EA040668B1 - HETEROARYL TRIFLUOROBORATE COMPOUNDS FOR THE TREATMENT OF MYCOBACTERIAL INFECTIONS - Google Patents

Description

Technical field

The present invention relates, for example, to compounds of formula (I)

and to pharmaceutical compositions containing said compounds. The compounds and compositions described herein are antibacterial agents and can be used to treat tuberculosis and other mycobacterial infections.

All documents cited or referenced below are expressly incorporated into this document by reference.

State of the art

The bacterium Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a devastating infectious disease. An estimated 2 million TB patients die each year worldwide. Failure to properly treat TB has caused global drug resistance in Mtb, and thus some drugs have become ineffective.

Pyrazinamide (PZA) is one of the four modern first-line anti-tuberculosis drugs. Its introduction in the 1970s and 80s reduced the duration of TB treatment from 9-12 months to 6 months. Despite the importance of this drug, the mechanism of action of PZA is not well understood. But it is generally accepted that PZA is a prodrug that is converted by pyrazinamidase (PncA) into Mtb to the active form of pyrazic acid (POA). The minimum inhibitory concentration of PZA against Mtb is high under standard culture conditions (>200 μM), and activity appears when the pH of the culture medium is about 5. It is believed that POA acidifies the cytoplasm of Mtb, which disrupts the membrane potential of Mtb and/or affects the synthesis pantothenate and CoA (Y. Zhang, W. Shi, W. Zhang, D. Mitchison, 2014, Microbiol Spectr. 2(4):MGM2-0023-2013). A feature of PZA is that it is more effective against resistant Mtb than fast growing Mtb. Another characteristic feature of PZA is that it synergistically combines with other anti-tuberculosis drugs, which is most pronounced with rifampicin or bedaquiline.

However, the effectiveness of PZA is reduced due to the occurrence of resistance. An estimated 16.2% of all TB cases are resistant to PZA, while among multidrug-resistant TB cases this number reaches 60.5% (M.G. Whitfield, H.M. Soeters, R.M. Warren, T. York, S.L. Sampson, E.M. Streicher , P.D. van Helden, A. van Rie, 2015, PLoS One 10(7):e0133869). Most resistance to PZA has been attributed to mutations in PncA, the enzyme that converts PZA to POA.

Therefore, there is a need in the art to identify new chemicals that can function similarly to POA but can also overcome PZA resistance. In addition, it is desirable that such an agent has improved safety and/or a more favorable FA profile compared to POA.

Brief description of the invention

The present invention relates to compounds of formula (I)

where X and Y, independently of each other, represent C or N, provided that X and Y do not represent both C;

M is Cs, K, Li, Na;

Ri is, in each case individually, hydrogen, halogen, _C1-6 alkoxy, _C1-6 alkyl, _C1-6 alkyl substituted with at least one halogen atom, CN, -NR3R4, _C3-6 cycloalkyl or heterocycloalkyl, where the specified heterocycloalkyl is a 4-6-membered monocyclic ring in which one carbon of the ring is replaced by nitrogen;

R ₂ is hydrogen, halogen, C _1-6 alkoxy, C _1-6 alkyl, C _1-6 alkyl substituted with at least one halogen atom, CN, -NR3R4, C _3-6 cycloalkyl or heterocycloalkyl, wherein said heterocycloalkyl is a 4-6-membered monocyclic ring in which one carbon of the ring is replaced by nitrogen;

R ₃ and R 4 , independently of each other, are C _1-6 alkyl;

n is 1 or 2;

p is 1 or 2;

q is 1, provided that the compound of formula (I) is not:

- 1 040668 potassium (2-methoxypyridin-3-yl) trifluoroborate, potassium (2-ethoxypyridin-3-yl) trifluoroborate, potassium (6-(trifluoromethyl) pyridin-3-yl) trifluoroborate, potassium (5-methoxypyridin-3- yl) trifluoroborate, potassium (5-bromopyridin-2-yl) trifluoroborate, potassium (5-bromo-pyridin-3-yl) trifluoroborate, potassium (5-bromo-3-methylpyridin-2-yl) trifluoroborate, potassium (5-bromo- 6-methylpyridin-2-yl)trifluoroborate, potassium (pyridin-3-yl)trifluoroborate, potassium (pyridin-2-yl)trifluoroborate.

The present invention also relates to pharmaceutical compositions containing the above compounds, and to methods for the treatment of microbial infections such as tuberculosis.

Brief description of graphic materials

In FIG. 1 shows the change in internal pH in Mtb when treated with PZA.

In FIG. 2 shows the change in internal pH in Mtb when treated with compound 1-4.

In FIG. 3 shows the change in internal pH in Mtb during treatment with isoniazid (INH, negative control compound).

Detailed description of the invention

It should be understood that the terminology used in the present description is intended to describe certain embodiments and is not intended to limit the present invention. In addition, some methods, devices, and materials will be described below, although any methods, devices, and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention.

The present invention relates to novel heteroaryl trifluoroborate salts, formulations containing them, and their use as medicaments for the treatment of tuberculosis and other mycobacterial infections, either alone or in combination with other anti-tuberculosis agents. These anti-tuberculosis agents include, but are not limited to, rifampicin, rifabutin, rifapentene, isoniazid, ethambutol, kanamycin, amikacin, capreomycin, clofazimine, cycloserine, para-aminosalicylic acid, linezolid, sutezolid, bedaquiline, delamanid, pretomanid, moxifloxacin, and levofloxacin.

As used herein, the term alkyl, alone or in combination with other groups, refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon radical containing one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms.

As used herein, the term alkenyl, alone or in combination with other groups, refers to a straight or branched chain hydrocarbon residue having an olefinic bond.

The term cycloalkyl refers to a monovalent mono- or polycarbocyclic radical containing three to ten carbon atoms, preferably three to six carbon atoms. This term is further illustrated by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, indanyl, and the like. In a preferred embodiment of the present invention, the cycloalkyl moieties may be optionally substituted with one, two, three or four substituents. Each substituent may independently be alkyl, alkoxy, halogen, amino, hydroxyl, or oxygen, unless specifically noted otherwise. Examples of cycloalkyl groups include, but are not limited to, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclopentenyl, optionally substituted cyclohexyl, optionally substituted cyclohexylene, optionally substituted cycloheptyl, and the like. or such groups, which are separately given in this document as an example.

The term heterocycloalkyl refers to a mono- or polycyclic alkyl ring where one, two or three carbon atoms in the ring are replaced by a heteroatom such as N, O or S. Examples of heterocycloalkyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxanyl, and the like. The heterocycloalkyl groups may be unsubstituted or substituted and the attachment may be via their carbon backbone or via their heteroatom(s) where appropriate.

As used herein, the term lower alkyl, alone or in combination with other groups, refers to a branched or straight chain alkyl radical containing one to nine carbon atoms, preferably one to six carbon atoms, more preferably one to four carbon atoms. . This term is further illustrated by radicals such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, 3-methylbutyl, n-hexyl, 2-ethylbutyl, and the like.

The term aryl refers to an aromatic mono- or polycarbocyclic radical containing 6-12 carbon atoms containing at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2dihydronaphthyl, indanyl, 1H-indenyl, and the like.

Alkyl, lower alkyl and aryl groups may be substituted or unsubstituted. In the case of substituted groups, eg 1 to 4 substituents are usually present. These substituents may optionally, together with the alkyl, lower alkyl or aryl group to which they are attached, form a ring. Substituents may include, for example: carbon-containing groups such as alkyl, aryl, arylalkyl (eg substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogenated groups such as haloalkyl (eg trifluoromethyl); oxygen-containing groups such as alcohols (eg hydroxyl, hydroxyalkyl, aryl(hydroxyl)alkyl), ethers (eg alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl, more preferably eg methoxy and ethoxy), aldehydes (eg carboxaldehyde), ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl), acids (e.g. carboxy, carboxyalkyl), acid derivatives such as esters (e.g. alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl), amides (e.g. aminocarbonyl, mono - or dialkylaminocarbonyl, aminocarbonylalkyl, mono- or dialkylaminocarbonylalkyl, arylaminocarbonyl), carbamates (eg alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyloxy, mono- or dialkylaminocarbonyloxy, arylaminocarbonyloxy) and ureas (eg mono- or dialkylaminocarbonylamino or arylaminocarbonylamino); nitrogen-containing groups such as amines (eg amino, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl), azides, nitriles (eg cyano, cyanoalkyl), nitro; sulfur-containing groups such as thiols, thioethers, sulfoxides and sulfones (eg alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arysulfinyl, arysulfonyl, arythioalkyl, arylsulfinylalkyl, arylsulfonylalkyl); as well as heterocyclic groups containing one or more heteroatoms (for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl , pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidine, hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, naphtrinolinyl, , quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanil, isochromanil, phthalazinyl and carbolinyl).

The term heteroaryl refers to an aromatic mono- or polycyclic radical of 5-12 atoms containing at least one aromatic ring containing one, two or three heteroatoms in the ring selected from N, O and S, while the remaining atoms in the ring are C. Examples of such groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, oxazolyl, thiazolyl, and the like.

The heteroaryl group described above may be independently substituted with one, two or three substituents. Substituents may include, for example: carbon-containing groups such as alkyl, aryl, arylalkyl (eg substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogenated groups such as haloalkyl (eg trifluoromethyl); oxygen-containing groups such as alcohols (e.g. hydroxyl, hydroxyalkyl, aryl(hydroxyl)alkyl), ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl), aldehydes (e.g. carboxaldehyde), ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl , arylalkylcarbonyl, arylcarbonylalkyl), acids (e.g. carboxy, carboxyalkyl), acid derivatives such as esters (e.g. alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl), amides (e.g. aminocarbonyl, mono- or dialkylaminocarbonyl, aminocarbonylalkyl, mono- or dialkylaminocarbonylalkyl, arylaminocarbonyl), carbamates (eg alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyloxy, mono- or dialkylaminocarbonyloxy, arylaminocarbonyloxy) and ureas (eg mono- or dialkylaminocarbonylamino or arylaminocarbonylamino); nitrogen-containing groups such as amines (eg amino, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl), azides, nitriles (eg cyano, cyanoalkyl), nitro; sulfur-containing groups such as thiols, thioethers, sulfoxides and sulfones (eg alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arysulfinyl, arysulfonyl, arythioalkyl, arylsulfinylalkyl, arylsulfonylalkyl); as well as heterocyclic groups containing one or more heteroatoms (for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl , pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidine, hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl, benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolinyl, isoquinolinyl, naphtrinolinyl, , quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenil,

- 3 040668 chromanil, isochromanil, phthalazinyl, benzothiazolyl and carbolinyl).

