ARYL fluorosulfate-based inhibitors as novel antitubercular agents

Abstract

The disclosure provides the identification and development of a first-in-class, small-molecule inhibitor (Compound 95) of Polyketide synthase 13 (Pks13), a critical node in cell wall biosynthesis for Mycobacterium tuberculosis (Mtb). Cell wall inhibitors are a critical component of TB treatment. Uniquely, the Compound 95 series has been shown to form a covalent adduct with serine residue 801 in the acyltransferase (AT) domain of Pks13. The inhibition of the Pks13 AT domain ultimately leads to disruption of mycolic acid synthesis, which is an essential component of the mycobacterial cell wall. While Pks13 is recognized as a high-value drug target, there are no Pks13 inhibitors in development and Compound 95 represents a new class of inhibitors for TB treatment.

Description

TSRI 2226.1PC ARYL FLUOROSULFATE-BASED INHIBITORS AS NOVEL ANTITUBERCULAR AGENTS CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. provisional patent application No.63 / 594,069 which was filed on October 30, 2023, and which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION

[0002] The disclosure provides the identification and development of a first-in-class, small- molecule inhibitor (Compound 95) of Polyketide synthase 13 (Pks13), a critical node in cell wall biosynthesis for Mycobacterium tuberculosis (Mtb). Cell wall inhibitors are a critical component of TB treatment. Uniquely, the Compound 95 series has been shown to form a covalent adduct with serine residue 801 in the acyltransferase (AT) domain of Pks13. The inhibition of the Pks13 AT domain ultimately leads to disruption of mycolic acid synthesis, which is an essential component of the mycobacterial cell wall. While Pks13 is recognized as a high-value drug target, there are no Pks13 inhibitors in development and Compound 95 represents a new class of inhibitors for TB treatment. BACKGROUND OF THE INVENTION

[0003] Before the COVID-19 global pandemic, tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), was the leading cause of death due to a single infectious agent.1People with TB need take multiple drug combo for standard 6 month, or even up to 2 years or longer for multi- and extensive-drug-resistant TB (MDR-TB / XDR-TB). The rising emergence of MDR- TB / XDR-TB is one of the most relevant public health problems worldwide.1,2For these reasons, there is an unmet medical need to deliver new drug candidates to expand the TB drug development pipeline and to shorten the treatment period. Click chemistry of sulfur (VI) fluorideTSRI 2226.1PC exchange (SuFEx) groups, developed by Sharpless and coworkers,3has been successfully introduced into many bioactive molecules in chemical biology and drug discovery, especially as a covalently binding warhead.4-8However, the application of SuFEx as anti-TB agents has not been reported. BRIEF DESCRIPTION OF THE FIGURES

[0004] Figure 1. Hit to early lead 3a from screening hit 1.

[0005] Figure 2. Chemical structure of aryl fluorosulfate 3a and its derivatization for the SAR study.

[0006] Figure 3. SuFEx is essential for anti-TB activity.

[0007] Figure 4. Dot plot representing the Log10CFU ± SEM in lungs of M. tuberculosis Erdman pFCA LuxAB infected mice. SUMMARY OF THE INVENTION

[0008] In collaboration with the Sharpless group, it was discovered that aryl fluorosulfate 1 (Figure 1) with a diazo linker has good anti-TB activity with an IC50= 1.1 µM from screening of a small library of 406 SuFEx compounds against Mtb in the attenuated lab H37Ra strain.

[0009] To address the photolabile issue of the diazo linker,9a formal hit assessment was carried out, exploring multiple linkers including amide, 1,2,3-triazole, olefin, and ether. While most of these linkers were much less active or inactive than compound 1, phenyl ether compound 2 exhibited comparable activity (H37Ra IC50= 1.3 µM). Further hit-to-lead optimization of compound 2 was then performed, focusing on replacement of the metabolically labile amide tail and generated the N1-1,2,4-triazole-containing early lead 3a, which showed only slightly decreased activity (H37Ra IC50= 1.5 µM) (Figure 1). Encouraged by these results, lead optimization of compound 1c was conducted via detailed structure−activity relationship (SAR) studies, as described herein. The SAR campaign led to Compound 95 with good anti-TB activity (H37Rv MIC = 0.06 µM) and favorable pharmacokinetic (PK) properties for further preclinical development.TSRI 2226.1PC

[0010] The bacterial cell wall is essential for bacterial growth and virulence but is absent in humans. It is an essential protective barrier against various cellular stresses and important for virulence in the host, and it has been the focus of countless efforts to identify small-molecule inhibitors of enzymes involved in its biogenesis. Compounds which inhibit essential components of the cell wall rapidly cause cell death; inhibitors to these pathways are in clinical use such as penicillin antibiotics, isoniazid and ethambutol antitubercular drug. Our SuFEx compounds, including compound 95, target cell wall biosynthesis, and therefore in addition to Mycobacterium tuberculosis, they should be effective against other bacterial infectious diseases.

[0011] The application provides a compound having the Formula (I) R1mQ is O, NH, CH2, or absent; ---- represents a single or double bond; X1is O, CH, CH2, NH, N(C1-C6) alkyl, C(=O), N, NHC(=O), or S(=O)2; X2is CH,CH2, C(=O), N, O, -CH2S(=O)2-, or -CH2C(=O)NH-; wherein if X1is O, then X2is CH2, and ---- represents a single bond; if X1is CH, then X2is CH, and ---- represents a double bond; if X1is N, then X2is N, and ---- represents a double bond; if X1is NH or N(C1-C6) alkyl, then X2is C(=O), and ---- represents a single bond; if X1is C(=O), then X2is NH, and ---- represents a single bond; if X1is NHC(=O), then X2is - CH2S(=O)2-, and ---- represents a single bond; if X1is S(=O)2, then X2is -CH2C(=O)NH-, and -- -- represents a single bond; if X1is CH2, then X2is O, and ---- represents a single bond; if X2is O, then X1is CH2, and ---- represents a single bond; and if Q is absent, then X1is O, X2is CH2, and ---- represents a single bond;TSRI 2226.1PC Y is absent, -C(=O)-, -C(=O)N(Y’)-, -(CH2)rC(=O)O-, -S(=O)2-, -C(=O)NHS(=O)2-, - NHC(=O)O-, -NHC(=O)NH-, -NHC(=O)-, -NH-, -NHS(=O)2-, -OCH2C(=O)NH-; or - S(=O)2NH-; Y’ is H or (C1-C6) alkyl; each Z is independently CH or N; A is H, halo, CN, NO2, (C1-C20) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, hetero (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C7) cycloalkyl, 3- to 7-membered heterocycloalkyl, (C6-C10) aryl, (C1-C6) alkyl (C6-C10) aryl, 5- to 10-membered heteroaryl, or (C1-C6) alkyl 5- to 10-membered heteroaryl, optionally substituted with one or more A’; each A’ is independently OH, halo, CN, oxo, -C(=O)(C1-C6) alkyl, -C(=O)OH, (C1-C6) alkyl, (C1-C6) alkoxy, -S(=O)2(C1-C6) alkyl, -NHS(=O)2(C1-C6) alkyl, -N((C1-C6) alkyl)S(=O)2(C1-C6) alkyl, halo (C1-C6) alkyl, -NH2, -NH(C1-C6) alkyl, -N((C1-C6) alkyl)2,- C(=O)O(C1-C6) alkyl, -C(=O)NH2, -C(=O)NH(C1-C6) alkyl, -C(=O)N((C1-C6) alkyl)2, - NHC(=O)(C1-C6) alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, hydroxy (C1-C6) alkyl, (C1-C6) heteroalkyl, (C6-C10) aryl, (C1-C6) alkyl (C6-C10) aryl, or 5- to 10- membered heteroaryl, wherein 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, (C6-C10) aryl, and 5- to 10-membered heteroaryl are each optionally substituted with one or more A’’; each A’’ is independently OH, halo, (C1-C6) alkyl, hetero (C1-C6) alkyl, or halo (C1-C6) alkyl, each R1is independently halo, OH, CN, (C1-C6) alkyl, or halo (C1-C6) alkyl; each R2is independently halo, OH, NH2, CN, -C(=O)OH, (C1-C6) alkyl, halo (C1-C6) alkyl, or hetero (C1-C6) alkyl; or A and R2together form a fused (C6-C10) aryl; or two R2together form a fused (C6-C10) aryl or 3- to 7-membered heterocycloalkyl, optionally substituted with one or more OH, halo, NH2, NHC(=O)O(C1-C6) alkyl, CN, oxo, (C1- C6) alkyl, hetero (C1-C6) alkyl, hydroxy (C1-C6) alkyl, halo (C1-C6) alkyl, or (C3-C7) cycloalkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; r is 0, 1, or 2;TSRI 2226.1PC with the proviso that Formula (I) is not 1) 4-(benzyloxy)phenyl sulfurofluoridate, 2) (E)-4- (phenyldiazenyl)phenyl sulfurofluoridate; 3) 3-(phenylcarbamoyl)phenyl sulfurofluoridate; 4) (E)-4-(3,5-dihydroxystyryl)phenyl sulfurofluoridate; 5) (E)-4-(3,5-dimethoxystyryl)phenyl sulfurofluoridate; 6) 4-(p-tolylcarbamoyl)phenyl sulfurofluoridate; 7) 4-((2- iodobenzyl)oxy)phenyl sulfurofluoridate; 8) (E)-3-hydroxy-5-(4-hydroxystyryl)phenyl sulfurofluoridate; 9) (Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)phenyl sulfurofluoridate; 10) ((E)- 2-((4-((fluorosulfonyl)oxy)phenyl)diazenyl)benzoic acid); 11) (E)-4-((3,5-dichloro-4- hydroxyphenyl)diazenyl)phenyl sulfurofluoridate; 12) (E)-3-((3,5-dichloro-4- hydroxyphenyl)diazenyl)phenyl sulfurofluoridate; 13) (E)-4-((4-hydroxy-3,5- dimethylphenyl)diazenyl)phenyl sulfurofluoridate; 14) (E)-3-((4-hydroxy-3,5- dimethylphenyl)diazenyl)phenyl sulfurofluoridate; 15) (E)-4-((4-hydroxyphenyl)diazenyl)phenyl sulfurofluoridate; 16) (E)-4-((4-aminophenyl)diazenyl)phenyl sulfurofluoridate; 17) (E)-4-((4- amino-3-chlorophenyl)diazenyl)-2-chlorophenyl sulfurofluoridate; 18) (E)-4-((4- chlorophenyl)diazenyl)phenyl sulfurofluoridate; 19) (E)-4-((4-bromophenyl)diazenyl)phenyl sulfurofluoridate; 20) (E)-4-(p-tolyldiazenyl)phenyl sulfurofluoridate; 21) (E)-2-chloro-4-((3- chlorophenyl)diazenyl)phenyl sulfurofluoridate; 22) 2-[4-[(fluorosulfonyl)oxy]phenyl]-5,6,7- trimethoxy-4H-1-benzopyran-4-one; 23) N-[4-[(fluorosulfonyl)oxy]phenyl]-3,4-dihydro-2- methyl-3-oxo-2H-1,4-benzothiazine-6-carboxamide; 24) N-[3-[(fluorosulfonyl)oxy]phenyl]-3,4- dihydro-2-methyl-3-oxo-2H-1,4-benzothiazine-6-carboxamide; 25) 4-[[4- [(fluorosulfonyl)oxy]phenyl]methoxy]-1,3-Benzenedicarboxaldehyde; 26) 4-[[4- [(fluorosulfonyl)oxy]phenyl]methoxy]-1,3-Benzenedimethanol; 27) N-[3-[[3- [(fluorosulfonyl)oxy]phenyl]methoxy]phenyl]-3,4-dihydro-2-methyl-3-oxo2H-1,4- benzothiazine-6-carboxamide; 28) N-[3-[[4-[(fluorosulfonyl)oxy]phenyl]methoxy]phenyl]-3,4- dihydro-2-methyl-3-oxo-2H-1,4-Benzothiazine-6-carboxamide; 29) 4-((3- aminophenoxy)methyl)phenyl sulfurofluoridate; 30) 3-((3-aminophenoxy)methyl)phenyl sulfurofluoridate; 31) methyl 4-((4-((fluorosulfonyl)oxy)benzyl)oxy)-3,5- bis(hydroxymethyl)benzoate; 32) 4-((2,4,6-tris(hydroxymethyl)phenoxy)methyl)phenyl sulfurofluoridate; 33) 4-((2,4-bis(bromomethyl)phenoxy)methyl)phenyl sulfurofluoridate; 34) 4- (((2-amino-4-((tert-butoxycarbonyl)amino)quinazolin-5-yl)oxy)methyl)phenyl sulfurofluoridate; or 35) 4-(((2,4-diaminoquinazolin-5-yl)oxy)methyl)phenyl sulfurofluoridate; 36) 3-chloro-4-TSRI 2226.1PC (pyridin-2-ylmethoxy)benzenesulfonyl fluoride; 37) 4-(benzyloxy)benzenesulfonyl fluoride; 38) 3-chloro-4-((3-fluorobenzyl)oxy)benzenesulfonyl fluoride; or 39) 4-((4- nitrobenzyl)oxy)benzenesulfonyl fluoride; including any enantiomers, scalemic or racemic mixtures, or pharmaceutically acceptable salts thereof.

