COMPOUNDS AND METHODS FOR TREATING TUBERCULOSIS
FIELD OF THE INVENTION
The present invention relates to pyrimidine isoxazole amide compounds, process for their preparation, pharmaceutical compositions thereof, and methods of use. In addition, the present invention relates to therapeutic methods for the treatment of tuberculosis.
BACKGROUND OF THE INVENTION
In order to overcome the threat of widespread multi-drug resistant organisms, there is an urgent need to develop new antitubercular agents particularly those with either a novel mechanism of action and/or containing new pharmacophoric groups.
The present invention aims at addressing such drawbacks in the art associated with the management and treatment of tuberculosis.
SUMMARY OF THE INVENTION
In accordance with the present invention, the applicants have hereby discovered compounds that possess the ability to act as antitubercular agents.
The present invention provides compounds of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein Rl and R2 are defined below.
The present invention also provides processes for the preparation of compounds of Formula (I), pharmaceutical compositions containing them as the active ingredient, their use as medicaments, methods of using such compounds, and their use in the manufacture of medicaments for the prevention and treatment of tuberculosis in warm blooded animals such as human being.
It is expected that typical compounds of Formula (I) possess beneficial efficacious, metabolic, toxicological, and/or pharmacodynamic properties.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from methyl, pyrrolidinyl optionally substituted with one or more of fluorine, methyl and hydroxyl, piperidinyl, morpholinyl, fluorobenzylazetidinyl, methylamino substituted with one or more of phenyl, methyl and chlorophenyl, and benzylhydroxylamino; and
R2 is selected from phenyl substituted with chlorine or -CF£F2, pyridinyl substituted with methyl or-CF£F2, -CF£F2, cyclopropyl and benzylpyrrolidinyl.

Effective Amount - As used herein, the phrase "effective amount" means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, the route of administration, and like factors within the knowledge and expertise of the attending physician.
Pharmaceutically Acceptable - As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Compounds of Formula (I) may form stable pharmaceutically acceptable acid or base salts, and in such cases administration of a compound as a salt may be appropriate. Examples of acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxy ethyl sulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, and undecanoate. Examples of base salts include ammonium salts; alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts such as aluminum, calcium and magnesium salts; salts with organic bases such as dicyclohexylamine salts and iV-methyl-d-glucamine; and salts with amino acids such as arginine, lysine, ornithine, and so forth. Also, basic nitrogen-containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; arylalkyl halides such as benzyl bromide and others. Non-toxic physiologically-acceptable

salts are preferred, although other salts may be useful, such as in isolating or purifying the product.
The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.
Compounds of Formula (I) have one or more chiral centres and/or geometric isomeric centres, and it is to be understood that the invention encompasses all such optical, diastereoisomers, and geometric isomers. The invention further relates to any and all tautomeric forms of the compounds of Formula (I).
It is also to be understood that certain compounds of Formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms.
Additional embodiments of the invention are as follows. These additional embodiments relate to compounds of Formula (I) and pharmaceutically acceptable salts thereof. Such specific substituents may be used, where appropriate, with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
In another aspect, the present invention provides a compound selected from:
Example 1: N-(3-chlorobenzyl)-5-((4,6-dimethylpyrimidin-2-yloxy)methyl)isoxazole-3-
carboxamide
Example 2: 5-((4-methyl-6-(pyrrolidin-l-yl)pyrimidin-2-yloxy)methyl)-N-((2-
methylpyridin-4-yl)methyl)isoxazole-3-carboxamide
Example 3: N-(3-(difluoromethyl)benzyl)-5-((4-methyl-6-(pyrrolidin-l-yl)pyrimidin-2-
yloxy)methyl)isoxazole-3-carboxamide
Example 4: (R)-N-(3-(difluoromethyl)benzyl)-5-((4-(3-fluoropyrrolidin-l-yl)-6-
methylpyrimidin-2-yloxy)methyl)isoxazole-3-carboxamide
Example 5: N-((2-(difluoromethyl)pyridin-4-yl)methyl)-5-((4-methyl-6-(pyrrolidin-l-

Example 6: N-((2-(difluoromethyl)pyridin-4-yl)methyl)-5-(((4-methyl-6-(pyrrolidin-l-
yl)pyrimidin-2-yl)oxy)methyl)isoxazole-3-carboxamide
Example 7: (S)-N-(3-(difluoromethyl)benzyl)-5-((4-(3-hydroxy-3-methylpyrrolidin-l-yl)-6-
methylpyrimidin-2-yloxy)methyl)isoxazole-3-carboxamide
Example 8: N-(3-(difluoromethyl)benzyl)-5-((4-methyl-6-morpholinopyrimidin-2-
yloxy)methyl)isoxazole-3-carboxamide
Example 9: N-(3-(difluoromethyl)benzyl)-5-((4-methyl-6-(piperidin-l-yl)pyrimidin-2-
yloxy)methyl)isoxazole-3-carboxamide
Example 10: N-((l-benzyl-5-oxopyrrolidin-3-yl)methyl)-5-((4,6-dimethylpyrimidin-2-
yloxy)methyl)isoxazole-3-carboxamide
Example 11: (R)-5-((4-methyl-6-(l-phenyl ethylamino)pyrimidin-2-yloxy)methyl)-N-((2-
methylpyridin-4-yl)methyl)isoxazole-3-carboxamide
Example 12: 5-(((4-((3-chlorobenzyl)amino)-6-methylpyrimidin-2-yl)oxy)methyl)-N-((2-
methylpyridin-4-yl)methyl)isoxazole-3-carboxamide
Example 13: 5-((4-(benzyloxyamino)-6-methylpyrimidin-2-yloxy)methyl)-N-((2-
methylpyridin-4-yl)methyl)isoxazole-3-carboxamide
Example 14: 5-((4-(3-(4-fluorobenzyl)azetidin-l-yl)-6-methylpyrimidin-2-yloxy)methyl)-
N-((2-methylpyridin-4-yl)methyl)isoxazole-3-carboxamide
Example 15: N-(cyclopropylmethyl)-5-((4-(3-(4-fluorobenzyl)azetidin-l-yl)-6-
methylpyrimidin-2-yloxy)methyl)isoxazole-3-carboxamide
Example 16: N-(2, 2-difluoroethyl)-5-((4-(3-(4-fluorobenzyl)azetidin-l-yl)-6-
methylpyrimidin-2-yloxy)methyl)isoxazole-3-carboxamide
or a pharmaceutically acceptable salt thereof.
Biological Activity
The compounds of Formula (I) are of interest due to their antitubercular effects. The ability of the invention compounds disclosed herein to achieve an antitubercular effect may be evaluated with regard to their ability to inhibit the growth of Mycobacterium tuberculosis using an assay based on the following protocol.
Antitubercular activity test;
The compounds of Formula (I) according to invention evaluated in antitubercular activity test
to determine their inhibitory activity against Mycobacterium tuberculosis.

