Antibacterial 4,5 diaryl-thiophen-2-yl hexafluoropropane-2-OLS

Abstract

Antibacterial and / or adjuvant compounds of formula (I) or a pharma- ceutically acceptable salt thereof are provided. In formula (I), R 1-6 has the meaning set forth herein. Other methods of use are also provided. [Formula 1] JPEG2025511361000007.jpg85101

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 327,386, filed April 5, 2022, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Infection is the invasion of a host organism by a foreign organism, usually resulting in the disruption of normal functions in the host. In the treatment of infections and post-infectious inflammatory diseases (e.g., septic shock) in humans and other animals, physicians usually rely on compounds known to have an antibiotic affect, such as antiviral, antibacterial, or antifungal compounds.

[0003] Unfortunately, many pathogens are becoming resistant to current antibiotic treatments. Multidrug-resistant (MDR) bacteria have been called a "catastrophic threat to the human population" and "nightmare bacteria" by Dame Sally Davies, former Chief Medical Officer of the UK, and Thomas Frieden, Director of the US Centers for Disease Control and Prevention (CDC), respectively. The World Health Organization (WHO) has identified antibiotic resistance as one of the three major threats to human health. The Review on Antibacterial Resistance declared that there is an urgent need to increase the supply of new antibacterial agents that are effective against drug-resistant bacteria. Currently, 700,000 people die annually from MDR bacteria worldwide, and this number is expected to increase to 10 million if new classes of antibacterial agents are not introduced into the clinic. Currently, there are fewer than 40 antibiotics currently in clinical trials, and none of them are new classes of drugs against new drug targets.

[0004] Therefore, there is a need for new antibacterial compounds. Summary of the Invention

[0005] The compounds of the present invention are useful for treating infectious diseases. In some cases, the compound itself is antibacterial. In some cases, the compound ("antibacterial adjuvant") has a beneficial effect in combination with a second antibacterial agent, and when administered in combination, reduces the dose of antibiotic required for antibacterial activity. In some cases, the compound is both antibacterial and antibacterial adjuvant.

[0006] Generally, in one embodiment, a compound of formula I

[0007] [ka] or a pharma- ceutically acceptable salt thereof, In the formula, R 1 and R 2 are each independently fluoro or chloro; R 3 and R 4 are methyl or -CH 2 OH, except that R 3 is methyl, R 4 Ha-CH 2 OH and vice versa, R 5 is hydrogen or alkyl, R 6 -C(CF 3 ) 2 OH. Implementations may include one or more of the following: R 1 and R 2Both are chloro. The compound is 2-(5-(4-chloro-2-(hydroxymethyl)phenyl)-4-(4-chloro-2-methylphenyl)thiophen-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (hereinafter referred to as "DNM94A"). The compound is 2-(4-(4-chloro-2-(hydroxymethyl)phenyl)-5-(4-chloro-2-methylphenyl)thiophen-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (hereinafter referred to as "DNM95A").

[0008] In general, in some embodiments, a method of treating a bacterial infection is provided that includes administering an effective amount of an antibacterial compound disclosed herein to a patient in need of such treatment. Implementations may include one or more of the following: The infection is caused by a gram-positive bacterium. The infection is caused by a gram-negative bacterium. The infection is caused by an acid-fast bacterium. The infection is caused by Bacillus anthracis. The infection is caused by Mycobacterium leprae.

[0009] In general, in some embodiments, a method of treating a bacterial infection is provided that includes administering to a patient in need of treatment thereof an effective amount of an antimicrobial adjuvant compound disclosed herein and an effective amount of an antimicrobial compound. Implementations may include one or more of the following: The infection is caused by a gram-positive bacterium. The infection is caused by a gram-negative bacterium. The infection is caused by an acid-fast bacterium. The infection is caused by Bacillus anthracis. The infection is caused by Mycobacterium leprae. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] definition Unless otherwise defined, terms used herein refer to the following definitions, as detailed below.

[0011] The term "administration" of a compound or "administering" a compound should be understood to mean providing the compound of the present invention to an individual in a form capable of introducing into the body of the individual in a prophylactically, therapeutically, or diagnostically effective amount, as applicable. Such forms may include, for example, oral dosage forms, injectable dosage forms, transdermal dosage forms, inhalant dosage forms, and rectal dosage forms.

[0012] The term "alkyl" as used herein means a straight or branched chain hydrocarbon containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1, 2, 3, 4, 5, or 6 carbons. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0013] The term "amide" as used herein means an amino, alkylamino, or dialkylamino group, as defined herein, appended to the parent molecular moiety through a carbonyl group. Representative examples of amide include, but are not limited to, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, and ethylmethylaminocarbonyl.

[0014] As used herein, the term "amino" refers to -NH 2 means a group.

[0015] The term "carbonyl" as used herein, means a -C(=O)- group.

[0016] The term "carboxy" as used herein refers to -COO-alkyl, which is a -COOH group that may be protected as an ester group.

[0017] As used herein, the term "cyano" refers to a -CN group.

[0018] The term "dialkylamino" as used herein refers to two independent alkyl groups, as defined herein, appended to the parent molecular moiety through a nitrogen atom. Representative examples of dialkylamino include, but are not limited to, dimethylamino, diethylamino, ethylmethylamino, and butylmethylamino.

[0019] As used herein, the term "fluoro" means --F.

[0020] The term "formyl" as used herein means a -C(O)H group.

[0021] The term "halo" or "halogen" as used herein means Cl, Br, I, or F.

[0022] As used herein, the term "hydroxy" refers to an --OH group.