[0012] The application provides the above compound, wherein the compound has any one of Formulae (Ia)-(Id): O FR1O m SR2F R1m Y A Y A .

[0013] The application provides a compound having the structure of Compound 95: O F F S NOmixtures, or pharmaceutically acceptable salts thereof.TSRI 2226.1PC

[0014] The application provides a compound having the structure of Compound 94: O F F S O or racemic mixtures, or pharmaceutically acceptable salts

[0015] The application further provides a composition comprising any one of the above compounds, further comprising one or more therapeutic compounds or compositions used for the treatment of a bacterial infection.

[0016] The application further provides a composition comprising any one of the above compounds, further comprising one or more therapeutic compounds or compositions used for the treatment of a TB infection.

[0017] The application further provides the above composition, wherein the one or more therapeutic compounds or compositions is selected from bedaquiline, pretomanid, linezolid, isoniazid, rifampin, rifabutin, rifapentine, pyrazinamide, ethambutol, ethionamide, moxifloxacin, tedizolid, radezolid, sutezolid, posizolid clofazimine, gatifloxacin, kanamycin, nitroimidazo- oxazine, delamanid, OPC-167832, streptomycin, prednisolone, an oxazolidinone, a fluoroquinolone, a corticosteroid, EMB analogue SQ109, a benzothiazinone, a dinitrobenzamide, and an antiviral agent including an antiretroviral agent.

[0018] The application further provides a method of covalently targeting Mycobacterium tuberculosis (Mtb) acyltransferase domain of Polyketide synthase 13, comprising treating intracellular and / or extracellular Mtb with any one of the above compounds or any one of the above compositions.

[0019] The application further provides a method of preventing, ameliorating, or treating a TB infection, comprising administering to a subject in need thereof a therapeutically effective amount of any one of the above compounds or any one of the above compositions. DETAILED DESCRIPTION OF THE INVENTIONTSRI 2226.1PC

[0020] The SAR was explored of the initial lead 3a in three regions (Figure 2). The general synthesis of aryl fluorosulfates started from a conversion of commercially available (4- bromophenyl)methanol derivatives (4) to 1-bromo-4-(chloromethyl)benzenes (5), followed by phenyl ether formation with methoxymethyl (MOM)-protected hydroquinones (6). After Buchwald amination with the corresponding triazoles (8), MOM was removed under an acidic condition. The resulting phenol (10) was converted to the desired aryl fluorosulfate 3a and their analogs by sulfuryl fluoride (SO2F2) gas or a shelf-stable SuFEx reagent, 4- (acetylamino)phenyl]imidodisulfuryl difluoride (AISF),10under a basic condition. a HO Cl b M A c B Br OMO O B BrBBr N N CK2CO3, DMF, rt, 12 h; c) 8, Pd2(dba)3, Me4-tBu-X-Phos, Cs2CO3, toluene, 100oC, 5h; d) FA, DCM, rt, 2h; e) SO2F2, TEA, DCM, rt, 30 min; or AISF, DBU, THF, 0oC, 30 min

[0021] A focused library of western phenyl (A) and middle phenyl (B) modified analogs was synthesized and evaluated for antitubercular activity by H37Rv MIC or CDC1551 IC90. The cytotoxicity against both HEK293T and HepG2 mammalian cells was also examined. Our early lead 3a moderated anti-TB activity with H37Rv MIC = 2.84 µM and CDC1551 IC90= 4.71 µM. The substitution SAR on the western phenyl ring revealed that a methoxy (OMe) group at the ortho position to the SuFEx group is not tolerated: compounds 3b was not active against Mtb. Replacement with a chloro group gave compound 3c with similar activity to 3a against CDC1551; however, 3c exhibited cytotoxicity against HEK293T and HepG2 cell lines. Next, attention was turned to middle phenyl modification. Testing began with mono-fluorinated and di- fluorinated analogs (3d-3i) against Mtb. In general, fluorination at the meta position to triazole increased potency: both 3d and 3i showed 4-fold increases in H37Rv MIC. While difluorinated analog 3i showed moderate cytotoxicity against HepG2 (IC50= 5.8 µM), it still had goodTSRI 2226.1PC selectivity index (SI = 9.6). Changing one fluoro to a more electron-deficient nitrile group gave compound 3j with much decreased potency (MIC = 5.0 µM)TSRI 2226.1PC Table 1. In vitro anti-TB inhibitory activity and cytotoxicity of aryl fluorosulfate 3a-3j N OFO2SOA BNNAnti-TB activity CytotoxicityTSRI 2226.1PC F h 1.25 ND 21.6 29.5

[0022] In the context of difluoro-substituted phenyl, further examined was the activity of isomeric triazoles and other 5-membered heterocycles. Analogs 3k-3m were made through a general route (Scheme 1). Compounds 19a-19j were synthesized using a modified procedure (Scheme 2) or through procedure showed in supporting document. Using a similar procedure as in Scheme 1, phenol ether 14 was obtained, then phenyl bromide was transformed into phenyl boronic ester 15. The following Suzuki coupling was used to install 5-membered heterocycles as exemplified by a trimethylsilylethoxymethyl (SEM)-protected triazole 16. The subsequent SuFEx installation following SEM removal gave desired fluorosulfates 19a and related analogs.TSRI 2226.1PC F F FHOa BrClBrbOHOBrK2CO3, DMF, rt, 5 h; c) Pin2B2, Pd(dppf)Cl2, KOAc, dioxane, 100oC, 2h; d) SEMCL, TEA, DCM, rt, 12h; e) 16, Pd(dppf)Cl2, K3PO4, dioxane / H2O, 80oC, 2h; f) AISF, DBU, THF, rt, 30 min; g) TFA, DCM, rt, 1h

[0023] Among isomeric triazoles, N2-1,2,3 triazole analog 3k showed 2-fold decreased activity, and N1-1,2,3 triaozle 3l and N1-1,3,4-triazole 3m had 3-fold increases in MIC.4H- 1,2,4-triazole analog 19a had an MIC <1.0 µM. Also synthesized were other 5-membered heterocyclic analogs including pyrazole 19c, imidazole 19d and 19f, and tetrazole 19g and 19h, and evaluated them for anti-TB activity. Some corresponding nitrogen-substituted methyl analogs, including 19b and 19e were also prepared. In general, these compounds had low activity compared to triazole analogs. In addition, oxadiazole 19i and isoxazole 19j were made and they exhibited MIC <1 µM against Mtb. All analogs had good cytotoxicity profiles in HEK293T and HepG2 cell lines, except one imidazole analog 19f that had a half maximal cellular cytotoxicity concentration 50 (CC50) < 10 µM.TSRI 2226.1PC Table 2. In vitro anti-TB inhibitory activity and cytotoxicity of aryl fluorosulfates 3j, 3i-3o, and 19a-19m F O CTB activity Cytotoxicity rin CTSRI 2226.1PC 19d H N 0.3 >40 30.14 N

[0024] Further examined was the substitution effect with the N1-1,2,4- triazole system. Most compounds were prepared through the general synthetic method as outlined in Scheme 1.3- Methyl-substituted analog 20a showed 2-fold increased potency, while ethyl- and isopropyl- substituted analogs 20b and 20c retained similar potency. The introduction of a more steric t- butyl (20d) resulted in 2-fold decreased activity with MIC = 1.2 µM.

[0025] Next synthesized was the 3,5-dimethyl analog disubstituted analog (20e), which had similar potency to 3-mono methyl analog 20a. Also investigated was an electronic effect by introducing electronic donating substituent methoxy (20f), and electronic withdrawing nitrile (20g). Both showed similar activity to non-substituted analog 3i. Dimethyl amine and methylTSRI 2226.1PC sulfone substituted triazole analogs 20h and 20i had slightly improved activity. The addition of COOH showed low activity with MIC = 1.25 µM (20j).