As used herein, the term alkoxy means alkyl-O-; and the term alkoil means alkyl-CO-. Substituting alkoxy groups or alkoxy-containing substituents may be substituted, for example, with one or more alkyl or halogen groups.

As used herein, the term halogen denotes a fluorine, chlorine, bromine or iodine radical, preferably a fluorine, chlorine or bromine radical.

The compounds of formula (I) may contain one or more asymmetric carbon atoms and may exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates. Optically active forms can be obtained, for example, by separation of racemates, asymmetric synthesis or asymmetric chromatography (chromatography with chiral adsorbents or eluent). The present invention covers all of these forms.

In the practice of the method of the present invention, an effective amount of any one of the compounds of the present invention, or a combination of any of the compounds of the present invention, is administered by any of the usual and acceptable methods known in the art, alone or in combination. Thus, these compounds or compositions can be administered, for example, in the eye, orally (for example, in the oral cavity), sublingually, parenterally (for example, intramuscularly, intravenously or subcutaneously), rectally (for example, via suppositories or by lavage), transdermally (for example , electroporation of the skin) or by inhalation (for example, using an aerosol) and in the form of solid, liquid or gaseous dosage forms, including tablets and suspensions. The introduction can be carried out in the form of a single dosage form with continuous therapy or ad libitum single therapy regimen. The therapeutic composition may also be in the form of an oily emulsion or dispersion in combination with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained release composition for subcutaneous or intramuscular administration.

Suitable pharmaceutical carriers for the preparation of compositions according to the present invention may be solids, liquids or gases. Thus, said compositions may be in the form of tablets, pills, capsules, suppositories, powders, enteric-coated or otherwise protected formulations (e.g., bound to ion exchange resins or packaged in lipid-protein vesicles), sustained release formulations, solutions, suspensions, elixirs, aerosols, etc. The carrier can be selected from a variety of oils, including oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are typical liquid carriers, especially (when isotonic with blood) for injectable solutions. For example, intravenous formulations include sterile aqueous solutions of the active ingredient(s) which are prepared by dissolving the solid active ingredient(s) in water to form an aqueous solution, which is then sterilized. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, ethanol and the like. Said compositions may be treated with conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers, and the like. Suitable pharmaceutical carriers and formulations thereof are described in E. W. Martin, Remington's Pharmaceutical Sciences. Such compositions will in any event contain an effective amount of the active compound, together with a suitable carrier, to prepare a suitable dosage form for proper administration to the recipient.

The dosage of a compound of the present invention will depend on a number of factors such as, for example, the route of administration, the age and body weight of the subject, and the health status of the subject being treated, and will ultimately be determined by the attending physician or veterinarian. Such amount of the active compound, as determined by the attending physician or veterinarian, is referred to in the present description and in the claims as a therapeutically effective amount. For example, the dosage of a compound of the present invention is typically in the range of about 1 to about 1000 mg per day. In one embodiment of the present invention, said therapeutically effective amount is from about 10 to about 500 mg per day.

It is clear that the compounds of general formula (I) and II according to the present invention can be derivatized at functional groups to obtain derivatives that are capable of converting back to the parent compound in vivo. Physiologically acceptable and metabolically labile derivatives which are capable of producing the parent compounds of general formula (I) in vivo are also within the scope of the present invention.

Compounds of the present invention can be prepared starting from commercially available starting materials and using general synthetic methods and procedures known to those skilled in the art.

- 4 040668 of this area. Chemicals are available from companies such as Aldrich, Argonaut Technologies, VWR and Lancaster. Chromatography supplies and equipment are available from companies such as AnaLogix, Inc, Burlington, Wisconsin, USA; Biotage AB, Charlottesville, Virginia, USA; Analytical Sales and Services, Inc., Pompton Plains, New Jersey, USA; Teledyne Isco, Lincoln, Nebraska, USA; VWR International, Bridgeport, New Jersey, USA; Varian Inc., Palo Alto, CA, USA; and Multigram II Mettler Toledo Instrument, Newark, DE, USA. Biotage, ISCO, and Analogix columns are prepackaged silica gel columns used in standard chromatography.

The compounds of formula (I) can be obtained in accordance with the following schemes. These organotrifluoroborate salts can be prepared by several standard methods presented by the method of E. Vedejs, R. W. Chapman, S. C. Fields, S. Lin, and M. R. Scrimf, J. Org. Chem. 1995, 60, 3020-3027, but more conveniently obtained by the recently developed method of J. J. Lennox and G. C. Llyod-Jones, Angew. Chem. Int. Ed., 2012, 51, 9385-9388.

Scheme 1

O

DMSO, 115-120 C

Scheme 2

Scheme 3

L-wine acid

R'=Deputy

Scheme 4

L-wine acid

R'=substituent CH3CN

Representative compounds according to the present invention, obtained by the methods described in the schemes above and in the examples below, are presented:

- 5 040668

- 6 040668

Examples

Synthetic methods for obtaining typical compounds according to the present invention are illustrated in the following examples. Starting materials are commercially available or they can be obtained in accordance with procedures known in the art or as shown in this document. The following examples are intended to help illustrate the present invention and are not intended to limit the scope of the present invention and should not be construed as such.

Example 1

Synthesis of [trifluoro(pyrazin-2-yl)boranyl]potassium(1+)

Synthesis of [trihydroxy(pyrazin-2-yl)boranyl]lithium(1+).

Stage 1. Synthesis of [triisopropoxy(pyrazin-2-yl)boranyl]lithium(1+)

OiPr x ^N ^ ^Br n-BuLi B(OiPr)3 N ^° ^lPr +

JJ -------------ί ^{OiPr Li 4} kA -100 °C 1h M

To a solution of 2-bromopyrazine (10 g, 62.90 mmol, 1 eq.) and triisopropyl borate (13.28 g, 69.19 mmol, 16.23 ml, 98% purity, 1.1 eq.) in THF ( 200 ml) was added n-BuLi (2.5 M in n-hexane, 26.42 ml, 1.05 eq.) dropwise at -90°C under N ₂ atmosphere. The temperature was maintained below -85°C. The mixture was stirred at -85°C for 20 min under N2. TLC (petroleum ether/ethyl acetate = 5:1) indicated that the starting material was completely consumed. This mixture was used directly in the next step. The crude product [triisopropoxy(pyrazin-2yl)boranyl]lithium (1+) (17.24 g, crude) in THF (200 ml) as a red/black solvent was used in the next step without further purification.

Step 2. Synthesis of 6-methyl-2-(pyrazin-2-yl)-1,3,6,2-dioxazaborocane-4,8-dione

To a solution of 2-[carboxymethyl(methyl)amino]acetic acid (27.76 g, 188.70 mmol, 3 eq.) in DMSO (160 mL) was added a solution of [triisopropoxy(pyrazin-2-yl)boranyl]lithium (1 +) (17.24 g, 62.90 mmol, 1 eq.) in THF (200 ml) at 120°C. This mixture was stirred at 120° C. for 20 minutes. TLC showed that reagent 2 was completely used up and many new spots formed. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate/acetonitrile = 3/1/0 to 0/10/1). The residue was washed with EtOAc (30 ml) and filtered. The filter cake was dried and washed with acetonitrile (200 ml x3), then filtered. The filtrate was concentrated under reduced pressure to give 6methyl-2-(pyrazin-2-yl)-1,3,6,2-dioxazaborocane-4,8-dione (14.2 g) as a white solid.

1H NMR (400 MHz, acetonitrile^) 8.81 (d, J=1.8 Hz, 1H), 8.73-8.68 (m, 1H), 8.56 (d, J=2.6 Hz , 1H), 4.20-4.13 (m, 2H), 4.05-3.98 (m, 2H), 2.62 (s, 3H).

Stage 3. Synthesis of potassium trifluoro(pyrazin-2-yl)borate 0^^ ______ o J KF (4 equiv.) _r B^ K

L-tartaric-ta [I 3 IL J O (2.05 equiv.) OL_______ N

1-4

To a solution of 6-methyl-2-pyrazin-2-yl-1,3,6,2-dioxazaborocane-4,8-dione (13.7 g, 58.30 mmol, 1 eq.) in MeCN (233 ml) KF (10 M in water, 23.32 ml, 4 eq.) and a solution of tartaric acid (17.94 g, 119.51 mmol, 2.05 eq.) in THF (90 ml) were added. The mixture was stirred at 25° C. for 12 hours. TLC showed that reagent 3 was completely consumed and one new spot formed. This mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was washed with MeCN (50 ml) and filtered. The filter cake was dried to give the product. The compound trifluoro(pyrazin-2-yl)potassium borate (6 g, 32.26 mmol, 55.34% yield) was obtained as a white solid.

Recrystallization: 1-4.

The target product was dissolved in CH3CN (1 g/40 ml) and heated to 90°C for 10

- 7 040668 min. The hot slurry was then filtered and the filtrate concentrated under reduced pressure to remove most of the CH3CN. The suspension was filtered and the filter cake was washed with CH3CN (10 ml) to give a white solid. The above procedure was repeated several times until good quality was achieved.

LC-MS (ESI) m/z 146.8 [MK] ^- .