The MICs of pyrimidine isoxazoles were determined in 7H9 broth as described earlier (Madhavapeddi et al., 2013). Briefly, the assay was performed in two sets of duplicates in a 96-well microtiter plate (catalog no. 900196; Tarsons, India), in which all the peripheral wells were filled with sterile distilled water. Serial two-fold dilutions of compound made in DMSO were placed in the remaining wells, with the concentrations ranging from 32 to 0.06 mg/liter. Column 11 contained no drug and served as culture controls. Middlebrook 7H9 medium supplemented with 0.2% glycerol, 0.05% Tween 80 (Sigma), and 10% albumin dextrose catalase (Difco Laboratories, Detroit, Mich.), was used as the diluent. Each well was inoculated with a final inoculum of approximately 5 x 105 CFU/mL. The plates were packed in gas permeable polythene bags and incubated at 37°C for 7 days. In one set of duplicate plates, 40ul of a freshly prepared 1:1 mixture of 10X Alamar Blue (Accumed International, Westlake, Ohio), and 10% Tween 80 was added to all the wells. The plates were incubated for an additional 24 hours at 37°C, and the colours of all wells were recorded. A blue colour in the well was interpreted as no growth, and a pink colour was scored as growth. Minimum Inhibitory Concentration (MIC) was defined as the lowest drug concentration which prevented the colour change from blue to pink.
Inhibitory activity against Mycobacterium tuberculosis, InhA (enoyl ACP reductase): InhA enzymatic reaction was set up as described below in assay buffer containing 30mM PIPES pH 6.8, 50mM NaCl, 0.05% CHAPS, 2mM DTT and O.lmM EDTA. lOul of InhA enzyme (0.3nM final) pre-incubated with NADH (50uM final) for 15min, was dispensed into 384 well plate containing lul of compound in 100%) DMSO (4% final) and appropriate reaction controls. After 10-15 min of incubation, reaction was started by the addition of ddcoA (lOOuM final) and allowed to continue for 40-45 min at 25°C. 50ul acetonitrile quench containing lOOng/ml Carbamazepine as internal standard was dispensed at the end of 45min to stop the reaction, followed by spinning the sample plate at 4000rpm, 10°C for 20min. The samples were then processed on LCMS to measure the substrate and product, and

In some embodiments, the invention pertains, at least in part, to a method of treating tuberculosis or a Mycobacterium infection in a subject comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
In some embodiments, the invention pertains, at least in part, to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of tuberculosis or & Mycobacterium infection.
In some embodiments, the invention pertains, at least in part, to the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of tuberculosis or a Mycobacterium infection.
In some embodiments, the invention pertains, at least in part, to a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, diluent or carrier.
In some embodiments, the invention pertains, at least in part, to a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of tuberculosis or & Mycobacterium infection.
The term "subject" includes warm blooded mammals, for example, primates, cows, sheep, dogs, cats, rabbits, rats, voles, seals and mice. In some embodiments, the subject is a primate, for example, a human. In some embodiments, the subject is suffering from & Mycobacterium infection or tuberculosis. In some embodiments, the subject is in need of treatment {e.g., the subject would benefit biologically or medically from treatment).

The language "treat," "treating" and "treatment" includes the reduction or inhibition of enzyme or protein activity related to a, Mycobacterium infection or tuberculosis in a subject, amelioration of one or more symptoms of a Mycobacterium infection or tuberculosis in a subject, or the slowing or delaying of progression of a Mycobacterium infection or tuberculosis in a subject. The language "treat," "treating" and "treatment" also includes the reduction or inhibition of the bacterial growth, replication or a reduction or inhibition of the bacterial load of Mycobacterium in a subject.
The language 'Mycobacterium infection" includes infections caused by one or more of the species of the Mycobacterium tuberculosis complex, e.g., Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, Mycobacterium caprae, Mycobacterium microti or Mycobacterium pinnipedii. In some embodiments, the Mycobacterium infection is & Mycobacterium tuberculosis infection.
The term "tuberculosis" refers to the disease caused by an infection in a subject of one or more species of the Mycobacterium tuberculosis complex. The term "tuberculosis" includes latent tuberculosis (LTBI), non-drug resistant tuberculosis, multiple drug resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XRD-TB). The language "latent tuberculosis" includes an infection of a subject caused by one or more species of Mycobacterium tuberculosis complex but where the subject does not necessarily exhibit symptoms a tuberculosis disease. The language "non-drug resistant tuberculosis" includes tuberculosis caused by an infection by one or more species of the Mycobacterium tuberculosis complex that exhibits no antibacterial resistance to standard tuberculosis therapy. The language "multiple drug resistant tuberculosis (MDR-TB)" includes tuberculosis caused by an infection by of one or more species of the Mycobacterium tuberculosis complex that is resistant to rifampicin and isoniazid. The language "extensively drug resistant tuberculosis (XRD-TB)" includes tuberculosis caused by an infection by one or more species of the Mycobacterium tuberculosis complex that is resistant to rifampicin and isoniazid, as well as any member of the quinolone family, and is also resistant to at least one of kanamycin, capreomycin and amikacin.
Process
If not commercially available, the necessary starting materials for the procedures such as
those described herein may be made by procedures which are selected from standard organic

chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the described procedure or the procedures described in the Examples.
It is noted that many of the starting materials for synthetic methods as described herein are commercially available and/or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of processes reported in the scientific literature. The reader is further referred to Advanced Organic Chemistry, 5 Edition, by Jerry March and Michael Smith, published by John Wiley & Sons 2001, for general guidance on reaction conditions and reagents.
It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in compounds. The instances where protection is necessary or desirable are known to those skilled in the art, as are suitable methods for such protection. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Greene, Protective Groups in Organic Synthesis, published by John Wiley and Sons, 1991) and as described hereinabove.
EXAMPLES
The invention is now illustrated by, but not limited to, the following Examples, for which,
unless otherwise stated:
(i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures
were carried out after removal of residual solids by filtration; (ii) temperatures are quoted as °C; operations were carried out at room temperature, that
is typically in the range 18-26 °C and without the exclusion of air unless otherwise
stated, or unless the skilled person would otherwise work under an inert atmosphere; (iii) column chromatography (by the flash procedure) was used to purify compounds and
was performed on Merck Kieselgel silica (Art. 9385) unless otherwise stated; (iv) in general, the course of reactions was followed by TLC, HPLC, or LC/MS and
reaction times are given for illustration only; yields are given for illustration only and
are not necessarily the maximum attainable; (v) the structure of the end-products of the invention was generally confirmed by NMR
and mass spectral techniques. Proton magnetic resonance spectra were generally
determined in DMSO-d6 unless otherwise stated, using a Bruker DRX-300

spectrometer or a Bruker DRX-400 spectrometer, operating at a field strength of 300 MHz, or 400 MHz, respectively. In cases where the NMR spectrum is complex, only diagnostic signals are reported. Chemical shifts are reported in parts per million downfield from tetramethylsilane as an external standard (8 scale) and peak multiplicities are shown thus: s, singlet; d, doublet; dd, doublet of doublets; dt, doublet of triplets; dm, doublet of multiplets; t, triplet, m, multiplet; br, broad. Fast-atom bombardment (FAB) mass spectral data were generally obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and, where appropriate, either positive ion data or negative ion data were collected or using Agilent 1100 series LC/MS equipped with Sedex 75ELSD, and where appropriate, either positive ion data or negative ion data were collected. The lowest mass major ion is reported for molecules where isotope splitting results in multiple mass spectral peaks (for example when chlorine is present). Reverse Phase HPLC was carried out using YMC Pack ODS-AQ (100x20 mmID, S-5u particle size, 12 nm pore size) on Agilent instruments;
each intermediate was purified to the standard required for the subsequent stage and was characterized in sufficient detail to confirm that the assigned structure was correct; purity was assessed by HPLC, TLC, or NMR and identity was determined by infra-red spectroscopy (IR), mass spectroscopy or NMR spectroscopy as appropriate; and
the following abbreviations may be used:
TLC is thin layer chromatography; HPLC is high pressure liquid chromatography; MPLC is medium pressure liquid chromatography; NMR is nuclear magnetic resonance spectroscopy; DMSO is dimethylsulfoxide; CDCI3 is deuterated chloroform; MeOD is deuterated methanol, i.e. D3COD; MS is mass spectroscopy; ESP (or ES) is electrospray; EI is electron impact; APCI is atmospheric pressure chemical ionization; THF is tetrahydrofuran; DCM is dichloromethane; MeOH is methanol; DMF is dimethylformamide; EtOAc is ethyl acetate; LC/MS is liquid chromatography/mass spectrometry; h is hour(s); min is minute(s); d is day(s); MTBD is N-methyl-l,5,7-triazabicyclo[4.4.0]dec-5-ene; TFA is trifluoroacetic acid; v/v is ratio of volume/volume; Boc denotes t-butoxycarbonyl; Cbz denotes benzyloxycarbonyl; Bz denotes benzoyl; atm denotes atmospheric pressure; rt denotes room temperature; mg denotes milligram; g denotes gram; uL denotes microliter; mL

denotes milliliter; L denotes liter; nM denotes nanomolar; uM denotes micromolar; mM denotes millimolar; M denotes molar; N denotes normal; nm denotes nanometer.
aReagents and conditions: (a) Cs2C03, DMF, 0-25°C, 3h, 27 % (b) NaOH, THF:water, 0-25°C, lh, 70-100 % (c) Amine, HATU, DCM, 0-25°C, 3h, 25-60 %
Intermediate 1 5-(bromomethyl)isoxazole-3-carboxylate
In a 100 mL round-bottomed flask 3-bromoprop-l-yne (11.38 mL, 105.58 mrnol) and (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (8 g, 52.79 mmol) were taken in ethyl acetate (150 mL) to give a yellow solution. Reaction mass was cooled to it and sodium bicarbonate (4108 mL, 105.58 mmol) in water (10 mL) was added slowly over 30 min. Reaction mass was then allowed to cool to 25 °C and stirred for 15h. Reaction mass was diluted with brine (150 mL) and extracted with dichloromethane (3x 200mL). DCM layers were collected and dried over sodium sulphate and concentrated to get crude mass which on purification over combiflash gave pure ethyl 5-(bromomethyl)isoxazole-3-carboxylate (8.30 g, 33.6 %) as crystalline solid. *HNMR (300 MHz, DMSO-d6) 5 ppm 1.25 - 1.36 (m, 3 H) 4.36 (q, .7=7.10 Hz, 2 H) 4.89 (s, 2 H) 6.99 (s, 1 H). MS (ES+), (M+H)+ = 236.22 for C7H8BrN03
Intermediate 2
Ethyl 5-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)isoxazole-3-carboxylate

In a 15 mL round-bottomed flask 4,6-dimethylpyrimidin-2-ol (1.65 g, 13.29 mmol) and ethyl 5-(bromomethyl)isoxazole-3-carboxylate (3.11 g, 13.29 mmol) was taken in DMF (5 mL) to give a purple solution. To this cesium carbonate (1064 mL, 13.29 mmol) was added at 0°C and stirred at 25°C for 3h. Reaction mass was purified on combiflash system to get ethyl 5-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)isoxazole-3-carboxylate (1.000 g, 27.1 %) and ethyl 5-((4,6-dimethyl-2-oxopyrimidin-l(2H)-yl)methyl)isoxazole-3-carboxylate (2.500 g, 67.8 %). *H NMR (300 MHz, DMSO-d6) 5 ppm 1.31 (t, .7=7.16 Hz, 3 H) 2.36 (s, 6 H) 4.36 (q, .7=7.16 Hz, 2 H) 5.55 (s, 2 H) 6.97 (d, 7=2.26 Hz, 2 H). MS (ES+), (M+H)+ = 278.31 for Ci3H15N304
Ethyl 5-((4,6-dimethyl-2-oxopyrimidin-l(2H)-yl)methyl)isoxazole-3-carboxylate
*H NMR (300 MHz, DMSO-d6) 5 ppm 0.91 (t, 7=7.16 Hz, 4 H) 1.84 (s, 3 H) 2.02 (s, 3 H) 3.96 (q, 7=7.16 Hz, 2 H) 4.98 (s, 2 H) 5.37 (s, 1 H) 5.98 (s, 1 H) 6.43 (s, 1 H) MS (ES+), (M+H)+ = 278.27 for C13H15N3O4
Intermediate 3 5-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)isoxazole-3-carboxylic acid
In 25ml round bottom flask ethyl 5-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)isoxazole-3-carboxylate (lg, 3.61 mmol) in THF (10 mL) was taken to give a red solution. Sodium hydroxide (433 mg, 10.82 mmol) in water (5.00 mL) was added at 0°C. The reaction mixture was stirred at RT for 20 min. The solvent was removed at 25°C under vacuum. The water layer was acidified with IN HC1 carefully at 10 °C, precipitated solid was filtered and dried