[0023] The term "hydroxy-protecting group" refers to a substituent that protects a hydroxyl group from undesired reactions during synthetic procedures. Examples of hydroxy-protecting groups include, but are not limited to, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyl, triphenylmethyl, 2,2,2-trichloroethyl, t-butyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, methylene acetal, acetonide benzylidene acetal, cyclic orthoester, methoxymethylene, cyclic carbonate, and cyclic boronate. Hydroxy-protecting groups can be prepared by reacting a compound containing a hydroxy group with a base, such as triethylamine, and an alkyl halide, alkyl trifilate, trialkylsilyl halide, trialkylsilyl triflate, aryldialkylsilyl triflate, or alkyl chloroformate, CH 2 I2 or a dihaloboronate ester, such as a reagent selected from methyl iodide, benzyl iodide, triethylsilyl triflate, acetyl chloride, benzyl chloride, or dimethyl carbonate. Protecting groups can also be added onto hydroxy groups by reaction of the compound containing the hydroxy group with an acid and an alkyl acetal.

[0024] The term "imino" means a -C(=NH)- group, as defined herein.

[0025] The term "mercapto" as used herein means a --SH group.

[0026] As used herein, the term "nitro" refers to -NO 2 means a group.

[0027] The term "nitrogen protecting group" as used herein means a group intended to protect a nitrogen atom from undesired reactions during synthetic procedures. Nitrogen protecting groups include carbamates, amides, N-benzyl derivatives, and imine derivatives. Preferred nitrogen protecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl, pivaloyl, tert-butoxycarbonyl (Boc), tert-butylacetyl, trifluoroacetyl, and triphenylmethyl (trityl). Nitrogen protecting groups are added onto primary or secondary amino groups by reacting a compound containing an amine group with a base such as triethylamine and a reagent selected from alkyl halides, alkyl triphylates, dialkyl anhydrides, such as represented by (alkyl-O)2C=O, dialkyl anhydrides, such as represented by (aryl-O)2C=O, acyl halides, alkyl chloroformates, or alkylsulfonyl halides, arylsulfonyl halides, or halo-CON(alkyl)2, such as acetyl chloride, benzoyl chloride, benzyl bromide, benzyloxycarbonyl chloride, formyl fluoride, phenylsulfonyl chloride, pivaloyl chloride, (tert-butyl-OC=O)2O, trifluoroacetic anhydride, and triphenylmethyl chloride.

[0028] The term "oxo" as used herein means (=O).

[0029] Unless otherwise indicated, the term "prodrug" includes pharma- ceutically acceptable esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts, and sulfonates of the compounds disclosed herein. Examples of prodrugs include compounds that contain a biohydrolyzable moiety (e.g., biohydrolyzable amides, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable esters, biohydrolyzable phosphates, or biohydrolyzable ureido analogs). Prodrugs of the compounds disclosed herein are easily envisioned and prepared by those skilled in the art. See, e.g., Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985; Bundgaard, hours., "Design and Application of Prodrugs," A Textbook of Drug Design and Development, Krosgaard-Larsen and hours. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, hours., Advanced Drug Delivery Review, 1992, 8, 1-38.

[0030] Unless otherwise indicated, the term "protecting group" or "protective group", when used to refer to a portion of a molecule that is subjected to a chemical reaction, means a chemical moiety that is not reactive under the conditions of that chemical reaction and can be removed to provide a portion that is reactive under those conditions. Protecting groups are well known in the art. See, for example, Greene, TW and Wuts, PGM, Protective Groups in Organic Synthesis (3rd ed., John Wiley & Sons: 1999); Larock, RC, Comprehensive Organic Transformations (2nd ed., John Wiley & Sons: 1999). Some examples include benzyl, diphenylmethyl, trityl, Cbz, Boc, Fmoc, methoxycarbonyl, ethoxycarbonyl, and phthalimide. Protecting groups include, for example, nitrogen protecting groups and hydroxy protecting groups.

[0031] As used herein, the term "sulfonyl" refers to -S(O) 2 - group.

[0032] Certain compounds of the present invention may exist as stereoisomers in which asymmetric or chiral centers exist. These stereoisomers are "R" or "S" depending on the configuration of the substituents around the chiral carbon atom. The terms "R" and "S" as used herein are as defined in the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl.Chem., 1976, 45:13-30. The present invention contemplates various stereoisomers and mixtures thereof, which are specifically included within the scope of the present invention. Stereoisomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers, or by preparation of racemic mixtures followed by resolution as is well known to those skilled in the art. These resolution methods are exemplified by (1) attachment of the mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and optional liberation of the optically pure product from the auxiliary, as described in Furniss, Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical Organic Chemistry”, 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, which is incorporated herein by reference for its disclosure of methods for separation and purification of diastereomers, or (2) direct separation of the mixture of optical enantiomers on a chiral chromatographic column, or (3) fractional recrystallization methods.

[0033] Certain compounds of the present invention may exist as cis or trans isomers, and the substituents on the ring may be attached so that they are on the same side of the ring relative to each other (cis) or on opposite sides of the ring relative to each other (trans). Such methods are well known to those skilled in the art and may include separation of isomers by recrystallization or chromatography. It is understood that compounds may have tautomeric forms and geometric isomers, and these also constitute aspects.

[0034] It should be noted that chemical moieties that form part of a larger compound may be described herein using the name that is normally given to it when it exists as a single molecule or the name that is normally given to its radical.For example, the terms "pyridine" and "pyridyl" are given the same meaning when used to describe a moiety that is attached to another chemical moiety.Thus, for example, the two phrases "XOH, where X is pyridyl" and "XOH, where X is pyridine" are given the same meaning and include the compounds pyridin-2-ol, pyridin-3-ol, and pyridin-4-ol.

[0035] Also, it should be noted that names of compounds having one or more chiral centers that do not specify the stereochemistry of those centers encompass pure stereoisomers and mixtures thereof. Furthermore, any atom with unsatisfied valences shown in the drawings is intended to be attached to sufficient hydrogen atoms to satisfy the valences. In addition, chemical bonds shown with a single solid line parallel to a single dashed line encompass both single and double (e.g., aromatic) bonds, where valences permit.