1H NMR (400 MHz, acetonitrile D) 9.16 (s, 1H), 8.92 (d, J=3.2 Hz, 1H), 8.53 (dd, J=1.3, 3.1 Hz , 1H).

¹⁹ F NMR (400 MHz, acetonitrile-d ₃ ) -145.6 (q, 3F).

11B NMR (400 MHz, acetonitrile-d ₃ ) 0.95 (q, 1B).

¹³ C NMR (101 MHz, acetonitrile-d ₃ ) 152.92 (br s, 1C), 146.42, 132.86 (br s, 1C).

Example 2

2-5

Stage 1. Synthesis of 2-bromo-6-methoxypyrazine

2

To a solution of 2,6-dibromopyrazine (67 g, 281.65 mmol, 1.00 eq.) in MeOH (670 ml) was added NaOMe (18.26 g, 337.99 mmol, 1.2 eq.). The mixture was stirred at 40° C. for 1 hour. LCMS indicated ~99% of the title compound. The reaction mixture was quenched by adding a saturated solution of NH ₄ Cl (80 ml) and concentrated under reduced pressure to obtain a solution (200 ml), then diluted with H ₂ O 200 ml and was extracted with EtOAc (200 ml x3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1:0 to 20:1). The compound 2-bromo-6-methoxypyrazine (45 g, 214.27 mmol, 76.08% yield, 90% purity) was obtained as a white solid.

LC-MS (ESI) m/z 188.9 [M+H]+

1H NMR (400 MHz, DMSO) 8.39 (s, 1H), 8.34 (s, 1H), 3.91 (s, 3H).

Stage 2. Synthesis ^{of [} triisopropoxy-(6-methoxypyrazin-2-yl)boranyl] ^lithium (1+) ----X ν-ΌίΡΓ Li

-100 °C, 1h H I

To a solution of 2-bromo-6-methoxypyrazine (20 g, 105.81 mmol, 1.00 eq.) in THF (200 ml) was added triisopropyl borate (23.88 g, 126.98 mmol, 29.19 ml, 1, 20 eq.), n-BuLi (2.5 M in n-hexane, 50.79 ml, 1.2 eq.) dropwise at -100° C. under N2. The mixture was stirred at -100° C. for 1 hour. TLC indicated that the starting material was completely consumed. The crude product [triisopropoxy-(6-methoxypyrazin-2-yl)boranyl]lithium(1+) (32 g, crude) in THF (200 ml) was used in the next step without further purification. 1 ml of the reaction mixture was added to 5 ml of MeOH. The mixture was concentrated under reduced pressure. 1H NMR showed the desired product.

1H NMR (400 MHz, CD3CN) 8.15 (s, 1H), 7.88 (s, 1H), 3.90 (s, 3H).

Stage 3. Synthesis of 2-(6-methoxypyrazin-2-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

To a solution of 2-[carboxymethyl(methyl)amino]acetic acid (23.22 g, 157.83 mmol, 1.50 eq.) in DMSO (190 mL) was added a solution of [triisopropoxy-(6-methoxypyrazin-2-yl) boranyl]lithium(1+) (32 g, 105.22 mmol, 1 eq.) in THF (200 ml) dropwise at 120°C. The mixture was stirred at 120°C for 1 hour. TLC showed that the starting material was completely consumed and new spots formed. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 5:1 to 0:1, ethyl acetate: MeCN = 5:1).

Compound 2-(6-methoxypyrazin-2-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (16 g, 57.35 mmol, 54.51% yield, 95% purity ) was obtained as a white solid.

¹ H NMR (400 MHz, CD3CN) 8.33 (s, 1H), 8.17 (s, 1H), 4.16-4.10 (d, J=16.8 Hz, 2H), 4.04 -3.98 (d, J=16.8 Hz, 2H), 3.89 (s, 3H), 2.65 (s, 3H).

Step 4. Synthesis of [trifluoro(6-methoxypyrazin-2-yl)boranyl]potassium(1+)o

2-5

To a solution of 2-(6-methoxypyrazin-2-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (31 g, 116.97 mmol, 1 eq.) in MeCN (470 ml) was added a solution of KF (27.18 g, 467.87 mmol, 10.96 ml, 4 equiv.) in H2O (47 ml) and a solution of L-tartaric acid (35.99 g, 239.78 mmol, 2, 05 eq.) in THF (176 ml). The mixture was stirred at 35° C. for 24 hours. TLC indicated that the starting material was completely consumed. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was triturated with MeCN (150 ml) and filtered. The filter cake was dried under reduced pressure to give the product. The compound [trifluoro(6-methoxypyrazin-2-yl)boranyl]potassium(1+) (25 g, crude) was obtained as a white solid.

recrystallization conditions.

g of the desired product was dissolved in CH ₃ CN (1000 ml) and heated to a temperature of 90°C for 10 min. The mixture solution was then filtered as soon as possible and then cooled to room temperature. The filtrate was cooled to a temperature of 25°C, crystals formed. The precipitate was then filtered off, the filter cake was collected and dried under reduced pressure to give white crystals.

LC-MS (ESI) m/z 159.0 [M-KF+H+] ⁺ .

1H NMR (400 MHz, acetonitrile D) 8.13 (s, 1H), 7.92 (s, 1H), 3.93 (s, 3H).

¹⁹ F NMR (400 MHz, acetonitrile^) -142.5 (q, 3F).

11B NMR (400 MHz, α-cetonitrile-d3) 2.45 (q, 1B).

Example 3

1.8 eq, KHF ₂ °C, 12 h

Stage 1. Synthesis of 6-bromo-N,N-dimethylpyrazine-2-amine

2

A mixture of 2,6-dibromopyrazine (39.00 g, 163.95 mmol, 1.00 eq.) and dimethylamine (89.59 g, 655.80 mmol, 100.66 ml, 33% purity in water, 4.00 equiv.) was stirred at 20° C. for 3 h. TLC showed that reagent 1 was completely consumed and many new spots formed. This mixture was diluted with water (200 ml) and extracted with DCM (150 ml x3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (ISCO®; 120 g SepaFlash® silica gel flash column, eluent with 0-15% ethyl acetate/petroleum ether gradient at 85 ml/min). The compound 6-bromo-N,N-dimethylpyrazine-2-amine (33.00 g, 163.33 mmol, 99.62% yield) was obtained as a light yellow solid.

1H NMR (400 MHz, chloroform-d) 7.88 (s, 1H), 7.85 (s, 1H), 3.12 (s, 6H).

- 9 040668

Step 2. Synthesis of [6-(dimethylamino)pyrazin-2-yl]boric acid compound; hydroxylithium

To a solution of 6-bromo-N,N-dimethylpyrazin-2-amine (9.90 g, 49.00 mmol, 1.00 eq.) and triisopropyl borate (11.06 g, 58.80 mmol, 13.49 ml , 1.20 eq.) in THF (100.00 ml) was added dropwise n-BuLi (2.5 M in n-hexane, 23.52 ml, 1.20 eq.) at -100°C. The mixture was stirred at -100°C for 1 h. TLC showed that reagent 2 was completely consumed. The crude product of [6(dimethylamino)pyrazin-2-yl]boric acid; hydroxylithium (9.00 g, 47.14 mmol, 96.20% yield) in THF (100 mL) was used in the next step without further purification. 0.5 ml of the mixture was quenched with MeOH (2 ml) and concentrated under reduced pressure as confirmed by high resolution NMR (ES5002-247-P1A).

¹ H NMR (400 MHz, deuterium oxide) 7.72 (s, 1H), 7.64 (s, 1H), 2.88 (s, 6H).

Step 3. Synthesis of 2-(6-(dimethylamino)pyrazin-2-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

To a solution of 2-[carboxymethyl(methyl)amino]acetic acid (10.75 g, 73.07 mmol, 1.50 eq.) in DMSO (100.00 ml) was added a solution of the -2-yl]boric acid; hydroxylithium (9.30 g, 48.71 mmol, 1.00 eq.) in THF (100 ml) dropwise at

120°C. The mixture was stirred at 120° C. for 1 h. TLC showed that reagent 3 was completely consumed. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , ethyl acetate/MeCN = 1/0 to 10/1). Compound 2-[6(dimethylamino)pyrazin-2-yl]-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (6.50 g, 23.38 mmol, yield

47.99%) was obtained as a white solid.

1H NMR (400 MHz, acetonitrile D) 8.07 (s, 1H), 7.98 (s, 1H), 4.12 (d, J=16.8 Hz, 2H), 4.01 (d, J =16.8

Hz, 2H), 3.07 (s, 6H), 2.67 (s, 3H).

Stage 4. Synthesis of (6-(dimethylamino)pyrazin-2-yl)potassium trifluoroborate

1.8 eq. CHF _2| °C, 12 h MeOH

3-5

To a solution of 2-[6-(dimethylamino)pyrazin-2-yl]-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (6.00 g, 21.58 mmol, 1.00 eq.) in MeOH (60.00 ml) was added KHF2 (4.5 M in water, 8.63 ml, 1.80 eq.). The mixture was stirred at 30° C. for 12 hours. TLC indicated that ~10% of reagent 4 remained and one major new spot with greater polarity was found. The mixture was filtered and the filter cake was dried to give the product. Compound potassium; 6-difluoroboranyl-N,N-dimethylpyrazin-2-amine; fluoride (3.40 g, 14.84 mmol, 68.79% yield) was obtained as a light yellow solid. LC-MS (ESI) m/z 172.1 [M-KF+H]+

1H NMR (400 MHz, acetonitrile D) 8.25 (s, 1H), 7.91 (s, 1H), 3.19 (s, 6H).

¹⁹ F NMR (377 MHz, acetonitrile-d ₃ ) -144.47 (br dd, J=43.5, 87.0 Hz, 3F).

11B NMR (128 MHz, acetonitrile-d ₃ ) 2.10-0.40 (m, 1B).

