CHANG MAYLAND (US)
SPERI ENRICO (US)
MOBASHERY SHAHRIAR (US)
CHANG MAYLAND (US)
SPERI ENRICO (US)
What is claimed is: 1. A compound of Formula I: (I) or a salt thereof, wherein Het is ; Q1 is O, absent, S, or NRw; Q2 is CH or N; each Rw is independently H, −(C1-C6)alkyl, or a protecting group; Rx, Ry, and Rz are each independently H, halo, OH, CN, CO2H, NO2, −(C1-C6)alkyl, −CO2(C1-C6)alkyl, −Ο(C1-C6)alkyl, or −ΟC(=O)(C1-C6)alkyl; R1 is ORa, SRa, halo, CN, NO , −(C1-C6)alkyl, NRw, or heterocyclyl, wherein each Ra is independently CF3, −(C1-C6)alkyl, −C(=O)(C1-C6)alkyl, or H; R2 is OH, −Ο(C1-C6)alkyl, −Ο(C3-C6)cycloalkyl, or −CCH; R3 is H, −(C1-C6)alkyl or −(C3-C6)cycloalkyl; R4 is H, −(C1-C6)alkyl, or −C(=O)R5 wherein R5 is OH, N(CH3)2, −Ο(C1-C6)alkyl, or heterocyclyl; Y1, Y2, Y3, and Y4 are each independently CH or N wherein at least one of Y1 to Y4 is N; Z1 is O, N, S, or CH; and Z2 is CH, O, or N; wherein each (C1-C6)alkyl moiety is independently saturated or unsaturated and optionally substituted. 2. The compound of claim 1 wherein Het is . 3. The compound of claim 2 wherein Q2 is CH. 4. The compound of claim 2 wherein Rx, Ry, and Rz are H. 5. The compound of claim 1 wherein Y1 is N, and Y2, Y3, and Y4 are CH. 6. The compound of claim 1 wherein R1 is ORa. 7. The compound of claim 1 wherein the compound is represented by Formula II: (II) or a salt thereof. 8. The compound of claim 7 wherein Q1 is O. 9. The compound of claim 7 wherein Ra is CF3. 10. The compound of claim 7 wherein R2 is OH. 11. The compound of claim 7 wherein the compound is 2-(4-(3-(trifluoromethoxy)phenoxy) picolinamido)benzo[d]oxazole-5-carboxylic acid (1): (1) or a salt thereof. 12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent, carrier, or excipient. 13. The composition of claim 12 wherein the compound is 2-(4-(3-(trifluoromethoxy)phenoxy) picolinamido)benzo[d]oxazole-5-carboxylic acid (1). 14. A method for treating a bacterial infection comprising administering to a subject in need thereof an effective antibacterial amount of a compound of claim 1 wherein the bacterial infection is thereby treated. 15. The method of claim 14 wherein the bacterial infection is a Clostridioides difficile (C. difficile) infection. 16. The method of claim 15 wherein the compound selectively inhibits the growth or proliferation of C. difficile. 17. The method of claim 16 wherein a minimum concentration to inhibit the growth or proliferation of 50 % of C. difficile (MIC50) is about 1 µg/mL or less. 18. The method of claim 16 wherein an effective antibacterial amount of the compound administered as a single dose is about 50 mg/kg or less. 19. The method of claim 14 wherein the compound is 2-(4-(3-(trifluoromethoxy)phenoxy) picolinamido)benzo[d]oxazole-5-carboxylic acid (1). 20. The method of claim 14 wherein the compound inhibits peptidoglycan biosynthesis. |
a NRS70 strain, resistant to erythromycin and spectinomycin; b ATCC 43255, ribotype 087. The SAR study then focused on optimizing the phenyl ring (SAR 3 ) with respect to the central pyridine ring (SAR 2 ), while leaving the oxazole group intact (Table 3). Table 3 shows the effect of substitution on the phenyl ring and its selective replacement. The presence of halides on the phenyl ring (32–48, 54) gave potent antibacterial activity, while many of the other substituents increased the MIC (49–53, 55, 56, 58–61). Replacement of the phenyl ring with an N-morpholinyl ring (62) abolished antibacterial activity, whereas its replacement by a small hydrophobic substituent such as CF 3 retained moderate antibacterial activity (63 –65). Further optimization focused on the modification of the pyridine segment. The resulting isonicotinamide series introduced a fluorine group in the pyridine at position 3 (66–69) and position 5 (70–74). The resulting MIC values were similar to their non-fluorinated counterparts. Various heterocyclic modifications were also studied in SAR 2 and SAR 3 , each with halides on the phenyl ring. The 2,5-substituted picolinamide (75–80), nicotinamide (81 and 82), pyrimidine (83–85), and pyrazine derivatives (86) were less active. Table 3. Activity of Picolinamides Analogs against MRSA and C. difficile (SAR 2 and SAR 3 ).
a NRS70 strain, resistant to erythromycin and spectinomycin; b ATCC 43255, ribotype 087; c selectivity is defined as MICMRSA/MICC. difficile. Introduction of an ether linkage between the pyridine core and the phenyl ring resulted in MIC values for C. difficile of ≤ 1 mg·L –1 (Table 4). The picolinamides (106–111) had significantly higher selectivity for C. difficile than the isonicotinamides (99–105). Unfortunately, the introduction of the ether linkage did not increase the antibacterial activity of the picolinamides. These SAR studies led us to introduce a carboxylate, either as a salt or as an ester (compounds 112-119; Table 5), which improved water solubility of the family while still maintaining potent activity against C. difficile (0.12 mg·L –1 for 5 and 0.50 mg·L –1 for 116). The most compelling modification was 3,5-substitution of the picolinamide (87–98). This substitution imparted the desired selectivity toward C. difficile compared to MRSA. Picolinamide 87, a constitutional isomer of compound 4, was inactive against MRSA (MIC = 128 mg L –1 ) yet active against C. difficile (MIC = 0.125 mg L –1 ). This exquisite selectivity of 1024-fold was achieved by the mere repositioning of one nitrogen atom. Moreover, compounds 87–98 lacked activity against MSSA and E. faecium (Table 10). X-Ray Crystal Structure for 87. Confirmation of the structure of picolinamide 87 was obtained by X-ray crystallography. The crystal structure of compound 87 has been deposited to the Cambridge Crystallographic Data Centre, deposition number CCDC2050429. Crystallization of 87 produced colorless block-like crystals. In Vitro Cytotoxicity. The XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H- carboxanilide) assay with HeLa cells was performed on representative compounds (Table 6). Most of the compounds tested had IC50 values >64 mg∙L –1 (except for picolinamides 94 and 114, and isonicotinamide 99). Compound 87 had IC50 of 95.2 ± 1.0 mg∙L –1 , 760-fold higher than its MIC (0.125 mg∙L –1 ). Table 6. XTT IC 50 of Selected Picolinamides Analogs with HeLa Cells. a Reported previously (ACS Infect. Dis.2020, 6, 2362) and included here for comparison. b NT, no detectable toxicity at the specified concentration. Picolinamide 87 Selectively Targets C. difficile. The picolinamide core in SAR 2 had exquisite selectivity against C. difficile compared to MRSA. We evaluated the activity of selected compounds against 20 additional strains of C. difficile (Table 7). The MIC values for the non- selective isonicotinamide compound (4) ranged from 0.0625 to 0.5 mg·L –1 . The MIC values for the C. difficile-selective picolinamide compounds (5, 87, and 108) ranged from 0.0625 to 1 mg·L -1 . Both type of compounds showed consistent antibacterial effects on C. difficile strains, even for those resistant to MTZ, VAN, and FDX. We also evaluated the activity of the picolinamides against the common gut bacteria: Bacteroides fragilis, Bifidobacterium longum, Corynebacterium spp., Fusobacterium nucleatum, Lactobacillus reuteri, Lactobacillus gasseri, Veillonella sp., and Eubacterium sp. An optimum antibacterial will target selectively the pathogenic bacterium and not the natural gut flora. Picolinamides 5 and 87 were more selective than 4 and more selective than the clinically used antibiotics VAN, MTZ, and FDX. Its selectivity is evident especially with respect to Bifidobacterium longum, a major gut bacterium that is reported to help repress CDI. For the purpose of comparison, the currently clinically used antibiotics, vancomycin and fidaxomicin have selectivities of 4- and 128-fold, respectively, toward C. difficile ATCC43255 relative to MRSA NRS70 (Table 7). Recurrence of CDI for the less selective vancomycin is 25%, while that for the somewhat more selective fidaxomicin is 15%. Picolinamide 87 is >1000-fold selective. As gut dysbiosis contributes to CDI recurrence, the importance of this high selectivity is self-evident. Selectivity in targeting C. difficile emerges as an important attribute as mere potency (low MIC) might become less significant given that a compound such as 87 has already a remarkably very low/potent MIC of 0.125 mg∙L –1 (nanomolar range). Table 7. MIC Values (mg∙L –1 ) for MTZ, VAN, FDX, and Compounds 4, 5, 87, and 108 against C. difficile, MRSA NRS70, and Major Gut Bacteria.
a Data reported previously (ACS Infect. Dis.2020, 6, 2362) and included for comparison. b MR = metronidazole-resistant. c FR = fidaxomicin-resistant. d VR = vancomycin-resistant. e Selectivity is defined as MIC MRSA NRS70 /MIC C. difficile ATCC43255 . f Strain HM-709, a Gram-negative, anaerobic bacterium that is commensal and critical to host immunity and a minor component of the human gut microflora (<1%). g Strain HM-846, an anaerobic, nonsporulating Gram-positive bacterium commonly found in the normal human intestinal microflora isolated from human feces. h Strain HM-784, an aerobic or facultatively anaerobic Gram-positive bacterium that occurs in the mucosa and normal skin flora of humans and animals. i Strain HM-992, an anaerobic, nonsporulating Gram-negative bacterium commonly found in the gastrointestinal tract. j Strain HM-102, an anaerobic Gram-positive bacterium commonly found in the normal human gastrointestinal tract, and used frequently as a probiotic to maintain the balance of gut microbial flora. k Strain HM-644, a facultative, anaerobic Gram-positive bacterium commonly found in the normal human gastrointestinal tract, used frequently in yogurt production as a probiotic to suppress Helicobacter pylori infections. l Strain HM-49, a nonsporulating Gram-negative bacterium commonly found in the intestinal tract of humans and animals. m Strain HM- 178, an anaerobic, nonsporulating Gram-positive bacterium commonly found in the gastrointestinal flora of humans and animals. In vivo Pharmacokinetics (PK). For the treatment of CDI, compounds that are poorly or not absorbed and achieve high concentrations in the gut are desirable. We selected compounds 4, 87, 107, 108, and 116 for in vivo PK studies in mice based on their potency, safety profile, solubility, and selectivity against C. difficile. Both plasma and feces were collected and analyzed for levels of the compounds and compared to those of compound 5. While all the compounds showed non-quantifiable concentrations in plasma, levels in feces were higher (Table 8). The selected compounds showed 2- to 50-fold higher concentrations in the feces over the MIC values. Table 8. Drug Concentrations in Fecal Samples of Selected Compounds. a Reported previously; included for ease of comparison. Conclusion. The lack of selective antibiotics for the treatment of CDI contributes to gut dysbiosis and recurrence of CDI. The picolinamide family of antibacterials shows exquisite potency and selectivity in targeting C. difficile. Starting with isonicotinamide 4, a compound that is equally active against MRSA and C. difficile, structure optimization gave the new picolinamide 87 with >1,000-fold selectivity for C. difficile compared to MRSA (Strain NRS70). Compound 87 shows exceptional selectivity against C. difficile while lacking activity against other, normal Gram-positive and Gram-negative gut microbiota. As gut dysbiosis contributes to CDI recurrence, the picolinamides have the potential for treatment of recurrent CDI. Pharmaceutical Formulations The compounds described herein can be used to prepare therapeutic pharmaceutical compositions, for example, by combining the compounds with a pharmaceutically acceptable diluent, excipient, or carrier. The compounds may be added to a carrier in the form of a salt or solvate. For example, in cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and β-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, halide, sulfate, nitrate, bicarbonate, and carbonate salts. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid to provide a physiologically acceptable ionic compound. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example, calcium) salts of carboxylic acids can also be prepared by analogous methods. The compounds of the formulas described herein can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms. The forms can be specifically adapted to a chosen route of administration, e.g., oral or parenteral administration by intravenous intramuscular topical or subcutaneous routes. The compounds described herein may be systemically administered in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. For oral administration, compounds can be enclosed in hard- or soft-shell gelatin capsules, compressed into tablets, or incorporated directly into the food of a patient's diet. Compounds may also be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations typically contain at least 0.1% of active compound. The percentage of the compositions and preparations can vary and may conveniently be from about 0.5% to about 60%, about 1% to about 25%, or about 2% to about 10%, of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions can be such that an effective dosage level can be obtained. The tablets, troches, pills, capsules, and the like may also contain one or more of the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; and a lubricant such as magnesium stearate. A sweetening agent such as sucrose, fructose, lactose or aspartame; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring, may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and flavoring such as cherry or orange flavor. Any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices. Useful dosages of the compounds described herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Patent No. 4,938,949 (Borch et al.). The amount of a compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will be ultimately at the discretion of an attendant physician or clinician. In general, however, a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day. The compound is conveniently formulated in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form. In one embodiment, the invention provides a composition comprising a compound of the invention formulated in such a unit dosage form. The compound can be conveniently administered in a unit dosage form, for example, containing 5 to 1000 mg/m 2 , conveniently 10 to 750 mg/m 2 , most conveniently, 50 to 500 mg/m 2 of active ingredient per unit dosage form. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye. The compounds described herein can be effective anti-bacterial agents and have higher potency and/or reduced toxicity as compared to vancomycin (VAN), metronidazole (MTZ), or fidaxomicin (FDX). Preferably, compounds of the invention are more potent and less toxic than VAN, MTZ, or FDX, and/or avoid a potential site of catabolic metabolism encountered with VAN, MTZ, or FDX, i.e., have a different metabolic profile than VAN, MTZ, or FDX. The invention provides therapeutic methods of treating a bacterial infection in a mammal, which involve administering to a mammal having a bacterial infection an effective amount of a compound or composition described herein. A mammal includes a primate, human, rodent, canine, feline, bovine, ovine, equine, swine, caprine, bovine and the like. A bacterial infection can refer to a Gram-positive or Gram-negative bacterial infection. The ability of a compound of the invention to treat a bacterial infection may be determined by using assays well known to the art. For example, the design of treatment protocols, toxicity evaluation, data analysis, quantification of cell kill. In addition, ability of a compound to treat a bacterial infection may be determined using the Tests as described below. The following Examples are intended to illustrate the above invention and should not be construed as to narrow its scope. One skilled in the art will readily recognize that the Examples suggest many other ways in which the invention could be practiced. It should be understood that numerous variations and modifications may be made while remaining within the scope of the invention. EXAMPLES Example 1. Synthesis of compounds. Scheme 5: Synthetic route for compound 1. 