6 by Da Settimo et al. and "Journal of Medicinal Chemistry" (1969), 12(5), 1010-15 and 1016-18 by Paget et al. disclose various benzimidazoles, however, such compounds have only been disclosed in the context of in vitro studies for anti-HIV and antitumor activity (or generally for immunosuppression and virulence inhibition).

International patent application WO 2005/023818 discloses the preparation of various compounds as pharmacologically active agents. However, this document does not disclose any benzopyrroles.

The structure-activity relationship of urea derivatives was disclosed in a journal article by Brown et al., Bioorganic & Medicinal Chemistry 19 (2011) 5585-5595. However, this document does not disclose or involve any fused bicyclic heteroaromatic structures.

Several other compounds have apparently been disclosed in the CAS Registry Database without a use assigned to them. For example, compounds with Registry Nos. 1045924-81-9 and 892821-81-7 are examples of such compounds without a use assigned to them.

The present invention aims to provide compounds for use in inhibiting bacterial growth, particularly the growth of streptococci, staphylococci or mycobacteria, and these compounds are therefore useful in treating bacterial diseases, particularly those caused by pathogenic bacteria such as Streptococcus pneumoniae, Staphylococcus aureus or Mycobacterium tuberculosis (including latent diseases and including drug-resistant Mycobacterium tuberculosis strains), Mycobacterium bovis, Mycobacterium leprae, Mycobacterium avium and Mycobacterium marinum. Such compounds may also be novel.

SUMMARY OF THE INVENTION

There is now provided a compound of formula (I) for use in the treatment of bacterial infections (such as mycobacterial infections), wherein the compound of formula (I) represents:

in

R ¹ , R ² , R ³ and R ⁴ each independently represent hydrogen, halogen, -CN, R ^t1 , -OR ^t2 , -C(O)N(R ^t3 )(R ^t4 ), -SO ₂ R ^t5 , -N(H)SO ₂ R ^t6 , -N(R ^t7 )(R ^t8 ) or aryl or heterocyclic group (wherein the latter two groups are themselves optionally substituted by one or more substituents selected from halogen and C _1-6 alkyl);

R ^t1 , R ^t2 , R ^t3 , R ^t4 , R ^t5 , R ^t6 , R ^t7 and R ^t8 independently represent hydrogen or C _1-6 alkyl optionally substituted by one or more halogen atoms, or R ^t3 and R ^t4 and/or R ^t7 and R ^t8 may be joined together with the nitrogen atom to which they are attached to form a 3- to 7-membered ring optionally containing one to three (e.g. one) additional heteroatoms and optionally containing one to three double bonds;

Z ^x represents O or S;

X stands for S or O;

Ring A represents:

R ^x represents hydrogen or C _1-6 alkyl optionally substituted by one or more substituents selected from fluorine, -CN, -OR ^x1 , -C(O)R ^x2 and -C(O)NR ^x3 ;

R ^x1 , R ^x2 and R ^x3 independently represent hydrogen or C _1-6 alkyl;

R ^y1 , R ^y2 and R ^y3 independently represent hydrogen, halogen (eg fluorine), C _1-6 alkyl, -OR ^y4 , -C(O)-R ^y5 or -CH ₂ -OR ^y6 ;

R ^y4 , R ^y5 and R ^y6 independently represent hydrogen or C _1-6 alkyl;

or a pharmaceutically acceptable salt (eg, an acid addition salt) thereof.

The above compounds of formula (I) (or salts thereof) may be referred to herein as "compounds of the invention". Such compounds are indicated as being useful in the treatment of bacterial infections. However, some of the above compounds may also be useful as pharmaceutical agents, and some compounds may be novel.

Thus, in a further embodiment of the invention there is a compound of formula I as defined herein for use as a medicament, but wherein:

R ¹ , R ² , R ³ and R ⁴ each independently represent hydrogen, fluorine or C _1-6 alkyl (optionally substituted with one or more halogen substituents). Such compounds may also be included in pharmaceutical formulations/compositions.

In a further embodiment of the present invention, there is provided a compound which is novel per se. In this aspect, there is provided a compound of formula I as defined herein, but wherein:

R ¹ , R ² , R ³ and R ⁴ each independently represent hydrogen, fluorine or a C _1-6 alkyl group optionally substituted by one or more halogen substituents (but the alkyl group thereof is preferably substituted by one or more halogen atoms);

For example, where:

One or two of R ¹ to R ⁴ represent fluorine, and the rest represent hydrogen;

One of R ¹ to R ⁴ represents -CF ₃ , and the rest represent hydrogen.

In embodiments of the present invention, in which novel compounds themselves are concerned, the following compounds are preferably excluded from the scope: compounds of formula I, wherein X represents S, Z ^x represents O, R ¹ and R ⁴ represent H, R ² represents -CH ₃ , ring A represents ring (ii) (in which R ^y2 and R ^y3 both represent hydrogen), and R ³ represents hydrogen or -CH ₃ .

The above-described embodiments of the invention (for use as a medicament and the compounds themselves being novel) may be combined with other preferred features of the invention (such as those described hereinafter).

Pharmaceutically acceptable salts include acid addition salts and base addition salts. Can be by conventional means, for example, by reacting the free acid or free base form of the compound of formula I with one or more equivalents of the appropriate acid or base, optionally in a solvent or in a medium in which the salt is insoluble, followed by standard techniques (for example, in a vacuum, by freeze drying or by filtering) to remove the solvent or the medium to form such salts. Can also be by exchanging a counter ion of the compound of the present invention in salt form with another counter ion, for example, using a suitable ion exchange resin, to prepare a variety of salts.

As mentioned above, pharmaceutically acceptable acid addition salts are meant to include non-toxic acid addition salt forms that can be formed, that are therapeutically active, of the compound of formula (I). These pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the base form with such appropriate acid. Suitable acids include, for example, inorganic acids, such as hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids, such as, for example, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid (i.e., oxalic acid), malonic acid, succinic acid (i.e., succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, etc.

For the purposes of the present invention, solvates, prodrugs, N-oxides and stereoisomers of the compounds of the present invention are also included within the scope of the invention.

The term "prodrug" of the relevant compounds of the present invention includes any compound that, following oral or parenteral administration, is metabolized in vivo to form an experimentally-detectable amount of the compound within a predetermined time period, such as a dosing interval of between 6 and 24 hours (i.e., once to four times daily). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration.

Prodrugs of the compounds of the present invention can be prepared by modifying the functional groups present on the compound in a manner such that when such prodrugs are administered to a mammalian subject, these modifications are cleaved in vivo. Typically, these modifications are accomplished by synthesizing a parent compound having a prodrug substituent. Prodrugs include compounds of the present invention in which the hydroxyl, amino, sulfhydryl, carboxyl, or carbonyl group in the compounds of the present invention is bound to any group that can be cleaved in vivo to regenerate a free hydroxyl, amino, sulfhydryl, carboxyl, or carbonyl group, respectively.

Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxyl functional groups, ester groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on prodrugs can be found, for example, in Bundegaard, H., "Design of Prodrugs," pp. 1-92, Elesevier, New York-Oxford (1985).

The compounds of the present invention may contain double bonds and therefore may exist as E (opposite-side) and Z (same-side) geometric isomers about each individual double bond. Positional isomers may also be included in the compounds of the present invention. All such isomers (e.g., if the compounds of the present invention contain a double bond or fused ring, both cis- and trans-forms are included) and mixtures thereof are included within the scope of the present invention (e.g., both single positional isomers and mixtures of positional isomers are included within the scope of the present invention).

The compounds of the present invention may also exhibit tautomerism. All tautomeric forms (or tautomers) and mixtures thereof are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions produced via prototropic isomerization, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions produced by the reorganization of some bonding electrons.

The compounds of the present invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical activity and/or diastereoisomerism. Conventional techniques, for example, chromatography or fractional crystallization may be used to separate diastereoisomers. Different stereoisomers may be separated by separating racemic mixtures or other mixtures of these compounds using conventional techniques, such as fractional crystallization or HPLC. Alternatively, the desired optical isomers may be prepared by reacting appropriate optically active starting materials under conditions that do not cause racemization or epimerization (i.e., a 'chiral pool' method); reacting appropriate starting materials with a 'chiral auxiliary' (e.g., with a pure chiral acid) that can be removed at an appropriate stage by derivatization (i.e., resolution, including dynamic resolution), followed by separation of the diastereomeric derivatives by conventional means (e.g., chromatography); or reacting with an appropriate chiral reagent or chiral catalyst, all under conditions known to those of ordinary skill in the art.