over vacuum to get pure white solid of 5-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)isoxazole-3-carboxylic acid (0.750 g, 83 %)
*H NMR (300 MHz, DMSO-d6) 5 ppm 2.33 - 2.39 (m, 6 H) 5.53 (s,2 H) 6.88 (s, 1H) 6.98(m, 1 H) 14.11 (br s, 1 H) MS (ES+), (M+H)+ = 250.30 for C11H11N3O4.
Example 1
N-(3-chlorobenzyl)-5-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)isoxazole-3-
carboxamide
In a 50 mL round-bottomed flask 5-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)isoxazole-3-carboxylic acid (110 mg, 0.44 mmol) was taken in dichloromethane (4 mL) to give a orange solution. Reaction mass was cooled to 0 °C and N,N'-Diisopropylethylamine (0.154 mL, 0.88 mmol) was added and stirred for 5 min. 0-(7-Azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (218 mg, 0.57 mmol) followed by (3-chlorophenyl)methanamine (0.054 mL, 0.44 mmol) was added and stirred at 0 °C for 15 min and then stirred at it for 2h. Reaction mass was diluted with DCM and washed with water. Organic layers were dried over sodium sulfate and concentrated to get crude mass, which on purification by reverse phase column chromatography gave N-(3-chlorobenzyl)-5-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)isoxazole-3-carboxamide (45.0 mg, 27.3 %) as white solid. *H NMR (300 MHz, DMSO-d6) □ ppm 2.36 (s, 6 H) 4.44 (d, .7=6.22 Hz, 2 H) 5.54 (s, 2 H) 6.89 (s, 1 H) 6.98 (s, 1 H) 7.25 - 7.38 (m, 4 H) 9.43 (t, .7=6.31 Hz, 1 H) MS (ES+), (M+H)+ =373.31 for Ci8Hi7ClN403.

Reagents and conditions: (a) tBuXPhos Pd Gl,CsF , Dioxane, 120°C, 12h, 50-90% (b) NaOH, THF:water, 0-25°C, lh, 70-100 % (c) Amine, HATU, DCM, 0-25°C, 3h, 25-60 %
Intermediate 4 2,4-dichloro-6-methylpyrimidine
In a 500 mL round-bottomed flask,6-methyluracil (158.59 mmol) taken in phosphorus oxychloride (1180.12 mmol) to give a brown suspension. The reaction mixture was refluxed for 6 h. Phosphorus oxychloride was distilled out under reduce pressure and remaining oil was diluted with THF (250mL) and ice (400 g). The reaction mixture was basified at pH 8 under cold condition. Reaction mass was extracted with ethylacetate (250 mL x 3). Organic layers were dried over sodium sulphate and solvent was removed under vacuum. The residue was purified by flash column chromatography using 15 % ethyl acetate in hexane to give 2,4-dichloro-6-methylpyrimidine (91 %). *H NMR (300 MHz, DMSO-d6) 5 ppm 2.51 (s, 3 H) 7.75 (s, 1 H), MS (ES+), (M+H)+ = 163.27 for C5H4CI2N2.
Intermediate 5 5-(Hydroxymethyl)isoxazole-3-carboxylate

In a 100 mL round-bottomed flask (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (164.96 mmol) and propargyl alcohol (824.82 mmol) were taken in tetrahydrofuran (200 mL) to give a yellow solution. Reaction mass was cooled to 0 °C and triethyl amine (197.96 mmol) in tetrahydrofuran (100 mL) was added slowly over 45 min. Reaction mass was then allowed to cool to 25 °C and stirred overnight. The reaction mass was diluted with brine (250 mL) and extracted with dichloromethane (3x 300 mL). Dichloromethane layers were collected and dried over sodium sulphate and concentrated to give crude mass which on purification over combiflash gave ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (81 %) as pure liquid. *H NMR (300 MHz, DMSO-d6) 5 ppm 3.82 (t, J=7.06 Hz, 3 H) 6.74 - 6.98 (m, 2 H) 7.08 - 7.18 (m, 2 H) 8.25 - 8.39 (m, 1 H) 9.25 (s, 1 H) MS (ES+), (M+H)+ = 172.26 for C9H9N04.
Synthesis of 3-(4-fluorobenzyl)azetidine
Reagents and conditions: (a) PPh3, toluene, 100°C, 16h, 97%; (b) KOtBu, DMF, 0-25-60°C, 16h, 40%; (c) H2,Pd/C, methanol, 25°C, 8h, 93 %; (d) HC1 (4N in Dioxane), 1,4-dioxane, 0-25°C 30min, 100 %.
Intermediate 6 (4-Fluorobenzyl)triphenylphosphonium Bromide
A solution of triphenyl phosphine (42.32 mmol) and 4-fluorobenzyl bromide (42.32 mmol) was refluxed overnight in toluene (100 mL) and allowed to cool to room temperature. The resulting precipitate was collected by filtration, washed with Et20, and dried in vacuo to yield (4-fluorobenzyl)triphenylphosphonium (97 %) as a white solid. The product was taken as it is for the next step. *H NMR (300 MHz, DMSO-d6) 5 ppm 5.21 (d, J=15.64 Hz, 2 H), 6.96 -