4-(3-(Trifluoromethoxy)phenoxy)picolinonitrile (3). Compound 2 (4.24 g, 23.8 mmol), 4- chloropyrimidine-2-carbonitrile (3.0 g, 21.7 mmol), K 2 CO 3 (23.8 mmol), and dry dimethylformamide (DMF, 40 mL) were added to a 125 mL oven-dried round-bottom flask and heated at 120 °C for 1 hour. The reaction mixture was cooled and concentrated under reduced pressure. Ethyl acetate (120 mL) was added and the organic phase was washed with water (2 × 120 mL) and brine (120 mL). The organic layer was dried over anhydrous Na 2 SO 4 . The suspension was filtered and the filtrate was evaporated under reduced pressure to give the crude product. Purification by silica-gel chromatography (gradient elution from 9:1 hexane/EtOAc to EtOAc) afforded the desired 3 as a colorless liquid in 70% yield (4.25 g). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.62 (d, J = 5.6 Hz, 1H), 7.76 (d, J = 2.7 Hz, 1H), 7.60–7.67 (m, 1H), 7.32–7.37 (m, 2H), 7.30 (ddd, J = 1.0, 2.3, 8.3 Hz, 1H), 7.26 (dd, J = 2.6, 5.8 Hz, 1H); 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 164.1, 154.0, 153.2, 149.41 (q, J = 6 Hz), 134.4, 132.1, 122.5 (q, J = 259 Hz), 119.7, 118.7, 118.4, 118.0, 117.0, 115.6, 114.1; 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –57.15; HRMS (m/z): [M + H] + , calcd for C13H8F3N2O , 281.0536; found, 281.0536. 4-(3-(Trifluoromethoxy)phenoxy)picolinic acid (4). Compound 3 (2.80 g, 10 mmol), ethanol (40 mL), and water (20 mL) were added to a 250 mL round-bottom flask. Sodium hydroxide (1.00 g, 25.1 mmol) was added. The reaction was stirred at reflux overnight. The solution was let to cool to room temperature The solvent was evaporated under reduced pressure to half of its volume. The desired product precipitated from the solution upon adjustment of pH to 3.0. The precipitate was filtered and washed with water (3 × 10 mL). The solid was dried (high vacuum overnight) to give 4 as a white solid in 84% yield (2.51 g). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.78 (br s, 1H), 8.67 (d, J = 5.9 Hz, 1H), 7.68 (t, J = 8.3 Hz, 1H), 7.57 (d, J = 2.5 Hz, 1H), 7.26–7.46 (m, 4H); 13 C NMR (101 MHz, DMSO-d6) δ ppm 165.8, 164.5, 154.1, 150.3, 149.3 (q, J = 7 Hz), –132.2, 122.5 (q, J = 258 Hz), 120.0, 118.7–118.6, 115.4, 114.3, 113.1; 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –56.94. HRMS (m/z): [M + H] + , calcd for C 13 H 9 F 3 NO 4 , 300.0478; found, 300.0482. Scheme 6: Synthetic route for compound 5. Methyl 2-aminobenzo[d]oxazole-5-carboxylate (5). Methyl 3-amino-4-hydroxybenzoate (1 g, 6 mmol), compound 9 (1.74 g, 10.8 mmol) and 70 mL of dry tetrahydrofuran (THF) were added to an oven-dried round-bottom flask, under an atmosphere of nitrogen. The solution was then aged at reflux for 2 h. The solvent was removed under reduced pressure. The resultant crude product was purified by silica-gel column chromatography (EtOAc/hexane 1:9 to EtOAc) affording a light yellow- colored powder. Yield 1.12 g, 89%. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.72 (d, J = 1.7 Hz, 1H), 7.67 (d, J = 1.7 Hz), 7.65–7.64 (m, 2H),, 7.44 (d, J = 8.3 Hz, 1H), 3.84 (s, 3H); 13 C NMR (101 MHz, DMSO-d6) δ ppm 166.3, 163.7, 151.3, 144.0, 125.3, 122.1, 115.8, 108.4, 52.0; HRMS (m/z): [M + H] + , calcd for C9H9N2O3, 193.0608; found, 193.0620. Methyl 2-(4-(3-(trifluoromethoxy)phenoxy)picolinamido)benzo[d]oxazo le-5-carboxylate (6). Compounds 4 (1.80 g, 6.00 mmol) and 5 (1.73 g, 9.00 mmol), pyridine (2 mL), and EtOAc (4 mL) were added to a 20 mL glass vial under an atmosphere of argon. The heterogeneous mixture was cooled to −20 °C and 50% propane phosphonic acid anhydride in dimethylformamide (T3P 50% DMF, 6 mL) was slowly added. The resulting solution was warmed to room temperature. The mixture was stirred overnight. The solution was chilled to −5 °C and 1.5 mL of a 0.5 M aqueous HCl was added, followed by stirring for 1 h. The resultant precipitate was filtered and rinsed with water (3 × 5 mL). The solid was taken up into EtOAc (20 mL) and was washed with a saturated solution of sodium bicarbonate (10 mL) and brine (10 mL). The removal under reduced pressure of the organic solvent afforded the product as a white solid in 71% yield (2.02 g). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.14 (br s, 1H), 8.70 (d, J = 5.6 Hz, 1H), 8.18 (d, J = 1.7 Hz, 1H), 7.97 (dd, J = 1.8, 8.4 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.68 (dd, J = 9 Hz, 9 Hz, 1H), 7.62 (d, J = 2.7 Hz, 1H), 7.27–7.47 (m, 4H), 3.89 (s, 3H); 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 165.9, 165.1, 161.9, 155.8, 154.3, 151.1, 150.9, 1507 1494 1321 1265 1225 (q J = 258 Hz) 1200 1196 1187 1185 1159 1143 1110 110.5, 52.3; 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –56.92; HRMS (m/z): [M + H] + , calcd for C 22 H 15 F 3 N 3 O 6 , 474.0907; found, 474.0909. 2-(4-(3-(Trifluoromethoxy)phenoxy)picolinamido)benzo[d]oxazo le-5-carboxylic acid (7). To a solution of sodium hydroxide (338 mg, 8.4 mmol) in 20 mL of dioxane and 20 mL of water was added 6 (1 g, 2.1 mmol). The reaction mixture was stirred at 60 °C for 3 h. The solvent was evaporated under reduced pressure. The resulting solid was taken up in water (10 mL). HC1 conc. was added dropwise until pH was 3.0, resulting in precipitation of the desired carboxylic acid. This precipitate was recovered by filtration and dried under high vacuum to give 7 as a white solid in 88% yield (848 mg): 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (br s, 1H), 12.17 (br s, 1H), 8.70 (d, J = 5.6 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.96 (dd, J = 1.7, 8.3 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.69 (t, J = 8.2 Hz, 1H), 7.62 (d, J = 2.7 Hz, 1H), 7.42–7.46 (m, 1H), 7.30–7.42 (m, 3H); 13 C NMR (101 MHz, DMSO-d6) δ ppm 166.8, 165.1, 161.9, 155.7, 154.1, 150.9, 150.5, 149.3 (q, J = 2 Hz), 132.1, 127.6, 122.4 (q, J = 258 Hz), 119.9, 119.4, 118.6, 118.4, 115.8, 114.3, 110.9, 110.2; 19 F NMR (376 MHz, DMSO-d6) δ ppm –56.91; HRMS (m/z): [M + H] + , calcd for C 21 H 13 F 3 N 3 O 6 , 460.0751; found, 460.0725. Sodium 2-(4-(3-(trifluoromethoxy)phenoxy)picolinamido)benzo[d]oxazo le-5-carboxylate (1). The carboxylic acid 7 (325 mg, 0.7 mmol) was dissolved in 6 mL of dimethylformamide (DMF) and was added to a 25-mL round-bottom flask. A 1.15 mL portion of a 50 g L -1 of sodium bicarbonate in water (0.7 mmol) was added dropwise during 5 min, and the solution was stirred at room temperature for 2 h. The organic solvent was removed under reduced pressure. The solid was filtered and washed with methanol (0.5 mL). The material was dried under high vacuum to produce compound 1 as a white solid in 94% yield (316 mg). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.71 (br s, 1H), 8.56 (d, J = 5.4 Hz, 1H), 8.00–8.14 (m, 1H), 7.73 (dd, J = 2.0, 8.3 Hz, 1H), 7.59–7.71 (m, 2H), 7.38–7.44 (m, 1H), 7.33–7.38 (m, 2H), 7.30 (ddd, J = 0.9, 2.2, 8.2 Hz, 1H), 7.09–7.19 (m, 1H); 13 C NMR (101 MHz, DMSO-d6) δ ppm 167.8, 164.0, 154.7, 150.7, 149.9, 149.2 (q, J = 2 Hz), 143.0, 131.9, 123.4, 122.5 (q, J = 258 Hz), 119.7, 118.6, 117.8, 114.0, 113.8, 111.1, 108.0; 19 F NMR (376 MHz, DMSO-d6) δ ppm –56.85; HRMS (m/z): [M + H] + , calcd for C 21 H 12 F 3 N 3 NaO 6 , 482.0570; found, 482.0572. Example 2. In-vitro and In-vivo Experimental. Antibiotics. Clindamycin, ciprofloxacin, oxacillin, rifaximin, kanamycin, gentamicin, colistin, vancomycin and metronidazole were purchased from Sigma-Aldrich (St. Louis, MO); linezolid was purchased from AmplaChem Inc., (Carmel, IN); and fidaxomicin was obtained from BOC Sciences (Shirley, NY). Bacterial strains. A total of 101 C. difficile strains were used in the study. Of the isolates, 86 were from Biodefense and Emerging Infections Research Resources Repository (BEI Resources, Manassas, VA), eight from American Type Culture Collection (ATCC, Manassas, VA) and seven resistant C. difficile isolates were obtained from Cleveland VA Medical Center. Other gut bacteria strains were obtained from BEI. MRSA strains NRS70 (N315) and NRS119 were obtained through the Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA). ATCC 29213 and E. faecium NCTC7171 (ATCC 19434) were purchased from ATCC (ATCC; Manassas, VA). All the strains were cultured and stored according to the supplier instructions. Minimum inhibitory concentrations (MIC). MICs for C. difficile strains and the common gut bacteria were determined using broth microdilution techniques as reported earlier using brucella broth supplemented with hemin and vitamin K or supplemented BHIS broth. Lactobacillus MRS broth was used for lactobacillus strains. Sodium lactate was supplemented in the media for Veillonella sp. The test compounds were added in 2-fold serial dilutions and the bacteria were added to a final concentration of 5x10 5 CFU mL -1 . All incubations, unless specified otherwise, were carried out at 24 h or 48 h at 37 °C in an anaerobic chamber (Whitley DG250 workstation, Microbiology International, Frederick, MD). Corynebacterium and Lactobacillus species were incubated aerobically. MIC50 and MIC90 values for compound 1 against 101 C. difficile strains were determined. XTT assay. Cytotoxicity assays were performed in triplicate against HeLa cells (ATCC CCL- 2). The IC50 values were calculated by nonlinear regression with GraphPad Prism 5 (San Diego, CA). Pharmacokinetics (PK) study. Mice (n = 2 per time point) were given a single 100 µL solution of 5 mg/mL of compound 1 (equivalent to 20 mg/kg). Terminal blood was collected in heparinized syringes by cardiac puncture at 30 min, 1 h, 2 h, 4 h, and 8 h. The two mice at the 8-h time point were place in metabolism cages for collection of feces. Compound 1 was dissolved in 5% DMSO/95% water with 96 mg/mL of sodium bicarbonate. Blood was centrifuged at 1,000 g for 20 min at 4 °C and plasma was separated and stored at -80 °C until analysis. A 45-µL aliquot of plasma was mixed with 5 µL of H 2 O:ACN (1:1) and was quenched with 100 µL of acetonitrile containing 20 µM of internal standard (compound 10). The sample was centrifuged at 21,000 g for 15 min at 4 °C to precipitate the proteins, and the resulting supernatant was analyzed by UPLC–TQD detector using multiple-reaction monitoring (MRM). Calibration curves for compound 1 were prepared from 0 to 102.4 µM using a control mouse plasma (50 µL). Peak area ratios relative to internal standard and linear regression was used from which the concentrations in plasma samples from the PK study were determined. An average of 250 mg of feces were collected at 8 h from two mice, and subsequently homogenized with 6 times the feces volume (1,500 µL of H 2 O:ACN 1:1) using a Bullet Blender (Next Advance, Inc., Troy, NY). The homogenate was centrifuged at 21,000 g for 5 min. The fecal supernatant (72 µL) was mixed with 8 µL of a solution of H 2 O:ACN (1:1) and 40 µL of 50 µM of the internal standard in ACN with 0.5% formic acid. A calibration curve was prepared from 0 µM to 102.4 µM in control mouse feces. Plasma and feces were analyzed on a Waters TQD tandem quadrupole detector (Waters Corporation, Milford, MA) using a YMC-Triart C18100 mm x 2.0 mm column (3 µ, YMC Co. Ltd, Kyoto, Japan). The chromatographic conditions consisted of elution with 30% H 2 O/70% ACN containing 0.1% formic acid for 5 min at a flow rate 0.5 mL/min. Mass Spectrometry acquisition was performed in the positive electrospray ionization mode with MRM. The capillary, cone, extractor and RF lens voltages were set at 2.8 kV, 40 V, 1 V and 0.1 V, respectively. The desolvation and cone gas (nitrogen) flow rates were 650 L/h and 50 L/h, respectively. The source temperature was set at 150 °C. The desolvation temperature was 350 °C. The MRM transitions used were 459.4 → 254.0 for compound 1, and 294.8 → 133.5 for the internal standard. Time-kill assay. For the time kill assay, stationary-phase cultures of C. difficile were incubated with compound 1 or VAN at 8×, 16×, and 32× MIC in pre-reduced supplemented brucella broth. A control tube without antibiotic was also included. At intervals of 4, 8, and 24 h, 100-µL aliquots of the cultures were plated onto pre-reduced brain heart infusion broth agar media for colony counts. The limit of detection was 50 cfu/mL and a ≥ 3 log10 reduction of colonies from the starting inoculum was considered bactericidal. The experiment was done in triplicate. Serial passage. Serial-passage assay for development of resistance in C. difficile strain ATCC43255 was performed in duplicate in pre-reduced supplemented brucella broth. The starting MIC for the strain against compound 1 and VAN using broth macrodilution assay was 0.125 µg/mL and 0.5 µg/mL respectively. Two-fold serial dilutions of the drugs were prepared from 2× MIC to 0.25× MIC, and cultures were added to a final concentration of 5×10 5 CFU/mL. Each day, wells with the highest concentration of drugs showing growth were used to inoculate the series of tubes the next day. The process was repeated for 25 passages. After 25 days, cultures showing a four-fold or higher increase in MIC were confirmed by three passages in drug-free media. Macromolecular synthesis assay. The macromolecular synthesis assay was performed by established methods. The radioactive precursors and positive controls were [2,8- 3 H]-adenine and ciprofloxacin for DNA, [5,6- 3 H]-uridine and rifaximin for RNA, l-[3,4,5- 3 H(N)]-leucine and linezolid for protein, and N-acetyl-d-[6- 3 H]glucosamine and oxacillin for the peptidoglycan synthesis. The radiolabeled precursors were purchased from Perkin Elmer (Waltham, MA, USA). Scanning-electron microscopy. Bacteria in mid-exponential growth phase were incubated overnight with 4× to 32× MIC of compound 1. Following incubation, the cells were washed with PBS (3×) and applied onto poly-l-lysine (Santa Cruz Biotechnology, Dallas, TX) coated microglass coverslips (Electron Microscopy Sciences, Hatfield, PA) and incubated for 15 min. The cells were fixed for 1 h with 2% glutaraldehyde, followed by a wash (3×) with sodium cacodylate buffer at pH 7.4. The samples were fixed with 1% osmium tetroxide for 1 h and rinsed (3×) in the buffer. The samples were then put through a graded ethanol series for dehydration, followed by critical point drying. The samples were then mounted on SEM stubs and sputter-coated with iridium. Microscopy and imaging were performed on a Magellan 400 XHR instrument (FEI, Hillsboro, OR). Animals. Female C57BL/6 mice weighing 18–20 g and 6–8 weeks of age were used for the efficacy study (Jackson, Bar Harbor, ME). Female CD-1 mice (24–31 g and 7–8 weeks of age) were used for the PK study. They were housed in groups of five mice in sterile polycarbonate shoeboxes with bedding consisting of ¼-inch corncob (The Andersons Ind., Maumee, OH) and Alpha-Dri (Shepherd Specialty Papers, Inc., Richland, MI). Mice were maintained on a 12-h light/dark cycle at 72 °F and were given Teklad 2918 irradiated extruded rodent diet and water ad libitum. All procedures were performed in accordance with and approved by the University of Notre Dame Institutional Animal Care and Use Committee. C. difficile infection model. The recurrent C. difficile infection model reported by Chen et al. was used (Gastroenterology 2008, 135, 1984). Mice (n = 10 per group, total 40 mice per study) were given antibiotic cocktail containing kanamycin (0.4 mg L –1 ), gentamicin (0.035 mg L –1 ), colistin (850 U mL –1 ), metronidazole (0.215 mg L –1 ) and vancomycin (0.045 mg L –1 ), in sterile drinking water containing 5% sucrose for 3 days, followed by 2 days of regular water. Subsequently, mice were given a 10 mg/kg intraperitoneal injection of clindamycin. The following day, the mice were infected intragastrically with 10 4 CFU of C. difficile ATCC 43255. Mice were given single oral doses of compound 1 at 20 mg/kg and 40 mg/kg, VAN at 50 mg/kg, or vehicle (5% DMSO/95% water) once a day for 5 days. Body weights and survival were recorded for 25 days. The study was repeated a second time. Table 9. MICs (µg/mL) of compound 1, VAN, MTZ, and FDX against C. difficile strains