All stereoisomers (including but not limited to diastereomers, enantiomers, and atropisomers) and mixtures thereof (eg, racemic mixtures) are encompassed within the scope of the present invention.

In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated as and included in the compounds of the present invention. Where stereochemistry is indicated by a solid wedge or dashed line representing a specific configuration, then that stereoisomer is indicated and defined.

The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc., and it is intended that the present invention embrace both solvated and unsolvated forms.

The present invention also includes isotopically labeled compounds of the present invention, which are identical to those listed herein, but in fact one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (or the most found in nature). All isotopes of any specific atom or element specified herein are considered to be within the scope of these compounds of the present invention. Exemplary isotopes that may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, and ¹²⁵ I. Certain isotopically labeled compounds of the present invention (e.g., those labeled with ³ H and ¹⁴ C) are useful in compounds and are used for substrate tissue distribution assays. Tritiated ( ³ H) and carbon-14 ( ¹⁴ C) isotopes are useful because they make preparation and detectability easy. In addition, substitution with heavier isotopes (such as deuterium) (i.e. , ² H) can provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) due to greater metabolic stability and therefore can be preferred under some circumstances. Positron emitting isotopes (such as ¹⁵ O, ¹³ N, ¹¹ C and ¹⁸ F) are useful for positron emission tomography (PET) studies to examine the occupancy of substrate receptors. Isotope-labeled compounds of the present invention can generally be prepared by the following methods similar to those described in Scheme 1 and/or the Examples below, by replacing non-isotopically labeled reagents with isotope-labeled reagents.

Unless otherwise indicated, the C _1-q alkyl groups defined herein (where q is the upper limit of the range) may be straight-chain or, when there are a sufficient number (i.e., at least two or three, if appropriate) of carbon atoms, branched and/or cyclic (thus forming a C _3-q -cycloalkyl group). Such cycloalkyl groups may be monocyclic or bicyclic and may further be bridged. In addition, when there are a sufficient number (i.e., at least four) of carbon atoms, such groups may also be partially cyclic. Such alkyl groups may also be saturated or, when there are a sufficient number (i.e., at least two) of carbon atoms, may be unsaturated (e.g., forming a C _2-q alkenyl or C _2-q alkynyl group).

C3 _-q cycloalkyl groups (where q is the upper limit of the range) that may be specifically mentioned may be monocyclic or bicyclic alkyl groups, which may further be bridged (thus forming, for example, a fused ring system, such as three fused cycloalkyl groups). Such cycloalkyl groups may be saturated or unsaturated (for example, forming a cycloalkenyl group) containing one or more double bonds. Multiple substituents may be attached to any site on the cycloalkyl group. In addition, such cycloalkyl groups may also be partially cyclic, provided there are a sufficient number (i.e., a minimum of four) of carbon atoms.

The term "halogen", when used herein, preferably comprises fluorine, chlorine, bromine and iodine.

Heterocyclic groups (when referred to herein) may include aromatic or non-aromatic heterocyclic groups, and thus include heterocycloalkyl and heteroaryl groups.

Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups, wherein at least one (e.g., one to four) of the atoms in the ring system is other than carbon (i.e., a heteroatom), and wherein the total number of atoms in the ring system is between 3 and 20 (e.g., between three and ten, e.g., between 3 and 8, such as 5- to 8-). Such heterocycloalkyl groups may also be bridged. In addition, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, thereby forming, for example, C _2-q heterocycloalkenyl (wherein q is the upper limit of the range). C 2-q heterocycloalkenyl groups that may be mentioned _2-q heterocycloalkyl groups include 7-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 6-azabicyclo[3.2.1]-octyl, 8-azabicyclo-[3.2.1]octyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridinyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazole 1,2,3,6-tetrahydropyridinyl, thietanyl, thiirane, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl, etc. Where appropriate, the substituents on the heterocycloalkyl group may be located on any atom (including heteroatoms) in the ring system. The point of attachment of the heterocycloalkyl group can be via any atom in the ring system (where appropriate), including heteroatoms (such as nitrogen-atoms), or atoms on any fused carbocyclic ring that may be present as part of the ring system. The heterocycloalkyl group can also be in the form of N- or S-oxidation. The heterocycloalkyl groups mentioned herein can be specifically designated as monocyclic or bicyclic.

Aryl groups that may be mentioned include C _6-20 , such as C _6-12 (e.g., C _6-10 ) aryl groups. Such groups may be monocyclic, bicyclic, or tricyclic and have between 6 and 12 (e.g., 6 and 10) ring carbon atoms, wherein at least one ring is aromatic. C _6-10 aryl groups include phenyl, naphthyl, etc., such as 1,2,3,4-tetrahydronaphthyl. The attachment point of the aryl group may be via any atom of the ring system. For example, when the aryl group is polycyclic, the attachment point may be via atoms, including atoms of non-aromatic rings. However, when the aryl group is polycyclic (e.g., bicyclic or tricyclic), they are preferably connected to the remainder of the molecule via an aromatic ring. The most preferred aryl group that may be mentioned herein is "phenyl."

Unless otherwise indicated, the term "heteroaryl" as used herein refers to an aromatic group containing one or more heteroatoms (e.g., one to four heteroatoms), preferably selected from N, O, and S. Heteroaryl groups include those having between 5 and 20 members (e.g., between 5 and 10 members) and may be monocyclic, bicyclic, or tricyclic, provided that at least one of the rings is aromatic (thus forming, for example, a mono-, bi-, or tricyclic heteroaryl). When the heteroaryl group is polycyclic, the point of attachment may be via any atom, including atoms of non-aromatic rings. However, when heteroaryl groups are polycyclic (e.g., bicyclic or tricyclic), they are preferably attached to the remainder of the molecule via an aromatic ring. Heteroaryl groups that may be mentioned include 3,4-dihydro-1H-isoquinolinyl, 1,3-dihydroisoindolyl, 1,3-dihydroisoindolyl (e.g., 3,4-dihydro-1H-isoquinolin-2-yl, 1,3-dihydroisoindol-2-yl, 1,3-dihydroisoindol-2-yl; i.e., a heteroaryl group linked via a non-aromatic ring), or, preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzoxepinyl, benzodioxolyl (including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiadiazolyl (including 2,1,3-benzothiadiazolyl), benzothiazolyl, benzoxadiazolyl (including 2,1,3-benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothiophenyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[1,2-a]pyridinyl, indazolyl, dihydroindole, indolyl, isobenzofuranyl, isochromanyl, isoindole, isoindole yl, isoquinolyl, isothiazolyl, isothiochromanyl, isoxazolyl, naphthyridinyl (including 1,6-naphthyridinyl or, preferably, 1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrakis(o)pyrimid ... , 1,2,3-triazolyl, 1,2,4-triazolyl and 1,3,4-triazolyl), etc. Where appropriate, the substituents on the heteroaryl group are located on any atom (including heteroatoms) in the ring system. The point of attachment of the heteroaryl group can be via any atom in the ring system (where appropriate), including heteroatoms (such as nitrogen atoms), or atoms on any fused carbocyclic ring that may be present as part of the ring system. The heteroaryl group can also be in the form of N- or S- oxidation. The heteroaryl groups mentioned here can be specifically designated as monocyclic or bicyclic. When the heteroaryl group is a polycyclic ring in which there is a non-aromatic ring, then the non-aromatic ring can be substituted by one or more =O groups. The most preferred heteroaryl groups that can be mentioned here are 5- or 6-membered aromatic groups containing 1, 2 or 3 heteroatoms (e.g., preferably selected from nitrogen, oxygen and sulfur).

It can be specifically indicated that the heteroaryl group is monocyclic or bicyclic. Where the heteroaryl group is specified to be bicyclic, it may consist of a five-, six- or seven-membered monocyclic ring (e.g., a monocyclic heteroaryl ring) fused to another five-, six- or seven-membered ring (e.g., a monocyclic aryl or heteroaryl ring).

Heteroatoms that may be mentioned include phosphorus, silicon, boron and, preferably, oxygen, nitrogen and sulfur.

For the avoidance of doubt, where it is stated that a group may be substituted with one or more substituents (e.g., selected from C _1-6 alkyl), then these substituents (e.g., alkyl groups) are independent of each other. That is, such groups may be substituted with the same substituent (e.g., the same alkyl substituent) or different (e.g., alkyl) substituents.

All individual features mentioned herein (eg preferred features) may be taken independently or in combination with any other features mentioned herein (including preferred features) (thus, preferred features may be taken in conjunction with other preferred features or independently of them).