Example 4

4-2

Stage 1. Synthesis of [trifluoro(5-fluoro-3-pyridyl)boranyl]potassium(1+)

- 10 040668

To a suspension of (5-fluoro-3-pyridyl)boric acid (30 g, 212.90 mmol, 1 eq.) in CH3CN (851 ml) was added KF (49.48 g, 851.62 mmol, 4 eq.) in H2O (85.1 ml) at 18°C. The mixture was stirred until the boric acid was completely dissolved, L-(+)-tartaric acid (65.51 g, 436.45 mmol, 2.05 equiv.) was dissolved in THF (319 ml) and added dropwise to the rapidly stirred biphasic mixture in within ten minutes. A white precipitate immediately formed and flocculated for 2 hours. TLC indicated that the starting material had been consumed. The mixture was filtered directly and the filter cake was washed with CH3CN (100 ml). The filtrate was concentrated under reduced pressure to give a residue. The residue was recrystallized from CH3CN (1 g/10 ml, 1 g/5 ml, 1 g/2.5 ml). The compound [trifluoro(5-fluoro-3-pyridyl)boranyl]potassium(1+) (15 g, 72.68 mmol, 34.14% yield, 98.35% purity) was obtained as a white solid.

LC-MS (ESI) m/z 146.0 [M-KF+H]+.

Ή NMR (400 MHz, acetonitrile^) 8.43-8.36 (m, 1H), 8.20 (d, J=2.3 Hz, 1H), 7.51 (br d, J=8, 4 Hz, 1H).

¹⁹ F NMR (400 MHz, acetonitrile^) -130.5 (s, 1F), -141.5 ~ -143.0 (m, 3F).

11B NMR (400 MHz, acetonitrile-d ₃ ) 1.5~-3.5 (q, 1B).

Example 5

Stage 1. Synthesis of the compound [trifluoro(5-fluoro-3-pyridyl)boranyl]potassium(1+) ES5002-466-P1

5-2

To a suspension of (5-chloro-3-pyridyl)boric acid (20 g, 127.09 mmol, 1 eq.) in CH3CN (508 ml) was added KF (29.54 g, 508.38 mmol, 4 eq.) in H2O (51 ml) at 18°C. The mixture was stirred until the boric acid was completely dissolved, L-(+)-tartaric acid (39.11 g, 260.54 mmol, 2.05 equiv.) was dissolved in THF (190 ml) and added dropwise to the rapidly stirred biphasic mixture in within 10 min. A white precipitate immediately formed and flocculated for 2 hours. TLC indicated that the starting material had been consumed. The mixture was filtered directly and the filter cake was washed with CH3CN (100 ml). The filtrate was concentrated under reduced pressure to give a residue. The residue was recrystallized from CH3CN (1 g/10 ml, 1 g/8 ml, 1 g/6 ml).

The compound [(5-chloro-3-pyridyl)trifluoroboranyl]potassium(1+) (10 g, 45.57 mmol, 35.86% yield, 100% purity) was obtained as a white solid.

LC-MS (ESI) m/z 162.0 [M-KF+H]+.

Ή NMR (400 MHz, acetonitrile^) 8.44 (s, 1H), 8.31 (s, 1H), 7.78 (s, 1H).

¹⁹ F NMR (400 MHz, acetonitrile-d ₃ ) -142.5 (q, 3F).

^P V NMR (400 MHz, acetonitrile-d ₃ ) 1.5-4.5 (q, 1B).

Example 6

To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (10.00 g, 47.37 mmol, 1.00 eq.) in MeOH (50, 00 ml) KHF2 (4.5 M, 31.58 ml in water, 3.00 eq.) was added. The mixture was stirred at 25° C. for 3 hours. TLC indicated that reagent 1 was completely consumed. The mixture was concentrated under reduced pressure. The mixture was washed with EtOAc (50 ml) and filtered. The filter cake was dried under reduced pressure to give a crude product. This crude product was washed with MeOH (20 ml) and filtered. The filtrate was concentrated under reduced pressure to give potassium trifluoro(thiazol-5-yl)borate (2.95 g, 15.44 mmol, 32.60% yield, 100% purity) as a white solid.

MS (ESI) m/z 134.0 [M-KF+H]+.

Ή NMR (400 MHz, acetonitrile-d ₃ ) 8.73 (s, 1H), 7.67 (s, 3H).

- 11 040668 ¹⁹ F NMR (377 MHz, acetonitrile-d ₃ ) -135.88 (br dd, J=44.8, 90.6 Hz, 3F).

^IB NMR (128 MHz, acetonitrile ^) 1.86, 2.39 (q, J=45.9 Hz, 1B).

Example 7

Stage 1. Synthesis of 2-bromo-6-pyrrolidin-1-ylpyrazine ^Β ^ ^Ν γ ^ΒΓ pyrrolidine

Meon

2

Pyrrolidine (1.79 g, 25.23 mmol, 2.11 ml, 3.00 equiv.). The mixture was stirred at 15° C. for 3 hours. TLC indicated that reagent 1 was completely consumed. The mixture was quenched with water (50 ml) and extracted with DCM (50 ml x3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (ISCO®; 24 g SepaFlash® silica gel flash column, eluent with 0-15% ethyl acetate/petroleum ether gradient at 35 ml/min). The compound 2-bromo-6-pyrrolidin-1-ylpyrazine (1.70 g, 7.45 mmol, 88.62% yield) was obtained as a white solid.

1H NMR (400 MHz, CDCI3) 7.82 (s, 1H), 7.73 (s, 1H), 3.48 (bt, J=6.5 Hz, 4H), 2.08-1, 98(m, 4H).

Stage 2. Synthesis of the hydroxylithium compound; (6-pyrrolidin-1-ylpyrazin-2-yl)boric acid

To a solution of 2-bromo-6-pyrrolidin-1-ylpyrazine (1.90 g, 8.33 mmol, 1.00 eq.) and triisopropyl borate (1.88 g, 10.00 mmol, 2.29 ml, 1 ,20 eq.) in THF (25.00 ml) was added dropwise n-BuLi (2.5 M in nhexane, 4.00 ml, 1.20 eq.) at -100°C. The mixture was stirred at -100°C for 1 h. TLC showed that reagent 2 was completely consumed. Crude product hydroxylithium; (6-pyrrolidin-1-ylpyrazin-2-yl)boric acid (1.80 g, 8.30 mmol, 99.60% yield) in THF (20 mL) was used in the next step without further purification. 0.5 ml of the mixture was quenched with MeOH (2 ml), concentrated under reduced pressure and determined by high resolution NMR.

1H NMR (400 MHz, D2O) 7.63 (s, 1H), 7.45 (s, 1H), 3.29-3.21 (m, 4H), 1.79 (br t, J=6 .5 Hz, 4H).

Stage 3. Synthesis of 6-methyl-2-(6-pyrrolidin-1-ylpyrazin-2-yl)-1,3,6,2-dioxazaborocan-4,8-dione

To a solution of 2-[carboxymethyl(methyl)amino]acetic acid ester (1.83 g, 12.45 mmol, 1.50 eq.) in DMSO (20.00 mL) was added a solution of the hydroxylithium compound; (6-pyrrolidin-1ylpyrazin-2-yl)boric acid (1.80 g, 8.30 mmol, 1.00 eq.) in THF (20 ml) dropwise at 120°C. The mixture was stirred at 120° C. for 1 h. TLC showed that reagent 3 was completely consumed. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , ethyl acetate/MeCN = 1/0 to 10/1).

Compound 6-methyl-2-(6-pyrrolidin-1-ylpyrazin-2-yl)-1,3,6,2-dioxazaborocane-4,8-dione (1.60 g, 5.26 mmol, yield 63, 39%) was obtained as a white solid.

1H NMR (400 MHz, CD3CN) 7.96 (s, 1H), 7.89 (s, 1H), 4.11 (d, J=16.8 Hz, 2H), 4.03 (d, J= 16.8 Hz, 2H), 3.48-3.42 (m, 4H), 2.70 (s, 3H), 2.04-1.99 (m, 4H).

Stage 4. Synthesis of the potassium compound; difluoro(6-pyrrolidin-1-ylpyrazin-2-yl)borane; fluoride

- 12 040668

To a solution of 6-methyl-2-(6-pyrrolidin-1-ylpyrazin-2-yl)-1,3,6,2-dioxazaborocan-4,8-dione (1.00 g,

3.29 mmol, 1.00 eq.) in MeOH (10.00 ml) was added KHF2 (4.5 M in water, 1.32 ml, 1.80 eq.). A mixture of re-

stirred at 30° C. for 1 h. TLC indicated that ~10% of reagent 4 remained and one major new spot was detected. The mixture was filtered and the filter cake was dried to give the product. The product has not been cleaned. Compound potassium; difluoro(6-pyrrolidin-1-ylpyrazin-2-yl)borane; fluoride (300.00 mg, 1.18 mmol, 35.75% yield) was obtained as a white solid.

LC-MS (ESI) m/z 198.1 [M-KF+H] ⁺ .

1H NMR (400 MHz, acetonitrile D) 8.38 (s, 1H), 7.94 (s, 1H), 3.61 (br t, J=6.4 Hz, 4H), 2.12-2 .06 (m, 4H).

¹⁹ F NMR (377 MHz, acetonitrile^) -145.13 (br dd, J=41.2, 82.4 Hz, 3F).

11B NMR (128 MHz, α-cetonitrile-d3) 1.48-0.17 (m, 1B).