[0026] Encouraged by these results, fine tuning with steric and electronic effects was further explored. Introduction of acetamide gave compound 20k a 4-fold increased anti-TB activity with MIC = 0.17 µM. The methyl amide analog 21a had a similar potency. Further improved activity with the methyl sulfonamide-substituted analog 21b (Compound 95) was observed which had an MIC = 0.06 µM and a 47-fold improvement in anti-TB activity compared to the initial lead 3a. Compound 21b (Compound 95) showed no cytotoxicity against both HEK293T and HepG2 cell lines. Also conducted was the additional SAR around sulfonamide. The reversed sulfonamide analog 20l had much lower activity than 21b (Compound 95). The N-methyl substituted analog 21c, also had 4-fold decreased activity compared to 21b (Compound 95), suggesting the free NH is needed for high potency. Exchanging methyl for ethyl in analog 21d provided similar potency. However, isopropyl and tertbutyl sulfonamide 21e and 21f had much lower anti-TB activity, with 21f having a MIC = 2.5 µM. Compound 21f, the phenol version of compound 21b, showed no activity in H37Rv MIC (Figure 3), which confirmed that SuFEx group is essential for anti- TB activity. Table 3. In vitro anti-TB inhibitory activity and cytotoxicity of aryl fluorosulfate 3i, 20a-20l, and 21a-21f F R N2Anti-TB CytotoxicityTSRI 2226.1PC (µM)TSRI 2226.1PC 21f H NHSO2tBu 2.5 >40 >40

[0027] The synthesis of methyl sulfonamide-substituted analog 21b is shown in Scheme 3. An optimized condition of step b, Chan-Lam Coupling, was used for the reaction of 3-nitro- 1,2,4-triazole 24 with tert-butyldimethylsilyl (TBDMS) protected phenyl boronic ester 23. The following hydrogenation (step c), TBDMS removal by tetra-n-butylammonium fluoride (TBAF) (step d) and SuFEx installation with ASIF (step e) gave amino triazole 28. The reaction of 28 with methylsulfonyl chloride gave di-substituted analog 29. Subsequent treatment with TBAF provided desired sulfonamide 21b (Compound 95). OTBDMS OTBDMS OTBDMS OH OTBDMS O F: dioxane, 100oC, 2h; b) 24, Cu(OAc)2, pyridine, boric acid, CH3CN, 90oC, 4h; c) Pd / C, H2,TSRI 2226.1PC THF; d) TABF, THF,0oC - rt, 1h; e) AISF, DBU, THF, 0oC, 30 min; f) MeSO2Cl, TEA, DCM, 0oC -rt, 1h; g) TBAF, THF, 0oC, 30 min

[0028] With compound 21b (Compound 95) exhibiting good in vitro anti-TB activity and clean cytotoxicity profile, its PK properties were next analyzed.21b (Compound 95) was administered to mice using both oral (PO) and intravenous (IV) routes at 20 mg / kg and 3 mg / kg in 75% PEG / 25% D5W solution, respectively. In the PO arm, in addition to plasma sampling, also examined was compound residence in lung at 8 and 24 h post-dosing with consideration for TB treatment. Overall, compound 21b (Compound 95) showed good oral plasma exposure with excellent bioavailability (F = 99.4%; Table 4). The 20 mg / kg PO dose achieved a near 24 h coverage of plasma and lung levels above the H37Rv MIC (MIC = 0.06 µM = 28 ng / mL) (Table 4). Both mouse plasma and lung protein binding of 21b (Compound 95) were further analyzed: the unbound levels were 0.8% and 1.6%, respectively. As a result, the unbound levels of plasma and lung coverage over MIC was near 8h at 20 mg / kg PO. These PK results supported advancing compound 21b (Compound 95) into a TB efficacy model. Table 4. Mouse PO / IV PK results of compound 21b (Compound 95) F Cplasm Clung Cplasm Clung Cma T1 / TSRI 2226.1PC Table 5. In vitro activity profiling of Compound 95 Compound 95a ce e o o pou o p ec ca ouse models of TB infection confirmed that Compound 95 had remarkable activity when dosed as a monotherapy and had lung CFU reduction of 3.1- and 1.9-log units at 20 and 7 mg / kg QD, respectively, in the acute Balb / c model. Efficacy at 20 mg / kg is comparable to a known TB drug Ethambutol (EMB) at 100 mg / kg (Figure 4a). Compound 95 also promoted 1.3-log lung CFU reduction with monotherapy at 50 mg / kg BID in chronic Balb / c model, comparable to Isoniazid (INH); and when dosed with Rifampin (RIF) in chronic Balb / c model, an additive effect was observed with 2.1-log lung CFU reduction achieved (Figure 4b). The efficacy value (near ED99) in acute TB model with 7 mg / kg dosing was used to support human equivalent dose predictions, which project a very low, daily human dose of 33- 71 mg. Given the promising profile of this compound, it has been advanced into non-GLP toxicity studies with a goal to advance to continue advancement into an IND filing and first-in-human studies within the next two years.

[0030] In conclusion, a new class of arylfluorosulfate compounds was developed with good in vitro activity against Mtb. Current lead 21b (Compound 95) has 0.06 µM H37Rv MIC, clean cytotoxicity profile and good mouse in vivo exposure. These aryl fluorosulfates added a novel chemotype for future evaluation in the TB drug development pipeline.TSRI 2226.1PC References 1. WHO, Global Tuberculosis Report 2022. https: / / www.who.int / teams / globaltuberculosis- programme / tb-reports / global-tuberculosis-report-2022 Retrieved 28 April 2023 2. G. Günthe. Multidrug-resistant and extensively drug-resistant tuberculosis: a review of current concepts and future challenges. Clin. Med. J.2014;14: 279-185. https: / / doi.org / 10.7861 / clinmedicine.14-3-279 3. J. Dong, K. B. Sharpless, L. Kwisnek, J.S. Oakdale, V.V. Fokin. SuFEx-based synthesis of polysulfates. Angew. Chem. Int. Ed.2014; 53: 9466–9470. https: / / doi.org / 10.1002 / anie.201403758 4. W. Chen, J. Dong, L. Plate, D. E. Mortenson, G. J. Brighty, S. Li, Y. Liu, A. Galmozzi, P. S. Lee, J. J. Hulce, B. F. Cravatt, E. Saez, E. T. Powers, I. A. Wilson, K. B. Sharpless, J. W. Kelly. Arylfluorosulfates inactivate intracellular lipid binding protein(s) through chemoselective SuFEx reaction with a binding site Tyr residue. J. Am. Chem. Soc.2016; 138: 7353–7364. https: / / doi.org / 10.1021 / jacs.6b02960 5. O. O. Fadeyi, L. R. Hoth, C. Choi, X. Feng, A. Gopalsamy, E. C. Hett, R. E. Kyne, R. P. Robinson, L. H. Jones. Covalent enzyme inhibition through fluorosulfate modification of a noncatalytic serine residue. ACS Chem. Biol.2017; 12: 2015–2020. https: / / doi.org / 10.1021 / acschembio.7b00403 6. L. H. Jones. Emerging utility of fluorosulfate chemical probes. ACS Med. Chem. Lett. 2018; 9: 584−586. https: / / doi.org / 10.1021 / acsmedchemlett.8b00276 7. Q. Zheng, J. L. Woehl, S. Kitamura, D. Santos-Martins, C. J. Smedley, G. Li, S. Forli, J. E. Moses, D. W. Wolan, K. B. Sharpless. SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase. Proc. Natl. Acad. Sci.2019; 116: 18808-18814. https: / / doi.org / 10.1073 / pnas.1909972116 8. J. E. Bolding, P. Martín-Gago, N. Rajabi, L. F. Gamon, T. N. Hansen, C. R. O. Bartling, K. Strømgaard, M. J. Davies, C. A. Olsen. Aryl fluorosulfate based inhibitors that covalently target the SIRT5 lysine deacylase. Angew. Chem. Int. Ed.2022; 61: e202204565. https: / / doi.org / 10.1002 / anie.202204565 9. S. Patai. The chemistry of the hydrazo, azo and azoxy groups. PATAI'S Chemistry of Functional Groups. John Wiley & Son, 1997. DOI:10.1002 / 0470023503TSRI 2226.1PC 10. H. Zhou, P. Mukherjee, R. Liu, E. Evrard, D. Wang, J. M. Humphrey, T. W. Butler, L. R. Hoth, J. B. Sperry, S. K. Sakata, C. J. Hela, C. W. am Ende. Introduction of a crystalline, shelf-stable reagent for the synthesis of sulfur(VI) fluorides. Org. Lett.2018; 20, 812– 815. https: / / doi.org / 10.1021 / acs.orglett.7b03950 Embodiments