The skilled artisan will appreciate that the compounds of the invention which are the subject of the present invention include those that are stable. That is, the compounds of the invention include those that are sufficiently robust to withstand isolation to a useful degree of purity from, for example, a reaction mixture.

Compounds of the invention which may be mentioned (either as such or for any of the uses mentioned herein) include those wherein:

R ² preferably does not represent -OR ^t2 ;

^R2 preferably represents hydrogen, halogen, -CN, ^Rt1 , -C(O)N( ^Rt3 )( ^Rt4 ), _-SO2Rt5 , ^-N (H) _SO2Rt6 , -N( ^Rt7 )( ^{Rt8 )} or an aryl or heterocyclyl group (wherein the latter two groups are themselves optionally substituted by one or more substituents selected from halogen and _C1-6alkyl );

None of R ¹ , R ² , R ³ and R ⁴ represents -OR ^t2 ; and/or

R ¹ , R ² , R ³ and R ⁴ preferably each independently represent hydrogen, halogen, -CN, R ^t1 , -C(O)N(R ^t3 )(R ^t4 ), -SO ₂ R ^t5 , -N(H)SO ₂ R ^t6 , -N(R ^t7 )(R ^t8 ) or aryl or heterocyclic group (wherein the latter two groups are themselves optionally substituted by one or more substituents selected from halogen and C _1-6 alkyl).

Preferred compounds of the present invention include those wherein:

When R ¹ , R ² , R ³ or R ⁴ represents an aryl group, then the aryl group is preferably naphthyl or especially phenyl (which group is preferably unsubstituted);

When R ¹ , R ² , R ³ or R ⁴ represents a heterocyclic group, then it is preferably a 5- or 6-membered heteroaryl group or a 3- to 6-membered heterocycloalkyl group (e.g. wherein the heteroaryl or heterocycloalkyl group contains one or two heteroatoms, which are preferably selected from nitrogen, oxygen and sulfur, thus forming, for example, furyl, imidazolyl, etc., and/or piperidinyl, piperazinyl, morpholinyl, azetidinyl, etc.);

When R ^t3 and R ^t4 and/or R ^t7 and R ^t8 are linked together, they preferably form a 5- or 6-membered ring, optionally containing an additional heteroatom (e.g. sulfur or preferably oxygen or nitrogen), and which is preferably saturated (thus forming, for example, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, etc.).

Preferred compounds of the present invention include those wherein:

R ^y3 represents hydrogen;

R ¹ , R ² , R ³ and R ⁴ each independently represent hydrogen, halogen, C _1-6 alkyl (optionally substituted by one or more halogen) or -OC _1-6 alkyl (wherein the alkyl portion is optionally substituted by one or more halogen substituents);

R ^t1 , R ^t2 , R ^t3 , R ^t4 , R ^t5 , R ^t6 , R ^t7 and R ^t8 independently represent hydrogen or C _1-6 (e.g., C _1-3 ) alkyl.

In one embodiment of the present invention, Ring A represents:

In another embodiment of the invention, which may be particularly preferred, ring A represents:

Additional preferred compounds of the present invention include those wherein:

R ^y1 represents fluorine, chlorine, C _1-6 alkyl, -OH, -C(O)R ^y5 or -CH ₂ -OR ^y6 ; and R ^y2 represents -OH, C _1-6 alkyl (eg, methyl), -C(O)R ^y5 or -CH ₂ -OR ^y6 ).

Preferred compounds of the present invention include those wherein:

R ¹ , R ² , R ³ and R ⁴ each independently represent hydrogen, halogen, -C(O)(NR ^t3 )(R ^t4 ), C _1-6 alkyl (optionally substituted by one or more halogen substituents), such as hydrogen, halogen, -CF ₃ or -CH ₃ ;

Preferably, there is at least one R ¹ , R ² , R ³ or R ⁴ (e.g. R ² ) substituent present and preferably one (e.g. at the R ² or R ³ position) or two substituents (e.g. R ² and R ³ or R ² and R ⁴ );

Z ^x represents O;

X represents O or S;

R ^t3 and R ^t4 independently represent hydrogen or preferably C _1-6 (eg C _1-3 ) alkyl (eg methyl);

R ^x represents hydrogen or C _1-6 alkyl;

R ^x1 and R ^x2 independently represent hydrogen or methyl;

R ^y1 and R ^y2 independently represent hydrogen, halogen (e.g., fluorine) or C _1-6 alkyl;

R ^y4 , R ^y5 and R ^y6 independently represent hydrogen or methyl.

Additional preferred compounds of the present invention include those wherein:

R ¹ , R ² , R ³ and R ⁴ each independently represent hydrogen, halogen (e.g. fluorine or chlorine), C _1-2 alkyl (optionally substituted by one or more fluorine atoms; thus forming, for example, CH ₃ or CF ₃ ) or —C(O)N(C _1-2 alkyl) ₂ (e.g. —C(O)N(CH ₃ ) ₂ );

At least two of R1, ^{R2 , R3} and ^R4 represent hydrogen, and the remainder may represent hydrogen or a substituent as defined herein (eg -C(O)N( _CH3 ) ₂ , _-CH3 or preferably halogen and/or _-CF3 ).

Still further preferred compounds of the present invention include those wherein:

R ¹ , R ² , R ³ and R ⁴ each independently represent hydrogen, halogen (such as fluorine or chlorine);

X stands for O;

R ^x represents hydrogen;

R ^x1 and R ^x2 independently represent hydrogen;

R ^y1 and R ^y2 independently represent hydrogen;

R ^y3 , R ^y4 and R ^y5 independently represent hydrogen.

Pharmacology

The compounds according to the present invention have surprisingly been shown to be suitable for the treatment of bacterial infections, including mycobacterial infections, in particular diseases caused by pathogenic mycobacteria, such as Mycobacterium tuberculosis (including latent and resistant forms thereof), Mycobacterium bovis, Mycobacterium leprae, Mycobacterium avium, Mycobacterium leprae and Mycobacterium marinum. The present invention therefore also relates to a compound of the present invention as defined above, a pharmaceutically acceptable salt thereof, a solvate thereof or an N-oxide form thereof, for use as a medicament, in particular for use as a medicament for the treatment of bacterial infections, including mycobacterial infections.

In addition, as described below, the present invention also relates to the use of the compounds of the present invention, their pharmaceutically acceptable salts, solvates or N-oxide forms thereof, together with any pharmaceutical compositions thereof, for the manufacture of a medicament for treating a bacterial infection (including a mycobacterial infection).

Thus, in another aspect, the present invention provides a method of treating a patient having or at risk of a bacterial infection, including a mycobacterial infection, comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition according to the present invention.

In addition to its activity against mycobacteria, the compounds according to the present invention are also active against other bacteria. Generally speaking, bacterial pathogens can be divided into Gram-positive or Gram-negative pathogens. Antibiotic compounds with activity against Gram-positive and Gram-negative pathogens are generally considered to have broad-spectrum activity. The compounds of the present invention are considered to be active against Gram-positive and/or Gram-negative bacterial pathogens, particularly Gram-positive bacterial pathogens. In particular, the compounds of the present invention are active against at least one Gram-positive bacterium, preferably against several Gram-positive bacteria, more preferably against one or more Gram-positive bacteria and/or one or more Gram-negative bacteria.

The compounds of the present invention have bactericidal or bacteriostatic activity.

Examples of Gram-positive and Gram-negative aerobic and anaerobic bacteria include Staphylococci, such as Staphylococcus aureus; Enterococci, such as Enterococcus faecalis; Streptococci, such as Streptococcus pneumoniae, Streptococcus mutans, Streptococcus pyogenes; Bacilli, such as Bacillus subtilis; Listeria, such as Listeria monocytogenes; Haemophilus, such as Haemophilus influenzae; Moraxella, such as Moraxella catarrhalis; Pseudomonas, such as Pseudomonas aeruginosa; and Escherichia, such as Escherichia coli.

Gram-positive pathogens such as Staphylococci, Enterococci and Streptococci are of particular importance due to the development of resistant strains that are difficult to treat and, once established, are difficult to eradicate from, for example, hospital environments. Examples of such strains are methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative Staphylococci (MRCNS), penicillin-resistant Streptococcus pneumoniae and multi-resistant Enterococcus faecium.

The compounds of the present invention also show activity against resistant bacterial strains.

The compounds of the invention are particularly active against S. pneumoniae and S. aureus, including resistant S. aureus, such as, for example, methicillin-resistant S. aureus (MRSA).