Example 8. o °; — n-BuLi, B(OiPr) ₃ * Χ/ ^Ν γΒ(ΟΗ) ₃ ύ MIDA, DMS VVS/ 13 equiv. KHF ₂ * BF ₃ ^κ ίτφ, -us °C * i20°c ° MeOH IL _n< J

2 3 8-4

Stage 1. Synthesis of the hydroxylithium compound; (6-methylpyrazin-2-yl)boric acid ES5002-267-P1

n-BuLi B(OiPr) ₃

THF, -100 °C

B(OH) ₃ Li

2

To a solution of 2-bromo-6-methylpyrazine (3.10 g, 17.92 mmol, 1.00 eq.) and triisopropyl borate (4.04 g, 21.50 mmol, 4.93 ml, 1.20 eq. ) in THF (30.00 ml) was added n-BuLi (2.5 M in n-hexane, 7.88 ml, 1.10 eq.) dropwise at -100°C. The mixture was stirred at -100° C. for 1 hour. TLC showed that reagent 1 had been completely consumed and many new spots had formed. Crude product hydroxylithium; (6-methylpyrazin-2-yl)boric acid (2.90 g, crude) in THF (30 ml) was used in the next step without further purification. 0.5 ml of the mixture was quenched with MeOH (3 ml) and detected by high resolution NMR.

1H NMR (400 MHz, D2O) δ 8.26 (s, 1H), 7.98 (s, 1H), 2.30 (s, 3H).

Stage 2. Synthesis of 6-methyl-2-(6-methylpyrazin-2-yl)-1,3,6,2-dioxazaborocan-4,8-dione

h

To a solution of 2-[carboxymethyl(methyl)amino]acetic acid (3.95 g, 26.87 mmol, 1.50 eq.) in DMSO (35.00 mL) was added a solution of the hydroxylithium compound; (6-methylpyrazin-2-yl)boric acid ester (2.90 g, 17.91 mmol, 1.00 eq.) in THF (30 mL) dropwise at 120°C. The mixture was stirred at 120° C. for 1 h. TLC showed that reagent 2 was completely consumed. The mixture was concentrated under reduced pressure. The residue was purified using column chromatography (SiO ₂ , petroleum ether/ethyl acetate/acetonitrile = 2/1/0 to 0/10/1). The compound 6-methyl2-(6-methylpyrazin-2-yl)-1,3,6,2-dioxazaborocane-4,8-dione (1.10 g, 4.42 mmol, 24.66% yield) was obtained as white solid.

1H NMR (400 MHz, acetonitrile-d3) 8.58 (s, 1H), 8.44 (s, 1H), 4.19-4.10 (m, 2H), 4.06-3.97 (m , 2H), 2.62 (s, 3H), 2.54 (s, 3H).

Stage 3. Synthesis of the potassium compound; difluoro(6-methylpyrazin-2-yl)borane; fluoride ES5002-277-P1

To a solution of 6-methyl-2-(6-methylpyrazin-2-yl)-1,3,6,2-dioxazaborocane-4,8-dione (400.00 mg, 1.61 mmol, 1.00 eq.) in MeOH (4.00 ml) was added KHF ₂ (4.5 M in water, 644.00 μl, 1.80 eq.). The mixture was stirred at 30° C. for 12 hours. TLC indicated that ~10% of reagent 3 remained and one major new spot with greater polarity was found. The mixture was filtered and the filter cake was dried to give the product. Compound potassium; difluoro(6-methylpyrazin-2-yl)borane; fluoride (120.00 mg, 582.74 µmol, 36.19% yield, 97.128% purity) was obtained as a white solid.

LC-MS (ESI) m/z 143.1 [M-KF+H]+.

¹ H NMR (400 MHz, acetonitrile D) 9.11 (s, 1H), 8.95 (s, 1H), 2.71 (s, 3H).

¹⁹ F NMR (377 MHz, acetonitrile-d ₃ ) -145.22 (br dd, J=40.1, 79.0 Hz, 3F).

11B NMR (128 MHz, acetonitrile-d ₃ ) 1.60-(-0.44) (m, 1B).

Example 9

Stage 1. Synthesis of [trifluoro(2-methylthiazol-5-yl)-λ ⁵ -boranyl]potassium (1+)

To a solution of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (0.5 g, 2.22 mmol, 1 eq.) in MeOH ( 5 ml) KHF2 (4.5 M in water, 888.43 μl, 1.8 eq.) was added. The mixture was stirred at 30° C. for 12 hours. TLC indicated that reagent 1 had been completely consumed. The mixture was concentrated under reduced pressure. The residue was triturated with MeCN (5 ml x3) and filtered. The filtrate was concentrated under reduced pressure. The residue was washed with EtOAc (10 ml x3) and filtered. The filter cake was dried and recrystallized from MeCN (5 ml) to give the product. The compound [trifluoro(2-methylthiazol-5-yl)-λ ⁵ -boranyl]potassium(1+) (150 mg, 731.53 µmol, 32.94% yield, 100% purity) was obtained as a white solid.

LC-MS (ESI) m/z 148.0 [M-KF+H]+.

¹ H NMR (400 MHz, acetonitrile^) 7.36 (s, 1H), 3.00 (s, 3H).

¹⁹ F NMR (377 MHz, acetonitrile-d3) -135.93 (br dd, J=44.6, 90.4 Hz, 3F).

11B NMR (128 MHz, α-cetonitrile-d3) 2.19 (br d, J=45.2 Hz, 1B).

Example 10

Stage 1. Synthesis of 6-bromopyrazine-2-amine

A mixture of 2,6-dibromopyrazine (20 g, 84.08 mmol, 1 eq.) and NH3-H2O (36.83 g, 294.27 mmol, 40.47 ml, 3.5 eq.) was stirred at 100° C for 12 hours in a sealed tube. TLC showed that reagent 1 was completely used up and one new spot formed. The mixture was filtered; the filter cake was washed with petroleum ether (200 ml x2) and dried in vacuo to give the product. The petroleum ether layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to recover reagent 1. This product was used directly in the next step without further purification. Compound 6-bromopyrazine-2-amine (50 g, 287.36 mmol, 68.36% yield) was obtained as a pale solid.

1H NMR (400 MHz, CDCl3) 7.99 (s, 1H), 7.88 (s, 1H), 4.78 (br s, 2H).

Stage 2. Synthesis of 2-bromo-6-fluoropyrazine

To a solution of 6-bromopyrazine-2-amine (50 g, 287.36 mmol, 1 eq.) in HBF4 (500 ml) NaNO ₂ (39.65 g, 574.72 mmol, 2 eq.) was added in portions at a temperature of 0 °C The mixture was stirred at 20°C for

- 14 040668 within 2 days. TLC showed that reagent 2 was completely used up and one new spot formed. This mixture was quenched with water (500 ml) and extracted with pentane (200 ml x5). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated by distillation to remove the pentane. The product was further purified by column chromatography (SiO ₂ , n-pentane/ethyl acetate = 1:0). Compound 2bromo-6-fluoropyrazine (55.5 g, 282.24 mmol, 98.22% yield, 90% purity) was obtained as a brown oil.

1 H NMR (400 MHz, CDCI3) 8.65 (d, J=4.0 Hz, 1H), 8.40 (d, J=8.0 Hz, 1H).

Stage 3. Synthesis of [(6-fluoropyrazin-2-yl)triisopropoxyboranyl]lithium(1+)

To a solution of 2-bromo-6-fluoropyrazine (37.7 g, 213.03 mmol, 1 eq.) and triisopropyl borate (44.97 g, 234.33 mmol, 54.97 ml, 98% purity, 1.1 eq.) in THF (400 ml) was added dropwise n-BuLi (2.5 M in nhexane, 89.47 ml, 1.05 eq.) at -90°C under N ₂ atmosphere. The temperature was maintained below -85°C. The mixture was stirred at -85°C for 20 min under N2. TLC (petroleum ether/ethyl acetate = 5:1) showed that the starting material was completely consumed. This mixture was used directly in the next step. The crude product [(6-fluoropyrazin-2yl)triisopropoxyboranyl]lithium(1+) (62.22 g, crude) in THF (400 ml) as a red/black solvent was used in the next step without further purification.

Stage 4. Synthesis of 2-(6-fluoropyrazin-2-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

To a solution of 2-[carboxymethyl(methyl)amino]acetic acid (93.99 g, 638.86 mmol, 3 eq.) in DMSO (300 mL) was added a solution of [(6-fluoropyrazin-2-yl)triisopropoxyboranyl]lithium( 1+) (62.2 g, 212.95 mmol, 1 eq.) in THF (400 ml) while maintaining the temperature at least 80°C. After this addition, the mixture was stirred at 120° C. for 30 minutes. TLC showed that reagent 4 was completely used up and many new spots formed. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate/acetonitrile = 1/1/0 to 0/50/1) to obtain a crude product. The crude product was washed with EtOAc (80 ml) and filtered; the filter cake was dried to give the product. The compound 2-(6-fluoropyrazin-2-yl)-6methyl-1,3,6,2-dioxazaborocane-4,8-dione (16.5 g, 65.22 mmol, 30.63% yield) was obtained as pink solid.

¹ H NMR (400 MHz, acetonitrile-be) 8.76 (d, J=4.8 Hz, 1H), 8.48 (d, J=8.0 Hz, 1H), 4.17 (d, J =17.2 Hz, 2H), 4.01 (d, J=16.8 Hz, 2H), 2.67 (s, 3H).

Stage 5. Synthesis of trifluoro(6-fluoropyrazin-2-yl)potassium borate

N

10-6

To a solution of 2-(6-fluoropyrazin-2-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (34.5 g, 136.37 mmol, 1 eq.) in MeCN (545 ml) was added KF (10 M, 54.55 ml, 4 eq.) and a solution of tartaric acid (41.96 g, 279.55 mmol, 2.05 eq.) in THF (204 ml). The mixture was stirred at 25° C. for 12 hours. TLC showed that reagent 5 was completely consumed and one new spot formed. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallized from MeCN (1.2 L). The compound trifluoro(6-fluoropyrazin-2-yl)potassium borate (6 g, 29.42 mmol, 21.57% yield) was obtained as a pale gray solid.

LC-MS (ESI) m/z 164.7 [MK] ^- .

1H NMR (400 MHz, acetonitrile-d3) 8.54 (d, J=6.0 Hz, 1H), 8.17 (d, J=8.3 Hz, 1H).

¹⁹ F NMR (400 MHz, acetonitrile-d3) -84.37 (br s, 1F), -144.77 (br dd, J=45.8, 93.8 Hz, 3F).