Example 3. Synthesis Experimental for SAR of the Picolinamide Antibacterials. General Synthetic Procedures. Solvents and chemicals were used as supplied. Reaction progress was monitored by analytical thin-layer chromatography (TLC) on Merck precoated silica gel aluminium plates (200 μm, 60 F254, Merck KGaA, Darmstadt, German) under 254 nm UV light. Purification of products was accomplished by silica chromatography using a Teledyne ISCO CombiFlash Rf 200i. Proton ( 1 H) and ( 13 C) NMR spectra were recorded on a Bruker Avance Ⅲ HD 400 Nanobay (400 MHz for 1 H and 101 MHz for 13 C, Bruker Biospin AG, Fallanden, France) at room temperature. The purity of the compounds was determined by a Waters Acquity UPLC system (Waters Corporation, Milford, MA, USA) with an Ascentis C18 column (3 μm, 2.1 mm i.d. × 100 mm, Supelco) with UV detection was at 245–300 nm. The purity of all final compounds was ≥95% by HPLC. High-resolution mass spectra (HRMS) were obtained on a Bruker-Q Ⅱ TOF electrospray mass spectrometer. The synthetic schemes (and the general procedures A, B, C, D, E, and F below) apply to all 108 analogs. Detailed syntheses of 112, 113 and 5 are known. The crystal structure of 87 was solved (Scheme 5 and Table 10) as unambiguous proof of its structure. Synthetic procedures and characterizations are provided on pages S2 and S5. Spectra for representative compounds are given on page S45. General procedure (A) for phenylnicotinonitrile, phenylisonicotinonitrile, phenylpicolinonitrile, 2-phenylpyrimidine-4-carbonitrile, and 6-phenyl-pyrazine-2-carbonitrile derivatives. Tetrahydrofuran (75 mL), water (30 mL), and K2CO3 (8.28 g, 60.0 mmol) were added with stirring to a 250-mL flask under an atmosphere of argon. The given boronic acid (23.8 mmol) and the respective bromonicotinonitrile, bromoisonicotinonitrile, bromopicolinonitrile, 2- chloropyrimidine-4-carbonitrile, or 6-chloropyrazine-2-carbonitrile (21.7 mmol) were added after 5 min of stirring. The reaction was purged with argon for 20 min. Tetrakis(triphenylphosphine)- palladium(0) (Pd(PPh3)4, 750 mg, 0.7 mmol) was added. The reaction mixture was heated to 80 °C overnight. The reaction was quenched by adjusting the solution to pH 4 with 1 M aqueous HCl. The resulting solution was washed with EtOAc (3 × 60 mL). The organic layers were combined, dried (Na2SO4), and evaporated to dryness in vacuo. The crude product was purified by silica chromatography using gradient elution from 9:1 hexanes/EtOAc to EtOAc, affording the desired phenylnicotinonitrile, phenylisonicotinonitrile, phenylpicolinonitrile, 2-phenylpyrimidine-4- carbonitrile, or 6-phenylpyrazine-2-carbonitrile. Isolated yields were typically 61 – 79%. General procedure (B) for phenoxyisonicotinonitrile and phenoxypicolinonitrile derivatives. The given phenol (23.8 mmol), the respective chloroisonicotinonitrile or chloropicolinonitrile (21.7 mmol), K 2 CO 3 (23.8 mmol), and dry DMF (40 mL) were added to a 125- mL oven-dried flask and heated at 120 °C for 1 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was taken up in EtOAc (120 mL). The organic solution was washed with water (2 × 120 mL) and brine (120 mL), dried (Na 2 SO 4 ), and evaporated under reduced pressure affording the crude material. Its purification used silica chromatography with gradient elution from 9:1 hexanes/EtOAc to EtOAc. The purified sample was evaporated to dryness to give the phenoxyisonicotinonitrile or phenylisopicolinonitrile. Isolated yields were typically 70–87%. General procedure (C) for nicotinic, isonicotinic, picolinic, pyrimidine-4-carbxylic, and pyrazine-2-carboxylic acid derivatives. The phenyl-nicotinonitrile, phenyl-isonicotinonitrile, phenyl-picolinonitrile, 2-phenylpyrimidine-4-carbonitrile, or 6-phenylpyrazine-2-carbonitrile (10 mmol), ethanol (40 mL), and water (20 mL) were added to a 250-mL flask. Sodium hydroxide (1.00 g, 25.1 mmol) was added after 5 min. The reaction was stirred at reflux overnight. The solution was cooled to room temperature, and the solvent was halved by evaporation under reduced pressure. The desired nicotinic, isonicotinic, picolinic, pyrimidine-4-carbxylic, or pyrazine-2-carboxylic acid precipitated from the solution upon acidification to pH 3. The precipitate was filtered and washed with water (3 × 10 mL). The solid was then dried under reduced pressure. Isolated yields were typically 57–97%. General procedure (D) for the amide formation on nicotinic, isonicotinic, picolinic, pyrimidine-4-carboxylic, and pyrazine-2-carboxylic acid derivatives. The nicotinic, isonicotinic, picolinic, pyrimidine-4-carbxylic, or pyrazine-2-carboxylic acid (6.00 mmol), the 1,3-oxazol-2-amine or other amine (9.00 mmol), pyridine (2 mL), and EtOAc (4 mL) were added to a 20-mL glass vial, under an atmosphere of argon. The heterogeneous mixture was cooled to below −20 °C and 50% propane phosphonic acid anhydride in DMF (T3P 50% DMF, 6 mL) was added slowly. The resulting solution was allowed to reach room temperature as it was stirred overnight. The solution was chilled at −5 °C and 1.5 mL of a 0.5 M aqueous HCl solution was added. The mixture was stirred for 1 h. The precipitate was filtered and rinsed with water (3 × 5 mL). The solid was dissolved with EtOAc (20 mL). This solution was washed with a saturated aqueous NaHCO3 (10 mL) and brine (10 mL), dried (Na2SO4), and filtered. The solvent from the filtrate was evaporated under reduced pressure to afford the crude product. The product was purified by silica chromatography using gradient elution from 9:1 hexanes/EtOAc to EtOAc. Isolated yields were typically 8–71%. General procedure (E) for the saponification of phenoxypicolinic derivatives. To a solution of NaOH (338 mg, 8.4 mmol) in 20 mL of dioxane and 20 mL of water, was added the respective phenoxypicolinic derivative containing ester (1 g, 2.1 mmol). The reaction mixture was stirred at 60 °C for 3 h. The solvent was evaporated under reduced pressure. The resulting solid was taken up in water (10 mL). Concentrated HCl was added dropwise to the solution to bring to pH 3. The precipitated carboxylic acid was collected by filtration and dried under reduced pressure. Isolated yields were typically 73–91%. General procedure (F) for the sodium salt preparation of phenoxypicolinic derivatives. The carboxylic acid obtained by the general procedure E (0.7 mmol) was dissolved in 6 mL of DMF and added to a 25 mL flask. A solution of NaHCO 3 (0.7 mmol: 1.15 mL of 50 g L –1 in water) was added dropwise over 5 min. The solution was stirred at room temperature for 2 h. The organic solvent was removed under reduced pressure. The solid was washed with methanol (0.5 mL) over a small Buchner funnel and dried under reduced pressure. Isolated yields were typically 91–94%. N-(3-(3,4-dichlorophenoxy)benzyl)oxazol-2-amine (3). A drop of acetic acid was added to a solution of 3-(3,4-dichlorophenoxy)benzaldehyde (0.78 g, 2.92 mmol) and 2-aminoxazole (0.26 g, 3.07 mmol) in CH 2 Cl 2 (10 mL). After 15 min of stirring, solid NaBH(OAc) 3 (0.68 g, 3.21 mmol) was added and the reaction was stirred at room temperature overnight. The solution was diluted with DCM (10 mL) and rinsed with water (20 mL, 3×). The organic phases were collected, dried (Na2SO4) and purified by silica chromatography (EtOAc/hexanes = 1/9), affording a colorless liquid (860 mg, 88%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.37 (d, J = 8.8 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.11–7.28 (m, 2H), 7.07 (d, J = 2.8 Hz, 1H), 7.01 (d, J = 1.8 Hz, 1H), 6.92 (ddd, J = 0.9, 2.4, 8.2 Hz, 1H), 6.84 (dd, J = 2.8, 8.8 Hz, 1H), 6.77 (s, 1H), 5.22 (br s, 1H), 4.51 (d, J = 3.2 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ ppm 156.8, 141.1, 133.5, 132.64, 132.61, 131.3, 130.5, 126.9, 126.6, 123.3, 120.7, 118.5, 118.4, 118.3, 47.1. HRMS (m/z): [M+H] + , calcd for C16H13Cl2N2O , 335.0349; found, 335.0345. Scheme 7. Synthetic route for accessing compound 4 2-(3,4-dichlorophenyl)isonicotinonitrile (7a). This compound was prepared by the general procedure A, affording 7a as a white powder in 72% yield (3.86 g). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.89 (dd, J = 1.0, 4.9 Hz, 1H), 8.57 (t, J = 1.2 Hz, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 2.2, 8.3 Hz, 1H), 7.86 (dd, J = 1.5, 4.9 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H); 13 C NMR (101 MHz, DMSO-d6) δ ppm 154.9, 151.2, 137.7, 133.3, 132.4, 131.5, 128.9, 127.2, 125.3, 123.0, 121.2, 117.2. HRMS (m/z): [M+H] + , calcd for C 12 H 7 C1 2 N 2 , 248.9981; found, 248.9993. 2-(3,4-dichlorophenyl)isonicotinic acid (8a). This compound was prepared by the general procedure C, affording 8a as a white powder in 84% yield (2.26 g). 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.79 (br s, 1H), 8.87 (dd, J = 0.9, 5.0 Hz, 1H), 8.36–8.41 (m, 2H), 8.14 (dd, J = 2.2, 8.3 Hz, 1H), 7.83 (dd, J = 1.5, 4.9 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H); 13 C NMR (101 MHz, DMSO-d6) δ ppm 166.0, 154.5, 150.8, 139.7, 138.4, 132.2, 131.9, 131.1, 128.5, 126.8, 122.3, 119.5. HRMS (m/z): [M+H] + , calcd for C 12 H 8 C1 2 NO 2 , 267.9927; found, 267.9934. 2-(3,4-Dichlorophenyl)-N-(oxazol-2-yl)isonicotinamide (4). This compound was prepared by the general procedure D (Scheme 7), affording 4 as a white powder in 21% yield (416 mg). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.98 (br s, 1H), 8.87 (d, J = 5.1 Hz, 1H), 8.52 (s, 1H), 8.39 (s, 1H), 8.16 (d, J = 8.6 Hz, 1H), 7.99 (br s, 1H), 7.87 (d, J = 5.4 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.25 (br s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 163.2, 154.3, 152.9, 150.6, 141.3, 138.5, 137.0, 132.3, 131.9, 131.1, 128.4, 127.0, 126.8, 121.5, 118.5; HRMS (m/z): [M+H] + , calcd for C 15 H 10 Cl 2 N 3 O 2 , 334.0145; found, 334.0157. 2-(3,4-Dichlorophenyl)-N-(4-methyloxazol-2-yl)isonicotinamid e (14). This compound was prepared by the general procedures A, C and D affording 14 as a colorless powder (97 mg, 19%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.94 (br s, 1H), 8.87 (d, J = 4.9 Hz, 1H), 8.50 (s, 1H), 8.31–8.43 (m, 1H), 8.08–8.22 (m, 1H), 7.84–7.95 (m, 1H), 7.75–7.84 (m, 1H), 7.66 (br s, 1H), 2.12 (d, J = 1.5 Hz, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 154.7, 151.0, 139.1, 132.7, 132.3, 131.6, 128.9, 127.2, 122.1, 118.9, 31.1. HRMS (m/z): [M+H] + , calcd for C16H12Cl2N3O , 348.0301; found, 348.0290. Ethyl 2-(2-(3,4-dichlorophenyl)isonicotinamido)oxazole-4-carboxyla te (15). This compound was prepared by the general procedures A, C and D affording 15 as a white powder (185 mg, 40%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.32 (br s, 1H), 8.81–8.99 (m, 1H), 8.74 (br s, 1H), 8.54 (br s, 1H), 8.40 (br s, 1H), 8.17 (d, J = 9.1 Hz, 1H), 7.68–7.94 (m, 2H), 4.30 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 163.5, 161.1, 154.8, 154.0, 151.2, 142.6, 141.6, 139.0, 132.8, 132.39, 132.35, 131.6, 128.9, 127.3, 122.0, 118.9, 61.1, 14.6. HRMS (m/z): [M+H] + , calcd for C18H14Cl2N3O4, 406.0356; found, 406.0376. 2-(3,4-Dichlorophenyl)-N-(thiazol-2-yl)isonicotinamide (16). This compound was prepared by the general procedures A, C and D affording 16 as a light yellow-colored powder (103 mg, 20%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.02 (br s., 1H), 8.87 (d, J = 5.4 Hz, 1H), 8.59–8.71 (m, 1H), 8.40 (d, J = 2.2 Hz, 1H), 8.18 (dd, J = 2.2, 8.6 Hz, 1H), 7.93 (dd, J = 1.6, 5.0 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 3.4 Hz, 1H), 7.36 (d, J = 3.4 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 163.9, 159.0, 154.7, 151.1, 141.1, 139.0, 138.0, 132.8, 132.3, 131.5, 128.8, 127.2, 122.0, 118.8, 114.9. HRMS (m/z): [M+H] + , calcd for C15H10Cl2N3OS, 349.9916; found, 349.9933. 2-(3,4-Dichlorophenyl)-N-(1H-imidazol-2-yl)isonicotinamide (17). This compound was prepared by the general procedures A, C, and D affording 17 as a colorless powder (146 mg, 29%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.09 (br s, 2H), 8.82 (d, J = 4.9 Hz, 1H), 8.56 (s, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.13 (dd, J = 2.2, 8.6 Hz, 1H), 7.93 (dd, J = 1.6, 5.0 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 6.89 (s, 2H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 166.8, 154.4, 150.8, 145.8, 145.0, 139.5, 132.5, 132.3, 131.6, 128.8, 127.1, 122.2, 119.0, 116.4. HRMS (m/z): [M+H] + , calcd for C 15 H 11 Cl 2 N 4 O, 333.0304; found, 333.0301. 2-(3,4-Dichlorophenyl)-N-(isoxazol-3-yl)isonicotinamide (18). This compound was prepared by the general procedures A, C and D affording 18 as a colorless powder (120 mg, 24%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.85 (s, 1H), 8.93 (d, J = 1.7 Hz, 1H), 8.88 (dd, J = 0.6, 5.0 Hz, 1H), 8.54–8.66 (m, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.19 (dd, J = 2.2, 8.6 Hz, 1H), 7.89 (dd, J = 1.6, 5.0 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 1.7 Hz, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 164.1, 161.0, 158.2, 154.7, 151.1, 141.9, 139.0, 132.8, 132.3, 131.6, 128.9, 127.3, 122.0, 118.8, 100.1. HRMS (m/z): [M+H] + , calcd for C 15 H 10 C1 2 N 3 O 2 , 334.0145; found, 334.0136. 2-(3,4-Dichlorophenyl)-N-(5-methyl-1,3,4-oxadiazol-2-yl)ison icotinamide (19). This compound was prepared by the general procedures A, C and D affording 19 as a colorless powder (129 mg, 25%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 13.90 (br s, 1H), 8.82–8.92 (m, 1H), 8.38 (d, J = 2.2 Hz, 2H), 8.14 (dd, J = 2.2, 8.3 Hz, 1H), 7.84 (dd, J = 1.5, 4.9 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 2.19–2.25 (m, 3H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 168.0, 165.5, 156.0, 153.9, 150.2, 139.4, 137.9, 131.6, 131.3, 130.5, 127.9, 126.2, 121.8, 118.9, 10.2. HRMS (m/z): [M+H] + , calcd for C 15 H 11 Cl 2 N 4 O 2 , 349.0254; found, 349.0249. 2-(3,4-Dichlorophenyl)-N-methylisonicotinamide (20). Compound 8a (200 mg, 0.7 mmol) was stirred in thionyl chloride (3 mL) at reflux overnight. The solvent was removed under vacuo. The residual solid was dissolved in 5 mL of a MeNH 2 solution 2.0 M in THF and stirred at room temperature for 4 h. The THF was removed under vacuo. The solid was dissolved in EtOAc (20 mL) and washed with a saturated solution of NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and evaporated under reduced pressure affording 20 as a colorless powder (168 mg, 80%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (br s, 1H), 8.79–8.83 (m, 1H), 8.33–8.42 (m, 2H), 8.09–8.20 (m, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.76 (dd, J = 1.5, 4.9 Hz, 1H), 2.85 (d, J = 4.7 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 165.2, 154.5, 150.9, 143.2, 139.2, 132.6, 132.3, 131.6, 128.8, 127.2, 121.5, 118.2, 26.7. HRMS (m/z): [M – H] – , calcd for C13H11Cl2N2O, 281.0243; found, 281.0249. N-(benzo[d]oxazol-2-yl)-2-(3,4-dichlorophenyl)isonicotinamid e (21). This compound was prepared by the general procedures A, C, and D affording 21 as a colorless powder (253 mg, 13%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.55–12.84 (m, 1H), 8.89 (d, J = 4.9 Hz, 1H), 8.56 (s, 1H), 8.32–8.48 (m, 1H), 8.09–8.24 (m, 1H), 7.93 (d, J = 5.6 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.65–7.73 (m, 1H), 7.56–7.65 (m, 1H), 7.27–7.45 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 157.3, 154.7, 151.1, 146.9, 142.8, 139.1, 132.7, 132.3, 131.6, 128.9, 127.2, 125.4, 124.6, 123.9, 122.2, 119.2, 115.7, 110.8, 108.8. HRMS (m/z): [M+H] + , calcd for C 19 H 12 C1 2 N 3 O , 384.0301; found, 384.0317. 2-(3,4-Dichlorophenyl)-N-(oxazolo[4,5-b]pyridin-2-yl)isonico tinamide (22). This compound was prepared by the general procedures A, C, and D affording 22 as a colorless powder (72 mg, 12%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.76 (br s, 1H), 8.89 (d, J = 4.9 Hz, 1H), 8.58 (s, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.38 (dd, J = 1.6, 5.0 Hz, 1H), 8.18 (dd, J = 2.2, 8.6 Hz, 1H), 8.04 (dd, J = 1.0, 7.8 Hz, 1H), 7.92 (dd, J = 1.6, 5.0 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.29 (dd, J = 5.1, 8.1 Hz, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 154.6, 151.0, 145.7, 140.7, 139.2, 132.7, 132.4, 131.7, 128.9, 127.3, 122.3, 119.3, 119.2, 117.7. HRMS (m/z): [M+H] + , calcd for C 18 H 11 Cl 2 N 4 O 2 , 385.0254; found, 385.0241. Ethyl 2-(2-(3,4-dichlorophenyl)isonicotinamido)oxazole-5-carboxyla te (23). This compound was prepared by the general procedures A, C, and D affording 23 as a colorless powder (500 mg, 33%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.40–12.68 (m, 1H), 8.90 (d, J = 5.6 Hz, 1H), 8.51–8.61 (m, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.18 (dd, J = 2.2, 8.3 Hz, 1H), 7.96–8.07 (m, 1H), 7.88 (dd, J = 1.6, 5.0 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 169.0, 168.5, 158.3, 153.9, 150.4, 149.4, 139.9, 137.1, 133.7, 132.2, 132.1, 131.6, 128.6, 127.0, 122.6, 119.5, 60.4, 14.8. HRMS (m/z): [M+H] + , calcd for C 18 H 14 Cl 2 N 3 O 4 , 406.0356; found, 406.0346. 