Therefore, as described below, the present invention also relates to the use of the compounds of the present invention, their pharmaceutically acceptable salts, solvates or N-oxide forms thereof, together with any pharmaceutical compositions thereof, for the manufacture of a medicament for treating a bacterial infection (including an infection caused by Staphylococcus and/or Streptococcus).

Thus, in another aspect, the present invention provides a method of treating a patient having or at risk of a bacterial infection, including an infection caused by Staphylococci and/or Streptococci, comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition according to the present invention.

Without being bound by any theory, it is taught that the activity of the compounds of the present invention is to inhibit FIFO ATP synthase, particularly the FO complex of FIFO ATP synthase, more particularly the subunit c of the FO complex of FIFO ATP synthase, thereby killing the bacteria by depleting their cellular ATP levels. Thus, the compounds of the present invention are particularly active against those bacteria that rely on the proper function of FIFO ATP synthase for their survival.

Bacterial infections that can be treated by the compounds of the present invention include, for example, central nervous system infections, external ear infections, middle ear infections, such as acute otitis media, dural sinus infections, eye infections, oral infections, such as infections of the teeth, gums and mucous membranes, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, sepsis, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis for surgery, and antibacterial prophylaxis in immunosuppressed patients (such as patients receiving cancer chemotherapy or organ transplant patients).

Whenever used herein above or below, the compounds can treat a bacterial infection means that the compounds can treat an infection by one or more bacterial strains.

The present invention also relates to a composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound according to the present invention. The compounds according to the present invention can be formulated into various pharmaceutical forms for administration purposes. Suitable compositions include all compositions commonly used for systemic administration of drugs. To prepare the pharmaceutical compositions of the present invention, an effective amount of the specific compound as the active ingredient, optionally in addition salt form, is combined in an intimate mixture with a pharmaceutically acceptable carrier, which can take various forms depending on the desired dosage form. Desirably, these pharmaceutical compositions are in unit dosage form, specifically, unit dosage forms suitable for oral administration or administration by injection. For example, in preparing pharmaceutical compositions in oral dosage forms, any common pharmaceutical media can be used, such as water, glycols, oils, alcohols, etc. in the case of oral liquid preparations (e.g., suspensions, syrups, elixirs, emulsions, and solutions); or solid carriers such as starch, sugar, kaolin, diluents, lubricants, binders, disintegrants, etc. in the case of powders, pills, capsules, and tablets. Tablets and capsules represent the most advantageous oral dosage unit forms because they are easily administered, and in this case, solid pharmaceutical carriers are obviously adopted. For parenteral compositions, the carrier will usually include sterile water that is at least a major part, but may also include other ingredients such as to assist solubility. For example, injectable solutions can be prepared in which the carrier includes a mixture of physiological saline solution, glucose solution or physiological saline and glucose solution. Injectable suspensions can also be prepared in which case, suitable liquid carriers, suspending agents, etc. are used. Also included are solid form preparations that are intended to be converted into liquid form preparations shortly before use.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05% to 99% by weight, more preferably from 0.1% to 70% by weight, even more preferably from 0.1% to 50% by weight of the active ingredient(s), and from 1% to 99.95% by weight, more preferably from 30% to 99.9% by weight, even more preferably from 50% to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

The pharmaceutical composition may additionally contain various other ingredients known in the art, such as lubricants, stabilizers, buffers, emulsifiers, viscosity regulators, surfactants, preservatives, flavorings, or coloring agents.

In order to facilitate the uniformity of administration and dosage, it is particularly advantageous that the above-mentioned pharmaceutical composition is formulated into unit dosage form. As used herein, the unit dosage form refers to a physical discrete unit suitable as a unit dosage, and each unit contains a predetermined amount of active ingredient, which is calculated to be combined with a required drug carrier to produce the desired therapeutic effect. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets (powderpacket), wafers (wafer), suppositories, injectable solutions or suspensions and similar dosage forms, and the multiple dose forms (multiples) separated thereof. Of course, the daily dose of the compound according to the present invention will vary with the compound adopted, the mode of administration, the desired treatment and the mycobacterial disease targeted. However, in general, when given according to the compound according to the present invention with a daily dose of no more than 1 gram (for example, in the range of from 10 to 50 mg/kg body weight), satisfactory results will be obtained.

In view of the fact that the compounds of formula (Ia) or (Ib) are active against bacterial infections, the compounds of the present invention can be combined with other antibacterial agents in order to effectively combat bacterial infections.

Therefore, the present invention also relates to a combination of (a) a compound according to the invention, and (b) one or more other antibacterial agents.

The present invention also relates to a combination of (a) a compound according to the invention, and (b) one or more other antibacterial agents, for use as a medicament.

The invention also relates to the use of a combination or pharmaceutical composition as defined directly above for treating a bacterial infection.

The present invention may also include a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredients, a therapeutically effective amount of (a) a compound according to the present invention, and (b) one or more other antibacterial agents.

When given as a combination, those of ordinary skill in the art can determine the weight ratio of (a) according to the compound of the present invention and (b) one or more other antibacterial agents.As known to those of ordinary skill in the art, the ratio and accurate dosage and the frequency of giving depend on the specific compound of the present invention and one or more other antibacterial agents used, the specific illness being treated, the severity of the illness being treated, the age, body weight, sex, diet, the time of giving and overall physical health, the other medicines that the mode of giving can take together with the individual.In addition, it is obvious that this effective daily dosage can reduce or improve, and this depends on the response of the experimenter being treated and/or depends on the assessment of the doctor who gives the compound of the present invention prescription.The specific weight ratio of the compound of the present invention and another antibacterial agent can be in the range of from 1/10 to 10/1, more especially from 1/5 to 5/1, even more especially from 1/3 to 3/1.

The compounds according to the invention and the one or more other antibacterial agents may be combined in a single formulation or they may be formulated as separate formulations such that they can be administered simultaneously, separately or sequentially. Therefore, the present invention also relates to a product comprising (a) a compound according to the invention and (b) one or more other antibacterial agents as a combined formulation for use simultaneously, separately or sequentially in the treatment of bacterial infections.

Other antibacterial agents that can be combined with the compounds of the present invention are, for example, antibacterial agents known in the art. Other antibacterial agents include antibiotics with β-lactam groups, such as natural penicillins, semisynthetic penicillins, natural cephalosporins, semisynthetic cephalosporins, cephamycins, 1-oxacephems, clavulanic acid, penicillins, carbapenems, nocardiacins, monobactams; tetracyclines, anhydrotetracyclines, anthracyclines; aminoglycosides; nucleosides, such as N-nucleosides, C-nucleosides, carbocyclic nucleosides, blasticidin S; macrolides, such as 12-membered ring macrolides, 14-membered ring macrolides, 16-membered ring macrolides; ansamycins; Peptides such as bleomycin, gramicidin, polymyxin, bacitracin, macrocyclic peptide antibiotics containing lactone bonds, actinomycin, amphomycin, capreomycin, distamycin, enramycin, micamycin, neocarzinostatin, streptomycin, puromycin, virginiamycin; cycloheximide; cycloserine; morphomycin; sarcomycin A; novobiocin; griseofulvin; chloramphenicol; mitomycin; fumagillin; monensin; pyrrolnitrin; fosfomycin; fusidic acid; D-(p-hydroxyphenyl)glycine; D-phenylglycine; enediyne.