11B NMR (400 MHz, acetonitrile^) 2.42-0.68 (m, 1B).

- 15 040668

Example 11.

Stage 1. Synthesis of (5-cyanopyridin-3-yl)potassium trifluoroborate

To a solution of (5-cyano-3-pyridyl)boric acid (50 g, 338.00 mmol, 1 eq.) in MeCN (1352 ml) was added a solution of KF (78.55 g, 1.35 mol, 31.67 ml , 4 eq.) in H2O (135.2 ml) and a solution of tartaric acid (104.00 g, 692.91 mmol, 2.05 eq.) in THF (507 ml). The mixture was stirred at 25° C. for 12 hours. TLC showed that reagent 1 was completely consumed and one new spot formed. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The compound [(5cyano-3-pyridyl)trifluoroboranyl]potassium(1+) (65 g, 309.52 mmol, 91.57% yield) was obtained as a white solid.

Recrystallization conditions: 11-2.

The starting material was dissolved in MeOH/CH ₃ CN (1/2, 1 g/30 ml). This suspension was heated to a temperature of 80° C. until the product had largely dissolved. The suspension solution was filtered just before being cooled to room temperature. The specified filtrate was cooled to a temperature of 20°C, then formed a crystal. The mixture was filtered and the filter cake was washed with CH ₃ CN/MeOH (2/1, 100 ml), the filter cake was dried under reduced pressure to give white crystals.

LC-MS (ESI) m/z 152.0 [M-KF+H]+.

1H NMR (400 MHz, acetonitrile-p) 8.76 (br s, 1H), 8.67 (br s, 1H), 8.10 (br s, 1H).

¹⁹ F NMR (400 MHz, acetonitrile-p) -142.15-142.56 (q, 3F).

11B NMR (400 MHz, acetonitrile-p) 3.0-2.05 (q, 1B).

¹³ C NMR (400 MHz, acetonitrile-p) 156.04 (s, 1C), 149.37 (s, 1C), 141.64 (s, 1C), 118.15 (s, 1C), 99.68 (s, 1C).

Example 12.

212-3

Stage 1. Synthesis of [5-(trifluoromethyl)-3-pyridyl]boric acid

FF OH .Br n-BuLi, B(OiPr) ₃ ^F >L . ά ^F lX ' ^F lT ^oh ΝN

To a solution of 3-bromo-5-(trifluoromethyl)pyridine (100 g, 442.49 mmol, 1 eq.) and triisopropyl borate (99.86 g, 530.99 mmol, 122.08 ml, 1.2 eq.) in THF (1000 ml) was added dropwise n-BuLi (2.5 M in nhexane, 194.70 ml, 1.1 eq.) at -78°C under N2 atmosphere. The mixture was stirred at -78°C for 1 h under N ₂ atmosphere. TCX indicated that reagent 1 was completely used up. The mixture was quenched with water (100 ml) at -10°C and acidified with HCl (1N) to pH 5.

The mixture was extracted with EtOAc (200 ml x3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was washed with EtOAc (100 ml) and filtered.

The filter cake was dried to give the product. The compound [5-(trifluoromethyl)-3pyridyl]boric acid (50.8 g, 266.09 mmol, 60.13% yield) was obtained as a white solid.

¹ H NMR (400 MHz, DMSO) 9.07 (s, 1H), 8.94 (s, 1H), 8.39 (s, 1H).

Stage 2. Synthesis of (5-cyanopyridin-3-yl)potassium trifluoroborate

12-3

To a solution of [5-(trifluoromethyl)-3-pyridyl]boric acid (50.8 g, 266.09 mmol, 1 eq.) in MeCN (1064 ml) was added a solution of KF (61.83 g, 1.06 mol, 24.93 ml, 4 equiv.) in H2O (106 ml) and tartaric

- 16 040668 acids (81.87 g, 545.48 mmol, 2.05 eq.) in THF (400 ml). The mixture was stirred at 30° C. for 12 hours. TLC showed that reagent 2 was completely consumed and one new spot formed. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was washed with MeOH (100 ml) and filtered. The filter cake was dried to give the product. The compound [trifluoro[5-(trifluoromethyl)-3-pyridyl]boranyl]potassium(1+) (70 g, crude) was obtained as a white solid.

'H NMR (400 MHz, acetonitrile-d ₃ ) 8.82 (s, 1H), 8.67 (s, 1H), 8.01 (br s, 1H).

recrystallization conditions.

The mixture was diluted with CH3OH (1 g/20 ml) and heated to 80°C and stirred for 1 h. crystalline substance.

The suspension was then filtered and the filter cake was dried under reduced pressure to give white crystals.

LC-MS (ESI) m/z 214.0 [MK] ^- .

'H NMR (400 MHz, acetonitrile-d3) 8.80 (s, 1H), 8.65 (s, 1H), 7.98 (br s, 1H).

¹⁹ F NMR (400 MHz, acetonitrile-d3) -57.58 (s, 3H), -137.5 - -138.5 (m, 3F).

‘‘B NMR (400 MHz, acetonitrile^) 3.32-2.15 (m, 1B).

¹³ C NMR (101 MHz, acetonitrile-d ₃ ) '56.55 (br s, 1C), '43.86 (br s, 1C), '35.68 (br s, 1C), 126, 4-123.7 (m, 1C), 125.10 (m, 1C).

Example 13

Scheme

IMe ₂ NN BF ₃ MeOSO ₂ CF ₃ Me ₃ NN BF _{3 +K} .- _O SO,CF.

IJ 727 IJ

N N

13-2

Compound 1 (prepared in Example 5-2) was dissolved in anhydrous acetonitrile and cooled in an ice bath under nitrogen. A dichloromethane solution of methyl trifluoromethanesulfonate (1.1 eq.) was added dropwise and the reaction mixture was slowly warmed to room temperature. The reaction was quenched by adding a small amount of water. The solvent was removed under reduced pressure, and the resulting precipitate was collected by filtration to give product 13-2.

Example 14

Scheme

Stage 1

l .

Me ₂ N^^B- ₀ A7 Me ₂ N^^BF ₃ K

J MeOHII J

NN

Compound 1 (N,N-dimethyl-5-(4,4,5,5)-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine is commercially available. KHF2 (3 equiv.) was added to a solution of compound 1 in MeOH at room temperature. The solution was stirred at room temperature for 3 hours.

The mixture was concentrated under reduced pressure and the residue was washed with EtOAc, the precipitate was collected by filtration to give compound 2.

Stage 2

^Μ θ2 ^N ^ _γΒΡ3Κ ^MeOSO2CF3

Ή J CH ₃ CN 11 J

14-3

Compound 2 was dissolved in anhydrous acetonitrile and cooled in an ice bath under nitrogen. A dichloromethane solution of methyl trifluoromethanesulfonate (1.1 eq.) was added dropwise and the reaction mixture was slowly warmed to room temperature. The reaction was quenched by adding a small amount of water. The solvent was removed under reduced pressure, and the resulting precipitate was collected by filtration to give product 14-3.

- 17 040668

Example 15

Scheme

khf ₂

Meon

Stage 1

2

Connection 1,6-chloro-N,N-dimethyl-2-pyrazinemethanamine is commercially available. To a solution of compound 1 and triisopropylborate in THF was added dropwise a solution of H-BuLi/hexane (1.2 eq.) at a temperature of -100°C. The crude product 2 was used directly in the next step. Stage 2

To a solution of 2-[carboxymethyl(methyl)amino]acetic acid (1.5 eq.) in DMSO was added dropwise a solution of compound 2 in THF at a temperature of 120°C. The mixture was stirred at 120°C for 1 hour, then the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 3.

Stage 3

O

KHF2 (1.8 equiv.) in water was added to a solution of compound 3 in MeOH. The mixture was stirred at 30°C for 12 hours. The precipitate was collected by filtration and dried to give compound 4.

Stage 4

CH ₃ CN

Compound 4 was dissolved in anhydrous acetonitrile and cooled in an ice bath under nitrogen. A dichloromethane solution of methyl trifluoromethanesulfonate (1.1 eq.) was added dropwise and the reaction mixture was slowly warmed to room temperature. The reaction was quenched by adding a small amount of water. The solvent was removed under reduced pressure and the resulting precipitate was collected by filtration to give product 15-5.

- 18 040668

Example 16

Scheme

Stage 1

Compound 1 is commercially available. KHF2 (1.8 equiv.) in water was added to a solution of compound 1 in MeOH. The mixture was stirred at 30°C for 12 hours. The precipitate was collected by filtration and dried to give compound 2.

Stage 2

MeOSO ₂ CF ₃

CH ₃ CN-16-3

Compound 2 was dissolved in anhydrous acetonitrile and cooled in an ice bath under nitrogen. A dichloromethane solution of methyl trifluoromethanesulfonate (1.1 eq.) was added dropwise and the reaction mixture was slowly warmed to room temperature. The reaction was quenched by adding a small amount of water. The solvent was removed under reduced pressure, and the resulting precipitate was collected by filtration to give product 16-3.

Example 16

biological experiments.

Determination of the MIC (minimum inhibitory concentration) of anti-tuberculosis drugs.

The antituberculous activity of each compound against Mtb H37Rv was measured by the green fluorescent protein reporter assay (LA Collins, M. N. Torrero, SG Franzblau, Antimicrob. Agents Chemother. 1998, 42, 344-347). Briefly, the compound was first dissolved in dimethyl sulfoxide (DMSO) and 2-fold dilutions were made in DMSO. The same amount of each compound solution dilution was added to 7H9 liquid medium in microplates. The original inoculum of 2x10 ⁵ CFU/ml Mtb H37Rv-GFP, which was grown in Middlebrook 7H9 medium, was exposed to the compound for 10 days. Fluorescence was measured on a Fluostar Optima microplate fluorometer (BMG Labtech, Germany) and MIC was defined as the lowest concentration of compounds that inhibited fluorescence by 90% compared to fluorescence in wells containing only bacteria. CFU = colony forming units.