[0036] As used herein, the term "pharmaceutically acceptable excipient" means any type of non-toxic inert solid, semi-solid or liquid filler, diluent, encapsulating material, or formulation auxiliary. Some examples of substances which may function as pharma- ceutically acceptable carriers are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth, malt, gelatin, talc, cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar-agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and phosphate buffers; as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and coloring agents, releasing agents, coating agents, sweetening agents, flavoring and perfuming agents, preservatives, and antioxidants may also be present in the composition, according to the judgment of one skilled in the art of formulation.

[0037] Unless otherwise indicated, a "therapeutically effective amount" of a compound is an amount sufficient to treat a disease or condition, or one or more symptoms associated with a disease or condition. In some embodiments, "treatment" may be determined by comparison to an untreated control.

[0038] The term "subject" is intended to include living organisms in which a disease can occur. Examples of subjects include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof.

[0039] The present invention is based at least in part on the design of compounds that inhibit acyl carrier protein (ACP) synthase (AcpS), the enzyme responsible for converting apo-ACP to holo-ACP. AcpS is present not only in Gram-positive and Gram-negative bacteria, but also in acid-fast bacteria such as Mycobacterium tuberculosis and even protozoa such as Plasmodium falciparum. Thus, AcpS inhibitors are expected to have a detrimental effect on the viability of many microorganisms. AcpS inhibitors are expected to have a detrimental effect on the maintenance of bacterial cell functions, including, for example, increasing the porosity of cell membranes and the dysfunction of efflux pumps in such membranes. In some embodiments, the compound is an AcpS inhibitor.

[0040] In some embodiments, the compounds have antibacterial effects when administered without other antibiotics. In some embodiments, the compounds may have antibacterial adjuvant ("adjuvant" or "probiotic") or other synergistic effects when co-administered with antibiotics such as colistin, azithromycin, erythromycin, ampicillin, rifampicin, clofazimine, or other antibiotic compounds described herein. In some embodiments, the compounds are antibacterial or antibacterial adjuvant with respect to gram-positive bacteria.

[0041] The usefulness of the compounds disclosed herein does not depend on them being AcpS inhibitors per se, but the design effect on that goal has at least partially resulted in the discovery of the compounds disclosed herein. Without wishing to be bound by a particular theory or hypothesis, the inventors believe that by inhibiting AcpS in bacteria, the compounds of the present invention interfere with the essential cellular function of lipid metabolism in bacteria. This interference with bacterial lipid metabolism has the potential to greatly affect the maintenance of bacterial cell membranes, which is expected to result in porous membranes that allow the entry of antibacterial compounds that would otherwise be unable to cross intact bacterial cell membranes. Furthermore, efflux pumps that are generally present in bacterial cell membranes are expected to be insufficient to remove the concentrations of antibacterial compounds possible in bacteria with porous membranes. These and other factors may be related to the mechanism of the antibacterial adjuvants described herein.

[0042] According to one embodiment, the compound, or a prodrug or pharma- ceutically acceptable salt thereof, has Formula I

[0043] [ka] is provided in relation to one of the following: In the formula, R 1 and R 2 are each independently fluoro or chloro; R 3 and R 4 are methyl or -CH 2 OH, except that R 3 is methyl, R 4 Ha-CH 2 OH and vice versa, R 5 is hydrogen or alkyl, R 6 , is -C(CF 3 ) 2 In some embodiments, R 1 and R 2are both chloro. In some embodiments, the compound is 2-(5-(4-chloro-2-(hydroxymethyl)phenyl)-4-(4-chloro-2-methylphenyl)thiophen-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol. In some embodiments, the compound is 2-(4-(4-chloro-2-(hydroxymethyl)phenyl)-5-(4-chloro-2-methylphenyl)thiophen-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol.

[0044] According to certain embodiments, a method of treating a bacterial infection is provided, comprising administering an effective amount of an antibacterial compound described herein to a patient in need of such treatment. In some embodiments, the gram-positive bacterium is Bacillus anthracis. In some embodiments, the gram-positive bacterium is Staphylococcus aureus. In some embodiments, the compound is antibacterial or an antibacterial adjuvant with respect to gram-negative bacteria. In some embodiments, the gram-negative bacterium is a Pseudomonas species, such as Pseudomonas aeruginosa. In some embodiments, the gram-negative bacterium is a Klebsiella species, such as Klebsiella pneumoniae. In some embodiments, the gram-negative bacterium is an Acinetobacter species, such as Acinetobacter baumanii. In some embodiments, the compound is antibacterial or an antibacterial adjuvant with respect to acid-fast bacteria. In some embodiments, the acid-fast bacterium is a Mycobacterium species, such as Mycobacterium leprae.

[0045] In some embodiments, the bacterial infection is substantially caused by a Gram-positive bacterium. In some embodiments, the bacterial infection is substantially caused by an Enterococcus species. In some embodiments, the bacterial infection is substantially caused by a Staphylococcus species. In some embodiments, the bacterial infection is substantially caused by a Bacillus species. In some embodiments, the bacterial infection is substantially caused by Staphylococcus epidermidis, Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus [MRSA]), Enterococcus species (including vancomycin-resistant Enterococcus [VRE]), Streptococcus species, Bacillus species, or Mycobacterium species. In some embodiments, the infection is polymicrobial. A bacterial infection "substantially caused" by a particular bacterium or species indicates that a given bacterial genus or species is believed to be primarily responsible for the pathology, epidemiology, or symptom profile of the bacterial infection and does not exclude the presence of other bacterial species (e.g., benignly colonizing bacteria). In some embodiments, the bacterial infection is, inter alia, an ulcerative skin and skin tissue infection, a wound infection, a diabetic foot infection, osteomyelitis, pneumonia, leprosy, anthrax infection, impetigo or a secondarily acquired traumatic lesion, gastroenteritis, meningitis, pneumonia, gonorrhea, peptic ulcer, hospital-acquired infection, or a bloodstream infection. In some embodiments, the described antibacterial agents are used, for example, as pharmaceutical compounds for treating humans, or as veterinary compounds for treating animals, poultry, livestock, etc., as well as in aquaculture and agricultural applications.