7.17 (m, 4 H), 7.59 - 7.83 (m, 12 H), 7.86 - 7.98 (m, 3 H). MS (ES+), (M+H)+ = 372.25 for C25H21FP+
Intermediate 7
*-Butyl 3-(4-fluorobenzylidene)azetidine-l-carboxylate
To a suspension of (4-fluorobenzyl)triphenylphosphonium bromide (16.86 mmol) in anhydrous DMF (35 mL) was added tert-butyl alcohol, potassium derivative (18.524 mmol). The mixture was stirred at room temperature for 10 mins before l-boc-3-azetidinone (8.43 mmol) was added. The reaction mixture was heated to 60°C overnight, quenched with ice water and extracted with diethyl ether (4 x 300 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residue was purified by flash column chromatogrphy eluating with ethyl acetate/hexane as eluent to give tert-butyl 3-(4-fluorobenzylidene)azetidine-l-carboxylate (40.5 %) as white solid. *H NMR (300 MHz, chloroform -d) 5 ppm 1.50 (s, 10H), 4.59-4.70 (m, 2H), 4.81 (q, .7=2.64 Hz, 2H), 6.24 (t, .7=2.17 Hz, 1H), 6.96-7.17 (m, 4H). MS (ES+), (M+H)+ = 264.40 for Ci5Hi8FN02.
Intermediate 8
*-Butyl 3-(4-fluorobenzyl)azetidine-l-carboxylate
In 100 ml parr shaker flask, tert-butyl 3-(4-fluorobenzylidene)azetidine-l-carboxylate (6.46 mmol) was taken in methanol (25 mL). To it Pd/C (1.88 mmol) was added and reaction mixture was subjected to hydrogenation in parr apparatus at 40 psi for 8 hr. The reaction mixture was filtered through celite washed with methanol and concentrated. The product was purified by flash chromatography eluating with ethyl acetate/hexane system to give pure tert-butyl 3-(4-fluorobenzyl)azetidine-l-carboxylate (93 %). XH NMR (300 MHz, chloroform-J) 5 ppm 1.36 (s, 8H), 1.57 (s, 1H), 2.60-2.76 (m, 1H), 2.77-2.87 (m, 2H), 3.55 (dd, .7=8.38, 5.18

Hz, 2H), 3.91 (t, J=8.19Hz, 2H), 6.83-6.97 (m, 2H), 6.98-7.10 (m, 2H). MS (ES+), (M+H)+ = 266.30 for Ci5H20FNO2.
Intermediate 9 3-(4-fluorobenzyl)azetidine hydrochloride
In alOOml round bottom flask, tert-butyl 3-(4-fluorobenzyl)azetidine-l-carboxylate (6.03 mmol) was taken in 1,4-dioxane (10 mL) and HC1 (4N in dioxane) (40.00 mmol) was added at 0-25 °C. The reaction mixture was then stirred at 0-25 °C for half an hour. The solvent was evaporated to dryness. The residue was then triturated with acetonitrile and ether. The solid was filtered and dried to give 3-(4-fluorobenzyl)azetidine (100 %) which was immediately used as it is for the next step. MS (ES+), (M+H)+ = 166.45 for Ci0Hi2FN.
Example 2
5-((4-methyl-6-(pyrrolidin-l-yl)pyrimidin-2-yloxy)methyl)-N-((2-methylpyridin-4-
yl)methyl)isoxazole-3-carboxamide
Example 2 was prepared using following different steps.
Intermediate 10 2-chloro-4-methyl-6-(pyrrolidin-l-yl)pyrimidine
In a 100 mL round-bottomed flask 2,4-dichloro-6-methylpyrimidine (1 g, 6.13 mmol) and pyrrolidine (0.436g, 6.13 mmol) were dissolved in DMF (10 mL) to give a colorless solution. N,N'-Diisopropylethylamine (2.137 mL, 12.27 mmol) was added and reaction mixture was stirred at room temperature for 15h. The reaction mixture was concentrated to

dryness and purified with combiflash using ethyl acetate in hexane (10-30%) as eluent to get two pure fractions. Late eluting fraction on evaporation yielded 2-chloro-4-methyl-6-(pyrrolidin-1-yl) pyrimidine (0.940 g, 78 %) as a white crystalline solid. XH NMR (300 MHz, DMSO-^e) 5 ppm 1.84 - 2.10 (m, 4 H) 2.29 (s, 3 H) 3.38 (m, J=6.12 Hz, 2 H) 3.50 (t, .7=6.12 Hz, 2 H) 6.41 (s, 1 H) MS (ES+), (M+H)+ = 198.00 for C9Hi2ClN3
Intermediate 11
Ethyl 5-(((4-methyl-6-(pyrrolidin-l-yl)pyrimidin-2-yl)oxy)methyl)isoxazole-3-
carboxylate
0
>=N o
In a 25 mL thermal reactor, 2-chloro-4-methyl-6-(pyrrolidin-l-yl)pyrimidine (300 mg, 1.52 mmol), ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (468 mg, 2.73 mmol) and cesium fluoride (346 mg, 2.28 mmol) were dissolved in anhydrous 1,4-dioxane (10 mL). The mixture was purged with nitrogen and tBuXPhos Pd Gl (52.1 mg, 0.08 mmol) was added to the mixture and again purged with nitrogen. The mixture was then refluxed overnight. The reaction mixture was then cooled to room temperature and filtered through celite bed. Filtrate was evaporated under vacuum and the residue was purified on combiflash using using ethyl acetate and hexane as eluents to afford ethyl 5-(((4-methyl-6-(pyrrolidin-l-yl)pyrimidin-2-yl)oxy)methyl)isoxazole-3-carboxylate (300 mg, 59.5 %) as a yellow colored solid. ^NMR (300 MHz, DMSO-^e) 5 ppm 1.31 (t, J=7.06 Hz, 3 H) 1.91 (br. s., 4H) 2.19 (s, 3 H) 3.30 (br. s., 2H) 3.44 (br. s., 2H) 4.35 (q, .7=7.16 Hz, 2 H) 5.46 (s, 2 H) 6.07 (s, 1 H) 6.91 (s, 1 H) MS (ES+), (M+H)+ = 333.00 for C16H20N4O4.
Intermediate 12 5-(((4-methyl-6-(pyrrolidin-l-yl)pyrimidin-2-yl)oxy)methyl)isoxazole-3-carboxylic acid