2-(2-(3,4-Dichlorophenyl)isonicotinamido)oxazole-5-carboxyli c acid (24). To a solution of LiOH (1.08 g, 25.8 mmol) in 48 mL of 1:1 THF/water, was added 23 (7 g, 17.2 mmol). The reaction mixture was stirred at 60 °C for 3 h. The solvent was evaporated under reduced pressure. The residual solid was taken up in water (25 mL). Concentrated HCl was added dropwise until pH 2, causing the precipitation of 24, which was filtered and dried under reduced pressure to afford a yellow-colored powder (5.51 g, 85%). 1 H NMR (400 MHz, CDCl3) δ ppm 13.57 (br s, 1H), 12.46 (br s, 1H), 8.90 (d, J = 5.1 Hz, 1H), 8.56 (s, 1H), 8.41 (d, J = 2.2 Hz, 1H), 8.18 (dd, J = 2.1, 8.4 Hz, 1H), 7.91 (s, 1H), 7.88 (dd, J = 1.6, 5.0 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ ppm 158.7, 154.7, 151.1, 139.0, 132.8, 132.3, 131.6, 128.9, 127.3, 122.1, 119.1. HRMS (m/z): [M+H] + , calcd for C16H10Cl2N3O4, 378.0043; found, 378.0056. Hept-6-yn-1-yl 2-(2-(3,4-dichlorophenyl)isonicotinamido)oxazole-5-carboxyla te (25).1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (200 mg, 0.6 mmol) was added to a solution of 24 (200 mg, 0.5 mmol) and 4-dimethylaminopyridine (71 mg, 0.6 mmol) in dry pyridine (5 mL) in an oven-dried flask, chilled to ice–water temperature under a nitrogen atmosphere. After 5 min, 6-heptyn-1-ol (60 mg, 0.5 mmol) was added via a syringe. The solution was allowed to warm to room temperature overnight. The reaction mixture was concentrated under reduced pressure. EtOAc (25 mL) was added and the organic solution was washed with water (2 × 25 mL) and brine (25 mL). The organic layer was dried (Na2SO4) and evaporated under reduced pressure affording the crude material, which was purified by silica chromatography using gradient elution from 9:1 hexanes/EtOAc to EtOAc, affording 25 as a light yellow-colored powder (62 mg, 25%). 1 H NMR (400 MHz, CDCl3) δ ppm 11.22 (br s, 1H), 8.89 (d, J = 5.4 Hz, 1H), 8.48 (br s, 1H), 8.21 (d, J = 2.2 Hz, 1H), 8.03 (br s, 1H), 7.97 (dd, J = 2.2, 8.6 Hz, 1H), 7.70 (s, 1H), 7.50–7.58 (m, 1H), 4.33 (t, J = 6.7 Hz, 2H), 2.19–2.27 (m, 2H), 1.97 (t, J = 2.7 Hz, 1H), 1.77 (quin, J = 7.0 Hz, 2H), 1.47–1.64 (m, 4H). 13 C NMR (101 MHz, CDCl 3 ) δ ppm 157.1, 155.8, 150.4, 137.7, 134.1, 133.3, 130.9, 129.0, 126.2, 120.9, 118.9, 84.1, 68.6, 65.8, 28.1, 27.9, 24.9, 18.3. HRMS (m/z): [M+H] + , calcd for C 23 H 20 Cl 2 N 3 O 4 , 472.0825; found, 472.0806. 6-Hydroxyhexyl 2-(2-(3,4-dichlorophenyl)isonicotinamido)oxazole-5-carboxyla te (26). This compound was prepared by the same procedure for 24, affording 26 as a colorless powder (225 mg, 44%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.52 (br s, 1H), 8.85–8.93 (m, 1H), 8.49–8.60 (m, 1H), 8.34–8.46 (m, 1H), 8.10–8.25 (m, 1H), 7.95–8.08 (m, 1H), 7.76–7.92 (m, 2H), 4.37 (br s, 1H), 4.22–4.33 (m, 2H), 3.39 (t, J = 6.4 Hz, 2H), 1.61–1.81 (m, 2H), 1.32–1.48 (m, 6H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 157.5, 154.8, 151.1, 139.0, 132.8, 132.4, 131.7, 128.9, 127.3, 122.1, 119.1, 65.4, 61.1, 32.9, 28.7, 25.7, 25.6. HRMS (m/z): [M+H] + , calcd for C 22 H 22 Cl 2 N 3 O 5 , 478.0931; found, 478.0945. 6-((Tert-butoxycarbonyl)amino)hexyl 2-(2-(3,4-dichlorophenyl)isonicotinamido) oxazole-5-carboxylate (27). This compound was prepared by the same procedure for 24, affording 27 as a light yellow-colored powder (653 mg, 43%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.69–8.78 (m, 1H), 8.49 (t, J = 1.22 Hz, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.06 (dd, J = 2.2, 8.6 Hz, 1H), 7.96 (dd, J = 1.5, 4.9 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.61 (s, 1H), 6.75–6.85 (m, 1H), 4.19 (t, J = 6.72 Hz, 2H), 2.91 (q, J = 6.8 Hz, 2H), 1.58–1.71 (m, 2H), 1.21–1.45 (m, 15H). 13 C NMR (101 MHz, DMSO- d6) δ ppm 167.7, 167.3, 157.3, 155.0, 152.9, 149.3, 148.3, 138.8, 136.2, 132.7, 131.2, 131.0, 130.5, 127.6, 125.9, 121.6, 118.4, 76.7, 63.2, 28.8, 27.7, 25.3, 24.5. HRMS (m/z): [M+H] + , calcd for C27H31Cl2N4O6, 577.1615; found, 577.1629. (2-(3,4-Dichlorophenyl)isonicotinamido)-N,N-dimethyloxazole- 5-carboxamide (28). This compound was prepared starting from 8a and 2-amino-N,N-dimethyloxazole-carboxamide , following the general procedure D affording 28 as a yellow-colored powder (162 mg, 11%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.36 (br s, 1H), 8.89 (d, J = 5.1 Hz, 1H), 8.56 (s, 1H), 8.35–8.50 (m, 1H), 8.13–8.27 (m, 1H), 7.88 (dd, J = 1.3, 5.0 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.73 (s, 1H), 3.16–3.31 (m, 3H), 2.90–3.11 (m, 3H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 157.8, 154.8, 151.1, 139.0, 132.8, 132.4, 131.6, 128.9, 127.3, 122.1, 119.1. HRMS (m/z): [M+H] + , calcd for C18H15Cl2N4O3, 405.0516; found, 405.0512. 2-(3,4-Dichlorophenyl)-N-(5-(morpholine-4-carbonyl)oxazol-2- yl)isonicotinamide (29). This compound was prepared by the same procedure for 28, affording 29 as a light yellow-colored powder (200 mg, 15%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (br s, 1H), 8.89 (d, J = 5.1 Hz, 1H), 8.54 (s, 1H), 8.40 (d, J = 2.2 Hz, 1H), 8.17 (dd, J = 2.2, 8.6 Hz, 1H), 7.88 (dd, J = 1.6, 5.0 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.75 (s, 1H), 3.72 (br s, 4H), 3.68 (br s, 4H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 156.9, 154.8, 151.1, 141.9, 140.6, 139.0, 132.8, 132.4, 131.6, 128.9, 127.3, 122.1, 119.1, 66.6. HRMS (m/z): [M+H] + , calcd for C20H17Cl2N4O4, 447.0621; found, 447.0614. Tert-butyl 4-(2-(2-(3,4-Dichlorophenyl)isonicotinamido)oxazole-5-carbon yl) piperazine- 1-carboxylate (30). This compound was prepared by the same procedure for 28, affording 30 as a colorless powder (345 mg, 20%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.42 (br s, 1H), 8.86 (d, J = 5.1 Hz, 1H), 8.52 (s, 1H), 8.38 (s, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 5.1 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.74 (s, 1H), 3.70 (br s, 4H), 3.43 (br s, 4H), 1.42 (s, 9H). 13 C NMR (101 MHz, DMSO- d 6 ) δ ppm 156.9, 154.7, 154.2, 151.1, 141.6, 140.7, 138.9, 132.8, 132.3, 131.6, 128.9, 127.2, 122.1, 119.0, 79.7, 28.5. HRMS (m/z): [M+H] + , calcd for C 25 H 26 Cl 2 N 5 O 5 , 546.1306; found, 546.1313. 2-(3,4-Dichlorophenyl)-N-(5-(piperazine-1-carbonyl)oxazol-2- yl)isonicotinamide dihydrochloride (31). Compound 30 (50 mg, 0.1 mmol) was added to 5 mL of 1 M HCl in dioxane and stirred overnight. The solvent was then removed under vacuo and the solid was triturated with Et 2 O (2 × 5 mL), affording 31 as a yellow-colored powder (38 mg, 82%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.53 (br s, 1H), 8.90 (d, J = 5.1 Hz, 1H), 8.60 (s, 1H), 8.44 (d, J = 2.2 Hz, 1H), 8.20 (dd, J = 2.1, 8.4 Hz, 1H), 7.87–7.93 (m, 1H), 7.79–7.87 (m, 2H), 5.44 (br s, 2H), 3.96 (br s, 4H), 3.63–3.74 (m, 2H), 3.42–3.54 (m, 2H), 3.39 (s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 157.3, 154.7, 151.1, 146.9, 142.9, 139.1, 132.7, 132.3, 131.6, 128.9, 127.2, 125.4, 124.6, 122.2, 119.2, 117.3, 110.8, 72.6, 71.0, 63.3, 60.6. HRMS (m/z): [M+H] + , calcd for C20H18Cl2N5O3, 446.0781; found, 446.0785. 2-(4-Chlorophenyl)-N-(oxazol-2-yl)isonicotinamide (32). This compound was prepared by the general procedures A, C, and D affording 32 as a colorless powder (159 mg, 35%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (br s, 1H), 8.86 (d, J = 5.1 Hz, 1H), 8.47 (s, 1H), 8.20 (d, J = 8.3 Hz, 2H), 7.98 (br s, 1H), 7.84 (d, J = 4.3 Hz, 1H), 7.60 (d, J = 8.7 Hz, 2H), 7.25 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 156.3, 151.2, 137.7, 135.2, 129.7, 129.2, 121.7, 118.9. HRMS (m/z): [M+H] + , calcd for C15H11ClN3O , 300.0534; found, 300.0523. 2-(3-Chlorophenyl)-N-(oxazol-2-yl)isonicotinamide (33). This compound was prepared by the general procedures A, C, and D affording 33 as a colorless powder (133 mg, 30%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.98 (br s, 1H), 8.88 (d, J = 4.9 Hz, 1H), 8.50 (s, 1H), 8.22 (s, 1H), 8.15 (d, J = 5.9 Hz, 1H), 8.00 (br s, 1H), 7.83–7.91 (m, 1H), 7.51–7.63 (m, 2H), 7.26 (br s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 155.7, 151.0, 140.6, 134.3, 131.3, 129.8, 126.9, 125.8, 121.9, 119.0. HRMS (m/z): [M+H] + , calcd for C15H11ClN3O , 300.0534; found, 300.0528. 2-(2-Chlorophenyl)-N-(oxazol-2-yl)isonicotinamide (34). This compound was prepared by the general procedures A, C, and D affording 34 as an off-white-colored powder (84 mg, 19%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.96 (br s, 1H), 8.89 (d, J = 5.4 Hz, 1H), 8.15 (br s, 1H), 7.80– 8.04 (m, 2H), 7.56–7.75 (m, 2H), 7.44–7.56 (m, 2H), 7.25 (br s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 157.5, 150.7, 138.8, 132.2, 131.6, 130.9, 130.5, 127.9, 123.0, 121.4. HRMS (m/z): [M+H] + , calcd for C15H11ClN3O , 300.0534; found, 300.0524. 2-(3,4-Difluorophenyl)-N-(oxazol-2-yl)isonicotinamide (35). This compound was prepared by the general procedures A, C, and D affording 35 as a colorless powder (164 mg, 36%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (br s, 1H), 8.87 (d, J = 4.9 Hz, 1H), 8.50 (s, 1H), 8.15–8.25 (m, 1H), 7.95–8.11 (m, 2H), 7.85 (d, J = 5.4 Hz, 1H), 7.56–7.69 (m, 1H), 7.26 (s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 166.6, 155.1, 151.0, 150.6 (dd, J CF = 53.1, 234.3 Hz, 1C), 141.5 (dd, J CF = 7.3, 40.2 Hz, 1C), 137.3, 136.2, 127.3, 124.2 (dd, J CF = 2.9, 6.4 Hz, 1C), 121.7, 119.7, 118.8, 117.4 (dd, J CF = 18.1, 231.5 Hz, 1C), 116.2. 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –137.93, –137.99. HRMS (m/z): [M+H] + , calcd for C 15 H 10 F 2 N 3 O 2 , 302.0736; found, 302.0741. 2-(4-Fluorophenyl)-N-(oxazol-2-yl)isonicotinamide (36). This compound was prepared by the general procedures A, C, and D affording 36 as a colorless powder (128 mg, 30%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.03 (br s., 1H), 8.85 (d, J = 4.9 Hz, 1H), 8.45 (s, 1H), 8.23 (dd, J = 5.6, 8.56 Hz, 2H), 8.00 (br s, 1H), 7.82 (d, J = 5.1 Hz, 1H), 7.38 (t, J = 8.9 Hz, 2H), 7.26 (s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 164.0, 163.6 (d, J CF = 246.7 Hz, 1C), 156.4, 153.4, 150.9, 141.6, 137.5, 135.1, 129.5 (d, J CF = 8.6 Hz, 2C), 127.4, 121.1, 118.5, 116.3 (d, J CF = 21.5 Hz, 2C). 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –112.37. HRMS (m/z): [M+H] + , calcd for C 15 H 11 FN 3 O 2 , 284.0830; found, 284.0843. 2-(3-Fluorophenyl)-N-(oxazol-2-yl)isonicotinamide (37). This compound was prepared by the general procedures A, C, and D affording 37 as a gray powder (142 mg, 33%). 1 H NMR (400 MHz, DMF-d 7 ) δ ppm 12.18 (br s, 1H), 8.94 (d, J = 5.1 Hz, 1H), 8.64 (s, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.95–8.08 (m, 3H), 7.57–7.69 (m, 1H), 7.21–7.43 (m, 2H). 13 C NMR (101 MHz, DMF-d 7 ) δ ppm 164.6, 156.0, 150.7, 141.2 (d, JCF = 8.7 Hz, 1C), 131.0 (d, JCF = 8.5 Hz, 1C), 122.89, 122.86, 121.5, 118.6, 116.3 (d, JCF = 21.6 Hz, 1C), 113.5 (d, JCF = 23.3 Hz, 1C), 100.0. 19 F NMR (376 MHz, DMSO- d6) δ ppm –112.73. HRMS (m/z): [M+H] + , calcd for C15H11FN3O , 284.0830; found, 284.0830. 2-(2-Fluorophenyl)-N-(oxazol-2-yl)isonicotinamide (38). This compound was prepared by the general procedures A, C, and D affording 38 as a slightly pink-colored powder (143 mg, 33%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.06 (br s, 1H), 8.91 (d, J = 4.9 Hz, 1H), 8.29 (br s, 1H), 7.94– 8.04 (m, 2H), 7.91 (d, J = 4.7 Hz, 1H), 7.49 - 7.58 (m, 1H), 7.33–7.44 (m, 2H), 7.26 (br s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 160.3 (d, JCF = 248.9 Hz, 1C), 153.9, 151.0, 131.8 (d, JCF = 8.5 Hz, 1C), 131.4 (d, JCF = 2.5 Hz, 1C), 126.9 (d, JCF = 11.2 Hz, 1C), 125.4 (d, JCF = 3.4 Hz, 1C), 122.6 (d, JCF = 7.7 Hz, 1C), 121.4, 116.9 (d, JCF = 22.6 Hz, 1C). 19 F NMR (376 MHz, DMSO-d6) δ ppm – 117.19. HRMS (m/z): [M + H] + , calcd for C15H11FN3O , 284.0830; found, 284.0826. 2-(4-Chloro-3-fluorophenyl)-N-(oxazol-2-yl)isonicotinamide (39). This compound was prepared by the general procedures A, C, and D affording 39 as a colorless powder (180 mg, 38%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.03 (br s, 1H), 8.87 (d, J = 5.1 Hz, 1H), 8.52 (s, 1H), 8.17 (d, J = 11.0 Hz, 1H), 8.06 (d, J = 8.07 Hz, 1H), 7.98 (br s, 1H), 7.79–7.93 (m, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.25 (br s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 158.1 (d, JCF = 246.1 Hz, 1C), 154.9, 151.1, 139.7 (d, JCF = 6.9 Hz, 1C), 131.6, 124.3 (d, JCF = 3.2 Hz, 1C), 122.1, 121.2 (d, JCF = 17.7 Hz, 1C), 119.0, 115.3 (d, JCF = 22.5 Hz, 1C). 19 F NMR (376 MHz, DMSO-d6) δ ppm –115.71. HRMS (m/z): [M+H] + , calcd for C15H10ClFN3O , 318.0440; found, 318.0439. 2-(3-Chloro-4-fluorophenyl)-N-(oxazol-2-yl)isonicotinamide (40). This compound was prepared by the general procedures A, C, and D affording 40 as a colorless powder (123 mg, 26%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.05 (br s, 1H), 8.86 (d, J = 4.9 Hz, 1H), 8.50 (s, 1H), 8.35 (d, J = 6.4 Hz, 1H), 8.19 (br s, 1H), 7.99 (br s, 1H), 7.86 (d, J = 4.2 Hz, 1H), 7.58 (t, J = 8.8 Hz, 1H), 7.27 (s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 13C NMR (101 MHz, DMSO) δ 158.5 (d, J CF = 249.5 Hz, 1C), 154.9, 151.0, 136.3 (d, J CF = 3.4 Hz, 1C), 129.2, 127.9 (d, J CF = 7.8 Hz, 1C), 121.7, 120.7 (d, J CF = 17.9 Hz, 1C), 118.8, 117.8 (d, J CF = 21.2 Hz, 1C). 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm – 115.59. HRMS (m/z): [M + H] + , calcd for C 15 H 10 ClFN 3 O 2 , 318.0440; found, 318.0455. 2-(3,5-Dichlorophenyl)-N-(oxazol-2-yl)isonicotinamide (41). This compound was prepared by the general procedures A, C and D affording 41 as a colorless powder (64 mg, 17%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.03 (br s, 1H), 8.89 (d, J = 4.9 Hz, 1H), 8.55 (s, 1H), 8.21 (d, J = 2.0 Hz, 2H), 8.01 (s, 1H), 7.90 (dd, J = 1.5, 4.9 Hz, 1H), 7.75 (t, J = 2.0 Hz, 1H), 7.26 (s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 154.3, 151.1, 141.9, 135.3, 129.30, 129.25, 126.7, 125.8, 122.5, 119.3, 100.0. HRMS (m/z): [M+H] + , calcd for C 15 H 10 C1 2 N 3 O 2 , 334.0145; found, 334.0143. 2-(3,5-Difluorophenyl)-N-(oxazol-2-yl)isonicotinamide (42). This compound was prepared by the general procedures A, C, and D affording 42 as a colorless powder (96 mg, 13%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.99 (br s, 1H), 8.89 (d, J = 5.1 Hz, 1H), 8.54 (s, 1H), 7.99 (br s, 1H), 7.79–7.95 (m, 3H), 7.40 (t, J = 9.1 Hz, 1H), 7.26 (s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 163.4 (dd, JCF = 245.7, 13.3 Hz, 2C), 154.6, 151.1, 142.2 (dd, JCF = 18.3, 9.2 Hz, 1C), 122.5, 119.2, 110.3 (d, JCF = 19.2, 7.4 Hz, 1C), 105.3 (t, JCF = 26.0 Hz, 1C). 19 F NMR (376 MHz, DMSO-d6) δ ppm –109.11. HRMS (m/z): [M+H] + , calcd for C15H10F2N3O , 302.0736; found, 302.0747. 2-(3-Chloro-5-fluorophenyl)-N-(oxazol-2-yl)isonicotinamide (43). This compound was prepared by the general procedures A, C, and D affording 43 as a colorless powder (253 mg, 24%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.03 (br s, 1H), 8.89 (d, J = 5.1 Hz, 1H), 8.55 (s, 1H), 8.11 (s, 1H), 7.94–8.04 (m, 2H), 7.90 (d, J = 4.2 Hz, 1H), 7.59 (td, J = 2.2, 8.6 Hz, 1H), 7.27 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 163.2 (d, JCF = 247.0 Hz, 1C), 154.4 (d, JCF = 2.9 Hz, 1C), 151.1, 142.2 (d, JCF = 9.0 Hz, 1C), 135.2 (d, JCF = 11.1 Hz, 1C), 123.3 (d, JCF = 2.8 Hz, 1C), 122.5, 119.3, 117.3 (d, JCF = 25.3 Hz, 1C), 113.0 (d, JCF = 23.2 Hz, 1C). 19 F NMR (376 MHz, DMSO-d6) δ ppm – 110.09. HRMS (m/z): [M+H] + , calcd for C15H10ClFN3O , 318.0440; found, 318.0439. N-(Oxazol-2-yl)-2-(4-(trifluoromethyl)phenyl)isonicotinamide (44). This compound was prepared by the general procedures A, C and D affording 44 as a light pink-colored powder (182 mg, 36%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.05 (br s, 1H), 8.87–8.97 (m, 1H), 8.57 (s, 1H), 8.40 (d, J = 8.3 Hz, 2H), 8.02 (br s, 1H), 7.92 (d, J = 8.6 Hz, 3H), 7.27 (br s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 165.5, 154.7, 150.4, 150.1, 141.3, 139.1, 129.0 (q, JCF = 32.0 Hz, 1C), 126.9, 125.2 (q, JCF = 3.6 Hz, 2C), 123.7 (q, JCF = 272.1 Hz, 1C), 121.9, 121.1, 119.1, 118.3. 