[0046] According to some embodiments, a method for treating bacterial infection is provided, comprising administering an effective amount of the antimicrobial adjuvant compound described herein and an effective amount of an antimicrobial compound to a patient in need of such treatment.In some embodiments, the antimicrobial adjuvant compound is itself antimicrobial to some degree.Therefore, it is possible to combine the compounds of the present invention with each other, as well as to combine the compounds of the present invention with known antimicrobial compounds. In some embodiments, the bacterial infection is an ulcerative skin and skin tissue infection, wound infection, leprosy, anthrax, diabetic foot infection, osteomyelitis, pneumonia, impetigo or secondarily acquired traumatic lesion, gastroenteritis, meningitis, pneumonia, sepsis, urinary tract infection, cochlea, peptic ulcer, hospital acquired infection, bloodstream infection, brucellosis, campylobacteriosis, cat scratch disease, cholera, legionnaires' disease, leptospirosis, Lyme disease, melioidosis, meningitis, whooping cough, plague, salmonellosis, shigellosis, syphilis, tularemia, typhoid, or a urinary tract infection. An effective amount of one or more of the above antibacterial agents may be used in the preparation of the above medicament for the treatment of a disease, disorder, or illness caused by a pathogenic bacterium selected from the group including, but not limited to, Escherichia, Klebsiella, Salmonella, Pseudomonas, Neisseria, Legionella, Haemophilus, Campylobacter, Helicobacter, and Shigella.

[0047] In another embodiment, there is provided a method of manufacturing a medicament for treating a bacterial infection comprising mixing an antimicrobial compound described herein with a suitable excipient.

[0048] In other embodiments, methods are provided for using the antibacterial compounds described herein for the treatment of bacterial infections.

[0049] In other embodiments, there is provided a method of manufacturing a medicament for treating a bacterial infection comprising combining an antimicrobial adjuvant described herein with a suitable antimicrobial compound.

[0050] In other embodiments, methods of using the antimicrobial adjuvants described herein to treat bacterial infections are provided. In some embodiments, the antimicrobial adjuvants are used in conjunction with or co-administered with antimicrobial compounds.

[0051] According to one embodiment, a pharmaceutical composition is provided comprising a compound of the invention and a pharma- ceutically acceptable excipient.

[0052] It should be noted that the antimicrobial agents or adjuvants may be prepared or formulated in a variety of ways and may be administered, for example, topically, orally, intravenously, intramuscularly, subcutaneously, intraperitoneally, intranasally, or by local or systemic intravascular injection means known to those of skill in the art and discussed below.

[0053] The antimicrobial compound or antimicrobial adjuvant compound may be prepared to be delivered at a concentration of about 1 nM to about 50 mM, or 10 nM to about 50 mM, or 100 nM to about 50 mM, or 1 μM to about 50 mM, or 10 μM to 50 mM, or 100 μM to 50 mM. As will be understood by those skilled in the art, this may be an "effective amount", i.e., a sufficient dosage is administered to achieve a concentration within one predicted range at the required location. In some antimicrobial embodiments, the effective amount will be informed, at least in part, by the minimum inhibitory concentration of the compound required to exert a bacteriostatic or bactericidal effect against the pathogen of interest. In some antimicrobial adjuvant embodiments, the effective amount may be informed, at least in part, by the approximate minimum concentration required to produce a desired adjuvant effect with a given known antibiotic against the pathogen of interest. In some embodiments, an effective amount may be measured to produce a serum concentration of 10 times or more the MIC (minimum inhibitory concentration), or 5 times or more the MIC, or 3 times or more the MIC, or the MIC in a subject with an infection. In some embodiments, an effective amount may be measured to produce an in situ concentration of 10 times or more the MIC (minimum inhibitory concentration), or 5 times or more the MIC, or 3 times or more the MIC, or the MIC.

[0054] An effective amount of a compound can be utilized in pure form or where such form exists in the form of a pharma-ceutically acceptable salt. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharma-ceutically acceptable carriers. However, it will be understood that the total daily usage of the compounds and compositions herein will be determined by the attending physician within the scope of sound medical judgment. The specific effective amount level for any particular subject will depend on a variety of factors, including: the disorder being treated and the severity of the disorder; the activity of the specific compound utilized; the specific composition utilized; the age, weight, health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound utilized; the duration of treatment; the risk / benefit ratio; drugs used in combination or concomitantly with the specific compound utilized; and similar factors well known in the medical field. For example, it is well within the skill of the art to begin administering a compound at a level lower than required to achieve the desired therapeutic effect, and then gradually increase the dosage until the desired effect is achieved.

[0055] The total daily dose of the compounds of the invention as administered to humans or lower animals may range from about 0.0003 to about 30 mg / kg body weight. For oral administration applications, more desirable dosages may range from about 0.0003 to about 1 mg / kg body weight. If desired, the effective daily dose may be divided into multiple doses for administration applications; thus, a single dose of the composition may contain such amounts or submultiples to make up the daily dose. For oral administration, the compositions are preferably provided in the form of tablets containing about 1.0, about 5.0, about 10.0, about 15.0, about 25.0, about 50.0, about 100, about 250, or about 500 milligrams of the active ingredient.

[0056] For best results, whether a particular compound is an antimicrobial agent or antimicrobial adjuvant against the pathogen of interest (and in the case of an adjuvant, with respect to the second antimicrobial compound) will generally be confirmed by a number of microbiological methods known in the art, including, for example, the methods disclosed in the Examples. It is well understood in the art that all "antimicrobial" compounds have an antimicrobial effect against at least one pathogen in one or more effective amounts, but antimicrobial compounds vary according to their range of activity and / or potency. Furthermore, all "antimicrobial adjuvants" have an adjuvant effect in conjunction with at least one antimicrobial compound against at least one pathogen in effective amounts of both the one or more antimicrobial compounds and the adjuvant, but antimicrobial adjuvant compounds vary according to their range of activity and potency and / or compatibility with a particular antimicrobial compound. As will be apparent to one skilled in the art, the total dosage will vary according to many factors, including, but by no means limited to, the weight, age, and condition of the individual or subject.