WO 2015/181799 PCT7IB2015/054076
21
This was prepared by using the same procedure as described above for intermediate 3 from intermediate 2. Yield: 84 % *H NMR (300 MHz, DMSO-d6) 5 ppm 1.85 - 2.09 (m, 4 H) 2.32 (s, 3 H) 3.46 - 3.58 (m, 2 H) 3.58 - 3.75 (m, 2 H) 5.74 (s, 2 H) 6.48 (s, 1 H) 7.03 (s, 1 H) 14.18 (br.s.; 1H) MS (ES+), (M+H)+ = 305.00 for C14H16N4O4
5-(((4-methyl-6-(pyrrolidin-l-yl)pyrimidin-2-yl)oxy)methyl)-N-((2-methylpyridin-4-yl)methyl)isoxazole-3-carboxamide
/5-N

U-N O
This was prepared as described above for example 1. Yield: 29.2 % *H NMR (300 MHz, DMSO-^e) 5 ppm 1.91 (m, 4 H) 2.20 (s, 3 H) 2.43 (s, 3 H) 3.43 (m, 4 H) 4.41 (d, 7=6.22 Hz, 2 H) 5.46 (s, 2 H) 6.07 (s, 1 H) 6.85 (s, 1 H)7.08 (d, 7=5.27 Hz, 1 H) 7.14 (s, 1 H) 8.36 (d, 7=5.09 Hz, 1 H) 9.36 - 9.47 (m, 1 H) MS (ES+), (M+H)+ = 408.19 for C2iH24N603.
Example 3
N-(3-(difluoromethyl)benzyl)-5-((4-methyl-6-(pyrrolidin-l-yl)pyrimidin-2-
yloxy)methyl)isoxazole-3-carboxamide
o

This was prepared by the procedure as described above for example 2. Yield: 48.8 % *H NMR (300 MHz, DMSO-d6) 5 ppm 1.90 (m, 4 H) 2.20 (s, 3 H) 3.43 (m., 4 H) 4.54 (d, 7=6.03 Hz, 2 H) 5.47 (s, 2 H) 5.76 (s, 1 H) 6.06 (s, 1 H) 6.85 (s, 1 H) 6.96 (t, 1H, CHF2) 7.48 (d, 7=5.09 Hz, 1 H) 7.61 (s, 1 H) 8.61 (d, 7=4.90 Hz, 1 H) 9.51 (t, 7=6.12 Hz, 1 H) MS (ES+), (M+H)+ =444.31 for C22H23F2N503.

Example 4
(R)-N-(3-(difluoromethyl)benzyl)-5-(((4-(3-fluoropyrrolidin-l-yl)-6-methylpyrimidin-2-
yl)oxy)methyl)isoxazole-3-carboxamide
This was prepared using the procedure as described above for example 2. Yield: 55.9 % XH NMR (300 MHz, DMSO-d6) 5 ppm 2.09 - 2.34 (m, 5 H) 3.40 (d, J=9.80 Hz, 1 H) 3.45 - 3.57 (m, 1 H) 3.63 (d, J=9.80 Hz, 2 H) 4.49 (d, J=6.40 Hz, 2 H) 5.48 (s, 2 H) 5.34-5.51(d, 0.5, 0.5 (l)H)6.14(s, 1H) 6.83-7.21 (m, 0.26,0.5,0.26 (1) H) 6.83 - 7.21 (m, 1 H CHF2) 1M - 7.53 (m, 4 H) 9.43 (t, J=6.22 Hz, 1 H) MS (ES+), (M+H)+ = 462.26 for CiiH^NjCh.
Example 5
(R)-N-((2-(difluoromethyl)pyridin-4-yl)methyl)-5-(((4-(3-fluoropyrrolidin-l-yl)-6-
methylpyrimidin-2-yl)oxy)methyl)isoxazole-3-carboxamide
This was prepared by the procedure as described above for example 2. Yield: 58.1% *H NMR (300 MHz, DMSO-d6) 5 ppm 2.24 (m, 5 H) 2.45 (s, 3 H) 3.42 - 3.96 (m, 4 H) 4.44 (d, J=6.03 Hz, 2 H) 5.32 - 5.59 (m, 1 H) 5.50 (s, 2 H) 6.16 (s, 1 H) 6.88 (s, 1 H) 7.10 (d, J=4.90 Hz, 1 H) 7.16 (s, 1 H) 8.38 (d, J=5.09 Hz, 1 H) 9.35 - 9.52 (m, 1 H) MS (ES+), (M+H)+ = 463.25 for C21H21F3N6O3.
Example 6
N-((2-(difluoromethyl)pyridin-4-yl)methyl)-5-(((4-methyl-6-(pyrrolidin-l-yl)pyrimidin-
2-yl)oxy)methyl)isoxazole-3-carboxamide

This was prepared by the procedure as described above for example 2. Yield: 47.0 % *H NMR (300 MHz, DMSO-d6) 5 ppm 1.91 (m, 4 H) 2.20 (s, 3 H) 3.43 (m, 4 H) 4.54 (d, J=6.22 Hz, 2 H) 5.47 (s, 2 H) 6.77-7.13 (t, 1 H, CHF2) 6.86 (s, 1 H) 7.48 (d, J=4.90 Hz, 1 H) 7.61 (s, 1 H) 8.62 (d, J=5.09 Hz, 1 H) 9.52 (t, .7=6.12 Hz, 1 H) MS (ES+), (M+H)+ = 445.27 for C21H22F2N6O3
Example 7
(S)-N-(3-(difluoromethyl)benzyl)-5-((4-(3-hydroxy-3-methylpyrrolidin-l-yl)-6-
methylpyrimidin-2-yloxy)methyl)isoxazole-3-carboxamide
This was prepared by the procedure as described above for example 2. XH NMR (300 MHz, DMSO-^e) 5 ppm 1.26 (s, 3 H) 1.58 - 1.90 (m, 2 H) 2.13 (s, 3 H) 3.09 - 3.20 (m, 2 H) 3.34 -3.65 (m, 2 H) 4.43 (d, J=6.03 Hz, 2 H) 4.65 - 4.86 (m, 1 H) 5.39 (s, 2 H) 5.97 (d, J=14.32 Hz, 1 H) 6.51 - 7.26 (m, J=57 Hz, 1 H) 6.77 (s, 1 H) 7.36 - 7.48 (m, 4 H) 9.36 (t, J=6.03 Hz, 1 H) MS (ES+), (M+H)+ = 474.29for C23H25F2N504.
Example 8
N-(3-(difluoromethyl)benzyl)-5-((4-methyl-6-morpholinopyrimidin-2-
yloxy)methyl)isoxazole-3-carboxamide