In the table below. 1 shows the activity of exemplary compounds of the present invention and pyrazinamide as a reference compound against pncA knockout strain Mtb H37Rv MtbH37Rv at pH 6.7 and 5.2. MIC6,7WT is the MIC for wild-type Mtb at pH 6.7, while MIC5,2WT is the MIC at pH 5.2 for wild-type Mtb. MIC6,7KO denotes the MIC against the pncA knockout Mtb strain at pH 6.7, while MIC5,2KO denotes the MIC against the same knockout strain at pH 5.2. The data in this table demonstrates that the resulting compounds are active against Mtb WT (wild-type) only at low pH values such as pH 5 like PZA, and that they are active against pncA knockout Mtb strain, suggesting that they active against PZA-resistant (due to mutations in pncA) strains of Mtb.

- 19 040668

Table 1

Connection ID Structure MIC 6.7 WT (mkM) MIC 5.2 wt (mkm) MIC 6.7 KO (mkM) MIC 5.2 KO (mkM) IC50 for Vero cells (mkM) K ⁺ 1-4 S U >200 100 >200 100 >100 ^to X Meck ,BT ₃ K ⁺ 2-5 Υϊ >200 50 >200 25 >100 ^k X 3-5 Me ₂ N N. ^BT ₃ K ⁺ j! NA NA NA NA NA Α' F^^ ,ΒΤ ₃ Κ ⁺ 4-2 k JJ N 200 50 100 25 >100 CK- B'F _3K ⁺ 5-2 U N 100 50 100 50 >100 6-2 _s BF ₃ K ⁺ >200 50 >200 50 >100 7-5 Ογ ^Ν ^BF ₃ K ⁺ ¥ >200 100 >200 50 >100 Α- me. ,N. ,B'F ₃ K ⁺ 8-4 Υ τ >200 50 >200 25 >100 Sr B'F _3K ⁺ 9-2 Me—4 J NA NA NA NA NA F. ,ΒΤ ₃ K ⁺ 10-6 L J >200 100 >200 100 >100 ^x ,BF _3K ⁺ 11-2 XY N >200 100 >200 100 >100 F ₃ C_^ ,BF ₃ 12-3 X J N >200 100 >200 100 >100 Pyrazinamide (PZA) _N CONH ₂ CJ >400 100 >400 >400 >100

MIC at pH 5.2.

The antituberculous activity of each compound against Mtb H37Rv at pH 5.2 was measured using a green fluorescent protein reporter assay. (L. A. Collins, M. N. Torrero, S. G. Franzblau, Antimicrob. Agents Chemother. 1998, 42, 344-347).

Briefly, the compound was first dissolved in dimethyl sulfoxide (DMSO) and 2-fold dilutions were made in DMSO. The same amount of each dilution of compound solution was added to 7H9 liquid medium in pH adjusted microplates. The original inoculum 2x10 ⁷ CFU/ml Mtb H37RvGFP, which was grown in Middlebrook 7H9 medium. The inoculum was harvested and resuspended in pH adjusted 7H9 liquid medium. The inoculum was exposed to the compound for 10 days. Fluorescence was measured on a Fluostar Optima microplate fluorometer (BMG Labtech, Germany) and MIC was defined as the lowest concentration of compounds that inhibited fluorescence by 80% compared to fluorescence in wells containing only bacteria.

Toxicity analysis in mammalian cells.

The cytotoxicity of the compound against mammalian Vero cells was measured using the non-radioactive cell proliferation assay CellTiter 96® (Promega). Briefly, the compound was first dissolved in dimethyl sulfoxide (DMSO) and 2-fold dilutions were made in DMSO. Vero cells were grown in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% heat-inactivated fetal bovine serum for 48 h. Cells were counted and suspended.

- 20 040668 cells to a final concentration of 1x10 ⁵ /ml in DMEM. 50 μl of cell suspension (5000 cells) was dispensed into all wells of a 96-well plate that had been pre-filled with 50 μl of medium and 2 μl of each compound dilution was added. The plate was incubated at 37°C for 72 h in a humidified atmosphere with 5% CO2. The assay was performed by adding a pre-mixed optimized dye solution to the culture wells of a 96-well plate. After 4 hours, the solubilization/stop solution was added to the culture wells to solubilize the formazan product and the absorbance at 570 nm was recorded using a 96-well plate reader. The IC ₅₀ was defined as the lowest concentration of compounds that inhibited uptake by 50% compared to uptake in wells containing only Vero cells.

Measurement of intracellular pH change in mycobacteria.

Change in intracellular pH in mycobacteria was measured using Mtb, which expressed the pH-sensitive green fluorescent protein PH-GFP. (O. H. Vandal, L. M. Pierini, D. Schnappinger, C. F. Nathan, S. Ehrt. NatMed. 2008,14, 849-854.) Briefly, first the compound was dissolved in dimethyl sulfoxide (DMSO) and made twofold dilutions in DMSO. The same amount of each compound solution dilution was added to 7H9 liquid medium adjusted to pH 5.2 in microplates. The original inoculum 2x107 cfu/ml Mtb H37Rv-PH-GFP, which was grown in Middlebrook 7H9 medium. The inoculum was harvested and resuspended in pH adjusted 7H9 liquid medium. The inoculum was exposed to the compound for 4 days. Fluorescence was measured on a Fluostar Optima microplate fluorometer (BMG Labtech, Germany) every day with excitation at an absorption of 395 and 475 nm and emission at an absorption of 510 nm. Absorption ratios of 395:475 were calculated and plotted against time.

Effect on internal pH of Mtb.

One of the characteristics of PZA is the decrease in the internal pH of Mtb when placed in an acidic environment. Internal pH can be measured using modified GFP (Green Fluorescence Protein). A typical time course and dose response for PZA is shown in FIG. 1. Changes in Mtb treatment with Compound 6 are shown in FIG. 2, these changes are similar to those observed for PZA. For comparison, in Fig. 3 shows the effect on pH of isoniazid (INH), another anti-tuberculosis drug that has no effect on internal pH.

Minimal inhibitory concentrations of PZA and compound 1-4 and activity against pncA knockout strain.

PZA shows a MIC of 100-200 µM against Mtb at pH 5.2, but it shows no MIC (MIC > 400 µM) at pH 6.7. Connection 6 shows a picture similar to PZA, as shown in table. 2.

table 2

Compound MHK6.7WT MHK5.2WT MIC6.7KO MIC5.2KO IC50 for (μM) cells

Vero

PZA >400 100 >400 >400 >100

Connection 1-4 >200 100 >200 100 >100

PZA action requires PncA to be hydrolyzed to POA and therefore PZA is not active against the pncA knockout Mtb strain. Compound 1-4 does not require PncA to act and therefore this compound is expected to be active against the Mtb pncA strain KO. Tab. 2 shows that compound 1-4 is active against Mtb pncA strain KO.

The present invention will be further described, without limitation, in the following numbered paragraphs.

1. Compound of formula (I)

where X and Y, independently of each other, are C, N, O or S, provided that X and Y are not both C, that X and Y are not both O or S, when n is 2, and that X is O or S and Y is N when n is 1;

M is Ca, Cs, K, Li, Mg, Na or a tetraalkylammonium ion (R ₃ )4N ⁺ ;

R1 is, in each case individually, hydrogen, halogen, alkoxy, haloalkoxy, lower alkyl, halo-lower alkyl, CN, -(CH2) _t CN, -NR3R4, cycloalkyl or heterocycloalkyl;

R2 is hydrogen, halogen, alkoxy, haloalkoxy, lower alkyl, halo-lower alkyl, CN, -(CH2) _t CN, -NR3R4 cycloalkyl or heterocycloalkyl;

- 21 040668

R ₃ and R 4 , independently of each other, are hydrogen or lower alkyl; or R ₃ and R ₄ together with the nitrogen atom to which they are attached, form a 4-7-membered ring;

n is 1 or 2; p is 1 or 2; q is 1 or 2; and t is 1, 2, 3, or 4.

2. A compound according to paragraph 1, characterized in that n is 2 and both

X and Y are N.

3. A compound according to paragraph 1, characterized in that n is 2, X is C and Y is N.

4. A compound according to paragraph 1, characterized in that n is 2, X is N and Y is C.

5. A compound according to paragraph 1, characterized in that n is 2 and M is K, Li or Na.

6. A compound according to paragraph 1, characterized in that n is 1 and M is Mg or Ca.

7. A compound according to paragraph 1, characterized in that Ri is, in each case individually, hydrogen, halogen, alkoxy, haloalkoxy, lower alkyl or halo-lower alkyl.

8. A compound according to paragraph 1, characterized in that R1 is individually in each case -CH2CN, -NR3R4 or cyano.

9. A compound according to paragraph 1, characterized in that R1, in each case individually, is cycloalkyl or heterocycloalkyl.

10. A compound according to paragraph 1, characterized in that R2 is hydrogen or halogen.

11. A compound according to paragraph 1, wherein R2 is alkoxy, haloalkoxy, lower alkyl or halo-lower alkyl.

12. A compound according to paragraph 1, characterized in that R ₃ and R ₄ are independently hydrogen or lower alkyl.

13. A compound according to paragraph 1, characterized in that R ₃ and R ₄ together with the nitrogen atom to which they are attached form a 4-7 membered ring.