[0057] In some embodiments, one or more of the antimicrobial compounds may be co-administered with one or more known antibiotics. In some embodiments, one or more of the antimicrobial adjuvant compounds may be co-administered with one or more antimicrobial compounds, in which case the combined effective amount of the antimicrobial compounds may be, for example, 8-fold or less, or 16-fold or less, or 32-fold or less, or 64-fold or less, or 125-fold or less, or 250-fold or less than the amount that would otherwise be required in the absence of the antimicrobial adjuvant. In some embodiments, the antimicrobial adjuvant compound is not antimicrobial itself. In some embodiments, the antimicrobial adjuvant compound is antimicrobial itself. In some embodiments, one or more of the antimicrobial adjuvant compounds may be combined with one or more antimicrobial compounds in a single dosage form. In some embodiments, the antimicrobial compound is an antimicrobial compound of the present invention. In some embodiments, the antibacterial compound is, for example, almecillin, amdinocillin, amikacin, amoxicillin, amphomycin, amphotericin B, ampicillin, azacitidine, azaserine, azithromycin, azlocillin, aztreonam, artemisinin, allopurinol, amicacin, aminoglycosides, amphotericin B, ampicillin, ansamycins, anthracyclines, antifungal agents. (antimycotics), azithromycin, bacampicillin, bacitracin, benzylpenicilloyl polylysine, bleomycin, brefeldin A, butoconazole, candicidin, capreomycin, carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cefdinir, cefepime, cefixime, cefinenoxime, cefinetazole, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefoxitin, cefpiramide,Cefpodoxime, cefprozil, cefsulodin, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, cephacetrile, cephalexin, cephaloglycin, cephaloridine, cephalothin, cephapirin, cephradine, chloramphenicol, cilastatin, cinnamycin, ciprofloxacin, clarithromycin, clavulanic acid, clindamycin, clioquinol, clofazimine , cloxacillin, colistimethate, colistin, cyclacillin, cycloserine, cyclosporine, cyclo-(Leu-Pro), camptothecin, cefataxime, cephalexin, cephalosporins, chalkomycin, shaltrusine, chlorotetracyclines, chlorothricin, chrymutasins, chrysomycin M M), chrysomycin V, clomocyclines, dactinomycin, dalbavancin, dalfopristin, daptomycin, daunorubicin, demeclocycline, detorubicin, dicloxacillin, dihydrostreptomycin, dirithromycin, doxorubicin, doxycycline, ellipticine, elsamicin, epirubicin, erythromycin, eveminomycin in), filipins, fluconazoles, fungichromins, fusidic acid, floxacillin, fosfomycin, gentamicin, gilvocarin, griseofulvin, griseoviridin, guamecyclines, gemifloxacin, gramicidin, hetacillin, idarubicin, imipenem, iseganan, ivermectin,Ilosamides, itraconazoles, kanamycin, laspartomycin, linezolid, loracarbef, lankamycin, lincomycin, magainin, meclocycline, meropenem, methacycline, mezlocillin, minocycline, mitomycin, moenomycin, moxalactam, moxifloxacin, mycophenolic acid, macrolides , methicillin, mitoxantrone, nafcillin, natamycin, neomycin, netilmicin, niphimycin, nitrofurantoin, novobiocin, nalidixic acid, norfloxin, nystatin, ofloxacin, oleandomycin, oxytetracyline, paromomycin, penicillamine, phenethicillin, piperacillin, plicamycin, pristinamycin, petirosin, penicillin s), pesticides, fosfomycin, pimarcin, platensimycin, polyenes, polymyxin B, polymyxin E, quinupristin, quinolones, rabidomycin, reserpines, rifamycin, ristocetin A and B, rifabutin, rifampicin, rifampin, rifamycin, rolitetracycline, sisomicin, spiramycin, spironolactone, sodium sulfacetamide, sulfonamides, spectrofluori spectrinomycin, streptomycin, streptozocin, sulbactam, sultamicillin, tacrolimus, tazobactam, teicoplanin, telithromycin, teramycins, tetracyclines, thiamphenicols, thiolutins, tobramycin, tyrothricin, ticarcillin, tigecycline, tobramycin, troleandomycin, tunicamycin, tyrothricin,Known antibacterial compounds such as vancomycin, vidarabine, viomycin, virginiamycin, and wortmannins, and the plural terms in the above list are meant to refer to one or more members of a family of antibacterial agents known in the art by their name. Which compound or compounds should be co-administered or formulated in combination with the compounds of the invention depends on a number of factors, including, but not necessarily limited to, the efficacy of the drug in the absence of the antibacterial adjuvant compound, the mechanism of action of the compound, the identity of the pathogen causing or progressing the disease state, or the severity of the disease state in the subject, as described below.

[0058] The pharmaceutical composition can be formulated for oral administration in solid or liquid form, for parenteral, intravenous, subcutaneous, intramuscular, intraperitoneal, intraarterial, or intradermal injection, or for vaginal, nasal, topical, or rectal administration.The pharmaceutical composition of the present invention suitable for oral administration can be provided as a discrete dosage form, such as tablets, chewable tablets, caplets, capsules, liquids, and flavored syrups.Such dosage forms contain a predetermined amount of active ingredient and can be prepared by a pharmaceutical method well known to those skilled in the art.See generally Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