This was prepared by the procedure as described above for example 2. XH NMR (300 MHz, DMSO-^e) 5 ppm 2.20 (s, 3 H) 3.58 (dd, .7=18.08, 5.09 Hz, 8 H) 4.48 (d, .7=6.03 Hz, 2 H) 5.45 (s, 2 H) 6.41 (s, 1 H) 6.83 (s, 1 H) 6.63-7.20 (s, J= 57 Hz, 1 H) 7.37 - 7.54 (m, 4 H) 9.41 (t, .7=6.12 Hz, 1 H). MS (ES+), (M+H)+ = 460.27 C22H23F2N5O4.
Example 9
N-(3-(difluoromethyl)benzyl)-5-((4-methyl-6-(piperidin-l-yl)pyrimidin-2-
yloxy)methyl)isoxazole-3-carboxamide
IN ^
*H NMR (300 MHz, DMSO-d6) 5 ppm 2.26 (d, .7=3.77 Hz, 4 H) 2.39 (d, .7=4.52 Hz, 2 H) 2.98 (s, 3 H) 4.28 - 4.41 (m, 4 H) 5.28 (d, .7=6.22 Hz, 2 H) 6.23 (s, 2 H) 7.18 (s, 1 H) 7.62 (s, 1 H) 7.63-8.00 (t, .7=54 Hz,l H) 8.22 - 8.32 (m, 4 H) 10.21 (t, .7=6.12 Hz, 1 H). MS (ES+), (M+H)+ = = 458.57 for C23H25F2N5O3.
Example 10
N-((l-benzyl-5-oxopyrrolidin-3-yl)methyl)-5-((4,6-dimethylpyrimidin-2-
yloxy)methyl)isoxazole-3-carboxamide
*H NMR (300 MHz, DMSO-d6) 5 ppm -2.13 - 2.31 (m, 1 H) 2.36 (s, 6 H) 2.40-2.44 (t, 1 H)2.56 - 2.66 (m, 1 H) 3.05-3.00 (m, 1 H) 3.23 - 3.32 (m, 3 H) 4.29 - 4.41 (m, 2 H) 5.53 (s, 2

H) 6.84 (s, 1 H) 6.98 (s, 1 H) 7.17 - 7.36 (m, 5 H) 8.98 (t, J=5.75 Hz, 1 H). MS (ES+), (M+H)+ = = 436.32for C23H25N5O4
Example 11
(R)-5-((4-methyl-6-(l-phenylethylamino)pyrimidin-2-yloxy)methyl)-N-((2-
methylpyridin-4-yl)methyl)isoxazole-3-carboxamide
This was prepared by the procedure as described above for example 2. Yield: 25.2 % XH NMR (300 MHz, DMSO-d6) 5 ppm 1.40 (d, J=6.97 Hz, 3 H), 2.07 - 2.17 (m, 3 H), 2.43 (s, 3 H), 4.42 (d, J=6.22 Hz, 2 H), 5.12 (br. s., 1 H), 5.37 (br. s., 2 H), 6.07 (br. s., 1 H), 6.76 (br. s., 1 H), 7.07 - 7.36 (m, 7 H), 7.89 (d, J=7.91 Hz, 1 H), 8.36 (d, J=5.09 Hz, 1 H), 9.41 (t, J=5.75 Hz, 1 H). MS (ES+), (M+H)+ = 459.39 for C25H26N6O3.
Example 12
5-(((4-((3-chlorobenzyl)amino)-6-methylpyrimidin-2-yl)oxy)methyl)-N-((2-
methylpyridin-4-yl)methyl)isoxazole-3-carboxamide
This was prepared by the procedure as described above for example 2. Yield: 25.02 % H NMR (300 MHz, DMSO-d6) 5 ppm 2.16 (s, 3 H), 2.44 (s, 3 H), 4.42 (d, J=6.03 Hz, 2 H), 4.49 (br. s., 2 H), 5.42 (s, 2 H), 6.11 (s, 1 H), 6.80 (br. s., 1 H), 7.11 (d, J=4.71 Hz, 1 H), 7.16 (s, 1 H), 7.19 - 7.40 (m, 4 H), 8.02 (br. s., 1 H), 8.37 (d, J=5.09 Hz, 1 H), 9.42 (t, J=6.03 Hz, 1 H). MS (ES+), (M+H)+ = 479.34 for C24H23CIN6O3.

Example 13
5-((4-(benzyloxyamino)-6-methylpyrimidin-2-yloxy)methyl)-N-((2-methylpyridin-4-
yl)methyl)isoxazole-3-carboxamide
This was prepared by the procedure as described above for example 2. *H NMR (300 MHz, DMSO-^g) 5 ppm 2.28 (s, 3 H) 2.46 (s, 3 H) 4.45 (d, J=6.03 Hz, 2 H) 4.87 (s, 2 H) 5.49 (s, 2 H) 6.34 (s, 1 H) 6.90 (s, 1 H) 7.09 - 7.18 (m, 2 H) 7.35 - 7.49 (m, 5 H) 8.38 (d, J=5.09 Hz, 1 H) 9.35 (t, .7=6.12 Hz, 1 H) 10.43 (s, 1 H). MS (ES+), (M+H)+ = 461.34 for C^H^NeCU.
Example 14
5-(((4-(3-(4-fluorobenzyl)azetidin-l-yl)-6-methylpyrimidin-2-yl)oxy)methyl)-N-((2-
methylpyridin-4-yl)methyl)isoxazole-3-carboxamide
This was prepared by the procedure as described above for example 2. Yield: 20.1 % XH NMR (300 MHz, DMSO-d6) 5 ppm 1.04 (d, .7=6.03 Hz, 2H), 2.19 (s, 3H), 2.43 (s, 3H), 2.86-3.11 (m, 3H), 3.64-3.77 (m, 2H), 3.97-4.11 (m, 2H), 4.36-4.50 (m, 2H), 5.44 (s, 2H), 5.91-6.01 (m, 1H), 6.84 (s, 1H), 7.13 (d, J=8.85 Hz, 4H), 7.27 (s, 2H), 8.30-8.41 (m, 1H), 9.34-9.48 (m, 1H) MS (ES+), (M+H)+ = 503.33 for CiyH^FNeCh.
Example 15
N-(cyclopropylmethyl)-5-(((4-(3-(4-fluorobenzyl)azetidin-l-yl)-6-methylpyrimidin-2-yl)oxy)methyl)isoxazole-3-carboxamide