19 F NMR (376 MHz, DMSO-d6) δ ppm –61.08. HRMS (m/z): [M + H] + , calcd for C16H11F3N3O , 334.0798; found, 334.0802. N-(Oxazol-2-yl)-2-(3-(trifluoromethyl)phenyl)isonicotinamide (45). This compound was prepared by the general procedures A, C, and D affording 45 as a colorless powder (147 mg, 29%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.11 (br s, 1H), 8.92 (d, J = 4.9 Hz, 1H), 8.58 (s, 1H), 8.42–8.54 (m, 2H), 8.01 (br s, 1H), 7.73–7.94 (m, 3H), 7.28 (s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 160.1, 155.6, 151.1, 139.5, 131.2, 130.6, 130.2 (q, J CF = 31.8 Hz, 1C), 126.5 (q, J CF = 3.6 Hz, 1C), 124.7 (q, J CF = 272.3 Hz, 1C), 123.6 (q, J CF = 3.9 Hz, 1C), 122.1, 119.1. 19 F NMR (376 MHz, DMSO- d 6 ) δ ppm –61.11. HRMS (m/z): [M+H] + , calcd for C 16 H 11 F 3 N 3 O 2 , 334.0798; found, 334.0794. N-(Oxazol-2-yl)-2-(4-(trifluoromethoxy)phenyl)isonicotinamid e (46). This compound was prepared by the general procedures A, C, and D affording 46 as a colorless powder (166 mg, 32%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.03 (br s, 1H), 8.88 (d, J = 5.1 Hz, 1H), 8.44–8.56 (m, 1H), 8.25–8.37 (m, 2H), 8.00 (br s, 1H), 7.79–7.93 (m, 1H), 7.46–7.63 (m, 2H), 7.26 (br s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 154.9, 150.0, 148.7, 136.7, 128.2, 120.7, 120.5, 119.5 (q, J CF = 256.8 Hz, 1C), 117.8. 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –56.65. HRMS (m/z): [M+H] + , calcd for C 16 H 11 F 3 N 3 O 3 , 350.0747; found, 350.0755. N-(Oxazol-2-yl)-2-(3-(trifluoromethoxy)phenyl)isonicotinamid e (47). This compound was prepared by the general procedures A, C, and D affording 47 as a light pink-colored powder (190 mg, 36%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.11 (br s, 1H), 8.81–8.99 (m, 1H), 8.54 (br s, 1H), 8.23 (d, J = 8.3 Hz, 1H), 8.15 (br s, 1H), 8.01 (br s, 1H), 7.81–7.94 (m, 1H), 7.60–7.79 (m, 1H), 7.44– 7.59 (m, 1H), 7.22–7.38 (m, 1H), 7.18 (d, J = 8.1 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 155.5, 151.1, 149.5, 142.3, 140.9, 137.8, 137.1, 131.5, 129.4, 128.7, 126.2, 125.8, 122.4, 122.0, 120.6 (q, JCF = 256.5 Hz, 1C), 119.5, 119.0. 19 F NMR (376 MHz, DMSO-d6) δ ppm –56.71. HRMS (m/z): [M+H] + , calcd for C16H11F3N3O3, 350.0747; found, 350.0741. 2-(4-Bromophenyl)-N-(oxazol-2-yl)isonicotinamide (48). This compound was prepared by the general procedures A, C and D affording 48 as a beige-colored powder (42 mg, 8%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (br s, 1H), 8.73–8.99 (m, 1H), 8.48 (br s, 1H), 8.07–8.25 (m, 2H), 7.94–8.06 (m, 1H), 7.80–7.94 (m, 1H), 7.75 (d, J = 8.56 Hz, 2H), 7.13–7.41 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 163.9, 156.2, 153.4, 151.0, 141.6, 137.7, 137.4, 132.3, 129.2, 127.5, 123.7, 121.5, 118.6. HRMS (m/z): [M+H] + , calcd for C15H11BrN3O , 344.0029; found, 344.0031. 2-(4-Nitrophenyl)-N-(oxazol-2-yl)isonicotinamide (49). This compound was prepared by the general procedures A, C, and D affording 49 as a yellow-colored powder (90 mg, 19%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.14 (br s, 1H), 8.94 (d, J = 5.1 Hz, 1H), 8.61 (s, 1H), 8.42–8.50 (m, 2H), 8.34–8.42 (m, 2H), 8.00 (br s, 1H), 7.95 (d, J = 5.6 Hz, 1H), 7.28 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 155.0, 151.3, 148.4, 144.4, 128.4, 124.5, 122.6, 119.9. HRMS (m/z): [M+H] + , calcd for C15H11N4O4, 311.0775; found, 311.0783. 2-(3-Nitrophenyl)-N-(oxazol-2-yl)isonicotinamide (50). This compound was prepared by the general procedures A, C, and D affording 50 as an off-white powder (72 mg, 15%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.15 (br s, 1H), 8.99 (s, 1H), 8.93 (d, J = 4.9 Hz, 1H), 8.58–8.67 (m, 2H), 8.30 - 8.39 (m, 1H), 8.01 (s, 1H), 7.93 (d, J = 4.9 Hz, 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.28 (s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 154.8, 151.2, 149.0, 140.1, 133.4, 132.0, 131.9, 131.1, 129.3, 129.2, 124.6, 122.4, 121.7, 119.2. HRMS (m/z): [M+H] + , calcd for C 15 H 11 N 4 O 4 , 311.0775; found, 311.0786. 2-(4-Methoxyphenyl)-N-(oxazol-2-yl)isonicotinamide (51). This compound was prepared by the general procedures A, C, and D affording 51 as an off-white powder (87 mg, 20%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.01 (br s, 1H), 8.81 (d, J = 5.1 Hz, 1H), 8.40 (s, 1H), 8.08–8.26 (m, 2H), 8.00 (br s, 1H), 7.63–7.86 (m, 1H), 7.27 (s, 1H), 6.96–7.19 (m, 2H), 3.85 (s, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 164.1, 161.0, 157.2, 153.5, 150.7, 141.4, 137.4, 131.0, 128.6, 127.4, 120.2, 117.7, 114.7, 55.7. HRMS (m/z): [M+H] + , calcd for C 16 H 14 N 3 O 3 , 296.1029; found, 296.1033. 2-(4-Isopropoxyphenyl)-N-(oxazol-2-yl)isonicotinamide (52). This compound was prepared by the general procedures A, C, and D affording 52 as a light yellow-colored powder (112 mg, 23%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.94 (br s, 1H), 8.80 (d, J = 5.1 Hz, 1H), 8.39 (s, 1H), 8.05– 8.18 (m, 2H), 8.01 (br s, 1H), 7.75 (br s, 1H), 7.25 (br s, 1H), 6.91–7.14 (m, 2H), 4.72 (td, J = 6.1, 12.0 Hz, 1H), 1.31 (d, J = 6.1 Hz, 6H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 164.1, 159.3, 157.2, 153.4, 150.7, 141.3, 137.5, 130.7, 128.7, 127.5, 120.1, 117.6, 116.1, 69.7, 22.3. HRMS (m/z): [M+H] + , calcd for C 18 H 18 N 3 O 3 , 324.1343; found, 324.1356. 2-(3,4-Dimethoxyphenyl)-N-(oxazol-2-yl)isonicotinamide (53). This compound was prepared by the general procedures A, C and D affording 53 as a light yellow-colored powder (138 mg, 28%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.92 (br s, 1H), 8.63–8.92 (m, 1H), 8.25–8.54 (m, 1H), 8.02 (br s, 1H), 7.60–7.88 (m, 3H), 7.24 (br s, 1H), 7.11 (d, J = 8.1 Hz, 1H), 3.84 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 163.2, 156.1, 152.3, 149.7, 149.6, 148.4, 140.3, 136.5, 130.1, 126.4, 119.1, 119.0, 116.8, 111.2, 109.3, 55.0. HRMS (m/z): [M+H] + , calcd for C17H16N3O4, 326.1135; found, 326.1140. 2-(3-Chloro-4-methoxyphenyl)-N-(oxazol-2-yl)isonicotinamide (54). This compound was prepared by the general procedures A, C, and D affording 54 as a light yellow-colored powder (83 mg, 17%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.98 (br s, 1H), 8.82 (d, J = 4.9 Hz, 1H), 8.44 (s, 1H), 8.20–8.29 (m, 1H), 8.05–8.20 (m, 1H), 8.00 (br s, 1H), 7.72–7.88 (m, 1H), 7.27–7.41 (m, 1H), 7.26 (s, 1H), 3.95 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 164.0, 156.1, 155.8, 153.4, 150.8, 141.5, 137.5, 131.9, 128.5, 127.5, 127.3, 122.2, 120.8, 118.0, 113.5, 56.8. HRMS (m/z): [M + H] + , calcd for C16H13ClN3O3, 330.0640; found, 330.0628. 2-(3-Cyanophenyl)-N-(oxazol-2-yl)isonicotinamide (55). This compound was prepared by the general procedures A, C, and D affording 55 as a colorless powder (101 mg, 23%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.07 (br s, 1H), 8.90 (d, J = 4.9 Hz, 1H), 8.58 (d, J = 8.6 Hz, 2H), 8.51 (d, J = 7.8 Hz, 1H), 7.93–8.03 (m, 2H), 7.89 (d, J = 4.9 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.26 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 155.2, 151.1, 142.5, 139.7, 136.7, 133.4, 131.8, 130.73, 130.70, 122.2, 119.2, 119.1, 112.6. HRMS (m/z): [M + H] + , calcd for C16H11N4O , 291.0877; found, 291.0869. 2-(4-(Benzyloxy)phenyl)-N-(oxazol-2-yl)isonicotinamide (56). This compound was prepared by the general procedures A, C and D affording 56 as a colorless powder (182 mg, 33%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.93 (br s, 1H), 8.80 (d, J = 5.1 Hz, 1H), 8.39 (s, 1H), 8.09–8.19 (m, J = 8.6 Hz, 2H), 8.00 (br s, 1H), 7.74 (br s, 1H), 7.47–7.54 (m, 2H), 7.39–7.45 (m, 2H), 7.31–7.39 (m, 1H), 7.24 (br s, 1H), 7.14–7.22 (m, 2H), 5.08–5.26 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 160.1, 157.1, 150.7, 137.4, 131.2, 128.9, 1128.6, 128.4, 128.3, 117.7, 115.6, 69.8. HRMS (m/z): [M+H] + , calcd for C 22 H 18 N 3 O 3 , 372.1343; found, 372.1358. 2-(3-(Benzyloxy)phenyl)-N-(oxazol-2-yl)isonicotinamide (57). This compound was prepared by the general procedures A, C, and D affording 57 as a light pink-colored powder (154 mg, 28%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.95 (br s, 1H), 8.86 (d, J = 5.1 Hz, 1H), 8.45 (s, 1H), 8.01 (br s, 1H), 7.73–7.88 (m, 3H), 7.38–7.53 (m, 5H), 7.31–7.38 (m, 1H), 7.21–7.28 (m, 1H), 7.15 (dd, J = 1.5, 8.3 Hz, 1H), 5.22 (s, 2H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 164.0, 159.4, 157.1, 153.4, 151.0, 150.8, 141.5, 140.1, 137.5, 130.5, 128.9, 128.3, 128.2, 121.3, 119.8, 118.8, 116.3, 113.6, 69.8. HRMS (m/z): [M+H] + , calcd for C 22 H 18 N 3 O 3 , 372.1343; found, 372.1354. Tert-butyl (4-(4-(oxazol-2-ylcarbamoyl)pyridin-2-yl)phenyl)carbamate (58). This compound was prepared by the general procedures A, C, and D affording 58 as a colorless powder (173 mg, 29%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.02 (br s, 1H), 9.60 (s, 1H), 8.80 (d, J = 4.9 Hz, 1H), 8.39 (s, 1H), 8.05–8.14 (m, 2H), 7.98 (s, 1H), 7.75 (dd, J = 1.5, 5.1 Hz, 1H), 7.55–7.67 (m, 2H), 7.25 (s, 1H), 1.49 (s, 9H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 157.2, 153.1, 150.7, 141.4, 137.0, 132.1, 127.7, 120.4, 118.5, 117.8, 79.8, 28.6. HRMS (m/z): [M+H] + , calcd for C20H 2 1N4O4, 381.1557; found, 381.1548. Tert-butyl (3-(4-(oxazol-2-ylcarbamoyl)pyridin-2-yl)phenyl)carbamate (59). This compound was prepared by the general procedures A, C, and D affording 59 as a colorless powder (143 mg, 25%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.01 (br s, 1H), 9.52 (s, 1H), 8.86 (d, J = 4.9 Hz, 1H), 8.38 (s, 2H), 7.84 (d, J = 5.1 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.47–7.59 (m, 1H), 7.34– 7.46 (m, 1H), 7.26 (br s, 1H), 1.49 (s, 9H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 166.7, 162.8, 157.4, 153.3, 150.8, 140.6, 139.1, 129.7, 129.6, 121.1, 121.0, 119.8, 119.3, 118.6, 116.9, 79.6, 28.6. HRMS (m/z): [M+H] + , calcd for C20H 2 1N4O4, 381.1557; found, 381.1552. N-(Oxazol-2-yl)-2-phenylisonicotinamide (60). This compound was prepared by the general procedures A, C, and D affording 60 as a yellow-colored powder (87 mg, 22%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.69 (d, J = 4.9 Hz, 1H), 8.35–8.56 (m, 1H), 7.98–8.14 (m, 2H), 7.77–7.97 (m, 1H), 7.36–7.57 (m, 4H), 6.89 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 167.2, 165.6, 156.4, 150.0, 149.4, 139.5, 131.8, 129.4, 129.3, 126.9, 126.8, 121.8, 119.2. HRMS (m/z): [M+H] + , calcd for C15H12N3O , 266.0924; found, 266.0917. N-(Oxazol-2-yl)-2-(quinolin-3-yl)isonicotinamide (61). This compound was prepared by the general procedures A, C, and D affording 61 as a beige-colored powder (170 mg, 36%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.01–12.26 (m, 1H), 9.68 (d, J = 2.2 Hz, 1H), 9.05–9.13 (m, 1H), 8.94 (d, J = 5.4 Hz, 1H), 8.68 (s, 1H), 8.14 (d, J = 6.6 Hz, 1H), 8.09 (d, J = 9.3 Hz, 1H), 8.00 (s, 1H), 7.91 (dd, J = 1.6, 5.0 Hz, 1H), 7.82 (ddd, J = 1.5, 6.9, 8.5 Hz, 1H), 7.63–7.72 (m, 1H), 7.28 (d, J = 1.0 Hz, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 155.2, 151.2, 149.5, 148.3, 142.5, 136.7, 134.3, 131.2, 130.9, 129.4, 129.2, 127.8, 127.7, 127.2, 121.8, 119.4. HRMS (m/z): [M+H] + , calcd for C 18 H 13 N 4 O 2 , 317.1033; found, 317.1046. 2-Morpholino-N-(oxazol-2-yl)isonicotinamide (62). This compound was prepared from commercial 2-morpholin-4-yl-isonicotinic acid following the general procedure D affording 62 as a pale yellow-colored powder (56 mg, 13%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.67 (br s, 1H), 8.28 (d, J = 5.1 Hz, 1H), 7.98 (br s, 1H), 7.32 (br s, 1H), 7.15–7.26 (m, 1H), 7.03–7.15 (m, 1H), 3.66– 3.77 (m, 4H), 3.46–3.57 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 158.9, 147.9, 136.4, 126.4, 110.4, 104.6, 65.3, 44.4. HRMS (m/z): [M+H] + , calcd for C 13 H 15 N 4 O 3 , 275.1139; found, 275.1149. N-(Oxazol-2-yl)-2-(trifluoromethyl)isonicotinamide (63). This compound was prepared from commercial 2-(trifluoromethyl)isonicotinic acid following the general procedure D affording 63 as a pale red-colored powder (42 mg, 11%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.43 (br s, 1H), 8.98 (d, J = 4.9 Hz, 1H), 8.36 (s, 1H), 8.23 (d, J = 4.9 Hz, 1H), 7.95 (s, 1H), 7.31 (s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 164.3, 151.0, 150.7, 146.5 (q, J CF = 34.1 Hz, 1C), 126.0, 125.2, 120.9 (q, JCF = 274.1 Hz, 1C), 118.9, 118.3 (q, JCF = 2.8 Hz, 1C). 19 F NMR (376 MHz, DMSO-d6) δ ppm – 66.58. HRMS (m/z): [M+H] + , calcd for C10H7F3N3O , 258.0485; found, 258.0486. Scheme 8: Synthetic route for accessing compounds 64 2-(2,2,2-Trifluoroethoxy)isonicotinonitrile (11a).2,2,2-Trifluoroethanol (2.71 g, 23.8 mmol) and 50 mL of dry THF were added to an oven-dry flask under a nitrogen atmosphere and cooled to –5 °C. Powdered NaH (570 mg, 23.8 mmol) was added in small portions over 10 min. The solution was stirred for 30 min, and solid 2-chloro-4-cyanopyridine (3.0 g, 21.7 mmol) was added in small portions over 10 min. After 1 h, the solution was heated at 50 °C for 1 h. The reaction mixture was cooled and a drop of water was added to quench the reaction. The solvent was removed in vacuo and the residue was purified by silica chromatography using gradient elution from 9:1 Hexane/EtOAc to EtOAc, affording 11a as a colorless liquid (3.45 g, 79%). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.33 (d, J = 5.1 Hz, 1H), 7.21 (td, J = 1.1, 5.1 Hz, 1H), 7.11–7.18 (m, 1H), 4.74–4.89 (m, 2H) 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 161.9, 148.2, 123.28, 123.27 (q, J CF = 277.5 Hz, 1C), 119.4, 116.0, 114.2, 62.5 (q, J CF = 36.4 Hz, 1C). 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –72.43. HRMS (m/z): [M + H] + , calcd for C 8 H 4 F 3 N 2 O, 201.0281; found, 201.0272. 2-(2,2,2-Trifluoroethoxy)isonicotinic acid (12a). This compound was prepared starting from 11a, following the general procedure C affording 12a as a white solid (3.45 g, 79%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 13.75 (br s, 1H), 8.34 (d, J = 5.4 Hz, 1H), 7.49 (d, J = 5.2 Hz, 1H), 7.30 (s, 1H), 4.77–5.06 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 165.9, 162.3, 148.2, 142.8, 124.4 (q, JCF = 277.8 Hz, 1C), 118.0, 110.7, 62.1 (q, JCF = 34.8 Hz, 1C). 19 F NMR (376 MHz, DMSO-d6) δ ppm –72.56. HRMS (m/z): [M + H] + , calcd for C8H7F3NO3, 222.0373; found, 222.0368. N-(Oxazol-2-yl)-2-(2,2,2-trifluoroethoxy)isonicotinamide (64). This compound was prepared starting from 12a by the general procedure D affording 64 as a white powder (87 mg, 20%). 1 H NMR (400 MHz DMSO-d6) δ ppm 1201 (br s 1H) 839 (d J = 54 Hz 1H) 796 (s 1H) 760 (d, J = 5.4 Hz, 1H), 7.48 (s, 1H), 7.26 (s, 1H), 5.07 (q, J = 9.1 Hz, 2H). 13 C NMR (101 MHz, DMSO- d 6 ) δ ppm 161.2, 147.0, 135.6, 123.5 (q, J CF = 277.8 Hz, 1C), 116.4, 108.9, 61.1 (q, J CF = 34.7 Hz, 1C). 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –72.38. HRMS (m/z): [M+H] + , calcd for C 11 H 9 F 3 N 3 O 3 , 288.0591; found, 288.0600. N-(Oxazol-2-yl)-2-(3,3,3-trifluoropropoxy)isonicotinamide (65). This compound was prepared by the same procedure for 64, affording 65 as a white powder (109 mg, 24%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.82 (br s, 1H), 8.36 (d, J = 5.4 Hz, 1H), 7.97 (br s, 1H), 7.41–7.60 (m, 1H), 7.34 (s, 1H), 7.24 (br s, 1H), 4.55 (t, J = 6.0 Hz, 2H), 2.70–2.93 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 162.5, 147.2, 136.4, 126.4, 126.2 (q, JCF = 276.9 Hz, 1C), 115.1, 108.8, 58.5, 31.9 (q, JCF = 27.7 Hz, 1C). 19 F NMR (376 MHz, DMSO-d6) δ ppm –63.06. HRMS (m/z): [M+H] + , calcd for C 12 H 11 F 3 N 3 O 3 , 302.0747; found, 302.0737. Scheme 9: Synthetic route for accessing compounds 66 2-(3,4-Dichlorophenyl)-3-fluoroisonicotinic acid (8b).1,4-Dioxane (75 mL) and a 2M aqueous solution of Na2CO3 (25 mL), were added to a 250 mL flask under an argon atmosphere.3,4- Dichlorobenzeneboronic acid (4.07 g, 21.36 mmol) and 2-chloro-3-fluoroisonicotinic acid (2.50 g, 14.24 mmol) were added after 5 min. Argon was bubbled through a needle into the solution for 20 min. Pd(PPh3)4 (493 mg, 0.4 mmol) was added. The reaction mixture was heated at reflux and aged overnight. The solution was allowed to cool to room temperature. The solvent was evaporated under reduced pressure to a quarter of the initial volume. Aqueous 6 M HCl was added to achieve a pH 3. The precipitate was collected by filtration and washed with water (3 × 10 mL). The solid was dried under reduced pressure, and crystallized from ethanol to afford 8b as an off-white-colored solid (3.20 g, 68%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 14.11 (br s, 1H), 8.63 (d, J = 4.9 Hz, 1H), 8.08 (dd, J = 0.9, 2.1 Hz, 1H), 7.86 (td, J = 1.8, 8.6 Hz, 1H), 7.72–7.82 (m, 2H). 