[0059] Parenteral dosage forms can be administered to patients by various routes, including subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically circumvents the subject's natural defenses against impurities, parenteral dosage forms can be specifically sterile or sterilized prior to administration to a subject. Examples of parenteral dosage forms include solutions ready for injection, dry products ready to be dissolved or suspended in a pharma- ceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. In some embodiments, injectable parenteral injections include pharma-ceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders that are reconstituted into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like, and suitable mixtures thereof), vegetable oils (such as olive oil), and injectable organic esters, such as ethyl oleate, or suitable mixtures thereof. The proper fluidity of the compound can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Such compositions can also contain adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable dosage form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0060] In some cases, it is often desirable to slow down the absorption of drugs from subcutaneous or intramuscular injections in order to prolong the effect of drugs.This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility.Then, the absorption rate of the drug depends on the dissolution rate, which can also depend on the size and crystalline form of the crystals.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0061] The suspension may contain, in addition to the active compound, a suspending agent such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, and mixtures thereof. If desired, and for more effective distribution, the compound may be incorporated into a sustained release or targeted delivery system, such as a polymer matrix, liposome, and microsphere. They may be sterilized, for example, by filtration through a bacterial retention filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or any sterile injectable medium immediately before use.

[0062] Injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled by the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues. The injectable preparations can be sterilized, for example, by filtration through a bacterial retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use.

[0063] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oils may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0064] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, one or more compounds are mixed with at least one inert pharma- ceutically acceptable carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and salicylic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and gum arabic; c) diluents, such as glycerin; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retardants, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glycerol monostearate; h) kaolin and bentonite clays. and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also comprise buffering agents.

[0065] Similar types of solid compositions can be employed as fillers in soft and hard filled gelatin capsules using lactose or milk sugar and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical compounding art. They can optionally contain opacifying agents, and can be of a composition that releases the active ingredient only, or preferentially, in a certain part of the gastric tract, in a delayed manner. Examples of materials that can serve to delay the release of the active agent can include polymeric substances and waxes.

[0066] The dosage form for topical administration may include powder, spray, ointment, and inhalant.The compound of the present invention may be mixed under sterile conditions with a pharma- ceutically acceptable carrier, and any necessary preservatives, buffers, or propellants that may be required.Ophthalmic preparations, eye ointments, powders, and solutions are contemplated as being within the scope of the present invention.Aqueous liquid compositions containing the compound are also contemplated.

[0067] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to active compound, liquid dosage forms can contain the inert diluent commonly used in the art, such as water or other solvent, solubilizer and emulsifier, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and mixtures thereof.

[0068] In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfuming agents. Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The desired compound is mixed under sterile conditions with a pharma- ceutically acceptable carrier and any necessary preservatives or buffers that may be required. Ophthalmic preparations, ear drops, eye ointments, powders, and solutions are also contemplated as being within the scope of the present invention. The ointments, pastes, creams, and gels may contain, in addition to the active compounds of the present invention, animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0069] Powders and sprays may contain, in addition to the compounds of this invention, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorohydrocarbons.

[0070] The compound may also be administered in the form of liposomes. As known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The present composition in liposome form may contain, in addition to the compound of the present invention, stabilizers, preservatives, etc. The preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins), used separately or together. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY, (1976), p 33 et seq.

[0071] In some embodiments, one or more of the above concentrations or dosages of antimicrobial agents or antimicrobial adjuvants may be combined with a pharma- ceutically or pharmacologically acceptable carrier, excipient, or diluent, either biodegradable or non-biodegradable.Typical examples of carriers include, but are in no way limited to, poly(ethylene-vinyl) acetate, copolymers of lactic and glycolic acid, poly(lactic acid), gelatin, collagen matrices, polysaccharides, poly(D,L lactide), poly(malic acid), poly(caprolactone), cellulose, albumin, starch, casein, dextran, polyester, ethanol, methacrylate, polyurethane, polyethylene, vinyl polymers, glycols, mixtures thereof, and the like. Standard excipients include gelatin, casein, lecithin, gum arabic, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, sugars, and starch.

[0072] As will be apparent to those skilled in the art, specific carriers and combinations of carriers known in the art can be selected based on their properties and release characteristics in view of the intended use. Specifically, carriers can be pH-sensitive, thermosensitive, thermogelling, and can be arranged for sustained release or immediate burst. In some embodiments, different classes of carriers can be used together for multiple effects, such as an immediate burst followed by sustained release.

[0073] In other embodiments, one or more of the antimicrobial agents or antimicrobial adjuvants at the above-mentioned concentrations or dosages may be encapsulated for delivery. Specifically, the compound may be encapsulated in biodegradable microspheres, microcapsules, microparticles, or nanospheres. The delivery vehicle may be composed of, for example, hyaluronic acid, polyethylene glycol, poly(lactic acid), gelatin, poly(E-caprolactone), or poly(lactic-glycolic) acid polymers. Combinations may also be used, for example, gelatin nanospheres may be coated with poly(lactic-glycolic) acid polymers. As will be apparent to those skilled in the art, these and other suitable delivery vehicles may be prepared and utilized for the delivery of the compound according to protocols known in the art.

[0074] It should be noted that the above-mentioned antimicrobial agents may be combined with penetration enhancers known in the art for improved delivery. Examples of penetration enhancers include, but are not limited to, those described in U.S. Patent Nos. 3,472,931; 3,527,864; 3,896,238; 3,903,256; 3,952,099; 4,046,886; 4,130,643; 4,130,667; 4,299,826; 4,335,115; 4,343,798; 4,472,115 ... Nos. 379,454; 4,405,616; 4,746,515; 4,788,062; 4,820,720; 4,863,738; 4,863,970; and 5,378,730; British Patent No. 1,011,949; and Idson, 1975, J. Pharm. Sci. 64:901-924.