[0031] Embodiment 1. A compound having the Formula (I) R1mQ is O, NH, CH2, or absent; ---- represents a single or double bond; X1is O, CH, CH2, NH, N(C1-C6) alkyl, C(=O), N, NHC(=O), or S(=O)2; X2is CH,CH2, C(=O), N, O, -CH2S(=O)2-, or -CH2C(=O)NH-; wherein if X1is O, then X2is CH2, and ---- represents a single bond; if X1is CH, then X2is CH, and ---- represents a double bond; if X1is N, then X2is N, and ---- represents a double bond; if X1is NH or N(C1-C6) alkyl, then X2is C(=O), and ---- represents a single bond; if X1is C(=O), then X2is NH, and ---- represents a single bond; if X1is NHC(=O), then X2is - CH2S(=O)2-, and ---- represents a single bond; if X1is S(=O)2, then X2is -CH2C(=O)NH-, and -- -- represents a single bond; if X1is CH2, then X2is O, and ---- represents a single bond; if X2is O, then X1is CH2, and ---- represents a single bond; and if Q is absent, then X1is O, X2is CH2, and ---- represents a single bond;TSRI 2226.1PC Y is absent, -C(=O)-, -C(=O)N(Y’)-, -(CH2)rC(=O)O-, -S(=O)2-, -C(=O)NHS(=O)2-, - NHC(=O)O-, -NHC(=O)NH-, -NHC(=O)-, -NH-, -NHS(=O)2-, -OCH2C(=O)NH-; or - S(=O)2NH-; Y’ is H or (C1-C6) alkyl; each Z is independently CH or N; A is H, halo, CN, NO2, (C1-C20) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, hetero (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C7) cycloalkyl, 3- to 7-membered heterocycloalkyl, (C6-C10) aryl, (C1-C6) alkyl (C6-C10) aryl, 5- to 10-membered heteroaryl, or (C1-C6) alkyl 5- to 10-membered heteroaryl, optionally substituted with one or more A’; each A’ is independently OH, halo, CN, oxo, -C(=O)(C1-C6) alkyl, -C(=O)OH, (C1-C6) alkyl, (C1-C6) alkoxy, -S(=O)2(C1-C6) alkyl, -NHS(=O)2(C1-C6) alkyl, -N((C1-C6) alkyl)S(=O)2(C1-C6) alkyl, halo (C1-C6) alkyl, -NH2, -NH(C1-C6) alkyl, -N((C1-C6) alkyl)2,- C(=O)O(C1-C6) alkyl, -C(=O)NH2, -C(=O)NH(C1-C6) alkyl, -C(=O)N((C1-C6) alkyl)2, - NHC(=O)(C1-C6) alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, hydroxy (C1-C6) alkyl, (C1-C6) heteroalkyl, (C6-C10) aryl, (C1-C6) alkyl (C6-C10) aryl, or 5- to 10- membered heteroaryl, wherein 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, (C6-C10) aryl, and 5- to 10-membered heteroaryl are each optionally substituted with one or more A’’; each A’’ is independently OH, halo, (C1-C6) alkyl, hetero (C1-C6) alkyl, or halo (C1-C6) alkyl, each R1is independently halo, OH, CN, (C1-C6) alkyl, or halo (C1-C6) alkyl; each R2is independently halo, OH, NH2, CN, -C(=O)OH, (C1-C6) alkyl, halo (C1-C6) alkyl, or hetero (C1-C6) alkyl; or A and R2together form a fused (C6-C10) aryl; or two R2together form a fused (C6-C10) aryl or 3- to 7-membered heterocycloalkyl, optionally substituted with one or more OH, halo, NH2, NHC(=O)O(C1-C6) alkyl, CN, oxo, (C1-C6) alkyl, hetero (C1-C6) alkyl, hydroxy (C1-C6) alkyl, halo (C1-C6) alkyl, or (C3-C7) cycloalkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; r is 0, 1, or 2;TSRI 2226.1PC with the proviso that Formula (I) is not 1) 4-(benzyloxy)phenyl sulfurofluoridate, 2) (E)-4- (phenyldiazenyl)phenyl sulfurofluoridate; 3) 3-(phenylcarbamoyl)phenyl sulfurofluoridate; 4) (E)-4-(3,5-dihydroxystyryl)phenyl sulfurofluoridate; 5) (E)-4-(3,5-dimethoxystyryl)phenyl sulfurofluoridate; 6) 4-(p-tolylcarbamoyl)phenyl sulfurofluoridate; 7) 4-((2- iodobenzyl)oxy)phenyl sulfurofluoridate; 8) (E)-3-hydroxy-5-(4-hydroxystyryl)phenyl sulfurofluoridate; 9) (Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)phenyl sulfurofluoridate; 10) ((E)- 2-((4-((fluorosulfonyl)oxy)phenyl)diazenyl)benzoic acid); 11) (E)-4-((3,5-dichloro-4- hydroxyphenyl)diazenyl)phenyl sulfurofluoridate; 12) (E)-3-((3,5-dichloro-4- hydroxyphenyl)diazenyl)phenyl sulfurofluoridate; 13) (E)-4-((4-hydroxy-3,5- dimethylphenyl)diazenyl)phenyl sulfurofluoridate; 14) (E)-3-((4-hydroxy-3,5- dimethylphenyl)diazenyl)phenyl sulfurofluoridate; 15) (E)-4-((4-hydroxyphenyl)diazenyl)phenyl sulfurofluoridate; 16) (E)-4-((4-aminophenyl)diazenyl)phenyl sulfurofluoridate; 17) (E)-4-((4- amino-3-chlorophenyl)diazenyl)-2-chlorophenyl sulfurofluoridate; 18) (E)-4-((4- chlorophenyl)diazenyl)phenyl sulfurofluoridate; 19) (E)-4-((4-bromophenyl)diazenyl)phenyl sulfurofluoridate; 20) (E)-4-(p-tolyldiazenyl)phenyl sulfurofluoridate; 21) (E)-2-chloro-4-((3- chlorophenyl)diazenyl)phenyl sulfurofluoridate; 22) 2-[4-[(fluorosulfonyl)oxy]phenyl]-5,6,7- trimethoxy-4H-1-benzopyran-4-one; 23) N-[4-[(fluorosulfonyl)oxy]phenyl]-3,4-dihydro-2- methyl-3-oxo-2H-1,4-benzothiazine-6-carboxamide; 24) N-[3-[(fluorosulfonyl)oxy]phenyl]-3,4- dihydro-2-methyl-3-oxo-2H-1,4-benzothiazine-6-carboxamide; 25) 4-[[4- [(fluorosulfonyl)oxy]phenyl]methoxy]-1,3-Benzenedicarboxaldehyde; 26) 4-[[4- [(fluorosulfonyl)oxy]phenyl]methoxy]-1,3-Benzenedimethanol; 27) N-[3-[[3- [(fluorosulfonyl)oxy]phenyl]methoxy]phenyl]-3,4-dihydro-2-methyl-3-oxo2H-1,4- benzothiazine-6-carboxamide; 28) N-[3-[[4-[(fluorosulfonyl)oxy]phenyl]methoxy]phenyl]-3,4- dihydro-2-methyl-3-oxo-2H-1,4-Benzothiazine-6-carboxamide; 29) 4-((3- aminophenoxy)methyl)phenyl sulfurofluoridate; 30) 3-((3-aminophenoxy)methyl)phenyl sulfurofluoridate; 31) methyl 4-((4-((fluorosulfonyl)oxy)benzyl)oxy)-3,5- bis(hydroxymethyl)benzoate; 32) 4-((2,4,6-tris(hydroxymethyl)phenoxy)methyl)phenyl sulfurofluoridate; 33) 4-((2,4-bis(bromomethyl)phenoxy)methyl)phenyl sulfurofluoridate; 34) 4- (((2-amino-4-((tert-butoxycarbonyl)amino)quinazolin-5-yl)oxy)methyl)phenyl sulfurofluoridate; or 35) 4-(((2,4-diaminoquinazolin-5-yl)oxy)methyl)phenyl sulfurofluoridate; 36) 3-chloro-4-TSRI 2226.1PC (pyridin-2-ylmethoxy)benzenesulfonyl fluoride; 37) 4-(benzyloxy)benzenesulfonyl fluoride; 38) 3-chloro-4-((3-fluorobenzyl)oxy)benzenesulfonyl fluoride; or 39) 4-((4- nitrobenzyl)oxy)benzenesulfonyl fluoride; including any enantiomers, scalemic or racemic mixtures, or pharmaceutically acceptable salts thereof.

[0032] Embodiment 2. The compound of Embodiment 1, wherein the compound has any one of Formulae (Ia)-(Id): O FR1O1SmR2F R mY A Y A .

[0033] Embodiment 3. A compound of Formula (II) R1mTSRI 2226.1PC wherein: each Z is independently CH or N; Y is absent, -C(=O)-, -C(=O)N(Y’)-, -(CH2)rC(=O)O-, -S(=O)2-, -C(=O)NHS(=O)2-, - NHC(=O)O-, -NHC(=O)NH-, -NHC(=O)-, -NH-, -NHS(=O)2-, -OCH2C(=O)NH-; or - S(=O)2NH-; Y’ is H or (C1-C6) alkyl; each Z is independently CH or N; A is H, halo, CN, NO2, (C1-C20) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, hetero (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C7) cycloalkyl, 3- to 7-membered heterocycloalkyl, (C6-C10) aryl, (C1-C6) alkyl (C6-C10) aryl, 5- to 10-membered heteroaryl, or (C1-C6) alkyl 5- to 10-membered heteroaryl, optionally substituted with one or more A’; each A’ is independently OH, halo, CN, oxo, -C(=O)(C1-C6) alkyl, -C(=O)OH, (C1-C6) alkyl, (C1-C6) alkoxy, -S(=O)2(C1-C6) alkyl, -NHS(=O)2(C1-C6) alkyl, -N((C1-C6) alkyl)S(=O)2(C1-C6) alkyl, halo (C1-C6) alkyl, -NH2, -NH(C1-C6) alkyl, -N((C1-C6) alkyl)2,- C(=O)O(C1-C6) alkyl, -C(=O)NH2, -C(=O)NH(C1-C6) alkyl, -C(=O)N((C1-C6) alkyl)2, - NHC(=O)(C1-C6) alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, hydroxy (C1-C6) alkyl, (C1-C6) heteroalkyl, (C6-C10) aryl, (C1-C6) alkyl (C6-C10) aryl, or 5- to 10- membered heteroaryl, wherein 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, (C6-C10) aryl, and 5- to 10-membered heteroaryl are each optionally substituted with one or more A’’; each A’’ is independently OH, halo, (C1-C6) alkyl, hetero (C1-C6) alkyl, or halo (C1-C6) alkyl, each R1is independently halo, OH, CN, (C1-C6) alkyl, or halo (C1-C6) alkyl; each R2is independently halo, OH, NH2, CN, -C(=O)OH, (C1-C6) alkyl, halo (C1-C6) alkyl, or hetero (C1-C6) alkyl; or A and R2together form a fused (C6-C10) aryl; or two R2together form a fused (C6-C10) aryl or 3- to 7-membered heterocycloalkyl, optionally substituted with one or more OH, halo, NH2, NHC(=O)O(C1-C6) alkyl, CN, oxo, (C1-C6) alkyl, hetero (C1-C6) alkyl, hydroxy (C1-C6) alkyl, halo (C1-C6) alkyl, or (C3-C7) cycloalkyl;TSRI 2226.1PC m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; r is 0, 1, or 2; with the proviso that Formula (II) is not 1) 3-bromo-5-(1-phenyl-1H-1,2,3-triazol-4-yl)phenyl sulfurofluoridate; 2) 3-((fluorosulfonyl)oxy)-5-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4- yl)benzoic acid; or 3) 3-((fluorosulfonyl)oxy)-5-(1-(p-tolyl)-1H-1,2,3-triazol-4-yl)benzoic acid; including any enantiomers, scalemic or racemic mixtures, or pharmaceutically acceptable salts thereof.

[0034] Embodiment 4. The compound of any one of Embodiments 1-3, wherein m is 0.

[0035] Embodiment 5. The compound of any one of Embodiments 1-4, wherein n is 0.

[0036] Embodiment 6. The compound any one of Embodiments 1-4, wherein n is 1.

[0037] Embodiment 7. The compound of any one of Embodiments 1-4, wherein n is 2.

[0038] Embodiment 8. The compound of any one of Embodiments 1-4 or 6-7, wherein R2is halo.

[0039] Embodiment 9. The compound of Embodiment 8, wherein halo is F.

[0040] Embodiment 10. The compound of any one of Embodiments 1-9, wherein Y is absent.

[0041] Embodiment 11. The compound of any one of Embodiments 1-9, wherein Y is - C(=O)-.

[0042] Embodiment 12. The compound of any one of Embodiments 1-9, wherein Y is - C(=O)O-.

[0043] Embodiment 13. The compound of any one of Embodiments 1-9, wherein Y is - NHC(=O)-.

[0044] Embodiment 14. The compound of any one of Embodiments 1-9, wherein Y is - C(=O)NH-.

[0045] Embodiment 15. The compound of any one of Embodiments 1-14, wherein A is H.

[0046] Embodiment 16. The compound of any one of Embodiments 1-14, wherein A is (C1- C12) alkyl.

[0047] Embodiment 17. The compound of any one of Embodiments 1-14, wherein A is 5- to 10-membered heteroaryl.TSRI 2226.1PC

[0048] Embodiment 18. The compound of any one of Embodiments 1-14, wherein A is (C6- C10) aryl.

[0049] Embodiment 19. The compound of any one of Embodiments 1-14, wherein A is 3- to 7-membered heterocycloalkyl.

[0050] Embodiment 20. The compound of any one of Embodiments 1-19, wherein X1is O, X2is CH2, and ---- represents a single bond.

[0051] Embodiment 21. The compound of any one of Embodiments 1-19, wherein X1is CH, X2is CH, and ---- represents a double bond.

[0052] Embodiment 22. The compound of any one of Embodiments 1-19, wherein X1is N, X2is N, and ---- represents a double bond.

[0053] Embodiment 23. The compound of any one of Embodiments 1-19, wherein X1is NH or N(C1-C6) alkyl, X2is C(=O), and ---- represents a single bond;

[0054] Embodiment 24. A compound having the structure of Compound 95: O F F S N O O NOOmixtures, or pharmaceutically acceptable salts thereof.

[0055] Embodiment 25. A compound having the structure of Compound 94: F O F Sor racemic mixtures, or pharmaceutically acceptable salts thereof.