Specific antibiotics that can be combined with the compounds of the present invention are, for example, benzylpenicillin (potassium, procaine, benzathine penicillin), phenoxymethylpenicillin (potassium), phenoxyethylpenicillin potassium, propicillin, carbenicillin (disodium, phenyl sodium, indanyl sodium), sulbenicillin, ticarcillin disodium, methicillin sodium, oxacillin sodium, cloxacillin sodium, dicloxacillin, flucloxacillin, ampicillin, mezlocillin, piperacillin sodium, amoxicillin, cyclohexylcillin, hectacillin, sulbactam sodium, talampicillin hydrochloride, bacampicillin hydrochloride, pivmecillin, cephalexin, cefaclor, cefepimexin, cephalosporin, cephalosporin, cefacillin ... Amoxicillin, cefradine, cefuroxime, cefapirin sodium, ceftriaxone sodium, cefuroxime sodium, cefuroxime sodium, ceftriaxone sodium, cefoperazone sodium, cefadroxil, ceftriaxone, ceftriaxone hydrochloride, cefuroxime, ceftriaxone sodium, ceftazidime, cefoxitin, cefmetazole, cefotetan, latamoxef, clavulanic acid, imipenem, aztreonam, tetracycline, chlortetracycline hydrochloride, demeclocycline, oxytetracycline, metacycline, doxycycline, rolicycline, minocycline, daunorubicin hydrochloride, doxorubicin, aclarubicin, kanamycin sulfate, kanamycin, toluidine Clothiocarb, gentamicin sulfate, dibekacin, amikacin, scutamicin, ribosomycin, neomycin sulfate, paromomycin sulfate, streptomycin sulfate, dihydrostreptomycin, hygromycin A, hygromycin B, apramycin, sisomicin, netilmicin sulfate, spectinomycin hydrochloride, astamicin hydrochloride, validamycin, kasugamycin, polyoxin, blasticidin S, erythromycin, erythromycin estolate, oleandomycin phosphate, tracetyloleandomycin, kitasamycin, josamycin, spiramycin, tylosin, ivermectin, midecamycin, bleomycin sulfate, peplomycin sulfate, gramicidin S, polymyxin B, bacitracin, colistin sulfate, colistin sodium methanesulfonate, enratoxin, mikamycin, virginiamycin, capreomycin sulfate, viomycin, enviromycin, vancomycin, actinomycin D, neocarcinostatin, bestatin, pepstatin, monensin, lasalocid, salinomycin, amphotericin B, nystatin, natamycin, trichostatin, plicamycin, lincomycin, clindamycin, clindamycin palmitate hydrochloride, flavomycin, cycloserine, pecillocin, griseofulvin, chloramphenicol, chloramphenicol palmitate, mitomycin C, pyrrolnitrin, fosfomycin, fusidic acid, dicyclam, tiamulin, sikanin.

Other mycobacterial agents that can be combined with the compounds of the present invention are, for example, rifampicin (= rifampin); isoniazid; pyrazinamide; amikacin; ethionamide; ethambutol; streptomycin; para-aminosalicylic acid; cycloserine; capreomycin; kanamycin; thiosemicarbazide; PA-824; quinolones/fluoroquinolones, such as, for example, moxifloxacin, gatifloxacin, ofloxacin, ciprofloxacin, sparfloxacin; macrolides, such as, for example, clarithromycin, clofazimine, amoxicillin and clavulanic acid; rifamycins; rifabutin; rifapentine; the compounds disclosed in WO 2004/011436.

General preparation

The compounds according to the invention can generally be prepared by a series of steps, each of which is known to the skilled person.

For example, compounds of formula (I) can be prepared by:

(i) making a compound of formula (II),

(wherein X, R ¹ , R ² , R ³ and R ⁴ are as defined above) and a compound of formula (III),

(wherein Ring A and Z ^x are as defined above) under standard reaction conditions known to those skilled in the art, for example in the presence of a base (for example an organic base, such as an amine base, for example Et ₃ N) and a suitable solvent (for example a polar aprotic solvent, such as THF);

(ii) making a compound of formula (IV),

(wherein LG represents a suitable leaving group (such as an imidazolyl group) or a suitable chloroformate group (e.g. 4-nitrophenyl chloroformate), and R ¹ , R ² , R ³ , R ⁴ , X and Z ^x are as defined above) and a compound of formula (V),

(wherein Ring A is as defined above) is reacted under standard reaction conditions, for example, nucleophilic substitution reaction conditions, which may be carried out in the presence of a suitable solvent such as dichloromethane.

Compounds of formula (IV) wherein LG represents imidazolyl may be prepared by reacting a compound of formula (II) as defined above with a compound of formula (VI)

or the like, wherein Z ^x is as defined above.

The compound of formula (V) can be prepared by the following method:

(i) making a compound of formula (VII),

(wherein Ring A is as defined above) is subjected to reductive amination under standard reductive amination conditions in the presence of ammonia or a form of ammonia and a hydrogen source (e.g., H ₂ gas). Reagents that can be employed to form compounds of formula (V) from compounds of formula (VII) include several known in the art, such as ammonium hydroxide, ammonia solution in methanol, ammonium formate, benzylamine, or the like, and the preparation can be via oxime (J. Org. Chem, 76 (11), 4432-4433) or via N ₃ ;

(ii) For compounds wherein Ring A represents Ring (i), i.e. wherein R ^x is present but represents an optionally substituted alkyl group (as defined above), by reacting a compound of formula (VIII)

(wherein R ^xx represents C _1-6 alkyl (eg tert-butyl) and ring A is as defined above) using a compound of formula (IX),

R ^x -T ^x (IX)

(wherein ^T represents, for example, an organometallic such as lithium (which can be generated in situ) or the like, and ^R is as defined above), followed by quenching with a proton source (e.g., water), and removal of the -S(O)-R ^moiety , for example, by hydrolysis (e.g., aqueous acid hydrolysis) or the like.

Compounds of formula (VIII) can be prepared by reacting a compound of formula (VII) as defined above with a compound of formula (X)

R ^xx -S(O)-NH ₂ (X)

(wherein R ^xx is as defined above), reacted with a compound of formula (V) as defined above, for example under condensation reaction conditions known to those skilled in the art.

Functional groups can also be converted into one another, for example, a -C(O)R ^y4 group can be reduced to a -CH ₂ -R ^y5 group (wherein these R ^y4 and R ^y5 moieties are the same, preferably the same alkyl group).

Experimental part

Preparation of compound 1

By 2-amino-4,6-difluoro-1,3-benzothiazole (119256-40-5, 0.22g, 1.18mmol), 1-adamantyl isocyanate (0.42g, 2.36mmol) and triethylamine (0.27mL, 1.97mmol) in THF (4mL) solution is stirred and heated at 60 DEG C overnight.The solution is cooled to room temperature.Water and DCM are added.The organic layer is separated, dried over _MgSO4 , filtered and evaporated.The residue is purified by preparative LC on (dry loading 25g+5g 15-40μm merck).Mobile phase (gradient from 90% heptane, 10% AcOEt to 70% heptane, 30% AcOEt).Pure part is collected and evaporated to give a white powder, 0.125g. This compound was then purified by chiral SFC on (diethylaminopropyl 5 μm 150 x 21.2 mm). Mobile phase (75% CO2, 25% MeOH). Pure fractions were collected and evaporated to a white powder, 0.09 g.

The residue was crystallized from DIPE, filtered off and dried at 60°C under vacuum to yield compound 1 as a white powder, 0.084 g, 20%, m.p. >260°C

¹ H NMR (400MHz, DMSO-d ₆ )δ10.67 (br.s., 1H), 7.70 (dd, J=1.5, 8.1Hz, 1H), 7.22-7.31 (m, 1H), 7.05 (d, J=8.1Hz, 1H), 3.84 (d, J=8.1Hz, 1H), 1.57-1.90 (m, 14H)

Preparation of compound 2

Compound 2 was prepared from 2-amino-5-chlorobenzoxazole (61-80-3, 0.2 g, 1.19 mmol) in the same manner as compound 1 to provide the desired compound 2, 0.161 g, 39%, m.p. > 250 °C

¹ H NMR (500MHz, DMSO-d ₆ ) δ 10.98 (br.s., 1H), 8.16 (br.s., 1H), 7.48-7.61 (m, 2H), 7.23 (dd, J=2.1, 8.7Hz, 1H), 1.95-2.15 (m, 9H), 1.66 (br.s., 6H)

Preparation of compound 3

A solution of 2-amino-4,6-difluoro-1,3-benzothiazole (3 g, 16.11 mmol) and 1,1'-carbonyldiimidazole (2.87 g, 17.72 mmol) in dichloromethane (60 mL) was stirred at room temperature overnight. The precipitate was filtered off, washed with EtOH and dried under vacuum at 60°C to provide intermediate A as a white powder, 2.49 g, 55%, which was used as such in the next step.

A solution of intermediate A (1.99 g, 7.1 mmol), 2-aminoadamantane hydrochloride (1.47 g, 7.81 mmol) and triethylamine (1.57 mL, 11.36 mmol) in THF (20 mL) was stirred at 60 ° C overnight. The solution was cooled to room temperature. Water and DCM were added. The organic layer was separated, dried over MgSO ₄ , filtered and evaporated. The residue was purified by preparative LC (stationary phase: irregular SiOH 15-40 μm, 300 g MERCK), mobile phase: 80% heptane, 20% AcOEt). The pure part was collected and the solvent was evaporated to give a white powder, 0.33 g. The compound was crystallized from DIPE, filtered off and dried at 60 ° C, under vacuum, to provide compound 3 as a white powder, 0.271 g, 10%, mp=272 ° C

¹ H NMR (500MHz, DMSO-d ₆ )δ10.56 (br.s., 1H), 7.68 (dd, J=1.6, 8.2Hz, 1H), 7.21-7.33 (m, 1H), 647 (s, 1H), 2.05 (br.s., 3H), 1.95 (br.s., 6H), 1.64 (br.s., 6H)

Preparation of compound 4

A solution of 2-amino-5-chlorobenzoxazole (61-80-3, 0.3 g, 1.78 mmol) and 1,1'-carbonyldiimidazole (0.32 g, 1.96 mmol) in dichloromethane (6 mL) was stirred at room temperature overnight. The precipitate was filtered off, washed with EtOH and dried under vacuum at 60 ° C to provide intermediate A as a white powder, 0.19 g, 40%, which was used as it was in the next step.