[0075] "Pharmaceutically acceptable salts" include salts that retain the desired biological activity of the parent antimicrobial compound or antimicrobial adjuvant compound and do not impart any undesired toxicological effects. Examples of such salts are salts of acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.; salts of acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, benzoic acid, pamoic acid, alginic acid, methanesulfonic acid, naphthalenesulfonic acid, etc. Also included are salts of cations such as sodium, potassium, lithium, zinc, copper, barium, bismuth, calcium, etc.; or organic cations such as trialkylammonium. Combinations of the above salts are also useful. It will be understood that both the compounds disclosed herein in salt-free form and analog compounds in the form of pharma-ceutically acceptable salts are compounds of the present invention. Additionally, prodrugs, for example, esters of the compounds disclosed herein, are compounds of the present invention. The preparation and use of acid addition salts, carboxylate salts, amino acid addition salts, and also zwitterionic salts of the compounds of this invention are considered to be pharma- ceutically acceptable if, within the scope of sound medical judgment, they are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio, and are effective for their intended use. Such salts may also include various solvates and hydrates of the compounds of this invention.

[0076] In some embodiments, the described antibacterial compounds are used as pharmaceutical compounds, e.g., for the treatment of humans, or as veterinary compounds, for the treatment of animals, poultry, livestock, etc., as well as for aquaculture and agricultural applications.

[0077] While various embodiments of the invention have been described above, it will be recognized and understood that modifications may be made therein and the appended claims are intended to cover all such modifications which fall within the spirit and scope of the invention.

[0078] Specific embodiments will now be illustrated using examples. EXAMPLES

[0079] Example 1 Synthesis of 2-(4-(4-chloro-2-(hydroxymethyl)phenyl)-5-(4-chloro-2-methylphenyl)thiophen-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

[0080] [ka]

[0081] Synthesis of 4-bromo-5-(4-chloro-2-methylphenyl)thiophene-2-carbaldehyde (2) 4,5-Dibromothiophene-2-carbaldehyde 1 (2.0 g, 7.41 mmol, 1.0 equiv.), 4-chloro-2-methylphenylboronic acid (1.2 g, 7.04 mmol, 0.95 equiv.), Pd(PPh 3 ) 4 (0.428g, 0.37mmol, 0.05eq), Na 2 CO 3 (1.57 g, 14.8 mmol, 2.0 equiv.) was placed in a flame-dried round-bottom flask. Dioxane:H 2 A mixture of 20 mL:6 mL of O was added and the resulting reaction mixture was purged with argon for 15 minutes. The reaction was heated at a temperature of approximately 95° C. for 12 hours, during which complete consumption of the starting material was observed by TLC. The reaction was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layers were washed with water and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (5% EtOAc in hexanes) to give the title compound 4-bromo-5-(4-chloro-2-methylphenyl)thiophene-2-carbaldehyde 2 (1.9 g, 82%) as a yellow-green liquid.

[0082] Synthesis of 1-(4-bromo-5-(4-chloro-2-methylphenyl)thiophen-2-yl)-2,2,2-trifluoroethan-1-ol (3) 4-Bromo-5-(4-chloro-2-methylphenyl)thiophene-2-carbaldehyde 2 (1.90 g, 6.03 mmol, 1.0 equiv.) in anhydrous THF (20 mL) at 0° C. was treated with trimethyl(trifluoromethyl)silane (1.20 mL, 7.84 mmol, 1.3 equiv.) followed by tetrabutylammonium fluoride solution (1 M in THF, 0.2 mL, 0.1 equiv.). The reaction was stirred at room temperature for 30 min. The formation of the OTMS intermediate was observed. A stoichiometric amount of tetrabutylammonium fluoride solution (1 M in THF, 2.0 mL, 1.0 equiv.) was added to the reaction mixture to cleave the OTMS intermediate. The reaction was continued to stir at room temperature for 3 h. After completion of the reaction, it was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water and diluted with Na 2 SO 4 The mixture was dried at 40° C. and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (10% EtOAc in hexane) to give the title compound 1-(4-bromo-5-(4-chloro-2-methylphenyl)thiophen-2-yl)-2,2,2-trifluoroethan-1-ol 3 (1.62 g, 70.1%) as a yellow liquid.

[0083] Synthesis of 1-(4-bromo-5-(4-chloro-2-methylphenyl)thiophen-2-yl)-2,2,2-trifluoroethan-1-one (4) 1-(4-Bromo-5-(4-chloro-2-methylphenyl)thiophen-2-yl)-2,2,2-trifluoroethan-1-ol 3 (1.62 g, 4.22 mmol, 1.0 equiv.) was dissolved in DCM (16 mL) and Dess-Martin periodinane (3.6 g, 8.43 mmol, 2 equiv.) was added stepwise over a period of 30 min at 0° C. The reaction was allowed to stir at room temperature for 3 h. After completion of the reaction, it was diluted with DCM and water. The aqueous layer was extracted with DCM and the combined organic layers were washed with water and diluted with NaCl. 2 SO 4The mixture was dried at 40° C. and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (3% EtOAc in hexane) to give the title compound 1-(4-bromo-5-(4-chloro-2-methylphenyl)thiophen-2-yl)-2,2,2-trifluoroethan-1-one 4 (1.40 g, 70.1%) as a white liquid.

[0084] Synthesis of 2-(4-bromo-5-(4-chloro-2-methylphenyl)thiophen-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (5) 1-(4-bromo-5-(4-chloro-2-methylphenyl)thiophen-2yl)-2,2,2-trifluoroethan-1-one 4 (1.40 g, 3.65 mmol, 1.0 equiv.) in anhydrous THF (14 mL) at 0 °C was treated with trimethyl(trifluoromethyl)silane (1.0 mL, 7.28 mmol, 2.0 equiv.) followed by tetrabutylammonium fluoride solution (1 M in THF, 0.1 mL, 0.1 equiv.). The reaction was stirred at room temperature for 30 min. The formation of the OTMS product was observed as an intermediate. A stoichiometric amount of tetrabutylammonium fluoride solution (1 M in THF, 1.0 mL, 1.0 equiv.) was added to the reaction mixture to cleave the OTMS intermediate. The reaction was stirred at room temperature for 7 h. After completion of the reaction, it was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water and washed with Na 2 SO 4 The mixture was dried at 40° C. and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (10% EtOAc in hexane) to give the title compound 2-(4-bromo-5-(4-chloro-2-methylphenyl)thiophen-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol 5 (0.86 g, 52.12%) as a viscous liquid.