13 C NMR (101 MHz, DMF-d 7 ) δ ppm 164.2, 155.0 (d, J CF = 270.5 Hz, 1C), 146.4 (d, J CF = 6.9 Hz, 1C), 144.7 (d, J CF = 11.8 Hz, 1C), 135.4 (d, J CF = 5.2 Hz, 1C), 132.8, 131.9, 131.3, 130.9 (d, J CF = 5.8 Hz, 1C), 129.3 (d, J CF = 6.8 Hz, 1C), 128.7, 125.2. 19 F NMR (376 MHz, DMSO-d6) δ ppm –124.59. HRMS (m/z): [M+H] + , calcd for C 12 H 7 Cl 2 FNO 2 , 285.9832; found, 285.9828. 2-(3,4-Dichlorophenyl)-3-fluoro-N-(oxazol-2-yl)isonicotinami de (66). This compound was prepared starting from 8c, following the general procedure D affording 66 as a colorless powder (98 mg, 19%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.15 (br s, 1H), 8.68 (d, J = 4.9 Hz, 1H), 8.09 - 8.21 (m, 1H), 7.88–8.02 (m, 2H), 7.80–7.87 (m, 1H), 7.69–7.79 (m, 1H), 7.21 (br s, 1H). 13 C NMR (101 MHz, DMF-d 7 ) δ ppm 154.1 (d, J CF = 265.4 Hz, 1C), 146.4 (d, J CF = 5.6 Hz, 1C), 144.0 (d, J CF = 10.8 Hz, 1C), 136.5, 135.7 (d, J CF = 4.4 Hz, 1C), 133.2, 132.9, 132.2, 131.3, 130.8 (d, J CF = 5.3 Hz, 1C), 129.1 (d, JCF = 6.7 Hz, 1C), 124.2. 19 F NMR (376 MHz, DMSO-d6) δ ppm –117.19. HRMS (m/z): [M+H] + , calcd for C 15 H 9 Cl 2 FN 3 O 2 , 352.0050; found, 352.0065. 2-(3-Chloro-4-fluorophenyl)-3-fluoro-N-(oxazol-2-yl)isonicot inamide (67). This compound was prepared by the same procedure for 66, affording 67 as a colorless powder (79 mg, 16%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.16 (br s, 1H), 8.67 (d, J = 4.7 Hz, 1H), 8.11 (d, J = 7.3 Hz, 1H), 7.96 (s, 2H), 7.74 (t, J = 5.0 Hz, 1H), 7.62 (t, J = 9.1 Hz, 1H), 7.21 (br s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 158.4 (d, JCF = 249.9 Hz, 1C), 153.6 (d, JCF = 264.9 Hz, 1C), 146.5 (d, JCF = 6.3 Hz, 1C), 144.1 (d, JCF = 11.0 Hz, 1C), 132.7 (dd, JCF = 5.3, 3.4 Hz, 1C), 132.5 (d, JCF = 2.8 Hz, 1C), 132.0 (d, JCF = 9.8 Hz, 1C), 131.2 (d, JCF = 5.5 Hz, 1C), 130.03 (d, JCF = 14.4 Hz, 1C), 130.02, 129.2 (d, JCF = 11.7 Hz, 1C), 124.0, 120.4 (d, JCF = 18.0 Hz, 1C), 117.8 (d, JCF = 21.3 Hz, 1C). 19 F NMR (376 MHz, DMSO-d6) δ ppm –114.61, –126.43. HRMS (m/z): [M+H] + , calcd for C15H9ClF2N3O , 336.0346; found, 336.0352. 2-(3,4-Difluorophenyl)-3-fluoro-N-(oxazol-2-yl)isonicotinami de (68). This compound was prepared by the same procedure as for 66, affording 68 as a colorless powder (201 mg, 42%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.13 (br s, 1H), 8.58 - 8.72 (m, 1H), 7.90 - 8.04 (m, 2H), 7.77– 7.86 (m, 1H), 7.73 (t, J = 4.8 Hz, 1H), 7.64 (td, J = 8.6, 10.8 Hz, 1H), 7.21 (br s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 153.6 (d, JCF = 264.9 Hz, 1C), 150.7 (dd, JCF = 248.7, 12.3 Hz, 1C), 149.9 (dd, JCF = 245.5, 12.6 Hz, 1C), 146.4 (d, JCF = 6.4 Hz, 1C), 144.1 (dd, JCF = 8.5, 3.3 Hz, 1C), 132.4 (dd, JCF = 9.4, 5.7 Hz, 1C), 126.4 (td, JCF = 6.9, 3.4 Hz, 1C), 123.9, 118.4 (d, JCF = 17.2 Hz, 1C), 118.2 (dd, JCF = 18.6, 5.1 Hz, 1C). 19 F NMR (376 MHz, DMSO-d6) δ ppm –19F NMR (376 MHz, DMSO) δ –126.48, –136.73 (d, J = 28.1 Hz), –137.90 (d, J = 24.4 Hz). HRMS (m/z): [M+H] + , calcd for C15H9F3N3O , 320.0641; found, 320.0653. 2-(3-Chlorophenyl)-3-fluoro-N-(oxazol-2-yl)isonicotinamide (69). This compound was prepared by the same procedure for 66, affording 69 as a colorless powder (123 mg, 26%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.15 (br s, 1H), 8.68 (d, J = 4.9 Hz, 1H), 7.95 (br s, 2H), 7.82–7.93 (m, 1H), 7.74 (t, J = 4.8 Hz, 1H), 7.54–7.64 (m, 2H), 7.21 (br s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 163.4, 155.2 (d, J CF = 244.0 Hz, 1C), 149.6 (d, J CF = 3.1 Hz, 1C), 149.4, 124.4, 123.2, 122.8 (d, J CF = 7.5 Hz, 1C), 121.2, 120.5 (d, J CF = 19.4 Hz, 1C), 118.0 (d, J CF = 22.7 Hz, 1C), 116.8, 115.0. 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –126.31. HRMS (m/z): [M+H] + , calcd for C 15 H 10 ClFN 3 O 2 , 318.0440; found, 318.0455. 2-(3,4-Dichlorophenyl)-5-fluoro-N-(oxazol-2-yl)isonicotinami de (70). This compound was prepared by the same procedure for 66, affording 70 as a colorless powder (130 mg, 25%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.20 (br s, 1H), 8.82 (s, 1H), 8.40 (d, J = 5.4 Hz, 1H), 8.34 (d, J = 2.2 Hz, 1H), 8.10 (dd, J = 2.2, 8.6 Hz, 1H), 7.97 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.22 (br s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 155.6 (d, J CF = 261.6 Hz, 1C), 150.7 (d, J CF = 4.8 Hz, 1C), 139.6 (d, J CF = 25.3 Hz, 1C), 138.1, 136.8, 132.6, 132.4, 131.6, 128.8, 127.1, 121.0, 100.0. 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –131.03. HRMS (m/z): [M+H] + , calcd for C 15 H 9 Cl 2 FN 3 O 2 , 352.0050; found, 352.0057. 2-(3-Chlorophenyl)-5-fluoro-N-(oxazol-2-yl)isonicotinamide (71). This compound was prepared by the same procedure for 66, affording 71 as a colorless powder (174 mg, 37%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.17 (br s, 1H), 8.83 (s, 1H), 8.36 (d, J = 5.4 Hz, 1H), 8.17 (s, 1H), 8.02–8.13 (m, 1H), 7.97 (s, 1H), 7.48–7.62 (m, 2H), 7.22 (br s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 151.7 (d, JCF = 4.6 Hz, 1C), 139.7, 139.5 (d, JCF = 24.9 Hz, 1C), 134.3, 131.3, 129.6, 126.8, 125.7, 120.9. 19 F NMR (376 MHz, DMSO-d6) δ ppm –131.60. HRMS (m/z): [M+H] + , calcd for C15H10ClFN3O , 318.0440; found, 318.0454. 2-(3,4-Difluorophenyl)-5-fluoro-N-(oxazol-2-yl)isonicotinami de (72). This compound was prepared by the same procedure for 66, affording 72 as a colorless powder (142 mg, 30%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.17 (br s, 1H), 8.82 (s, 1H), 8.35 (d, J = 5.4 Hz, 1H), 8.10–8.24 (m, 1H), 7.91–8.06 (m, 2H), 7.59 (q, J = 9.3 Hz, 1H), 7.22 (br s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 155.4 (d, JCF = 261.0 Hz, 1C), 151.1 (d, JCF = 4.3 Hz, 1C) ,150.7 (dd, JCF = 14.9, 250.8 Hz, 1C) ,150.3 (dd, JCF = 15.1, 247.4 Hz, 1C), 139.4 (d, JCF = 24.7 Hz, 1C), 136.8, 135.2 (t, JCF = 4.6 Hz, 1C), 131.7, 124.0 (t, JCF = 4.7 Hz, 1C), 120.6, 118.5 (t, JCF = 8.9 Hz, 1C), 116.1 (dd, JCF = 4.3, 14.8 Hz, 1C), 107.3. 19 F NMR (376 MHz, DMSO-d6) δ ppm –131.82, –137.88, –137.94. HRMS (m/z): [M+H] + , calcd for C15H9F3N3O , 320.0641; found, 320.0647. 2-(3-Chloro-4-fluorophenyl)-5-fluoro-N-(oxazol-2-yl)isonicot inamide (73). This compound was prepared by the same procedure for 66, affording 73 as a colorless powder (161 mg, 30%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.12 (br s, 1H), 8.82 (s, 1H), 8.27–8.42 (m, 2H), 8.08– 8.19 (m, 1H), 7.97 (br s, 1H), 7.58 (t, J = 8.9 Hz, 1H), 7.22 (br s, 1H). 13 C NMR (101 MHz, DMSO- d6) δ ppm 158.4 (d, JCF = 249.5 Hz, 1C), 151.0 (d, JCF = 4.6 Hz, 1C), 145.6, 139.6 (d, JCF = 1.9 Hz, 1C), 135.4 (d, JCF = 1.4 Hz, 1C), 129.2, 127.8 (d, JCF = 7.9 Hz, 1C), 120.8, 120.7 (d, JCF = 9.0 Hz, 1C), 117.9 (d, J CF = 21.2 Hz, 1C). 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –115.77, –131.85. HRMS (m/z): [M+H] + , calcd for C 15 H 9 ClF 2 N 3 O 2 , 336.0346; found, 336.0342. 2-(4-Chloro-3-fluorophenyl)-5-fluoro-N-(oxazol-2-yl)isonicot inamide (74). This compound was prepared by the same procedure for 66, affording 74 as a colorless powder (142 mg, 27%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.19 (br s, 1H), 8.84 (s, 1H), 8.39 (d, J = 5.4 Hz, 1H), 8.14 (dd, J = 2.0, 11.0 Hz, 1H), 7.90–8.05 (m, 2H), 7.75 (t, J = 8.2 Hz, 1H), 7.22 (br s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 158.1 (d, J CF = 246.0 Hz, 1C), 155.5 (d, J CF = 260.0 Hz, 1C), 154.2, 150.92 (d, J CF = 2.2 Hz, 1C), 150.87 (d, J CF = 2.2 Hz, 1C), 139.6 (d, J CF = 24.9 Hz, 1C), 138.7 (d, J CF = 7.1 Hz, 1C), 131.7, 124.2 (d, J CF = 2.8 Hz, 1C), 121.1 (d, J CF = 17.5 Hz, 1C), 120.9, 115.2 (d, J CF = 22.8 Hz, 1C). 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –115.63, –131.09. HRMS (m/z): [M+H] + , calcd for C 15 H 9 ClF 2 N 3 O 2 , 336.0346; found, 336.0344. 6-(3,4-Dichlorophenyl)-N-(oxazol-2-yl)picolinamide (75). This compound was prepared by the general procedures A, C, and D affording 75 as a colorless powder (219 mg, 44%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.59 (s, 1H), 8.81 (s, 1H), 8.38 (d, J = 7.8 Hz, 2H), 8.14–8.22 (m, 1H), 8.09–8.14 (m, 1H), 8.07 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.27 (s, 1H). 13 C NMR (101 MHz, DMSO- d 6 ) δ ppm 162.6, 152.4, 152.0, 147.9, 138.9, 137.2, 137.1, 131.9, 131.4, 130.2, 128.6, 126.8, 126.6, 123.6, 121.7. HRMS (m/z): [M+H] + , calcd for C 15 H 10 C1 2 N 3 O , 334.0145; found, 334.0137. 6-(3-Chlorophenyl)-N-(oxazol-2-yl)picolinamide (76). This compound was prepared by the general procedures A, C, and D affording 76 as a colorless powder (245 mg, 55%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H), 8.59 (s, 1H), 8.25–8.39 (m, 2H), 8.17 (t, J = 7.7 Hz, 1H), 8.11 (dd, J = 1.0, 7.8 Hz, 1H), 8.02–8.08 (m, 1H), 7.50–7.60 (m, 2H), 7.27 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 162.7, 153.4, 152.0, 147.9, 138.8, 137.1, 133.4, 129.9, 129.0, 126.6, 126.5, 125.3, 123.6, 121.5. HRMS (m/z): [M + H] + , calcd for C15H11ClN3O , 300.0534; found, 300.0526. 6-(3-Chloro-4-fluorophenyl)-N-(oxazol-2-yl)picolinamide (77). This compound was prepared by the general procedures A, C, and D affording 77 as a colorless powder (233 mg, 49%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.49–11.63 (m, 1H), 8.72–8.84 (m, 1H), 8.41 (tdd, J = 2.0, 4.5, 8.7 Hz, 1H), 8.31–8.37 (m, 1H), 8.12–8.19 (m, 1H), 8.08–8.12 (m, 1H), 8.07 (s, 1H), 7.53–7.62 (m, 1H), 7.27 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 162.6, 157.6 (d, JCF = 249.6 Hz, 1C), 152.6, 152.1, 147.8, 138.8, 137.1, 134.4 (d, JCF = 3.3 Hz, 1C), 129.1, 127.5 (d, JCF = 7.7 Hz, 1C), 126.6, 123.4, 121.4, 119.7 (d, JCF = 17.8 Hz, 1C), 116.5 (d, JCF = 21.1 Hz, 1C). 19 F NMR (376 MHz, DMSO- d6) δ ppm –115.32. HRMS (m/z): [M+H] + , calcd for C15H10ClFN3O , 318.0440; found, 318.0429. 6-(4-Chloro-3-fluorophenyl)-N-(oxazol-2-yl)picolinamide (78). This compound was prepared by the general procedures A, C, and D affording 78 as a colorless powder (250 mg, 52%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.47–11.66 (m, 1H), 8.70 (d, J = 11.5 Hz, 1H), 8.32–8.43 (m, 1H), 8.25 (d, J = 8.6 Hz, 1H), 8.15–8.21 (m, 1H), 8.09–8.15 (m, 1H), 8.07 (s, 1H), 7.68–7.81 (m, 1H), 7.24–7.33 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 169.7, 162.5, 157.2 (d, JCF = 245.3 Hz, 1C), 152.5, 152.0, 147.8, 138.9, 137.9 (d, J CF = 7.2 Hz, 1C), 137.1, 130.2, 126.6, 123.6 (d, J CF = 17.4 Hz, 1C), 121.7, 120.3 (d, J CF = 17.8 Hz, 1C), 115.2 (d, J CF = 22.8 Hz, 1C). 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –115.96. HRMS (m/z): [M+H] + , calcd for C 15 H 10 ClFN 3 O 2 , 318.0440; found, 318.0436. 6-(4-Fluorophenyl)-N-(oxazol-2-yl)picolinamide (79). This compound was prepared by the general procedures A, C, and D affording 79 as a colorless powder (270 mg, 64%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.48 (s, 1H), 8.42–8.56 (m, 2H), 8.29 (d, J = 7.8 Hz, 1H), 8.14 (t, J = 7.8 Hz, 1H), 8.00–8.10 (m, 2H), 7.30–7.40 (m, 2H), 7.26 (s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 163.8 (d, J CF = 247.3 Hz, 1C), 163.6, 155.0, 153.2, 148.8, 139.6, 138.0, 134.2 (d, J CF = 2.8 Hz, 1C), 130.1 (d, J CF = 8.5 Hz, 2C), 127.7, 124.1, 121.8, 116.0 (d, J CF = 21.4 Hz, 2C). 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –112.12. HRMS (m/z): [M+H] + , calcd for C 15 H 11 FN 3 O 2 , 284.0830; found, 284.0836. 6-(3,4-Difluorophenyl)-N-(oxazol-2-yl)picolinamide (80). This compound was prepared by the general procedures A, C, and D affording 80 as a colorless powder (259 mg, 57%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (s, 1H), 8.66–8.80 (m, 1H), 8.30–8.39 (m, 1H), 8.20–8.28 (m, 1H), 8.17 (t, J = 7.8 Hz, 1H), 8.00–8.13 (m, 2H), 7.51–7.65 (m, 1H), 7.19–7.32 (m, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 162.6, 152.7, 152.1, 149.9 (dd, J CF = 12.5, 248.5 Hz, 1C), 149.4 (dd, J CF = 12.2, 244.2 Hz, 1C), 147.8, 138.8, 137.1, 134.3 (dd, JCF = 3.4, 6.2 Hz, 1C), 126.6, 123.6 (dd, JCF = 3.2, 6.7 Hz, 1C), 123.3, 121.4, 117.1 (d, JCF = 17.1 Hz, 1C), 116.2 (d, JCF = 18.7 Hz, 1C). 19 F NMR (376 MHz, DMSO-d6) δ ppm 19F NMR (376 MHz, DMSO) –138.29 (d, J = 22.3 Hz, 1F), –137.44 (d, J = 22.3 Hz, 1F). HRMS (m/z): [M+H] + , calcd for C15H10F2N3O , 302.0736; found, 302.0738. 5-(3-Chloro-4-fluorophenyl)-N-(oxazol-2-yl)nicotinamide (81). This compound was prepared by the general procedures A, C and D affording 81 as a colorless powder (37 mg, 8%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (br s, 1H), 9.14 (br s, 1H), 9.10 (br s, 1H), 8.63 (br s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.99 (br s, 1H), 7.89 (br s, 1H), 7.61 (t, J = 9.1 Hz, 1H), 7.25 (br s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 158.0 (d, JCF = 248.5 Hz, 1C), 151.2 (d, JCF = 2.8 Hz, 1C), 149.0, 134.6 (d, JCF = 3.9 Hz, 1C), 134.2, 133.4, 129.8, 128.4 (d, JCF = 7.6 Hz, 1C), 120.9 (d, JCF = 17.9 Hz, 1C), 118.1 (d, JCF = 21.2 Hz, 1C). 19 F NMR (376 MHz, DMSO-d6) δ ppm –116.85. HRMS (m/z): [M + H] + , calcd for C15H10ClFN3O , 318.0440; found, 318.0432. 5-(3,4-Difluorophenyl)-N-(oxazol-2-yl)nicotinamide (82). This compound was prepared by the general procedures A, C, and D affording 82 as a colorless powder (84 mg, 19%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.96 (br s, 1H), 9.13 (s, 1H), 9.10 (s, 1H), 8.63 (t, J = 2.2 Hz, 1H), 7.92– 8.08 (m, 2H), 7.71–7.80 (m, 1H), 7.63 (td, J = 8.6, 10.7 Hz, 1H), 7.25 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 170.8, 151.5 (t, JCF = 12.1 Hz, 1C), 150.1 (d, JCF = 216.0 Hz, 1C), 149.1 (t, JCF = 13.0 Hz, 1C), 134.3 (dd, JCF = 2.9, 5.9 Hz, 1C), 134.2, 133.5, 124.6 (dd, JCF = 3.4, 6.6 Hz, 1C), 117.8 (dd, JCF = 17.8, 191.8 Hz, 1C). 19 F NMR (376 MHz, DMSO-d6) δ ppm –137.65, –137.71. HRMS (m/z): [M + H] + , calcd for C15H10F2N3O , 302.0736; found, 302.0728. 2-(3,4-Dichlorophenyl)-N-(oxazol-2-yl)pyrimidine-4-carboxami de (83). This compound was prepared by the general procedures A, C and D affording 83 as a colorless powder (209 mg, 42%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.98 (s, 1H), 9.23 (d, J = 5.1 Hz, 1H), 9.00 (s, 1H), 8.65 (d, J = 8.8 Hz, 1H), 8.09 (s, 1H), 8.06 (dd, J = 1.1, 5.0 Hz, 1H), 7.85 (dd, J = 1.2, 8.3 Hz, 1H), 7.30 (s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 161.5, 160.6, 160.1, 155.4, 151.7, 137.3, 136.2, 133.7, 131.3, 130.4, 129.7, 127.9, 126.7, 117.2. HRMS (m/z): [M+H] + , calcd for C 14 H 9 Cl 2 N 4 O 2 , 335.0097; found, 335.0089. 2-(3-Chlorophenyl)-N-(oxazol-2-yl)pyrimidine-4-carboxamide (84). This compound was prepared by the general procedures A, C, and D affording 84 as a colorless powder (175 mg, 39%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.96 (s, 1H), 9.23 (d, J = 4.4 Hz, 1H), 8.81 (br s, 1H), 8.64 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 8.07 (d, J = 4.9 Hz, 1H), 7.52–7.70 (m, 2H), 7.33 (s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 162.6, 162.4, 161.0, 156.4, 152.8, 138.7, 138.3, 134.3, 131.7, 131.0, 128.7, 127.8, 127.5, 118.1. HRMS (m/z): [M+H] + , calcd for C 14 H 10 ClN 4 O 2 , 301.0487; found, 301.0494. N-(Oxazol-2-yl)-2-(3-(trifluoromethyl)phenyl)pyrimidine-4-ca rboxamide (85). This compound was prepared by the general procedures A, C, and D affording 85 as a colorless powder (168 mg, 38%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.02 (br s, 1H), 9.27 (d, J = 4.9 Hz, 1H), 9.04 (d, J = 8.3 Hz, 1H), 8.98 (s, 1H), 8.07–8.15 (m, 2H), 7.93–8.01 (m, 1H), 7.77–7.88 (m, 1H), 7.33 (d, J = 1.0 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 162.3, 161.1, 156.6, 152.8, 138.2, 137.7, 133.0, 130.3, 130.1 (q, JCF = 32.1 Hz, 1C), 128.3 (q, JCF = 3.6 Hz, 1C), 127.7, 125.4 (q, JCF = 3.8 Hz, 1C), 124.7 (q, JCF = 272.0 Hz, 1C), 118.3. 19 F NMR (376 MHz, DMSO-d6) δ ppm –60.97. HRMS (m/z): [M+H] + , calcd for C15H10F3N4O , 335.0750; found, 335.0763. 