[0056] Embodiment 26. A compound having any one of the formulae selected from the group consisting of:TSRI 2226.1PC methyl 3-fluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)benzoate; methyl 4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)benzoate; 4-((4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-carbamoylbenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(pyridin-3-ylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(but-3-en-1-ylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; (E)-4-(4-acetamidostyryl)phenyl sulfurofluoridate; (E)-4-((4-acetamidophenyl)diazenyl)phenyl sulfurofluoridate; (E)-4-((4-(pyridin-3-ylcarbamoyl)phenyl)diazenyl)phenyl sulfurofluoridate; 4-((4-(nicotinamido)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(cyclopropylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(ethylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; methyl 2-(4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)acetate; 4-((4-(morpholine-4-carbonyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(methylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(propylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(pyrrolidine-1-carbonyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(phenethylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-cyanobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-acetamidobenzyl)oxy)phenyl sulfurofluoridate; (E)-3-chloro-4-(4-(fluorocarbonyl)styryl)phenyl sulfurofluoridate; 4-((2-chlorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-acetamidobenzyl)oxy)-3-fluorophenyl sulfurofluoridate; (E)-4-((4-acetamidophenyl)diazenyl)-3-fluorophenyl sulfurofluoridate; 4-((4-(isopropylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)benzoic acid; 4-((4-(benzylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate;TSRI 2226.1PC 4-((4-(dimethylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-((4-phenylbutyl)carbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(piperidine-1-carbonyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(phenylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(phenylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(butylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(heptan-2-ylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(1-methyl-1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-acetamidobenzyl)oxy)-3-chlorophenyl sulfurofluoridate; 4-((4-propionamidobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(methylsulfonyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(pyrazin-2-yl)benzyl)oxy)phenyl sulfurofluoridate; (E)-4-((4-(pyridin-4-ylcarbamoyl)phenyl)diazenyl)phenyl sulfurofluoridate; 4-((4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(cyclohexylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; (E)-4-((4-acetamidophenyl)diazenyl)-3-methylphenyl sulfurofluoridate; 4-((4-(4-methylpiperidine-1-carbonyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-acetamidobenzyl)oxy)-3-methylphenyl sulfurofluoridate; 4-((4-(4-methylpiperazine-1-carbonyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-ethynylbenzyl)oxy)phenyl sulfurofluoridate; (E)-4-((4-(4-oxopiperidine-1-carbonyl)phenyl)diazenyl)phenyl sulfurofluoridate; (E)-4-((4-(diethylcarbamoyl)phenyl)diazenyl)phenyl sulfurofluoridate; 4-((2-fluoro-5-(trifluoromethyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(undecylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(quinolin-3-ylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; (E)-4-((4-((fluorosulfonyl)oxy)phenyl)diazenyl)benzoic acid; 4-((4-chlorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(octadec-9-en-1-ylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((3-chlorobenzyl)oxy)phenyl sulfurofluoridate; (E)-4-((4-(morpholine-4-carbonyl)phenyl)diazenyl)phenyl sulfurofluoridate;TSRI 2226.1PC 4-((4-(trifluoromethyl)benzyl)oxy)phenyl sulfurofluoridate; 3-((4-acetamidophenyl)carbamoyl)phenyl sulfurofluoridate; 2-(4-((fluorosulfonyl)oxy)phenyl)benzo[d]thiazole-6-carboxylic acid; 2-((4-acetamidophenyl)carbamoyl)pyridin-4-yl sulfurofluoridate; 4-(1-(4-aminophenyl)-1H-1,2,3-triazol-4-yl)phenyl sulfurofluoridate; 4-((4-(benzyl(methyl)carbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(hexadecylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 3-(1-(4-aminophenyl)-1H-1,2,3-triazol-4-yl)phenyl sulfurofluoridate; 3-(1-(4-acetamidophenyl)-1H-1,2,3-triazol-4-yl)phenyl sulfurofluoridate; N-(4-((4-hydroxyphenoxy)methyl)phenyl)acetamide; 4-(4-acetamidobenzamido)phenyl sulfurofluoridate; 3-(4-acetamido-N-methylbenzamido)phenyl sulfurofluoridate; 2-(pyrrolidin-1-yl)benzo[d]thiazol-6-yl sulfurofluoridate; 4-(2-((4-fluorophenyl)sulfonyl)acetamido)phenyl sulfurofluoridate; 4-((2-((5-chloropyridin-2-yl)amino)-2-oxoethyl)sulfonyl)phenyl sulfurofluoridate; methyl 2-(4-((fluorosulfonyl)oxy)phenyl)-4-oxo-4H-chromene-6-carboxylate; (E)-4-(4-aminostyryl)phenyl sulfurofluoridate; methyl (E)-4-(2-chloro-4-((fluorosulfonyl)oxy)styryl)benzoate; 4-(3-(4-acetamidophenoxy)oxetan-3-yl)phenyl sulfurofluoridate; 4-((4-methylbenzyl)oxy)phenyl sulfurofluoridate; 4-(naphthalen-2-ylmethoxy)phenyl sulfurofluoridate; 4-([1,1'-biphenyl]-4-ylmethoxy)phenyl sulfurofluoridate; 4-((4-(2H-tetrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-((fluorosulfonyl)carbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)benzenesulfonyl fluoride; (4-((4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl)sulfamoyl fluoride; methyl 4-((4-((fluorosulfonyl)methyl)phenoxy)methyl)benzoate; 3-((4-acetamidophenoxy)methyl)phenyl sulfurofluoridate; 4-((4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenol;TSRI 2226.1PC methyl 3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)benzoate; ethyl 1-(3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)-5-(trifluoromethyl)-1H-1,2,3- triazole-4-carboxylate; 4-((2,6-difluoro-4-(5-methyl-3-(methylsulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-3-(3-(methylsulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(methylsulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-(ethylsulfonamido)-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(1-(4-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-(methylsulfonamido)-1H-1,2,3-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-hydroxypyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(4-carbamoyl-1H-imidazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-(methylcarbamoyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-acetamido-1H-pyrazol-5-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(4-carbamoyl-1H-1,2,3-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1H-1,2,3-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(methoxymethyl)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-acetamido-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-carbamoyl-1-methyl-1H-pyrazol-5-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-carbamoyl-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4H-1,2,4-triazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(4-carbamoyl-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(4-cyano-5-methyl-1H-imidazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-hydroxy-6-methylpyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate;TSRI 2226.1PC 4-((2,6-difluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(pyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(pyridazin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(pyridin-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-methyl-1H-imidazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-(difluoromethyl)-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(4-acetamido-1H-1,2,3-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1H-imidazol-2-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-methyl-1H-imidazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(6-oxo-1,6-dihydropyridin-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(pyrimidin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-3-(methylcarbamoyl)-1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2-fluoro-4-(2-hydroxy-6-methylpyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-((methoxycarbonyl)amino)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-((1-methylethyl)sulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(2-chloropyridin-4-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-(dimethylamino)-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; methyl 5-(3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)-1-methyl-1H-pyrazole-3- carboxylate; 4-((4-(2,4-dimethyl-1H-imidazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-3-(methylsulfonamido)-1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(2-carbamoylpyridin-4-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(N-methylmethylsulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(methylsulfonamido)-1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1H-imidazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(5-hydroxypyrazin-2-yl)benzyl)oxy)phenyl sulfurofluoridate;TSRI 2226.1PC 4-((3-((1H-1,2,4-triazol-1-yl)methyl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(hydroxymethyl)-5-methyl-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)benzoic acid; 4-((2,6-difluoro-4-(3-(methylsulfonyl)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1H-tetrazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-carbamoyl-5-methyl-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-cyano-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-(methylamino)-2-oxoethoxy)benzyl)oxy)phenyl sulfurofluoridate; 4-((3-fluoro-5-(3-(methylsulfonamido)-1H-1,2,4-triazol-1-yl)pyridin-2-yl)methoxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-sulfamoyl-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-methyl-1H-1,2,3-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(methylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-methyl-1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-3-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,4-difluoro-5-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 1-(3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)-5-(trifluoromethyl)-1H-1,2,3- triazole-4-carboxylic acid; 4-((2,6-difluoro-4-(2-methylpyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-ethyl-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-isopropyl-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(4-cyano-1H-1,2,3-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-(trifluoromethyl)pyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2-chloro-6-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate;TSRI 2226.1PC 4-((4-(3-cyano-1H-pyrazol-5-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-amino-1H-pyrazol-5-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-1H-imidazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-methoxy-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(pyrazin-2-yl)benzyl)oxy)phenyl sulfurofluoridate; methyl 4-(3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)picolinate; 4-((4-(2-aminopyridin-4-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(2-cyanopyridin-4-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(pyridin-2-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-methyl-4H-1,2,4-triazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-methoxypyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(5-methyl-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-fluoro-2-methylpyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-hydroxypyridin-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(2-acetamidopyridin-4-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(5-fluoro-2-methylpyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-morpholino-1H-imidazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2-fluoro-4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-((3-(methylsulfonamido)-1H-1,2,4-triazol-1-yl)methyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(5-(methylsulfonyl)-1H-1,2,4-triazol-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(2-(difluoromethyl)pyridin-4-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-hydroxy-2-oxo-1,2-dihydropyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate;TSRI 2226.1PC 4-((2,6-difluoro-4-(3-(methylsulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)-3-fluorophenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-morpholino-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-((1H-1,2,4-triazol-1-yl)methyl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(isoxazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-fluoro-3-((4-((fluorosulfonyl)oxy)phenoxy)methyl)benzoic acid; 4-((2,6-difluoro-4-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-chloro-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(methylsulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)-2-methylphenyl sulfurofluoridate; 4-((4-((4H-1,2,4-triazol-4-yl)methyl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(methylsulfonamido)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(pyrimidin-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(trifluoromethyl)-1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-nitro-1H-1,2,3-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2-cyano-6-fluoro-4-(1H-1,2,3-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1H-imidazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(4-amino-1H-1,2,3-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-(tert-butyl)-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 3-cyano-5-fluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)benzoic acid; 4-((2-cyano-6-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 1-(3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid; 4-((4-(1-(l1-oxidaneyl)-1l4-pyridin-4-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(2-(dimethylamino)pyridin-4-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2H-1,2,3-triazol-2-yl)benzyl)oxy)phenyl sulfurofluoridate; 6-((2,6-difluoro-4-(3-(methylsulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)pyridin-3-yl sulfurofluoridate; 4-((4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; isopropyl 3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)benzoate;TSRI 2226.1PC 4-((2,3-difluoro-4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,5-difluoro-4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(pyrimidin-2-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(pyridazin-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 1-(3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)-1H-1,2,4-triazole-3-carboxylic acid; 4-((2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-amino-1-methyl-1H-pyrazol-5-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-acetamido-1-methyl-1H-pyrazol-5-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-1H-imidazol-2-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-oxo-2,3-dihydropyridazin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-((3-methyl-1H-1,2,4-triazol-1-yl)methyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-((5-methyl-1H-1,2,4-triazol-1-yl)methyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-((1H-1,2,3-triazol-1-yl)methyl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-((2H-1,2,3-triazol-2-yl)methyl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-(hydroxymethyl)-6-methylpyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(5-fluoro-2-hydroxypyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(2-chloro-6-hydroxypyridin-4-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-2-fluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,3-difluoro-5-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(methylsulfonamido)isoxazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(methylsulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)-3-methylphenyl sulfurofluoridate; 4-((3-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((3-fluoro-4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate;TSRI 2226.1PC ethyl 1-(3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)-4-(trifluoromethyl)-1H-1,2,3- triazole-5-carboxylate; 4-((3,4-difluoro-5-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,4-difluoro-3-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2-cyano-5-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-(methylsulfonamido)pyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(6-hydroxypyrimidin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-((3,5-dimethyl-1H-1,2,4-triazol-1-yl)methyl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-methylureido)benzyl)oxy)phenyl sulfurofluoridate; 4-((5-((1H-1,2,4-triazol-1-yl)methyl)-2,4-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(4-cyano-1H-imidazol-1-yl)-2-fluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2-fluoro-4-(2-hydroxy-6-methylpyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(1-acetyl-3-amino-1H-pyrazol-5-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-3-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-hydroxy-6-(trifluoromethyl)pyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-((1,1-dimethylethyl)sulfonamido)-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-acetamidobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((3-fluoro-5-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methoxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1H-tetrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1H-pyrazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2-cyano-6-fluoro-4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-morpholinobenzyl)oxy)phenyl sulfurofluoridate; 4-((3-cyano-5-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((3-fluoropyridin-2-yl)methoxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(5-hydroxyisoxazol-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(6-oxo-1,6-dihydropyridazin-4-yl)benzyl)oxy)phenyl sulfurofluoridate;TSRI 2226.1PC 5-(3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid; 4-((2,5-difluoro-3-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2-fluoro-5-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,4-difluoro-5-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,3-difluoro-5-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2-fluoro-4-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-((4-cyano-1H-imidazol-1-yl)methyl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,5-difluoro-3-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((3,5-difluoro-4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-(1-(2,6-difluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)ethoxy)phenyl sulfurofluoridate; 4-(3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)picolinic acid; 4-((2,6-difluoro-4-(3-methoxy-1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-hydroxy-1,2,5-oxadiazol-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2-fluoro-3-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((3-fluoro-5-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-fluoro-3-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-((4-cyano-5-methyl-1H-imidazol-1-yl)methyl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate 4-((2,6-difluoro-4-(1H-pyrazol-5-yl)benzyl)oxy)phenol; and 4-((4-(3-carbamoyl-1H-pyrazol-5-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate.