[0085] Synthesis of 2-(4-(4-chloro-2-(hydroxymethyl)phenyl)-5-(4-chloro-2-methylphenyl)thiophen-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (6) 2-(4-bromo-5-(4-chloro-2-methylphenyl)thiophen-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol 5 (0.86 g, 1.89 mmol, 1.0 equiv.), (4-chloro-2-(hydroxymethyl)phenyl)boronic acid (0.42 g, 2.27 mmol, 1.2 equiv.), Pd(Pd(PPh 3 ) 4 (0.11g, 0.094mmol, 0.05eq), Na 2 CO 3 (0.6 g, 5.68 mmol, 3.0 equiv.) was placed in a flame-dried round-bottom flask. Dioxane:H 2 A mixture of 10 mL:5 mL of O was added and the resulting reaction mixture was purged with argon for 15 minutes. The reaction was then heated at a temperature of approximately 100° C. for 12 hours, during which complete consumption of the starting material was observed by TLC. The reaction was cooled to room temperature, diluted with water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with water and diluted with Na 2 SO 4 The mixture was dried at 40° C. and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (20% EtOAc in hexanes) followed by lyophilization to give the title compound 2-4-(4-chloro-2-(hydroxymethyl)phenyl)-5-(4-chloro-2-methylphenyl)thiophen-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol 6 (0.62 g, 64%) as a colorless solid. 1 H NMR (300 MHz, CDCl 3 )δ(ppm)7.47(d,J=2.1Hz,1H),7.35(s,1H),7.19-7.07(m,4H),6.94(d,J=8.2Hz,1H),4.41(s,2H),2.00(s,3H); 13 C NMR (75 MHz, CDCl 3)δ(ppm)140.94,140.05,139.10,137.44,134.86,134.30,132.80,132.66,131.98,131.25,130.6 8,130.60,130.32,128.58,127.95,126.23,124.10,120.29,77.36,76.42,62.50,20.36;ESI-HRMS C 21 H 14 Cl 2 F 6 O 2 Calculated value of S: 513.9996 Measured value m / z: 512.9940 [MH] - ; HPLC purity: 98.85% (tR = 9.89 min).

[0086] Example 2 Synthesis of 2-(5-(4-chloro-2-(hydroxymethyl)phenyl)-4-(4-chloro-2-methylphenyl)thiophen-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol This compound was synthesized generally according to the method of Example 1, except that the order of addition of the boronic acids was reversed, i.e., (4-chloro-2-(hydroxymethyl)phenyl)boronic acid was used in the first step and 4-chloro-2-methylphenylboronic acid in the last step.

[0087] Example 3 Minimum inhibitory concentration (MIC) determination B. anthracis inoculum was prepared by suspending colonies in sheep blood agar plates (BAP) for 18–24 h. B. anthracis plates were incubated at 35°C for 36–48 h. MICs were determined by 96-well microplate microdilution method according to CLSI guidelines (Clinical and Laboratory Standards Institute, 2015).

[0088] The following table shows the results of experiments with compounds DNM94A, DNM95A, ciprofloxacin, and colistin (GT64=>64 micrograms / mL) demonstrating antibacterial effects against multiple strains of Bacillus anthracis.

[0089] [Table 1]

Claims

1. Formula I 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, In the formula, R １ and R ２ are each independently fluoro or chloro, and R ３ and R ４ are each methyl or —CH ２ OH, with the proviso that R ３ is methyl, R ４ Ha-CH ２ OH and vice versa, and R ５ is hydrogen or alkyl, and R ６ is -C(CF ３ ) ２ OH or a pharmaceutically acceptable salt thereof.

2. R １ and R ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of is chloro.

3. R ３ is methyl, and R ４ Ga-CH ２ OH and R ５ 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein:

4. R ３ Ga-CH ２ OH and R ４ is methyl, and R ５ 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein:

5. A pharmaceutical composition for use in a method for treating a bacterial infection, comprising administering an effective amount of a compound described in any one of claims 1 to 4 as an antibacterial compound to a patient in need of treatment for the bacterial infection.

6. The pharmaceutical composition of claim 5 , wherein the bacterial infection is substantially caused by a gram-positive bacterium.

7. 7. The pharmaceutical composition of claim 6, wherein the bacterial infection is substantially caused by Bacillus anthracis.

8. The pharmaceutical composition of claim 5 , wherein the bacterial infection is substantially caused by an acid-fast bacterium.

9. 9. The pharmaceutical composition of claim 8, wherein the bacterial infection is substantially caused by Mycobacterium leprae.

10. The pharmaceutical composition of claim 5 , wherein the bacterial infection comprises an enterococcal infection.

11. 6. The pharmaceutical composition of claim 5, wherein the bacterial infection is substantially caused by a bacterial species selected from Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, Bacillus cereus, and Streptococcus sp.

12. A pharmaceutical composition for use in a method for treating a bacterial infection, comprising administering to a patient in need of treatment an effective amount of a compound described in any one of claims 1 to 4 as an antibacterial adjuvant, and an effective amount of an antibacterial compound.

13. The pharmaceutical composition of claim 12, wherein the bacterial infection is substantially caused by a gram-negative bacterium.

14. 13. The pharmaceutical composition of claim 12, wherein the bacterial infection is substantially caused by a gram-positive bacterium.

15. 13. The pharmaceutical composition of claim 12, wherein the bacterial infection is polymicrobial.

16. 13. The pharmaceutical composition of claim 12, wherein the bacterial infection is substantially caused by a bacterial species selected from Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumanii, and Escherichia coli.

17. 13. The pharmaceutical composition of claim 12, wherein the antibacterial compound is selected from the group consisting of colistin, ampicillin, erythromycin, and azithromycin.

18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient.

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