6-(3,4-Dichlorophenyl)-N-(oxazol-2-yl)pyrazine-2-carboxamide (86). This compound was prepared by the general procedures A, C, and D affording 86 as a colorless powder (168 mg, 33%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (br s, 1H), 9.62 (s, 1H), 9.24 (s, 1H), 8.77–8.91 (m, 1H), 8.47 (dd, J = 2.2, 8.6 Hz, 1H), 8.09 (d, J = 1.0 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H), 7.30 (d, J = 1.0 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 162.7, 152.9, 148.1, 145.8, 143.6, 143.2, 138.1, 135.7, 133.9, 132.6, 131.5, 129.9, 128.0, 127.7. HRMS (m/z): [M+H] + , calcd for C14H9Cl2N4O , 335.0097; found, 335.0112. Scheme 10. Synthetic route for accessing compound 87 (3,4-Dichlorophenyl)picolinonitrile (7b). This compound was prepared by the general procedure A, affording 7b as a white powder in 71% yield (3.80 g). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.83 (dd, J = 0.6, 5.3 Hz, 1H), 8.52 (dd, J = 0.7, 2.0 Hz, 1H), 8.26 (d, J = 2.5 Hz, 1H), 8.15 (dd, J = 1.9, 5.4 Hz, 1H), 7.93 (dd, J = 2.2, 8.6 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 152.3, 146.6, 136.2, 134.0, 133.6, 132.8, 131.9, 129.7, 127.9, 127.1, 125.5, 118.0. HRMS (m/z): [M–H] – , calcd for C 12 H 5 Cl 2 N 2 , 246.9835; found, 246.9842. 4-(3,4-Dichlorophenyl)picolinic acid (8c). This compound was prepared by the general procedure C, affording 8c as a white powder in 87% yield (1.40 g). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.77 (dd, J = 0.6, 5.0 Hz, 1H), 8.32 (dd, J = 0.7, 2.0 Hz, 1H), 8.16 (d, J = 2.2 Hz, 1H), 8.01 (dd, J = 1.8, 5.0 Hz, 1H), 7.86 (dd, J = 2.2, 8.3 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 166.5, 150.6, 149.7, 146.5, 137.5, 133.0, 132.7, 131.8, 129.5, 127.8, 124.9, 122.5. HRMS (m/z): [M–H]– calcd for C12H6Cl2NO 2659781; found 2659793. 4-(3,4-Dichlorophenyl)-N-(oxazol-2-yl)picolinamide (87). This compound was prepared by the general procedure D, affording 87 as a colorless powder in 58% yield (293 mg). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.52 (s, 1H), 8.79 (d, J = 5.1 Hz, 1H), 8.37 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 2.2 Hz, 1H), 8.06 (dd, J = 2.0, 5.1 Hz, 1H), 7.95–8.04 (m, 1H), 7.88 (dd, J = 2.2, 8.6 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.22 (d, J = 1.0 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 163.2, 153.0, 150.0, 149.9, 146.9, 137.8, 137.4, 133.1, 132.7, 131.8, 129.6, 127.9, 127.7, 125.4, 120.7. HRMS (m/z): [M+H] + , calcd for C 15 H 10 C1 2 N 3 O 2 , 334.0145; found, 334.0156. 4-(4-Chlorophenyl)-N-(oxazol-2-yl)picolinamide (88). This compound was prepared by the general procedures A, C and D affording 88 as a colorless powder (222 mg, 49 %). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (br s, 1H), 8.79 (d, J = 5.1 Hz, 1H), 8.37 (s, 1H), 8.02 (d, J = 3.2 Hz, 1H), 7.89–7.99 (m, 2H), 7.59–7.67 (m, 2H), 7.18 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 162.8, 150.1, 150.0, 136.6, 129.8, 129.7, 129.3, 129.0, 127.3, 124.4, 120.6. HRMS (m/z): [M+H] + , calcd for C15H11ClN3O , 300.0534; found, 300.0545. 4-(4-Fluorophenyl)-N-(oxazol-2-yl)picolinamide (89). This compound was prepared by the general procedures A, C and D affording 89 as a light yellow-colored powder (133 mg, 31%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (s, 1H), 8.77 (d, J = 5.4 Hz, 1H), 8.30–8.38 (m, 1H), 7.99– 8.05 (m, 2H), 7.91–7.99 (m, 2H), 7.33–7.43 (m, 2H), 7.22 (d, J = 1.0 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 163.7 (d, JCF = 247.6 Hz, 1C), 163.3, 153.0, 150.0, 149.8, 148.4, 137.8, 133.2 (d, JCF = 3.1 Hz, 1C), 129.9 (d, JCF = 8.7 Hz, 2C), 127.7, 125.2, 120.4, 116.8 (d, JCF = 21.6 Hz, 2C). 19 F NMR (376 MHz, DMSO-d6) δ ppm –111.81. HRMS (m/z): [M+H] + , calcd for C15H11FN3O , 284.0830; found, 284.0824. 4-(3,4-Difluorophenyl)-N-(oxazol-2-yl)picolinamide (90). This compound was prepared by the general procedures A, C, and D affording 90 as a colorless powder (165 mg, 37%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H), 8.65–8.88 (m, 1H), 8.38 (dd, J = 0.6, 1.8 Hz, 1H), 8.01–8.13 (m, 3H), 7.76–7.84 (m, 1H), 7.62 (td, J = 8.6, 10.5 Hz, 1H), 7.25 (d, J = 1.2 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 163.2, 153.0, 150.9 (dd, JCF = 252.5, 15.6 Hz, 1C), 150.4 (dd, JCF = 255.2, 21.8 Hz, 1C), 150.0, 149.9, 147.3, 137.8, 134.3 (dd, JCF = 6.2, 3.7 Hz, 1C), 127.6, 125.3, 124.8 (dd, J CF = 6.8, 3.4 Hz, 1C), 120.5, 118.8 (d, J CF = 17.2 Hz, 1C), 117.0 (d, J CF = 18.2 Hz, 1C). 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –137.05, –137.11, –137.33, –137.39. HRMS (m/z): [M+H] + , calcd for C 15 H 10 F 2 N 3 O 2 , 302.0736; found, 302.0730. 4-(3-Chloro-4-fluorophenyl)-N-(oxazol-2-yl)picolinamide (91). This compound was prepared by the general procedures A, C, and D affording 91 as a colorless powder (63 mg, 13%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.51 (s, 1H), 8.80 (d, J = 5.4 Hz, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.21 (dd, J = 2.5, 7.09 Hz, 1H), 8.08 (dd, J = 2.0, 5.1 Hz, 1H), 8.01 (s, 1H), 7.90–7.99 (m, 1H), 7.61 (t, J = 8.9 Hz, 1H), 7.22 (s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 163.3, 158.6 (d, J CF = 249.9 Hz, 1C), 153.0, 150.0, 149.9, 147.2, 137.8, 134.7 (d, J CF = 3.7 Hz, 1C), 130.0, 128.6 (d, J CF = 7.8 Hz, 1C), 127.7, 125.4, 121.1 (d, J CF = 17.9 Hz, 1C), 120.7, 118.2 (d, J CF = 21.2 Hz, 1C). 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –115.06. HRMS (m/z): [M+H] + , calcd for C 15 H 10 C1FN 3 O 2 , 318.0440; found, 318.0438. 4-(4-Chloro-3-fluorophenyl)-N-(oxazol-2-yl)picolinamide (92). This compound was prepared by the general procedures A, C, and D affording 92 as a colorless powder (38 mg, 8%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (s, 1H), 8.82 (d, J = 5.1 Hz, 1H), 8.36 - 8.46 (m, 1H), 8.03– 8.12 (m, 2H), 8.01 (s, 1H), 7.73–7.87 (m, 2H), 7.22 (s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 162.2, 157.1 (d, J CF = 246.9 Hz, 1C), 151.9, 149.0, 148.9, 146.1 (d, J CF = 1.7 Hz, 1C), 136.84 (d, J CF = 7.4 Hz, 1C), 136.77, 130.9, 126.6, 124.3, 123.9 (d, JCF = 3.5 Hz, 1C), 120.5 (d, JCF = 17.6 Hz, 1C), 119.5, 115.1 (d, JCF = 22.4 Hz, 1C). 19 F NMR (376 MHz, DMSO-d6) δ ppm –115.10. HRMS (m/z): [M+H] + , calcd for C15H10ClFN3O , 318.0440; found, 318.0453. 4-(3-Fluorophenyl)-N-(oxazol-2-yl)picolinamide (93). This compound was prepared by the general procedures A, C, and D affording 93 as a colorless powder (35 mg, 8%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (s, 1H), 8.82 (d, J = 5.1 Hz, 1H), 8.33 - 8.44 (m, 1H), 8.08 (dd, J = 2.0, 5.1 Hz, 1H), 8.01 (s, 1H), 7.71–7.85 (m, 2H), 7.62 (dt, J = 6.1, 8.1 Hz, 1H), 7.38 (dt, J = 2.7, 8.6 Hz, 1H), 7.22 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 162.3, 162.2 (d, JCF = 244.3 Hz, 1C), 151.9, 149.0, 148.9, 147.1 (d, JCF = 2.2 Hz, 1C), 138.2 (d, JCF = 8.0 Hz, 1C), 136.8, 130.8 (d, JCF = 8.4 Hz, 1C), 126.6, 124.4, 122.7 (d, JCF = 2.7 Hz, 1C), 119.6, 116.0 (d, JCF = 21.1 Hz, 1C), 113.5 (d, JCF = 22.8 Hz, 1C). 19 F NMR (376 MHz, DMSO-d6) δ ppm –112.08. HRMS (m/z): [M+H] + , calcd for C15H11FN3O , 284.0830; found, 284.0833. 4-(3,5-Difluorophenyl)-N-(oxazol-2-yl)picolinamide (94). This compound was prepared by the general procedures A, C, and D affording 94 as a colorless powder (132 mg, 29%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (s, 1H), 8.83 (d, J = 5.1 Hz, 1H), 8.41 (s, 1H), 8.05–8.20 (m, 1H), 8.01 (s, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.43 (t, J = 9.2 Hz, 1H), 7.22 (s, 1H). 13 C NMR (101 MHz, DMSO- d6) δ ppm 162.4 (dd, JCF = 246.6, 13.5 Hz, 2C), 162.2, 151.9, 149.02, 148.98, 146.0, 139.4 (t, JCF = 9.9 Hz, 1C), 136.8, 126.6, 124.5, 119.8, 110.1 (dd, JCF = 19.1, 7.6 Hz, 2C), 104.5 (t, JCF = 25.9 Hz, 1C). 19 F NMR (376 MHz, DMSO-d6) δ ppm –108.59. HRMS (m/z): [M+H] + , calcd for C15H10F2N3O , 302.0736; found, 302.0740. N-(Oxazol-2-yl)-4-(4-(trifluoromethoxy)phenyl)picolinamide (95). This compound was prepared by the general procedures A, C and D affording 95 as a colorless powder (101 mg, 19%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.51 (s, 1H), 8.82 (d, J = 5.1 Hz, 1H), 8.30–8.50 (m, 1H), 7.87– 8.13 (m, 4H), 7.56 (d, J = 8.8 Hz, 2H), 7.22 (s, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 162.3, 151.9, 149.0, 148.8, 147.0, 136.8, 135.0, 128.8, 126.6, 124.3, 121.1, 119.54, 119.45 (q, J CF = 256.9 Hz, 1C). 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –56.69. HRMS (m/z): [M+H] + , calcd for C 16 H 11 F 3 N 3 O 3 , 350.0747; found, 350.0755. N-(Oxazol-2-yl)-4-(3-(trifluoromethoxy)phenyl)picolinamide (96). This compound was prepared by the general procedures A, C and D affording 96 as an off-white-colored powder (149 mg, 28%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.54 (s, 1H), 8.83 (d, J = 5.1 Hz, 1H), 8.40 (d, J = 1.2 Hz, 1H), 8.10 (dd, J = 2.0, 5.1 Hz, 1H), 8.00–8.05 (m, 1H), 7.90–8.00 (m, 2H), 7.72 (t, J = 8.0 Hz, 1H), 7.50–7.60 (m, 1H), 7.23 (d, J = 1.0 Hz, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 162.2, 151.9, 149.0, 148.9, 148.5, 146.7, 138.2, 136.8, 130.8, 126.6, 125.8, 124.5, 121.6, 119.7, 119.5 (d, J CF = 256.6 Hz, 1C), 119.4. 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –56.68. HRMS (m/z): [M+H] + , calcd for C16H11F3N3O3, 350.0747; found, 350.0745. N-(Oxazol-2-yl)-4-(4-(trifluoromethyl)phenyl)picolinamide (97). This compound was prepared by the general procedures A, C, and D affording 97 as a white powder (126 mg, 25%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H), 8.86 (d, J = 5.1 Hz, 1H), 8.42 (s, 1H), 8.07–8.19 (m, 3H), 8.01 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.23 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 162.2, 151.9, 149.1, 148.9, 146.9, 139.8, 136.8, 129.3 (q, JCF = 32.1 Hz, 1C), 127.6, 126.6, 125.6 (q, JCF = 3.7 Hz, 2C), 124.6, 123.5 (q, JCF = 272.2 Hz, 1C), 119.8. 19 F NMR (376 MHz, DMSO-d6) δ ppm –61.20. HRMS (m/z): [M+H] + , calcd for C 16 H 11 F 3 N 3 O , 334.0798; found, 334.0797. N-(Oxazol-2-yl)-4-(3-(trifluoromethyl)phenyl)picolinamide (98). This compound was prepared by the general procedures A, C, and D affording 98 as a colorless powder (119 mg, 24%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.58 (s, 1H), 8.85 (d, J = 4.9 Hz, 1H), 8.45 (dd, J = 0.5, 1.7 Hz, 1H), 8.18 - 8.27 (m, 2H), 8.15 (dd, J = 2.0, 5.1 Hz, 1H), 8.04 (d, J = 1.0 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.81 (t, J = 7.7 Hz, 1H), 7.26 (d, J = 1.0 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 163.3, 153.0, 150.0, 149.9, 147.9, 138.0, 137.8, 131.8, 130.9, 130.6 (q, JCF = 31.9 Hz, 1C), 127.7, 126.8 (q, JCF = 3.7 Hz, 1C), 125.6, 124.5 (q, JCF = 272.6 Hz, 1C), 124.3 (q, JCF = 3.8 Hz, 1C), 120.9. 19 F NMR (376 MHz, DMSO-d6) δ ppm –61.07. HRMS (m/z): [M+H] + , calcd for C16H11F3N3O , 334.0798; found, 334.0792. 2-(3,4-Dichlorophenoxy)-N-(oxazol-2-yl)isonicotinamide (99). This compound was prepared by the general procedures B, C, and D affording 99 as a colorless powder (184 mg, 35%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.05 (br s, 1H), 8.32 (dd, J = 0.8, 4.72 Hz, 1H), 7.93 (br s, 1H), 7.60–7.75 (m, 2H), 7.47–7.60 (m, 2H), 7.12–7.31 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 163.6, 153.6, 149.0, 132.4, 131.9, 127.8, 126.6, 124.4, 122.7, 118.6, 111.0. HRMS (m/z): [M+H] + , calcd for C15H10Cl2N3O3, 350.0094; found, 350.0110. 2-(3-Chlorophenoxy)-N-(oxazol-2-yl)isonicotinamide (100). This compound was prepared by the general procedures B, C, and D affording 100 as a light pink-colored powder (157 mg, 33%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.07 (br s, 1H), 8.34 (d, J = 5.4 Hz, 1H), 7.95 (br s, 1H), 7.62–7.69 (m, 1H), 7.55 (s, 1H), 7.43–7.52 (m, 1H), 7.29–7.36 (m, 2H), 7.26 (s, 1H), 7.18 (td, J = 1.5, 8.6 Hz, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 162.6, 153.9, 147.7, 133.0, 130.6, 124.3, 121.0, 119.6, 117.1, 109.6. HRMS (m/z): [M+H] + , calcd for C 15 H 11 ClN 3 O 3 , 316.0483; found, 316.0480. 2-(3-Chloro-4-fluorophenoxy)-N-(oxazol-2-yl)isonicotinamide (101). This compound was prepared by the general procedures B, C, and D affording 101 as a light pink-colored powder (119 mg, 24%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.93 (br s, 1H), 8.33 (d, J = 5.1 Hz, 1H), 7.96 (br s, 1H), 7.64 (d, J = 5.4 Hz, 1H), 7.42–7.59 (m, 3H), 7.14–7.31 (m, 2H). 13 C NMR (101 MHz, DMSO- d 6 ) δ ppm 162.7, 153.9 (d, J CF = 243.6 Hz, 1C), 149.2, 147.6, 123.2, 121.7 (d, J CF = 7.4 Hz, 1C), 119.3 (d, J CF = 19.3 Hz, 1C), 116.9 (d, J CF = 22.6 Hz, 1C), 109.4. 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm – 121.22. HRMS (m/z): [M+H] + , calcd for C 15 H 10 ClFN 3 O 3 , 334.0389; found, 334.0381. 2-(4-Chloro-3-fluorophenoxy)-N-(oxazol-2-yl)isonicotinamide (102). This compound was prepared by the general procedures B, C, and D affording 102 as a colorless powder (221 mg, 44%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.12 (br s, 1H), 8.35 (d, J = 5.1 Hz, 1H), 7.96 (s, 1H), 7.61– 7.77 (m, 2H), 7.53–7.61 (m, 1H), 7.43 (dd, J = 2.7, 10.5 Hz, 1H), 7.27 (s, 1H), 7.11 (ddd, J = 1.4, 2.6, 8.7 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 162.4, 156.8 (d, JCF = 247.3 Hz, 1C), 152.8 (d, JCF = 10.1 Hz, 1C), 147.7, 130.4, 118.3 (d, JCF = 3.5 Hz, 1C), 117.3, 114.9 (d, JCF = 17.6 Hz, 1C), 110.3 (d, JCF = 23.5 Hz, 1C), 109.6. 19 F NMR (376 MHz, DMSO-d6) δ ppm –113.37. HRMS (m/z): [M–H] – , calcd for C 15 H 10 C1FN 3 O 3 , 334.0389; found, 334.0403. N-(Oxazol-2-yl)-2-(3-(trifluoromethyl)phenoxy)isonicotinamid e (103). This compound was prepared by the general procedures B, C, and D affording 103 as a light-pink-colored powder (103 mg, 20%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.98 (br s, 1H), 8.35 (d, J = 5.1 Hz, 1H), 7.97 (br s, 1H), 7.66–7.74 (m, 2H), 7.56–7.66 (m, 3H), 7.47–7.56 (m, 1H), 7.28 (br s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 163.6, 154.4, 148.7, 131.5, 131.0 (q, JCF = 32.1 Hz, 1C), 126.2, 124.2 (q, JCF = 272.4 Hz, 1C), 122.0 (q, JCF = 3.6 Hz, 1C), 118.8 (q, JCF = 3.8 Hz, 1C), 118.2, 110.8. 19 F NMR (376 MHz, DMSO-d6) δ ppm –61.07. HRMS (m/z): [M+H] + , calcd for C16H11F3N3O3, 350.0747; found, 350.0762. N-(Oxazol-2-yl)-2-(4-(trifluoromethoxy)phenoxy)isonicotinami de (104). This compound was prepared by the general procedures B, C, and D affording 104 as a colorless powder (163 mg, 30%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.03 (br s, 1H), 8.34 (d, J = 5.1 Hz, 1H), 7.97 (br s, 1H), 7.67 (d, J = 5.9 Hz, 1H), 7.59 (s, 1H), 7.40–7.51 (m, 2H), 7.30–7.39 (m, 2H), 7.27 (br s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 166.0, 164.0, 163.8, 152.8, 148.9, 148.7, 145.3, 144.1, 123.5, 123.1, 120.6 (q, JCF = 256.0 Hz, 1C), 118.0, 110.6. 19 F NMR (376 MHz, DMSO-d6) δ ppm –57.14. HRMS (m/z): [M+H] + , calcd for C16H11F3N3O4, 366.0696; found, 366.0702. N-(Oxazol-2-yl)-2-(3-(trifluoromethoxy)phenoxy)isonicotinami de (105). This compound was prepared by the general procedures B, C, and D affording 105 as a white powder (170 mg, 31%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm (br s, 1H), 8.34 (d, J = 5.4 Hz, 1H), 7.95 (br s, 1H), 7.67 (d, J = 5.4 Hz, 1H), 7.50–7.62 (m, 2H), 7.18–7.32 (m, 4H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 163.5, 155.1, 149.40, 149.38, 148.7, 131.5, 121.0, 120.5 (q, J CF = 256.8 Hz, 1C), 118.3, 117.6, 115.0, 110.8. 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –56.94. HRMS (m/z): [M+H] + , calcd for C 16 H 11 F 3 N 3 O 4 , 366.0696; found, 366.0691. 4-(3,4-Difluorophenoxy)-N-(oxazol-2-yl)picolinamide (106). This compound was prepared by the general procedures B, C, and D affording 106 as a colorless powder (140 mg, 29%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.47 (s, 1H), 8.64 (d, J = 5.6 Hz, 1H), 7.83–8.11 (m, 1H), 7.46–7.70 (m, 3H), 7.29 (dd, J = 2.7, 5.6 Hz, 1H), 7.10–7.24 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 164.8, 161.8, 151.8, 150.4, 150.3, 149.3 (dd, J CF = 248.4, 14.0 Hz, 1C), 148.7 (dd, J CF = 8.9, 2.8 Hz, 1C), 146.9 (dd, J CF = 244.0, 12.5 Hz, 1C), 136.8, 126.6, 118.2 (d, J CF = 18.8 Hz, 1C), 117.4 (dd, J CF = 6.6, 3.6 Hz, 1C), 114.7, 110.8 (d, J CF = 19.7 Hz, 1C), 109.8. 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm – 134.15, –141.35. HRMS (m/z): [M+H] + , calcd for C 15 H 10 F 2 N 3 O 3 , 318.0685; found, 318.0684. 