A solution of intermediate A (0.19 g, 0.72 mmol), 2-aminoadamantane hydrochloride (0.15 g, 0.79 mmol) and triethylamine (0.16 mL, 1.15 mmol) in THF (4 mL) was stirred at 60 ° C overnight. The solution was cooled to room temperature. Water and DCM were added. The organic layer was separated, dried over MgSO ₄ , filtered and evaporated. Purified by flash chromatography on silica gel (40 g, 15-40 μm, heptane/EtOAc from 90/10 to 70/30). The pure part was collected and the solvent was removed. The residue was crystallized from DIPE, filtered off and dried at 60 ° C, under vacuum, to provide compound 4, 0.081 g, 33%, mp＞250 ° C as a white powder.

¹ H NMR (500MHz, DMSO-d ₆ )δ11.24 (br.s., 1H), 8.81 (d, J=7.6Hz, 1H), 7.52-7.63 (m, 2H), 7.25 (dd, J=2.1, 8.7Hz, 1H), 3.91 (d, J=7.6Hz, 1H), 1.58-1.99 (m, 14H)

Preparation of compound 5

A solution of 2-amino-6-(trifluoromethyl)-benzothiazole (777-12-8, 0.3 g, 1.39 mmol) and 1,1'-carbonyldiimidazole (0.25 g, 1.53 mmol) in dichloromethane (6 mL) was stirred at room temperature overnight. The precipitate was filtered off, washed with EtOH and dried under vacuum at 60°C to provide intermediate A as a white powder, 0.231 g, 53%, which was used as such in the next step.

A solution of intermediate A (0.231 g, 0.74 mmol), 2-aminoadamantane hydrochloride (0.15 g, 0.81 mmol) and triethylamine (0.16 mL, 1.18 mmol) in THF (8 mL) was stirred at 60 ° C overnight. The solution was cooled to room temperature. Water and DCM were added. The organic layer was separated, dried over MgSO ₄ , filtered and evaporated. Purified by flash chromatography on silica gel (40 g, 15-40 μm, heptane/EtOAc from 80/20 to 60/40). The pure part was collected and the solvent was removed. The residue was crystallized from DIPE, filtered off and dried at 60 ° C, under vacuum, to provide compound 5, 0.141 g, 48%, mp＞250 ° C as a white powder.

¹ H NMR (500MHz, DMSO-d ₆ )δ10.69 (br.s., 1H), 8.39 (s, 1H), 7.77 (d, J=8.5Hz, 1H), 7.66 (dd, J=1.6, 8.5Hz, 1H) , 7.12 (d, J=7.9Hz, 1H), 3.84 (d, J=7.9Hz, 1H), 1.69-1.91 (m, 13H), 1.55-1.64 (m, 1H)

Preparation of compound 6

A solution of 2-amino-5,6-dimethyl-benzothiazole (29927-08-0, 0.25 g, 1.39 mmol) and 1,1'-carbonyldiimidazole (0.25 g, 1.53 mmol) in dichloromethane (6 mL) was stirred at room temperature overnight. The precipitate was filtered off, washed with EtOH and dried under vacuum at 60°C to provide intermediate A as a white powder, 0.351 g, 93%, which was used as such in the next step.

A solution of intermediate A (0.351 g, 1.29 mmol), 2-aminoadamantane hydrochloride (0.27 g, 1.42 mmol) and triethylamine (0.29 mL, 2.06 mmol) in THF (8 mL) was stirred at 60 ° C overnight. The solution was cooled to room temperature. Water and DCM were added. The organic layer was separated, dried over MgSO ₄ , filtered and evaporated. Purified by flash chromatography on silica gel (40 g, 15-40 μm, heptane/EtOAc from 90/10 to 70/30). The pure part was collected and the solvent was removed. The residue was crystallized from DIPE, filtered off and dried at 60 ° C, under vacuum, to provide compound 6, 0.038 g, 8%, mp＞260 ° C as a white powder.

¹ H NMR (500MHz, DMSO-d ₆ )δ10.36 (br.s., 1H), 7.60 (s, 1H), 7.40 (s, 1H), 7.17 (br.s., 1H), 3.82 (d, J=7.2Hz, 1H), 2.28 (d, J=4.7Hz, 6H), 1.54-1.89 (m, 14H)

Preparation of compound 7

A solution of 2-amino-benzothiazole-6-carboxylic acid methyl ester (0.3 g, 1.46 mmol) and 1,1'-carbonyldiimidazole (0.26 g, 1.6 mmol) in dichloromethane (6 mL) was stirred at room temperature overnight. The precipitate was filtered off, washed with EtOH and dried under vacuum at 60°C to provide intermediate A as a white powder, 0.426 g, 97%, which was used as such in the next step.

A solution of intermediate A (0.426 g, 1.41 mmol), 2-aminoadamantane hydrochloride (0.29 g, 1.55 mmol) and triethylamine (0.31 mL, 2.25 mmol) in THF (8 mL) was stirred at 60 ° C overnight. The solution was cooled to room temperature. Water and CH ₂ Cl ₂ were added. The organic layer was separated, dried over MgSO ₄ , filtered and evaporated. The residue was purified by chiral SFC (stationary phase: diethylaminopropyl 5 μm 150x 21.2 mm), mobile phase: 85% CO 2, 15% MeOH). The pure fractions were collected and the solvent was evaporated to give intermediate B, 0.23 g, 42% as a white powder.

Lithium hydroxide monohydrate (0.22 g, 2.88 mmol) was added portionwise to a solution of intermediate B (0.222 g, 0.58 mmol) in THF (3 mL) and water (0.3 mL). The solution was stirred and heated at 60° C. for 2 hours. The THF was evaporated and the mixture was acidified with HCl 3N. AcOEt was added and the organic layer was separated, dried over MgSO ₄ , filtered and evaporated to give 0.085 g, 40%.

A solution of this intermediate (0.085 g, 0.23 mmol), dimethylamine hydrochloride (0.028 g, 0.34 mmol), 1-hydroxybenzotriazole (0.037 g, 0.27 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.053 g, 0.27 mmol) and N,N-diisopropylethylamine (0.082 mL, 0.46 mmol) in CH ₂ Cl ₂ (2 mL) was stirred at room temperature overnight. Water and CH ₂ Cl ₂ were added. The organic layer was extracted, washed twice with brine, dried over MgSO ₄ , filtered and evaporated.

Purification was carried out by flash chromatography on silica gel (15-40 μm, 24 g, CMA from 100/0/0 to 97/3/0.1). The pure fractions were collected and the solvent was evaporated to give compound B as a white powder, 0.036 g, 39%, m.p. = 224°C.

¹ H NMR (500MHz, DMSO-d ₆ )δ10.56 (br.s., 1H), 7.97 (s, 1H), 7.62 (d, J=8.2Hz, 1H), 7.39 (dd, J=1.4, 8.2Hz, 1H ), 7.14 (d, J = 5.7Hz, 1H), 3.84 (d, J = 5.7Hz, 1H), 2.97 (br.s., 6H), 1.54-1.91 (m, 14H)

Analytical methods

LCMS

The masses of some compounds were recorded by LCMS (Liquid Chromatography Mass Spectrometry).The methods used are described below.

General Procedure A

Use Alliance HT 2795 (Waters (Waters)) system to carry out HPLC measurement, this system comprises a quaternary pump with degasser, an automatic sample injector, a diode array detector (DAD) and a post as described in detail in each method below, and this post is maintained at 30 ℃ temperature.Stream from this post is shunted to MS spectrometer.MS detector is configured with an electrospray ionization source.Capillary needle voltage is 3.15kV and is maintained at 110 ℃ in source temperature at ZQ ^™ (simple quadrupole Zspray ^™ mass spectrometer from Waters).Use nitrogen as nebulizer gas.Carry out data acquisition with Waters-MicromassMasLynx-Openlynx data system.