This was prepared by the procedure as described above for example 2. Yield: 26.5 % *H NMR (300 MHz, DMSO-d6) 5 ppm 0.17-0.28 (m, 2H), 0.33-0.49 (m, 2H), 0.38-0.48 (m, 2H), 0.96-1.10 (m, 1H), 2.21 (s, 3H), 2.88-2.97 (m, 2H), 3.07-3.16 (m,2H), 3.65-3.84 (m, 2H), 4.04-4.19 (m, 2H), 5.37-5.55 (m, 2H), 5.95-6.08 (m, 1H), 6.76-6.87 (m, 1H), 7.03-7.20 (m, 2H), 7.20-7.33 (m, 2H), 8.23-8.32 (m,lH), 8.77-8.92 (m, 1H). MS (ES+), (M+H)+ = 452.35 for C24H26F3N503.
Example 16
N-(2,2-difluoroethyl)-5-(((4-(3-(4-fluorobenzyl)azetidin-l-yl)-6-methylpyrimidin-2-yl)oxy)methyl)isoxazole-3-carboxamide
This was prepared by the procedure as described above for example 2. Yield: 26.0 % XH NMR (300 MHz, DMSO-d6) 5 ppm 2.18 (s, 3H), 2.86-3.09 (m, 3H), 3.56-3.77 (m, 4H), 3.93-4.11 (m, 2H), 5.44 (s, 2H), 5.95-6.34 (m, J=57 Hz 1H), 6.07-6.16 (m, lH),6.27-6.34 (m, 1H), 6.84 (s, 1H), 7.06-7.18 (m, 2H), 7.22-7.35 (m, 2H), 9.07-9.20 (m, 1H). MS (ES+), (M+H)+ = 462.31 for C22H22F3N503.

Claims
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from methyl, pyrrolidinyl optionally substituted with one or more of fluorine, methyl and hydroxyl, piperidinyl, morpholinyl, fluorobenzylazetidinyl, methylamino substituted with one or more of phenyl, methyl and chlorophenyl, and benzylhydroxylamino; and
R2 is selected from phenyl substituted with chlorine or -CHF2, pyridinyl substituted with methyl or-CHF2, -CHF2, cyclopropyl and benzylpyrrolidinyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein

4. The compound of Formula (I), wherein the compound is selected from:
N-(3-chlorobenzyl)-5-((4,6-dimethylpyrimidin-2-yloxy)methyl)isoxazole-3-
carboxamide
5-((4-methyl-6-(pyrrolidin-l-yl)pyrimidin-2-yloxy)methyl)-N-((2-methylpyridin-
4-yl)methyl)isoxazole-3-carboxamide
N-(3-(difluoromethyl)benzyl)-5-((4-methyl-6-(pyrrolidin-l-yl)pyrimidin-2-
yloxy)methyl)isoxazole-3-carboxamide
(R)-N-(3-(difluoromethyl)benzyl)-5-((4-(3-fluoropyrrolidin-l-yl)-6-methylpyrimidin-2-yloxy)methyl)isoxazole-3-carboxamide N-((2-(difluoromethyl)pyridin-4-yl)methyl)-5-((4-methyl-6-(pyrrolidin-l-yl)pyrimidin-2-yloxy)methyl)isoxazole-3-carboxamide N-((2-(difluoromethyl)pyridin-4-yl)methyl)-5-(((4-methyl-6-(pyrrolidin-l-yl)pyrimidin-2-yl)oxy)methyl)isoxazole-3-carboxamide
(S)-N-(3-(difluoromethyl)benzyl)-5-((4-(3-hydroxy-3-methylpyrrolidin-l-yl)-6-methylpyrimidin-2-yloxy)methyl)isoxazole-3-carboxamide N-(3-(difluoromethyl)benzyl)-5-((4-methyl-6-morpholinopyrimidin-2-yloxy)methyl)isoxazole-3-carboxamide
N-(3-(difluoromethyl)benzyl)-5-((4-methyl-6-(piperidin-l-yl)pyrimidin-2-yloxy)methyl)isoxazole-3-carboxamide
N-((l-benzyl-5-oxopyrrolidin-3-yl)methyl)-5-((4,6-dimethylpyrimidin-2-yloxy)methyl)isoxazole-3-carboxamide
(R)-5-((4-methyl-6-(l-phenylethylamino)pyrimidin-2-yloxy)methyl)-N-((2-methylpyridin-4-yl)methyl)isoxazole-3-carboxamide
5-(((4-((3-chlorobenzyl)amino)-6-methylpyrimidin-2-yl)oxy)methyl)-N-((2-methylpyridin-4-yl)methyl)isoxazole-3-carboxamide 5-((4-(benzyloxyamino)-6-methylpyrimidin-2-yloxy)methyl)-N-((2-methylpyridin-4-yl)methyl)isoxazole-3-carboxamide
5-((4-(3-(4-fluorobenzyl)azetidin-l-yl)-6-methylpyrimidin-2-yloxy)methyl)-N-((2-methylpyridin-4-yl)methyl)isoxazole-3-carboxamide N-(cyclopropylmethyl)-5-((4-(3-(4-fluorobenzyl)azetidin-l-yl)-6-methylpyrimidin-2-yloxy)methyl)isoxazole-3-carboxamide N-(2, 2-difluoroethyl)-5-((4-(3-(4-fluorobenzyl)azetidin-l-yl)-6-methylpyrimidin-2-yloxy)methyl)isoxazole-3-carboxamide; as well as pharmaceutical^ acceptable salts, complexes, hydrates, solvates, tautomers, polymorphs, racemic mixtures,

optically active forms and pharmaceutically active derivative thereof.
5. A pharmaceutical composition comprising a compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, excipien or carrier.
6. A method of treating and preventing tuberculosis or & Mycobacterium infection in a subject, comprising administering to the subect in need thereof an effective amount of a compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof.
7. The method of claim 6, wherein the subject is a human being.
8. Use of a compound of any one of claims 1-4 in the manufacture of a medicament for treating and preventing tuberculosis or & Mycobacterium infection.
9. Use of a compound of any one of claims 1-4 for treating tuberculosis or a Mycobacterium infection.
10. A pharmaceutical composition comprising a compound of any one of claims 1-4 for treating tuberculosis or & Mycobacterium infection.