[0057] Embodiment 27. A composition comprising the compound of any one of Embodiments 1-26, admixed with a pharmaceutically acceptable carrier, diluent, or excipient.

[0058] Embodiment 28. The composition of Embodiment 27, further comprising one or more therapeutic compounds or compositions used for the treatment of a mycobacterial disease.

[0059] Embodiment 29. The composition of Embodiment 27, further comprising one or more therapeutic compounds or compositions used for the treatment of a TB infection.

[0060] Embodiment 30. The composition of Embodiment 29, wherein the one or more therapeutic compounds or compositions is selected from bedaquiline, pretomanid and linezolid.

[0061] Embodiment 31. The composition of Embodiment 29, wherein the one or more therapeutic compounds or compositions is Nix-TB.TSRI 2226.1PC

[0062] Embodiment 32. The composition of Embodiment 29, wherein the one or more therapeutic compounds or compositions is selected from bedaquiline, pretomanid, linezolid, isoniazid, rifampin, rifabutin, rifapentine, pyrazinamide, ethambutol, ethionamide, moxifloxacin, tedizolid, radezolid, sutezolid, posizolid clofazimine, gatifloxacin, kanamycin, nitroimidazo-oxazine, delamanid, OPC-167832, streptomycin, prednisolone, an oxazolidinone, a fluoroquinolone, a corticosteroid, EMB analogue SQ109, a benzothiazinone, a dinitrobenzamide, and an antiviral agent including an antiretroviral agent.

[0063] Embodiment 33. The composition of any one of Embodiments 27-31, wherein the composition is suitable for oral administration.

[0064] Embodiment 34. A method of preventing, ameliorating, or treating a bacterial infection, comprising administering to a subject in need thereof a therapeutically effective amount the compound of any one of Embodiments 1-26 or the composition of any one of Embodiments 27-33.

[0065] Embodiment 35. A method of covalently targeting Mycobacterium tuberculosis (Mtb) acyltransferase domain of Polyketide synthase 13, comprising treating intracellular and / or extracellular Mtb with the compound of any one of Embodiments 1-26 or the composition of any one of Embodiments 27-33.

[0066] Embodiment 36. A method of preventing, ameliorating, or treating a mycobacterial disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of Embodiments 1-26 or the composition of any one of Embodiments 27-33.

[0067] Embodiment 37. A method of preventing, ameliorating, or treating a TB infection, comprising administering to a subject in need thereof a therapeutically effective amount the compound of any one of Embodiments 1-26 or the composition of any one of Embodiments 27- 33.

[0068] Embodiment 38. Any compound, composition, or method as described herein.

[0069] In the various embodiments described herein, the mtb inhibitor of any one of Formulae I-II or pharmaceutically acceptable salt and / or stereoisomer thereof, is one selected from Compounds 1-297 in Table 1 shown below.TSRI 2226.1PC H37Ra # Structures IC50Compound Name h e h e p e x x lTSRI 2226.1PC H N e i o l yl h aTSRI 2226.1PC O N 4-((4-(morpholine-4- e z z e b nTSRI 2226.1PC H N 4-((4- p e l) n l- yl - e bTSRI 2226.1PC O OH 4-((4- h z e l e z zTSRI 2226.1PC O N 4-((4- y x - lTSRI 2226.1PC O N N (E)-4-((4-(pyridin-4- i ) e e - eTSRI 2226.1PC O 4-((4- e n l n x h nTSRI 2226.1PC O O F S 4-((4-(octadec-9-en-1- 58OO H 11.96 ylcarbamoyl)benzyl)ox n - n l a h - a m lTSRI 2226.1PC ONN 4-((4-(3-methyl-1,2,4- b p e n l )aTSRI 2226.1PC O O 4-((2-((5- S FClchloropyridin- OON2- n h o- t e nTSRI 2226.1PC O O S O F 4-((4-(2H-tetrazol-5- l- e s yl t l- olTSRI 2226.1PC H37Rv # Structures MIC Com ound Name - o - o 3- - - - lTSRI 2226.1PC O O S 4-((4-(1-(4- O F O hydroxyphenyl)-1H-1,2,3- 97 0106 - l 3- )- lTSRI 2226.1PC O O F S 4-((2,6-difluoro-4-(3- O F (hydroxymethyl)-1H-1,2,4- 104 O 015 l 4- l - l lTSRI 2226.1PC O O F S O F 4-((2,6-difluoro-4-(6- O hd idi 2 l 3- l - l -TSRI 2226.1PC O O F S O F 4-((2,6-difluoro-4-(3- 1- n- n- 3-TSRI 2226.1PC O O F S O F 4-((4-(3-(difluoromethyl)- O 1H-124-triazol-1-l)-26- l l -TSRI 2226.1PC O O 4-((2,6-difluoro-4-(1- F S O F methyl-3- - ) - )- - l - - l - oTSRI 2226.1PC O O F S O F 4-((4-(2,4-dimethyl-1H- O i id l1 l 26 l - - l )- -TSRI 2226.1PC F N N 4-((3-((1H-1,2,4-triazol-1- 143NO OF0.378 yl)methyl)-2,6- yl l- o - - l - lTSRI 2226.1PC O F O N 4-((2,6-difluoro-4-(2- 150 O H 0456 (methylamino)-2- e - 2- l- - - )o teTSRI 2226.1PC O O F S O F 4-((2,6-difluoro-4-(1H- 3- o 3- dTSRI 2226.1PC O O F S O F 4-((2,6-difluoro-4-(2- O methylpyridin-4- l l- 3- - l -TSRI 2226.1PC O O F S O F 4-((2-chloro-6-fluoro-4-(3- thl1H124ti l1- l- l l- l - n- - o atTSRI 2226.1PC O O F S O F 4-((4-(2-aminopyridin-4- 17 O yl)-26- l l n- - )- -TSRI 2226.1PC O O F S O F 4-((2,6-difluoro-4-(2- - l - 1- - 4-TSRI 2226.1PC O O F S O F 4-((2,6-difluoro-4-(1- - - n - - l -TSRI 2226.1PC O O F S 4-((2,6-difluoro-4-(1- O F hydroxy-2-oxo-1,2- 196 O 0625 - - l - oTSRI 2226.1PC O O F S O F - l - - l ylTSRI 2226.1PC O O F S O F 4-((2,6-difluoro-4- - - l lTSRI 2226.1PC O N HO 3-cyano-5-fluoro-4-((4- o - - o c 4- l - lTSRI 2226.1PC O O FN SF 6-((2,6-difluoro-4-(3- O (methylsulfonamido)-1H- l - oTSRI 2226.1PC O O F S O F 4-((2,6-difluoro-4- o c l - l - lTSRI 2226.1PC O O F S 4-((2,6-difluoro-4-(1- O F methyl-5-oxo-1,5-dihydro- - - n - n - l - lTSRI 2226.1PC O O F S O F 4-((2,6-difluoro-4-(5- 4- - l - lTSRI 2226.1PC O O F S O F 4((26difl 4(3 z l - - - - o 3-TSRI 2226.1PC F F 4-((3,4-difluoro-5-(1H- - i l - lTSRI 2226.1PC O O F S F 4-((2,6-di 260Ofluoro-4-(3- O O 25 )p - l - l -TSRI 2226.1PC F H 4-((4-(3-((1,1- O dimethylethyl)sulfonamid 7N No) 26ONS25 6- l n - -TSRI 2226.1PC O O F S O F 4-((2-cyano-6-fluoro-4- e - -TSRI 2226.1PC O O F S 5-(3,5-difluoro-4-((4- O F O ((fluorosulfonyl)oxy)pheno l- l- - lTSRI 2226.1PC O O N F S N F N O 4-((2,5-difluoro-3-(1H- - o ic 3- l-TSRI 2226.1PC O O S FON 4-((3-fluoro-5-(1H-pyrazol- l- - )- l lDefinitions

[0070] The phrase “a” or “an” entity as used herein refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. As such, the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.

[0071] The phrase "as defined herein above" refers to the broadest definition for each group as provided in the Summary of the Invention, the Detailed Description of the Invention, the Experimentals, or the broadest claim. In all other embodiments provided below, substituentsTSRI 2226.1PC which can be present in each embodiment and which are not explicitly defined retain the broadest definition provided in the Summary of the Invention.

[0072] As used in this specification, whether in a transitional phrase or in the body of the claim, the terms "comprise(s)" and "comprising" are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes at least the recited features or components, but may also include additional features or components.

[0073] As used herein, unless specifically indicated otherwise, the word "or" is used in the "inclusive" sense of "and / or" and not the "exclusive" sense of "either / or".

[0074] The term "independently" is used herein to indicate that a variable is applied in any one instance without regard to the presence or absence of a variable having that same or a different definition within the same compound. Thus, in a compound in which “R” appears twice and is defined as "independently selected from” means that each instance of that R group is separately identified as one member of the set which follows in the definition of that R group. For example, “each R1and R2is independently selected from carbon and nitrogen" means that both R1and R2can be carbon, both R1and R2can be nitrogen, or R1or R2can be carbon and the other nitrogen or vice versa.

[0075] When any variable occurs more than one time in any moiety or formula depicting and describing compounds employed or claimed in the present invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and / or variables are permissible only if such compounds result in stable compounds.

[0076] The symbols "*" at the end of a bond or a line drawn through a bond or “~~~~” drawn through a bond each refer to the point of attachment of a functional group or other chemical moiety to the rest of the molecule of which it is a part.