General Procedure B

Use Acquity UPLC (Waters) system to carry out LC measurement, this system comprises binary pump, sample organizer (sample organizer), column heater (being set to 55 ℃), diode array detector (DAD) and the post as specified in following corresponding method.The stream from this post is shunted to MS spectrometer.MS detector is configured with an electrospray ionization source.By using the dwell time of 0.02 second in 0.18 second from 100 to 1000 scan acquisition mass spectrum.Capillary needle voltage is 3.5kV and this source temperature is maintained at 140 ℃.Use nitrogen as nebulizer gas.Carry out data acquisition with Waters-Micromass MassLynx-Openlynx data system.

General Program C

Use Agilent (Agilent) 1100 series liquid chromatography system to carry out HPLC measurement, this liquid chromatography system comprises the binary pump with degasser, automatic sampler, column oven, UV detector and the post as described in detail in each method hereinafter.The stream from this post is shunted to MS spectrometer.MS detector is configured with an electrospray ionization source.Capillary voltage is 3kV, quadrupole temperature is maintained at 100 ℃, and desolvation temperature is 300 ℃.Use nitrogen as nebulizer gas.Use Agilent Chemstation data system to carry out data acquisition.

General Program D

Use UPLC (ultra-performance liquid chromatography) Acquity (Waters) system to carry out LC measurement, this system comprises the binary pump with degasser, automatic sample injector, diode array detector (DAD) and the post as specified in each method below, and the temperature of this post is maintained at 40 ℃.The stream from this post is introduced into MS detector.MS detector is configured with an electrospray ionization source.On Quattro (triple quadrupole mass spectrometer from Waters), capillary needle voltage is 3kV and source temperature is maintained at 130 ℃.Use nitrogen as nebulizer gas.Carry out data acquisition with Waters-Micromass MassLynx-Openlynx data system.

Method 1

HPLC (HPLC) is carried out by using a 0.8 ml/min flow rate. The HPLC is carried out using a 1.2 ml/min flow rate. The HPLC is carried out using a 0.8 ml/min flow rate. The HPLC is run using a 1.2 ml/min flow rate rate. The HPLC is run using a 0.8 ml/min flow rate ...

Method 2

HPLC is carried out by HPLC.Except general procedure A: on a Sunfire C18 (3.5 μ m, 4.6x 100mm) post, the initial flow rate of 0.8 ml/min is used to carry out reversed-phase HPLC.Adopt two mobile phases (mobile phase A: 25% 7mM ammonium acetate+50% acetonitrile+25% formic acid (2 ml/l); Mobile phase B: 100% acetonitrile) run gradient condition: from 100%A (maintain 1 minute), in 4 minutes to 100%B, at 100%B place, maintain 4 minutes with the flow velocity of 1.2 ml/min and use initial condition rebalance to continue 3 minutes.Use the injection volume of 10 μ l.The cone voltage that is used for positive ionization mode and negative ionization mode is 20V.By using the inner scan delay of 0.3 second, scan from 100 to 1000 and gather mass spectrum in 0.4 second.

Method 3

In addition to General Procedure B: Reverse-phase HPLC (ultra-performance liquid chromatography) was performed on a bridged ethylsiloxane/silica hybrid (BEH) C18 column (1.7 μm, 2.1 x 50 mm, Waters Acquity) using a flow rate of 0.8 ml/min. A gradient of 95% A and 5% B to 5% A and 95% B in 1.3 minutes and held for 0.2 minutes was run using two mobile phases (mobile phase A: 0.1% formic acid in H ₂ O/methanol 95/5; mobile phase B: methanol). An injection volume of 0.5 μl was used. The cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.

Method 4

In addition to General Procedure C: Reverse phase HPLC was performed on a YMC-Pack ODS-AQ C18 column (4.6 x 50 mm) using a flow rate of 2.6 ml/min. A gradient was run from 95% water and 5% acetonitrile to 95% acetonitrile over 7.30 minutes and held for 1.20 minutes. Mass spectra were collected by scanning from 100 to 1000. The injection volume was 10 μl. The column temperature was 35°C.

Method 5

In addition to general procedure A: on a Sunfire C18 (3.5 μm, 4.6x 100mm) column, an initial flow rate of 0.8 ml/min was used to perform reverse phase HPLC. Two mobile phases (mobile phase A: 35% 6.5 mM ammonium acetate + 30% acetonitrile + 35% formic acid (2 ml/l); mobile phase B: 100% acetonitrile) were used to run gradient conditions: from 100% A (maintained for 1 minute), to 100% B in 4 minutes, at 100% B, a flow rate of 1.2 ml/min was maintained for 4 minutes and rebalanced with initial conditions for 3 minutes. An injection volume of 10 μl was used. Positive ionization mode was used with four different cone voltages (20 V, 40 V, 50 V, 55 V). Mass spectra were collected by scanning from 100 to 1000 in 0.4 seconds using an internal scan delay of 0.1 second.

Method 6

In addition to General Procedure D: Reversed-phase UPLC was performed on a Waters Acquity BEH (bridged ethylsiloxane/silica hybrid) C18 column (1.7 μm, 2.1×100 mm) using a flow rate of 0.35 ml/min. Two mobile phases (mobile phase A: 95% 7 mM ammonium acetate/5% acetonitrile; mobile phase B: 100% acetonitrile) were used. A gradient was run from 90% A and 10% B (hold 0.5 min) over 3.5 min to 8% A and 92% B, hold 2 min, and back to starting conditions over 0.5 min, hold 1.5 min. An injection volume of 2 μl was used. Cone voltages were 20 V, 30 V, 45 V, and 60 V for positive ionization mode. Mass spectra were acquired by scanning from 100 to 1000 in 0.2 s with an interscan delay of 0.1 s.

Method 7

In addition to General Procedure D: Reverse phase UPLC was performed on a Thermo Hypersil Gold C18 column (1.9 μm, 2.1 x 100 mm) at a flow rate of 0.40 ml/min. Two mobile phases (mobile phase A: 95% 7 mM ammonium acetate/5% acetonitrile; mobile phase B: 100% acetonitrile) were used. A gradient was run from 72% A and 28% B (hold 0.5 min) over 3.5 min to 8% A and 92% B, hold 2 min, and back to starting conditions over 0.5 min, hold 1.5 min. An injection volume of 2 μl was used. Cone voltages were 20 V, 30 V, 45 V, and 60 V for positive ionization mode. Mass spectra were collected by scanning from 100 to 1000 in 0.2 s with an interscan delay of 0.1 s.

Method 8

In addition to General Procedure D: Reversed-phase UPLC was performed on a Waters Acquity BEH (bridged ethylsiloxane/silica hybrid) C18 column (1.7 μm, 2.1×100 mm) using a flow rate of 0.35 ml/min. A gradient was run using two mobile phases (mobile phase A: 100% 7 mM ammonium acetate; mobile phase B: 100% acetonitrile): from 75% A and 25% B (for 0.5 min), to 8% A and 92% B over 3.5 min, held for 2 min, and re-equilibrated with the initial conditions for 2 min. An injection volume of 2 μl was used. Cone voltages were 20 V, 30 V, 45 V, and 60 V for positive ionization mode. Mass spectra were acquired by scanning from 100 to 1000 in 0.2 s with an interscan delay of 0.1 s.

Method 9

In addition to General Procedure D: Reversed-phase UPLC was performed on a Thermo Hypersil Gold C18 column (1.9 μm, 2.1 x 100 mm) at a flow rate of 0.50 ml/min. Two mobile phases (mobile phase A: 95% 7 mM ammonium acetate/5% acetonitrile; mobile phase B: 100% acetonitrile) were used. A gradient was run from 40% A and 60% B (hold 0.5 min) over 3.5 min to 5% A and 95% B, hold 2 min, and back to starting conditions over 0.5 min, hold 1.5 min. An injection volume of 2 μl was used. Cone voltages were 20 V, 30 V, 45 V, and 60 V for positive ionization mode. Mass spectra were acquired by scanning from 100 to 1000 in 0.2 s with an interscan delay of 0.1 s.

Method 10

In addition to general procedure A: reverse phase HPLC was performed on a Varian Pursuit Diphenyl column (5 μm, 4 x 100 mm) at a flow rate of 0.8 ml/min. Two mobile phases (mobile phase A: 100% 7 mM ammonium acetate; mobile phase B: 100% acetonitrile) were used to run a gradient of 80% A, 20% B (for 0.5 min) to 90% B in 4.5 min, 90% B for 4 min and 3 min of re-equilibration with the initial conditions. An injection volume of 10 μl was used. For positive ionization mode, the cone voltages were 20 V, 40 V, 50 V, 55 V. Mass spectra were collected by scanning from 100 to 1000 in 0.3 sec with an inter-scan delay of 0.05 sec.