4-(3-Fluorophenoxy)-N-(oxazol-2-yl)picolinamide (107). This compound was prepared by the general procedures B, C, and D affording 107 as a colorless powder (172 mg, 38%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.47 (s, 1H), 8.65 (d, J = 5.6 Hz, 1H), 7.99 (d, J = 1.2 Hz, 1H), 7.48– 7.63 (m, 2H), 7.31 (dd, J = 2.6, 5.5 Hz, 1H), 7.19–7.29 (m, 3H), 7.09–7.15 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 165.6, 163.4 (d, JCF = 246.2 Hz, 1C), 162.8, 154.9 (d, JCF = 11.0 Hz, 1C), 152.8, 151.4, 151.3, 137.9, 132.4 (d, JCF = 9.7 Hz, 1C), 127.7, 117.5 (d, JCF = 3.2 Hz, 1C), 116.1, 113.5 (d, JCF = 21.0 Hz, 1C), 111.0, 109.3 (d, JCF = 24.3 Hz, 1C). 19 F NMR (376 MHz, DMSO-d6) δ ppm –109.76. HRMS (m/z): [M+H] + , calcd for C15H11FN3O3, 300.0779; found, 300.0774. N-(Oxazol-2-yl)-4-(3-(trifluoromethoxy)phenoxy)picolinamide (108). This compound was prepared by the general procedures B, C, and D affording 108 as a colorless powder (148 mg, 27%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (s, 1H), 8.66 (d, J = 5.4 Hz, 1H), 7.99 (d, J = 1.00 Hz, 1H), 7.67 (t, J = 8.2 Hz, 1H), 7.56 (d, J = 2.7 Hz, 1H), 7.29–7.43 (m, 4H), 7.21 (d, J = 1.2 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 165.5, 162.8, 154.8, 152.8, 151.5, 151.4, 149.8, 137.9, 132.6, 127.6, 120.5, 120.4 (q, JCF = 257.1 Hz, 1C), 118.9, 116.1, 114.8. 19 F NMR (376 MHz, DMSO- d6) δ ppm –56.95. HRMS (m/z): [M + H] + , calcd for C16H11F3N3O4, 366.0696; found, 366.0701. N-(Oxazol-2-yl)-4-(4-(trifluoromethoxy)phenoxy)picolinamide (109). This compound was prepared by the general procedures B, C, and D affording 109 as a colorless powder (131 mg, 24%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.47 (s, 1H), 8.65 (d, J = 5.6 Hz, 1H), 7.99 (d, J = 1.00 Hz, 1H), 7.49–7.60 (m, 3H), 7.36–7.47 (m, 2H), 7.30 (dd, J = 2.7, 5.6 Hz, 1H), 7.20 (d, J = 1.00 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 164.7, 161.8, 151.8, 151.5, 150.4, 150.3, 145.1, 136.8, 126.6, 122.9, 122.3, 119.5 (q, JCF = 256.4 Hz, 1C), 114.9, 109.9. 19 F NMR (376 MHz, DMSO-d6) δ ppm – 56.09. HRMS (m/z): [M+H] + , calcd for C16H11F3N3O4, 366.0696; found, 366.0683. N-(Oxazol-2-yl)-4-(4-((trifluoromethyl)thio)phenoxy)picolina mide (110). This compound was prepared by the general procedures B, C, and D affording 110 as a colorless powder (281 mg, 49%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.49 (s, 1H), 8.68 (d, J = 5.6 Hz, 1H), 7.99 (d, J = 0.7 Hz, 1H), 7.80–7.93 (m, 2H), 7.59 (d, J = 2.7 Hz, 1H), 7.40–7.47 (m, 2H), 7.37 (dd, J = 2.6, 5.5 Hz, 1H), 7.20 (d, J = 1.0 Hz, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 164.0, 161.7, 155.6, 151.7, 150.5, 150.4, 138.3, 136.8, 129.0 (q, J CF = 307.9 Hz, 1C), 126.6, 121.4, 119.2 (q, J CF = 2.1 Hz, 1C), 115.6, 110.5. 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –42.37. HRMS (m/z): [M+H] + , calcd for C 16 H 11 F 3 N 3 O 3 S, 382.0468; found, 382.0465. 4-(4-Methoxyphenoxy)-N-(oxazol-2-yl)picolinamide (111). This compound was prepared by the general procedures B, C, and D affording 111 as a colorless powder (162 mg, 35%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.44 (s, 1H), 8.58 (d, J = 5.6 Hz, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.44 (d, J = 2.5 Hz, 1H), 7.14–7.26 (m, 4H), 6.98–7.12 (m, 2H), 3.80 (s, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 166.8, 163.1, 157.5, 153.3, 151.4, 151.2, 146.8, 137.6, 127.6, 122.7, 116.0, 115.4, 110.1, 56.0. HRMS (m/z): [M+H] + , calcd for C 16 H 14 N 3 O 4 , 312.0979; found, 312.0966. Methyl 2-(4-(3,4-difluorophenoxy)picolinamido)benzo[d]oxazole-5-car boxylate (114). This compound was prepared by the general procedures B, C, and D affording 114 as a white powder (2.08 g, 65%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.17 (br s, 1H), 8.65 (d, J = 5.6 Hz, 1H), 8.15 (d, J = 1.5 Hz, 1H), 7.87–8.00 (m, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.52–7.70 (m, 3H), 7.28 (dd, J = 2.6, 5.5 Hz, 1H), 7.14–7.24 (m, 1H), 3.89 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 165.3, 164.8, 161.3, 155.3, 150.4, 150.3, 150.1, 149.4 (dd, JCF = 241.6, 12.2 Hz, 1C), 148.7 (dd, JCF = 8.9, 2.7 Hz, 1C), 146.9 (dd, JCF = 236.7, 13.2 Hz, 1C), 140.4, 125.9, 125.1, 119.0, 118.2 (d, JCF = 18.8 Hz, 1C), 117.4 (dd, JCF = 6.4, 3.6 Hz, 1C), 114.9, 110.8 (d, JCF = 19.8 Hz, 1C), 110.2, 110.0, 51.8. 19 F NMR (376 MHz, DMSO-d6) δ ppm –134.09 (d, J = 22.7 Hz, 1F), –141.33 (d, J = 22.8 Hz, 1F). HRMS (m/z): [M+H] + , calcd for C21H14F2N3O5, 426.0896; found, 426.0902. 2-(4-(3,4-Difluorophenoxy)picolinamido)benzo[d]oxazole-5-car boxylic acid (115). This compound was prepared starting from 114, following the general procedure E affording 115 as an off- white-colored powder (780 mg, 81%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br s, 1H), 12.14 (br s, 1H), 8.68 (d, J = 5.6 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.96 (dd, J = 1.7, 8.3 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.54–7.70 (m, 3H), 7.32 (dd, J = 2.5, 5.6 Hz, 1H), 7.13–7.26 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 13 C NMR (101 MHz, DMSO) δ 166.4, 164.8, 161.4, 155.1, 150.4, 150.1, 149.3 (dd, JCF = 248.4, 14.0 Hz, 1C), 148.7 (dd, JCF = 8.9, 2.8 Hz, 1C), 146.9 (dd, JCF = 244.0, 12.4 Hz, 1C), 140.1, 127.1, 125.3, 119.1, 118.2 (d, JCF = 18.8 Hz, 1C), 117.4 (dd, JCF = 6.6, 3.6 Hz, 1C), 114.9, 110.8 (d, JCF = 19.7 Hz, 1C), 110.2, 109.7. 19 F NMR (376 MHz, DMSO-d6) δ ppm –134.08 (d, J = 22.8 Hz, 1F), –141.31 (d, J = 22.8 Hz, 1F). HRMS (m/z): [M + H] + , calcd for C 20 H 12 F 2 N 3 O 5 , 412.0740; found, 412.0726. Sodium 2-(4-(3,4-difluorophenoxy)picolinamido)benzo[d]oxazole-5-car boxylate (116). This compound was prepared starting from 115, following the general procedure F affording 116 as an off-white-colored powder (228 mg, 91%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (d, J = 5.4 Hz, 1H), 8.15 (s, 1H), 7.75 (d, J = 2.7 Hz, 1H), 7.66–7.73 (m, 1H), 7.56–7.65 (m, 1H), 7.49–7.56 (m, 1H), 7.11–7.17 (m, 2H), 7.07 (dd, J = 2.7, 5.6 Hz, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 171.6, 167.4, 166.9, 164.1, 156.1, 150.2, 149.30, 149.27 (dd, J CF = 248.2, 13.9 Hz, 1C), 149.1 (dd, J CF = 8.8, 2.7 Hz, 1C), 146.7 (dd, J CF = 243.5, 12.3 Hz, 1C), 142.2, 127.2, 123.3, 118.1 (d, J CF = 18.8 Hz, 1C), 117.7, 117.3 (dd, J CF = 6.4, 3.3 Hz, 1C), 113.2, 110.7 (d, J CF = 19.5 Hz, 1C), 110.2, 107.7. 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –136.57 (d, J = 20.6 Hz, 1F), –144.06 (d, J = 20.6 Hz, 1F). HRMS (m/z): [M+H] + , calcd for C 20 H 11 F 2 N 3 NaO 5 , 434.0559; found, 434.0561. Hept-6-yn-1-yl 2-(4-(3,4-difluorophenoxy)picolinamido)benzo[d]oxazole-5-car boxylate (117). Dicyclohexylcarbodiimide (55 mg, 0.3 mmol) was added to a solution of 115 (100 mg, 0.2 mmol) and 4-dimethylaminopyridine (33 mg, 0.3 mmol) in dry DCM (5 mL) in an oven-dried flask, chilled to ice–water temperature, under an N 2 atmosphere. After 5 min, 6-heptyn-1-ol (27 mg, 0.2 mmol) was added via a syringe. The solution was stirred and allowed to warm to room temperature overnight. The reaction mixture was concentrated under reduced pressure. EtOAc (10 mL) was added. The solution was washed with water (2 × 10 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and evaporated under reduced pressure. The crude material was purified by silica chromatography using gradient elution from 9:1 hexanes/EtOAc to EtOAc, affording 117 as a colorless powder (81 mg, 67%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.15 (br s, 1H), 8.67 (d, J = 5.6 Hz, 1H), 8.18 (d, J = 1.7 Hz, 1H), 7.97 (dd, J = 1.7, 8.6 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.56– 7.68 (m, 3H), 7.32 (dd, J = 2.7, 5.6 Hz, 1H), 7.14–7.24 (m, 1H), 4.30 (t, J = 6.5 Hz, 2H), 2.76 (t, J = 2.7 Hz, 1H), 2.15–2.24 (m, 2H), 1.69–1.80 (m, 2H), 1.47–1.56 (m, 4H). 13 C NMR (101 MHz, DMSO- d6) δ ppm 165.9, 162.4, 156.3, 151.5, 151.4, 151.1, 150.4 (dd, JCF = 248.3, 14.1 Hz, 1C), 149.7 (dd, JCF = 8.9, 2.9 Hz, 1C), 148.0 (dd, JCF = 244.1, 12.4 Hz, 1C), 141.4, 127.2, 126.1, 120.0, 119.3 (d, JCF = 18.7 Hz, 1C), 118.5 (dd, JCF = 6.6, 3.4 Hz, 1C), 116.0, 111.9 (d, JCF = 19.7 Hz, 1C), 111.2, 111.0, 84.9, 71.7, 65.2, 28.1, 28.0, 25.1, 18.1. 19 F NMR (376 MHz, DMSO-d6) δ ppm –134.08 (d, J = 22.7 Hz, 1F), –141.31 (d, J = 22.9 Hz, 1F). HRMS (m/z): [M+H] + , calcd for C27H 2 2F2N3O5, 506.1522; found, 506.1515. 2-(4-(4-(Trifluoromethoxy)phenyl)picolinamido)benzo[d]oxazol e-6-carboxylic acid (118). This compound was prepared by the general procedures A, C, D, and E affording 118 as a colorless powder (180 mg, 73%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br s, 1H), 12.18 (br s, 1H), 8.86 (d, J = 5.4 Hz, 1H), 8.41–8.46 (m, 1H), 8.18 (d, J = 1.7 Hz, 1H), 8.11 (dd, J = 2.0, 5.1 Hz, 1H), 8.04–8.09 (m, 2H), 7.97 (dd, J = 1.8, 8.4 Hz, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 8.8 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 167.5, 162.8, 156.3, 151.2, 150.1, 149.9, 149.7, 148.1, 141.3, 136.0, 129.8, 128.1, 126.3, 125.7, 122.2, 120.9, 120.5 (q, JCF = 256.9 Hz, 1C), 120.1, 110.7. 19 F NMR (376 MHz, DMSO-d6) δ ppm –56.69. HRMS (m/z): [M+H] + , calcd for C21H13F3N3O5, 444.0802; found, 444.0791. 2-(4-(3-(Trifluoromethoxy)phenyl)picolinamido)benzo[d]oxazol e-6-carboxylic acid (119). This compound was prepared by the general procedures A, C, D, and E affording 119 as a colorless powder (198 mg, 81%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 13.11 (br s, 1H), 12.19 (br s, 1H), 8.87 (d, J = 5.1 Hz, 1H), 8.46 (s, 1H), 8.18 (d, J = 1.7 Hz, 1H), 8.08–8.16 (m, 1H), 7.91–8.04 (m, 3H), 7.80 (d, J = 8.6 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.49–7.62 (m, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 166.4, 161.8, 155.3, 150.1, 147.1, 148.8, 148.52, 148.51, 146.8, 140.3, 138.1, 130.8, 127.1, 125.9, 125.2, 124.8, 121.6, 120.1, 119.51 (q, J CF = 256.7 Hz, 1C), 119.46, 119.1, 109.7. 19 F NMR (376 MHz, DMSO-d 6 ) δ ppm –56.68. HRMS (m/z): [M+H] + , calcd for C 21 H 13 F 3 N 3 O 5 , 444.0802; found, 444.0790. Example 4. General Biological Methods for SAR of the Picolinamide Antibacterials. Screening for Pan-Assay-Interference Structures (PAINS). Active compounds were checked for pan assay interference structures (PAINS) using the PAINS remover Antibiotics. VAN and MTZ were purchased from Sigma-Aldrich (St. Louis, MO); FDX was purchased from BOC Sciences (Shirley, NY). Bacterial Strains. C. difficile strains used in the study were obtained from Biodefense and Emerging Infections Research Resources Repository (BEI Resources, Manassas, VA) and from American Type Culture Collection (ATCC, Manassas, VA). Seven resistant clinical isolates of C. difficile were obtained from Cleveland VA Medical Center. Gut bacteria strains were obtained from BEI. MRSA strains (NRS70 and NRS119) were obtained from the Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA). ATCC 29213 and E. faecium NCTC7171(ATCC 19434) were purchased from ATCC (ATCC; Manassas, VA). All the strains were cultured and stored according to the supplier instructions. Minimum-inhibitory Concentration Determination. MICs for C. difficile strains and other gut bacteria were determined with the broth microdilution method as previously described (J. Antimicrob. Chemother.2013, 68, 515). ESKAPE panel and MRSA MICs were determined as described in the Clinical & Laboratory Standards Institute guidelines. Table 10. Activity of Picolinamide Analogs against MSSA (ATCC 29213) and E. faecium (NCTC 7171). XTT assay. XTT assays were performed with HeLa cells (ATCC CCL-2) in triplicate, as previously described (Lancet 2008, 371, 1486). IC50 values were determined by nonlinear regression using GraphPad Prism 5 (San Diego, CA). Pharmacokinetics (PK) Studies. Compounds 4, 87, 107, and 108 were dissolved in 10% DMSO, 25% propylene glycol, 15% Tween 80 and 50% water at concentrations of 5 mg/mL or 10 mg/mL. Compound 116 was dissolved in 5% DMSO, 95% water with 96 mg/mL of sodium bicarbonate. Mice (n = 2 per time point) were given a single 100 μL oral gavage of the test compound (equivalent to either 10 mg/kg and/or 20 mg/kg), and terminal blood was collected in heparinized syringes by cardiac puncture at 30 min, 1 h, 2 h, 4 h, and 8 h. An average of 250 mg of feces were collected after 8 h from two mice housed in metabolism cages in each group for further analysis. Blood was centrifuged at 1000g for 2 min at 4 °C to obtain plasma. Plasma and fecal samples were stored at -80 °C until analysis. A 45-µL aliquot of plasma was mixed with 5 µL of 50% acetonitrile/50% water and 100 µL of 20 µM solution of internal standard in acetonitrile. The precipitated protein was centrifuged at 21000g for 15 min at 4 °C. The supernatant was analyzed on a Waters Acquity UPLC (Waters Corporation, Milford, MA) with a triple quadrupole detector. Feces were homogenized in 1500 µL of 50% acetonitrile/50% water and centrifuged at 21000g for 5 min. A 72-µL aliquot of the fecal supernatant was mixed with 8 µL of 50% acetonitrile/50% water and 40 µL of 50 µM solution of internal standard in 0.5% formic acid/99.5% acetonitrile. Concentrations in plasma and feces were determined from calibration curves in control plasma and feces relative to internal standard. The chromatographic conditions consisted of an Acquity UPLC YMC – Triart C18 2.0 mm x 100 mm column eluted with 0.5 mL/min of 30% water/70% acetonitrile for 5 min. Mass spectrometry was performed in positive mode electrospray ionization. The capillary, cone, extractor, and RF lens voltages were 2.8 kV, 40V, 1 V, and 0.1 V, respectively. The desolvation and cone gas (nitrogen) flow rates were 650 L/h and 50 L/h, respectively. The source and desolvation temperatures were 150 °C and 350 °C, respectively. The multiple-reaction monitoring transitions used for each compound were: 333.40 → 223.10 for 4, 333.70 → 221.60 for 87, 300 → 188.10 for 107, 365.90 → 254.10 for 108, 411.70 → 205.90 for 116, and 294.80 → 133.50 for the internal standard. Animals. Female CD-1 mice (7−8 weeks old, 24−31 g body weight, Jackson Laboratories, Bar Harbor, ME) were used for the PK studies (. Mice were housed in sterile polycarbonate shoeboxes containing 1 inch of corncob (The Andersons Ind., Maumee, OH) and Alpha-Dri (Shepherd Specialty Papers, Inc., Richland, MI) bedding under 72 °F with a 12 h light/dark cycle. Mice were given a Teklad 2918 irradiated extruded rodent diet (Envigo, Indianapolis, IN) and water ad libitum. All procedures were conducted in accordance with and approved by the University of Notre Dame Institutional Animal Care and Use Committee (IACUC). Example 5. Pharmaceutical Dosage Forms. The following formulations illustrate representative pharmaceutical dosage forms that may be used for the therapeutic or prophylactic administration of a compound of a formula described herein, a compound specifically disclosed herein, or a pharmaceutically acceptable salt or solvate thereof (hereinafter referred to as 'Compound X'): (i) Tablet 1 mg/tablet 'Compound X' 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesium stearate 3.0 300.0 (ii) Tablet 2 mg/tablet 'Compound X' 20.0 Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg/capsule 'Compound X' 10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0 These formulations may be prepared by conventional procedures well known in the pharmaceutical art. It will be appreciated that the above pharmaceutical compositions may be varied according to well-known pharmaceutical techniques to accommodate differing amounts and types of active ingredient 'Compound X'. Aerosol formulation (vi) may be used in conjunction with a standard, metered dose aerosol dispenser. Additionally, the specific ingredients and proportions are for illustrative purposes. Ingredients may be exchanged for suitable equivalents and proportions may be varied, according to the desired properties of the dosage form of interest. While specific embodiments have been described above with reference to the disclosed embodiments and examples, such embodiments are only illustrative and do not limit the scope of the invention. Changes and modifications can be made in accordance with ordinary skill in the art without departing from the invention in its broader aspects as defined in the following claims. All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. No limitations inconsistent with this disclosure are to be understood therefrom. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.