14. A compound according to paragraph 1, characterized in that n is 1, X is S and Y is N.

15. A compound according to paragraph 1, characterized in that n is 1, X is N and Y is S.

16. A compound according to paragraph 1, characterized in that n is 1, X is O and Y is N.

17. A compound according to paragraph 1, characterized in that n is 1, X is N and Y is O.

18. A compound according to paragraph 1, characterized in that p is equal to 1.

19. Connection in accordance with paragraph 1, characterized in that q is equal to 1.

20. A compound according to paragraph 1, characterized in that said compound is:

21. A compound according to paragraph 1, characterized in that said compound is:

- 22 040668

hf _2co

B'F _3M ⁺

M2 ⁺

22. A compound according to paragraph 1, characterized in that said compound is:

S^B' ^F 3 ^m+

F ₂ HCO-4 T

N^H

S~^ ^B ' ^F 3 M ⁺ fh ₂ co-T ^Ν Ή _S B'F ₃ M ⁺ S^ ^B ' ^F 3 ^M+ S^ ^B ' ^F 3 M ⁺ _s ,ΒΈ ₃ M ⁺

4Ϊ ".τ ".τ ^N CF ₃ n^chf, n^ _C h ₂ f n-^ _C h _2CN

23. A compound according to paragraph 1, characterized in that said compound is /N_BF ₃

N

24. A pharmaceutical composition containing a compound according to paragraph 1 and one or more pharmaceutically acceptable carriers and/or additives.

25. Pharmaceutical composition in accordance with paragraph 24, additionally containing one or more additional anti-infective agents.

26. Pharmaceutical composition according to paragraph 24, characterized in that said additional anti-infective agent is rifampicin, rifabutin, rifapentene, isoniazid, ethambutol, kanamycin, amikacin, capreomycin, clofazimine, cycloserine, para-aminosalicylic acid, linezolid, sutezolid, bedaquiline, delamanid , pretomanid, moxifloxacin or levofloxacin, or combinations thereof.

27. A method of treating a mycobacterial infection, comprising the step of administering a therapeutically effective amount of a compound of formula (I) to a patient in need thereof.

28. The method according to paragraph 27, characterized in that said mycobacterial infection is caused by Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium abscessus or Mycobacterium chelonae.

29. The method according to paragraph 27, characterized in that said mycobacterial infection is caused by Mycobacterium tuberculosis.

-23040668

30. Compound of formula (II)

where X and Y, independently of each other, are C, N, O or S, provided that X and Y are not both C, that X and Y are not both O or S, when n is 2, and that X is O or S and Y is N when n is 1;

R ₁ is [(R ₃ ) ₃ N ⁺ ]- or [(R 3 )3N ⁺ (CH 2 ) _s ]- provided that R ₁ is not [(R ₃ ) ₃ N ⁺ ]- when n is 1;

R ₂ is hydrogen, halogen, alkoxy, haloalkoxy, lower alkyl or halo lower alkyl;

each R ₃ is independently lower alkyl or two R ₃ together with the nitrogen atom to which they are attached form a 4-7 membered ring;

n is 1 or 2;

p is 1 or 2; and s is 1, 2, 3, 4, 5, or 6.

31. A compound according to paragraph 30, characterized in that R1 is

..s Me ₃ N

Me ₃ N - I ⁰

Me ₃ N

32. A compound according to paragraph 30 having the formula (IIa) (R ₃ ) ₃ N* N BF ₃ ^N (Pa), where each R ₃ is independently methyl, ethyl, propyl or isopropyl, together with a nitrogen atom, to to which they are attached, form a 3-5-membered ring.

33. A compound according to paragraph 30 having formula (IIb) or two R3 co(R ₃ ) ₃ n.

bf ₃

N (Pb), where each R ₃ independently represents methyl, ethyl, propyl or isopropyl, together with the nitrogen atom to which they are attached, form a 3-5-membered ring.

34. Compound according to paragraph 30 having formula (IIc)

N(R ₃ ) ₃ (CH ₂ ) _S . _N BF ₃ or two R3 with ^N (Ps), where each R ₃ independently represents methyl, ethyl, propyl or isopropyl, or two R3 together with the nitrogen atom to which they are attached, form a 3-5-membered ring; and s is 1, 2, 3, or 4.

35. The compound according to paragraph 30 having the formula (IId) InW(CH ₂ ) _s .,. BF ₃ ^N (lid), where each R ₃ is independently methyl, ethyl, propyl or isopropyl, or two R ₃ together with the nitrogen atom to which they are attached, form a 3-5-membered ring; and s is 1, 2, 3, or 4.

36. Compound according to paragraph 30 having the formula (IIe) S^ ^BF 3

1|

N (Pe), where each R ₃ independently represents methyl, ethyl, propyl or isopropyl, or two R ₃ together with the nitrogen atom to which they are attached, form a 3-5-membered ring; and s is 1, 2, 3, or 4.

37. A pharmaceutical composition containing a compound according to paragraph 30 and one or more pharmaceutically acceptable carriers and/or additives.

38. Pharmaceutical composition in accordance with paragraph 37, additionally containing one or more additional anti-infective agents.

39. A pharmaceutical composition according to paragraph 36, characterized in that said additional anti-infective agent is rifampicin, rifabutin, rifapentene, isoniazid, ethambutol, kanamycin, amikacin, capreomycin, clofazimine, cycloserine, para-aminosalicylic acid, linezolid, sutezolid, bedaquiline, delamanid , pretomanid, moxiflox-

-

Claims (21)

cyn or levofloxacin, or combinations thereof. 40. A method of treating a mycobacterial infection, comprising the step of administering a therapeutically effective amount of a compound according to paragraph 30 to a patient in need thereof. 41. The method according to paragraph 40, characterized in that said mycobacterial infection is caused by Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium abscessus or Mycobacterium chelonae. 42. The method according to paragraph 40, characterized in that said mycobacterial infection is caused by Mycobacterium tuberculosis. It should be understood that the present invention is not limited to certain embodiments of the invention described above, as certain implementation options can be changed, and such implementation options still fall within the scope of the appended claims. CLAIM 1. Compound of formula (I) ^R2 (I), where X and Y, independently of each other, represent C or N, provided that X and Y do not simultaneously represent C; M is Cs, K, Li, Na; R ₁ is, in each case individually, hydrogen, halogen, C _1-6 alkoxy, O _1-6 alkyl, C _1-6 alkyl substituted with at least one halogen atom, CN, -NR ₃ R ₄ , C _{3 -6} cycloalkyl or heteroseksualci, where the specified heteroseksualci is a 4-6-membered monocyclic ring in which one carbon of the ring is replaced by nitrogen; R ₂ is hydrogen, halogen, C _1-6 alkOksi, C _1-6 alkyl, C _1-6 alkyl substituted with at least one halogen atom, CN, -NR ₃ R ₄ , C _3-6 cycloalkyl or heterocycloalkyl, where the specified heterocycloalkyl is a 4-6-membered monocyclic ring in which one carbon of the ring is replaced by nitrogen; R ₃ and R ₄ , independently of each other, are C _1-6 alkyl; n is 1 or 2; p is 1 or 2; q is 1, provided that the compound of formula (I) is not: potassium (2-methoxypyridin-3-yl)trifluoroborate, potassium (2-ethoxypyridin-3-yl)trifluoroborate, potassium (6-(trifluoromethyl)pyridin-3-yl)trifluoroborate, potassium (5-methoxypyridin-3-yl)trifluoroborate , potassium (5-bromopyridin-2-yl) trifluoroborate, potassium (5-bromopyridin-3-yl) trifluoroborate, potassium (5-bromo-3-methylpyridin-2-yl) trifluoroborate, potassium (5-bromo-6-methylpyridine -2-yl)trifluoroborate, potassium (pyridin-3-yl)trifluoroborate, potassium (pyridin-2-yl)trifluoroborate. 2. A compound according to claim 1, wherein n is 2 and both X and Y are N. 3. A compound according to claim 1, wherein n is 2, X is C and Y is N. 4. A compound according to claim 1, wherein n is 2, X is N and Y is C. 5. A compound according to claim 1 wherein n is 2 and M is K, Li or Na. 6. The compound according to claim 1, where R ₁ represents, in each case individually, hydrogen, halogen, C _1-6 alkoxy, C _1-6 alkyl or C _1-6 alkyl, substituted with at least one halogen atom. 7. The compound according to claim 1, where R ₁ represents, in each case individually, -NR ₃ R ₄ or cyano. 8. A compound according to claim 1 wherein R ₁ , in each occurrence individually, is C _3-6 cycloalkyl or heterocycloalkyl, wherein said heterocycloalkyl is a 4-6 membered monocyclic ring in which one carbon of the ring is replaced by nitrogen. 9. A compound according to claim 1, wherein R2 is hydrogen or halogen. 10. A compound according to claim 1 wherein R2 is C _1-6 alkoxy, C _1-6 alkyl or C _1-6 alkyl substituted with at least one halogen atom. 11. The compound according to claim 1, where R ₃ and R 4 independently of each other represent C _1-6 alkyl. 12. The connection according to claim 1, where p is equal to 1. - 25 040668 13. The compound according to claim 1, where the specified connection is: 14. The compound according to claim 1, where the specified connection is: 15. A compound according to claim 1, wherein said compound is 16. Pharmaceutical composition for the treatment of mycobacterial infection, containing the compound of formula (I) according to claim 1 and one or more pharmaceutically acceptable carriers and/or additives. 17. Pharmaceutical composition according to claim 16, further comprising one or more additional anti-infective agents selected from rifampicin, rifabutin, rifapentene, isoniazid, ethambutol, kanamycin, amikacin, capreomycin, clofazimine, cycloserine, para-aminosalicylic acid, linezolid, sutezolid, bedaquiline, delamanid , pretomanid, moxifloxacin or levofloxacin, or combinations thereof. 18. A method of treating a mycobacterial infection, comprising the step of administering a therapeutically effective amount of a compound of formula (I) according to claim 1 to a patient in need thereof. 19. The method according to claim 18, characterized in that said mycobacterial infection is caused by Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium abscessus or Mycobacterium chelonae. 20. The method of claim 18, wherein said mycobacterial infection is caused by Mycobacterium tuberculosis. 21. Compound of formula (II) where X and Y, independently of each other, represent C or N, provided that X and Y do not represent both C; R1 is [(R ₃ ) ₃ N ⁺ ]- or [(R 3 ) 3 N ⁺ (CH 2 )s]- provided that R 1 is not [(R 3 ) ₃ N ⁺ ]- when n is 1; -