When a compound is a mixture of isomers giving different peaks in the LCMS method, only the retention time of the major component is given in the LCMS table.

D. Pharmacology Examples

MIC ₉₀ determination of test compounds against M. tuberculosis

Flat-bottomed sterile 96-well plastic microtiter plates were filled with 100 μl Middlebrook (1x) 7H9 broth. Subsequently, an additional 100 μl culture medium was added to column 2. The stock solution of the compound (200x final test concentration) was added to a series of replicates in column 2 with a 2 μl volume to allow evaluation of its effect on bacterial growth. Serial 2-fold dilutions were prepared directly from column 2 to column 11 in the microtiter plate using a multichannel pipette gun. Pipette tips were replaced after every 3 dilutions to minimize pipetting errors for highly hydrophobic compounds. Untreated control samples with (column 1) and without (column 12) inoculum were included in each microtiter plate. Approximately 10,000 CFU of Mycobacterium tuberculosis (strain H37RV) per well in a 100 μl volume in Middlebrook (1x) 7H9 broth was added to rows A to H, except column 12. The same volume of broth medium without inoculum was added to column 12 of rows A to H. The cultures were incubated at 37° C. in a humidified atmosphere for 7 days (incubator with open air valve and continuous ventilation). On day 7, the bacterial growth was checked visually.

The 90% minimum inhibitory concentration ( _MIC90 ) was determined as the concentration at which there was no visible bacterial growth.

Time-kill assay

In the time-kill assay, the bactericidal or antibacterial activity of the compound can be determined using the broth dilution method. In the time-kill assay for Mycobacterium tuberculosis (strain H37RV), the starting inoculum of Mycobacterium tuberculosis was 10 ⁶ CFU/ml in Middlebrook (Middlebrook) (1x) 7H9 broth. Antibacterial compounds were used at a concentration of 0.1 to 10 times MIC _90. The tubes that did not receive the antibacterial agent constituted the culture growth control. The tubes containing microorganisms and test compounds were incubated at 37°C. After incubation for 0, 1, 4, 7, 14 and 21 days, samples were taken to determine the viable count by serial dilution (10 ^-1 to 10 ^-6 ) in Middlebrook (Middlebrook) 7H9 culture medium and plating (100 μl) on Middlebrook (Middlebrook) 7H11 agar. These plates were incubated at 37°C for 21 days and the number of colonies was determined. By plotting the log ₁₀ CFU per ml against time, a bactericidal curve can be constructed. Bactericidal efficacy is generally defined as a 3-log ₁₀ reduction in the number of CFU per ml compared to untreated inoculum. Potential carryover effects of drugs are eliminated by serial dilution and counting colonies at the highest dilution used for plating.

MIC value

The experiments were performed in microplates; starting from dry powder.

Killing dynamics

Claims (18)

1. Use of a compound having chemical formula (I) in the preparation of a medicament for treating mycobacterial infections, wherein such a compound having chemical formula (I) represents: in ^R1 , ^R2 , ^R3 and ^R4 each independently represent hydrogen, halogen, -CN, ^Rt1 , ^-ORt2 , -C(O)N( ^Rt3 )( ^Rt4 ), ^-SO2Rt5 _, ^-N (H) _SO2Rt6 , -N( ^Rt7 )( ^Rt8 ) or aryl or heterocyclic groups (where the latter two groups are optionally substituted by one or more substituents selected from halogens and _C1-6 alkyl groups); ^Rt1 , ^Rt2 , ^Rt3 , ^Rt4 , ^Rt5 , ^Rt6 , ^Rt7 , and ^Rt8 independently represent hydrogen or a _C1-6 alkyl group optionally substituted with one or more halogen atoms, or ^Rt3 and ^Rt4 and/or ^Rt7 and ^Rt8 may be linked together with the nitrogen atom to which they are attached to form a 3- to 7-membered ring, which optionally contains one to three additional heteroatoms and optionally contains one to three double bonds; Z ^x represents O or S; X represents S or O; Ring A represents: (i) or (ii) R ^x represents hydrogen or a _C1-6 alkyl group optionally substituted with one or more substituents selected from fluorine, -CN, -OR ^x1 , -C(O)R ^x2 and -C(O)NR ^x3 ; ^Rx1 , ^Rx2 , and ^Rx3 independently represent hydrogen or _C1-6 alkyl; ^Ry1 , ^Ry2 , and ^Ry3 independently represent hydrogen, halogen, _C1-6 alkyl, ^-ORy4 , -C(O) ^-Ry5 , or _-CH2 - ^ORy6 ; ^Ry4 , ^Ry5 , and ^Ry6 independently represent hydrogen or _C1-6 alkyl; Or its pharmaceutically acceptable salt. 2. The use as claimed in claim 1, wherein ^Rt3 and ^Rt4 and/or ^Rt7 and ^Rt8 may be linked together with the nitrogen atom to which they are attached to form a 3- to 7-membered ring, the 3- to 7-membered ring optionally containing an additional heteroatom and optionally containing one to three double bonds. 3. The use as described in claim 1, wherein ^Ry1 , ^Ry2 and ^Ry3 independently represent fluorine. 4. The use as claimed in claim 1, wherein the compound is in the form of its acid addition salt. 5. The use as described in claim 1, wherein ring A represents: (ii) 6. The use as claimed in any of the preceding claims, wherein ^Ry1 represents fluorine, chlorine, _C1-6 alkyl, -OH, -C(O) ^Ry5 or _-CH2 - ^ORy6 ; and ^Ry2 represents -OH, _C1-6 alkyl, -C(O) ^Ry5 or _-CH2 - ^ORy6 . 7. The use as described in claim 1, wherein ^Ry2 represents methyl. 8. The use as described in claim 1 or 5, wherein ^R1 , ^R2 , ^R3 and ^R4 each independently represent hydrogen; Z ^x represents O; X represents O or S; and/or ^Rx represents hydrogen. 9. The use as described in claim 1, wherein ^R1 , ^R2 , ^R3 and ^R4 each independently represent hydrogen, fluorine or a _C1-6 alkyl group substituted with one or more halogen substituents. 10. The use as described in claim 1, wherein: ^R1 , ^R2 , ^R3 and ^R4 each independently represent a _C1-6 alkyl group that is hydrogen, fluorine or optionally substituted with one or more halogen substituents; The condition is that the following compounds having chemical formula I are excluded: Where X represents S, ^Zx represents O, ^R1 and ^R4 represent H, ^R2 represents _-CH3 , ring A represents the ring (ii) in which ^Ry2 and ^Ry3 both represent hydrogen, and ^R3 represents those that are hydrogen or _-CH3 . 11. The use as described in claim 10, wherein ^R1 , ^R2 , ^R3 and ^R4 each independently represent an unsubstituted _C1-6 alkyl group. 12. The use as described in claim 10, wherein one or two of ^R1 to ^R4 represent fluorine, and the remainder represent hydrogen. 13. The use as claimed in claim 10, wherein one of ^R1 to ^R4 represents _-CF3 , and the remainder represents hydrogen. 14. Use of a combination in the preparation of a medicament for treating mycobacterial infections, wherein the combination comprises: (i) a compound as defined in any one of claims 1 to 13; and (ii) another therapeutic agent used in the treatment of bacterial infections. 15. The use as described in claim 1 or 14, wherein the mycobacterial infection is Mycobacterium tuberculosis. 16. Use of a pharmaceutical composition in the preparation of a medicament for treating bacterial infections, the pharmaceutical composition comprising a compound as defined in claim 9 and a pharmaceutically acceptable carrier. 17. A method for preparing the composition of claim 16, wherein a therapeutically effective amount of the compound of claim 9 is tightly mixed with a pharmaceutically acceptable carrier. 18. A method for preparing a compound as defined in claim 10, the method comprising: (i) to make a compound having the chemical formula (II), Wherein X, ^R1 , ^R2 , ^R3 and ^R4 are as defined in claim 1, reacting with a compound having chemical formula (III), Wherein rings A and ^Zx are as defined in claim 1; (ii) To make a compound having the chemical formula (IV), Wherein LG represents a suitable leaving group, and ^R1 , ^R2 , ^R3 , ^R4 , X, and ^Zx are as defined in claim 1, reacting with a compound having chemical formula (V). Wherein ring A is as defined in claim 1.