[0077] A bond drawn into ring system (as opposed to connected at a distinct vertex) indicates that the bond may be attached to any of the suitable ring atoms.TSRI 2226.1PC

[0078] The term “optional” or “optionally” as used herein means that a subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted” means that the “optionally substituted” moiety may incorporate a hydrogen or a substituent.

[0079] The phrase “optional bond” means that the bond may or may not be present, and that the description includes single, double, or triple bonds. If a substituent is designated to be a "bond" or "absent", the atoms linked to the substituents are then directly connected.

[0080] The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 20%.

[0081] Certain compounds disclosed herein may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertable species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate an individual tautomers usually produce a mixture whose chemical and physical properties are consistent with a mixture of compounds. The position of the equilibrium is dependent on chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates while; in phenols, the enol form predominates. Common prototropic tautomers include keto / enol (-C(=O)-CH- ^ -C(-OH)=CH-), amide / imidic acid (-C(=O)-NH- ^ -C(-OH)=N-) and amidine (- C(=NR)-NH- ^ -C(-NHR)=N-) tautomers. The latter two are particularly common in heteroaryl and heterocyclic rings and the present invention encompasses all tautomeric forms of the compounds.

[0082] In this disclosure, a “pharmaceutically acceptable salt” is a pharmaceutically acceptable, organic or inorganic acid or base salt of a compound described herein. Representative pharmaceutically acceptable salts include, e.g., alkali metal salts, alkali earth salts, ammonium salts, water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate,TSRI 2226.1PC bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. A pharmaceutically acceptable salt can have more than one charged atom in its structure. In this instance the pharmaceutically acceptable salt can have multiple counterions. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterions.

[0083] Technical and scientific terms used herein have the meaning commonly understood by one of skill in the art to which the present invention pertains, unless otherwise defined. Reference is made herein to various methodologies and materials known to those of skill in the art. Standard reference works setting forth the general principles of pharmacology include Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10thEd., McGraw Hill Companies Inc., New York (2001). Any suitable materials and / or methods known to those of skill can be utilized in carrying out the present invention. However, preferred materials and methods are described. Materials, reagents and the like to which reference are made in the following description and examples are obtainable from commercial sources, unless otherwise noted.

[0084] The definitions described herein may be appended to form chemically-relevant combinations, such as “heteroalkylaryl,” “haloalkylheteroaryl,” “arylalkylheterocyclyl,” “alkylcarbonyl,” “alkoxyalkyl,” and the like. When the term “alkyl” is used as a suffix following another term, as in “phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkyl group, as defined above, being substituted with one to two substituents selected from the other specifically-named group. Thus, for example, “phenylalkyl” refers to an alkyl group having one to two phenyl substituents, and thus includes benzyl, phenylethyl, and biphenyl. AnTSRI 2226.1PC “alkylaminoalkyl” is an alkyl group having one to two alkylamino substituents. “Hydroxyalkyl" includes 2-hydroxyethyl, 2-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, and so forth. Accordingly, as used herein, the term “hydroxyalkyl” is used to define a subset of heteroalkyl groups defined below. The term -(ar)alkyl refers to either an unsubstituted alkyl or an aralkyl group. The term (hetero)aryl or (het)aryl refers to either an aryl or a heteroaryl group.

[0085] The term “acyl” as used herein denotes a group of formula -C(=O)R wherein R is hydrogen or lower alkyl as defined herein. The term or "alkylcarbonyl" as used herein denotes a group of formula C(=O)R wherein R is alkyl as defined herein. The term C1-6acyl refers to a group -C(=O)R contain 6 carbon atoms. The term "arylcarbonyl" as used herein means a group of formula C(=O)R wherein R is an aryl group; the term "benzoyl" as used herein an "arylcarbonyl" group wherein R is phenyl.

[0086] The term “alkyl” as used herein denotes an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 12 carbon atoms. The term “lower alkyl” or “C1-C6alkyl” as used herein denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms. "C1-12alkyl" as used herein refers to an alkyl composed of 1 to 12 carbons. Examples of alkyl groups include, but are not limited to, lower alkyl groups include methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

[0087] When the term “alkyl” is used as a suffix following another term, as in “phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkyl group, as defined above, being substituted with one to two substituents selected from the other specifically-named group. Thus, for example, “phenylalkyl” denotes the radical R'R"-, wherein R' is a phenyl radical, and R" is an alkylene radical as defined herein with the understanding that the attachment point of the phenylalkyl moiety will be on the alkylene radical. Examples of arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl. The terms “arylalkyl” or "aralkyl" are interpreted similarly except R' is an aryl radical. The terms "(het)arylalkyl" or "(het)aralkyl" are interpreted similarly except R' is optionally an aryl or a heteroaryl radical.TSRI 2226.1PC

[0088] When a range of values is listed, it is intended to encompass each value and sub– range within the range. For example, “C1–6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6alkyl.

[0089] “Alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20alkyl”). In some embodiments, an alkyl group has 1 to 15 carbon atoms (“C1–15alkyl”). In some embodiments, an alkyl group has 1 to 14 carbon atoms (“C1–14alkyl”). In some embodiments, an alkyl group has 1 to 13 carbon atoms (“C1–13alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1–12alkyl”). In some embodiments, an alkyl group has 1 to 11 carbon atoms (“C1–11alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1–10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1–9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1–8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1–7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1–5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1–4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1–2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2–6alkyl”). Examples of C1–6alkyl groups include methyl (C1), ethyl (C2), n–propyl (C3), isopropyl (C3), n–butyl (C4), tert–butyl (C4), sec–butyl (C4), iso–butyl (C4), n–pentyl (C5), 3–pentanyl (C5), amyl (C5), neopentyl (C5), 3–methyl–2–butanyl (C5), tertiary amyl (C5), and n–hexyl (C6). Additional examples of alkyl groups include n–heptyl (C7), n–octyl (C8) and the like.

[0090] “Alkenyl” or “olefin” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 10 carbon atoms and 1, 2, 3, or 4 carbon-carbon double bonds (“C2–10alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2–9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2–8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2–7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2–6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2–5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2–4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbonTSRI 2226.1PC atoms (“C2–3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon–carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl). Examples of C2–4alkenyl groups include ethenyl (C2), 1– propenyl (C3), 2–propenyl (C3), 1–butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like. Examples of C2–6alkenyl groups include the aforementioned C2–4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.

[0091] “Alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2–10alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2–9alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2–8alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2–7alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2–6alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2–5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2–4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2–3alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carbon–carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl). Examples of C2–4alkynyl groups include, without limitation, ethynyl (C2), 1–propynyl (C3), 2–propynyl (C3), 1–butynyl (C4), 2–butynyl (C4), and the like. Examples of C2–6alkenyl groups include the aforementioned C2–4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like.

[0092] The terms “haloalkyl” or “halo-lower alkyl” or “lower haloalkyl” refers to a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms wherein one or more carbon atoms are substituted with one or more halogen atoms.

[0093] The term "alkylene" or "alkylenyl" as used herein denotes a divalent saturated linear hydrocarbon radical of 1 to 10 carbon atoms (e.g., (CH2)n)or a branched saturated divalent hydrocarbon radical of 2 to 10 carbon atoms (e.g., -CHMe- or -CH2CH(i-Pr)CH2-), unless otherwise indicated. Except in the case of methylene, the open valences of an alkylene group are not attached to the same atom. Examples of alkylene radicals include, but are not limited to,TSRI 2226.1PC methylene, ethylene, propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene, 2- ethylbutylene.

[0094] The term "alkoxy" as used herein means an -O-alkyl group, wherein alkyl is as defined above such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t- butyloxy, pentyloxy, hexyloxy, including their isomers. "Lower alkoxy" as used herein denotes an alkoxy group with a "lower alkyl" group as previously defined. "C1-10alkoxy" as used herein refers to an-O-alkyl wherein alkyl is C1-10.

[0095] The term "hydroxyalkyl" as used herein denotes an alkyl radical as herein defined wherein one to three hydrogen atoms on different carbon atoms is / are replaced by hydroxyl groups.

[0096] The terms "alkylsulfonyl" and "arylsulfonyl" as used herein refers to a group of formula -S(=O)2R wherein R is alkyl or aryl respectively and alkyl and aryl are as defined herein. The term “heteroalkylsulfonyl” as used herein refers herein denotes a group of formula - S(=O)2R wherein R is “heteroalkyl” as defined herein.

[0097] The terms "alkylsulfonylamino" and "arylsulfonylamino"as used herein refers to a group of formula -NR'S(=O)2R wherein R is alkyl or aryl respectively, R' is hydrogen or C1-3alkyl, and alkyl and aryl are as defined herein.

[0098] The term “cycloalkyl” as used herein refers to a saturated carbocyclic ring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. "C3-7cycloalkyl" as used herein refers to an cycloalkyl composed of 3 to 7 carbons in the carbocyclic ring.

[0099] The term carboxy-alkyl as used herein refers to an alkyl moiety wherein one, hydrogen atom has been replaced with a carboxyl with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom. The term “carboxy” or “carboxyl” refers to a –CO2H moiety.

[0100] The term "heteroaryl” or "heteroaromatic" as used herein means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing four to eight atoms per ring, incorporating one or more N, O, or S heteroatoms, the remaining ring atoms being carbon, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. As well known to those skilled in the art, heteroaryl rings have lessTSRI 2226.1PC aromatic character than their all-carbon counter parts. Thus, for the purposes of the invention, a heteroaryl group need only have some degree of aromatic character. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms include, but is not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazol, isoxazole, thiazole, isothiazole, triazoline, thiadiazole and oxadiaxoline which can optionally be substituted with one or more, preferably one or two substituents selected from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo, lower haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino,dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino and arylcarbonylamino. Examples of bicyclic moieties include, but are not limited to, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzoxazole, benzisoxazole, benzothiazole and benzisothiazole. Bicyclic moieties can be optionally substituted on either ring; however the point of attachment is on a ring containing a heteroatom.

[0101] The term "heterocyclyl", “heterocycloalkyl” or "heterocycle" as used herein denotes a monovalent saturated cyclic radical, consisting of one or more rings, preferably one to two rings, including spirocyclic ring systems, of three to eight atoms per ring, incorporating one or more ring heteroatoms (chosen from N,O or S(O)0-2), and which can optionally be independently substituted with one or more, preferably one or two substituents selected from hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, lower haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, unless otherwise indicated. Examples of heterocyclic radicals include, but are not limited to, azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl.

[0102] “Heterocyclyl” or “heterocyclic” refers to a group or radical of a 3– to 14–membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 memberedTSRI 2226.1PC heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon–carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.

[0103] In some embodiments, a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0104] Exemplary 3–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5–membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl,TSRI 2226.1PC pyrrolidinyl, dihydropyrrolyl, and pyrrolyl–2,5–dione. Exemplary 5–membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5–membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6–membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6–membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8– membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro–1,8–naphthyridinyl, octahydropyrrolo[3,2–b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H–benzo[e][1,4]diazepinyl, 1,4,5,7–tetrahydropyrano[3,4–b]pyrrolyl, 5,6–dihydro–4H–furo[3,2–b]pyrrolyl, 6,7–dihydro– 5H–furo[3,2–b]pyranyl, 5,7–dihydro–4H–thieno[2,3–c]pyranyl, 2,3–dihydro–1H–pyrrolo[2,3– b]pyridinyl, 2,3–dihydrofuro[2,3–b]pyridinyl, 4,5,6,7–tetrahydro–1H–pyrrolo[2,3–b]pyridinyl, 4,5,6,7–tetrahydrofuro[3,2–c]pyridinyl, 4,5,6,7–tetrahydrothieno[3,2–b]pyridinyl, 1,2,3,4– tetrahydro–1,6–naphthyridinyl, and the like.

[0105] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1– naphthyl (α-naphthyl) and 2–naphthyl (β-naphthyl)). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups whereinTSRI 2226.1PC the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.

[0106] “Heteroaryl” refers to a radical of a 5–14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl).

[0107] In some embodiments, a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”). In some embodiments, the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, theTSRI 2226.1PC 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0108] Exemplary 5–membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5–membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5–membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5–membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6– membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6–membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6–membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7– membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6–bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6– bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.

[0109] “Saturated” refers to a ring moiety that does not contain a double or triple bond, i.e., the ring contains all single bonds.

[0110] Alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may be optionally substituted. Optionally substituted refers to a group which may be substituted or unsubstituted. In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a non-hydrogen substituent, and which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Heteroatoms such as nitrogen, oxygen, and sulfurTSRI 2226.1PC may have hydrogen substituents and / or non-hydrogen substituents which satisfy the valencies of the heteroatoms and results in the formation of a stable compound.

[0111] Exemplary non-hydrogen substituents wherein a moiety is “optionally substituted” as used herein means the moiety may be substituted with any additional moiety selected from, but not limited to, the group consisting of halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –ORaa, – N(Rbb)2, –N(ORcc)Rbb, –SH, –SRaa, –C(=O)Raa, –CO2H, –CHO, –CO2Raa, –OC(=O)Raa, – OCO2Raa, –C(=O)N(Rbb)2, –OC(=O)N(Rbb)2, –NRbbC(=O)Raa, –NRbbCO2Raa, – NRbbC(=O)N(Rbb)2, –C(=NRbb)Raa, –C(=NRbb)ORaa, –OC(=NRbb)Raa, –OC(=NRbb)ORaa, – C(=NRbb)N(Rbb)2, –OC(=NRbb)N(Rbb)2, –NRbbC(=NRbb)N(Rbb)2, –C(=O)NRbbSO2Raa, – NRbbSO2Raa, –SO2N(Rbb)2, –SO2Raa, –S(=O)Raa, –OS(=O)Raa, -B(ORcc)2, C1–10alkyl, C2–10alkenyl, C2–10alkynyl, C3–14carbocyclyl, 3– to 14- membered heterocyclyl, C6–14aryl, and 5– to 14- membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups, or two geminal hydrogens on a carbon atom are replaced with the group =O; each instance of Raais, independently, selected from the group consisting of C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C3–14carbocyclyl, 3– to 14- membered heterocyclyl, C6–14aryl, and 5– to 14- membered heteroaryl, or two Raagroups are joined to form a 3– to 14- membered heterocyclyl or 5– to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from the group consisting of hydrogen, –OH, –ORaa, –N(Rcc)2, –CN, –C(=O)Raa, –C(=O)N(Rcc)2, –CO2Raa, –SO2Raa, – SO2N(Rcc)2, –SORaa, C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C3–14carbocyclyl, 3– to 14- membered heterocyclyl, C6–14aryl, and 5– to 14- membered heteroaryl, or two Rbbgroups are joined to form a 3– to 14- membered heterocyclyl or 5– to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from the group consisting of hydrogen, C1–10alkyl, C1–10perhaloalkyl, C2–10alkenyl, C2–10alkynyl, C3–14carbocyclyl, 3– to 14- membered heterocyclyl, C6–14aryl, and 5– to 14- membered heteroaryl, or two Rccgroups are joined to form a 3– to 14- membered heterocyclyl or 5– to 14- membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,TSRI 2226.1PC carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; and each instance of Rddis, independently, selected from the group consisting of halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OC1–6alkyl, –ON(C1–6alkyl)2, –N(C1–6alkyl)2, –N(OC1–6alkyl)(C1–6alkyl), –N(OH)(C1–6alkyl), –NH(OH), –SH, –SC1–6alkyl, – C(=O)(C1–6alkyl), –CO2H, –CO2(C1–6alkyl), –OC(=O)(C1–6alkyl), –OCO2(C1–6alkyl), – C(=O)NH2, –C(=O)N(C1–6alkyl)2, –OC(=O)NH(C1–6alkyl), –NHC(=O)( C1–6alkyl), –N(C1–6alkyl)C(=O)( C1–6alkyl), –NHCO2(C1–6alkyl), –NHC(=O)N(C1–6alkyl)2, –NHC(=O)NH(C1–6alkyl), –NHC(=O)NH2, –C(=NH)O(C1–6alkyl),–OC(=NH)(C1–6alkyl), –OC(=NH)OC1–6alkyl, –C(=NH)N(C1–6alkyl)2, –C(=NH)NH(C1–6alkyl), –C(=NH)NH2, –OC(=NH)N(C1–6alkyl)2, – OC(NH)NH(C1–6alkyl), –OC(NH)NH2, –NHC(NH)N(C1–6alkyl)2, –NHC(=NH)NH2, – NHSO2(C1–6alkyl), –SO2N(C1–6alkyl)2, –SO2NH(C1–6alkyl), –SO2NH2,–SO2C1–6alkyl, - B(OH)2, -B(OC1–6alkyl)2,C1–6alkyl, C1–6perhaloalkyl, C2–6alkenyl, C2–6alkynyl, C3–10carbocyclyl, C6–10aryl, 3–to 10- membered heterocyclyl, and 5- to 10- membered heteroaryl; or two geminal Rddsubstituents on a carbon atom may be joined to form =O.

[0112] “Halo” or “halogen” refers to fluorine (fluoro, –F), chlorine (chloro, –Cl), bromine (bromo, –Br), or iodine (iodo, –I).

[0113] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combination of the specified ingredients.

[0114] “Salt” includes any and all salts. “Pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1–19. Pharmaceutically acceptable salts include those derived from inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such asTSRI 2226.1PC ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0115] Unless otherwise indicated, compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC). Compounds described herein can be in the form of individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0116] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, replacement of a carbon by a13C- or14C- enriched carbon, and / or replacement of an oxygen atom with18O, are within the scope of the disclosure. Other examples of isotopes include15N,18O,17O,31P,32P,35S,18F,36Cl and123I.TSRI 2226.1PC Compounds with such isotopically enriched atoms are useful, for example, as analytical tools or probes in biological assays.

[0117] Certain isotopically-labelled compounds (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability.

[0118] Certain isotopically-labelled compounds of Formula (I) can be useful for medical imaging purposes, for example, those labeled with positron-emitting isotopes like11C or18F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like123I can be useful for application in Single Photon Emission Computed Tomography (SPECT). Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and hence, may be preferred in some circumstances. Additionally, isotopic substitution at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time. Isotopically labeled compounds of Formula (I), in particular those containing isotopes with longer half-lives (t1 / 2>1 day), can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.

[0119] If there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure controls. Additionally, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. In some cases, however, where more than one chiral center exists, the structures and names may be represented as single enantiomers to help describe the relative stereochemistry. Those skilled in the art of organic synthesis will know if the compounds are prepared as single enantiomers from the methods used to prepare them.TSRI 2226.1PC EXAMPLES Abbreviations

[0120] Commonly used abbreviations include: acetyl (Ac), azo-bis-isobutyrylnitrile (AIBN), atmospheres (Atm), 9-borabicyclo[3.3.1]nonane (9-BBN or BBN), tert-butoxycarbonyl (Boc), di-tert-butyl pyrocarbonate or boc anhydride (BOC2O), benzyl (Bn), butyl (Bu), Chemical Abstracts Registration Number (CASRN), benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI), 1,4-diazabicyclo[2.2.2]octane (DABCO), diethylaminosulfur trifluoride (DAST), dibenzylideneacetone (dba), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), N,N'-dicyclohexylcarbodiimide (DCC), 1,2- dichloroethane (DCE), dichloromethane (DCM), diethyl azodicarboxylate (DEAD), di-iso- propylazodicarboxylate (DIAD), di-iso-butylaluminumhydride (DIBAL or DIBAL-H), 1,3- Diisopropylcarbodiimide (DIC), di-iso-propylethylamine (DIPEA), N,N-dimethyl acetamide (DMA), 4-N,N-dimethylaminopyridine (DMAP), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,1'-bis-(diphenylphosphino)ethane (dppe), 1,1'-bis- (diphenylphosphino)ferrocene (dppf), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), ethyl (Et), ethyl acetate (EtOAc), ethanol (EtOH), 2-ethoxy-2H- quinoline-1-carboxylic acid ethyl ester (EEDQ), diethyl ether (Et2O), O-(7-azabenzotriazole-1- yl)-N, N,N’N’-tetramethyluronium hexafluorophosphate acetic acid (HATU), acetic acid (HOAc), 1-N-hydroxybenzotriazole (HOBt), high pressure liquid chromatography (HPLC), iso- propanol (IPA), lithium hexamethyl disilazane (LiHMDS), methanol (MeOH), melting point (mp), MeSO2- (mesyl or Ms), , methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA), mass spectrum (ms), methyl t-butyl ether (MTBE), N-bromosuccinimide (NBS), N- carboxyanhydride (NCA), N-chlorosuccinimide (NCS), N-methylmorpholine (NMM), N- methylpyrrolidone (NMP), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), phenyl (Ph), propyl (Pr), iso-propyl (i-Pr), pounds per square inch (psi), pyridine (pyr), room temperature (rt or RT), tert-butyldimethylsilyl or t-BuMe2Si (TBDMS), triethylamine (TEA or Et3N), 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), triflate or CF3SO2- (Tf), trifluoroacetic acid (TFA), 1,1'-bis-2,2,6,6-tetramethylheptane-2,6-dione (TMHD), O-benzotriazol-1-yl- N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), thin layer chromatography (TLC),TSRI 2226.1PC tetrahydrofuran (THF), trimethylsilyl or Me3Si (TMS), p-toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C6H4SO2- or tosyl (Ts), N-urethane-N-carboxyanhydride (UNCA),. Conventional nomenclature including the prefixes normal (n), iso (i-), secondary (sec-), tertiary (tert-) and neo have their customary meaning when used with an alkyl moiety. (J. Rigaudy and D. P. Klesney, Nomenclature in Organic Chemistry, IUPAC 1979 Pergamon Press, Oxford.). Representative Synthetic Procedures 4-((2-fluoro-4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate (Compound 187) F a F F HO Cl b MOMO O c Br Br (8)Reagents and conditions: a) SOCl2, DMF / DCM, rt, 2 h; b) 6, K2CO3, DMF, rt, 12 h; c) 8, Pd2(dba)3, Me4-tBu-X-Phos, Cs2CO3, toluene, 100oC, 5h; d) FA, DCM, rt, 2h; e) SO2F2, TEA, DCM, rt, 30 min; or AISF, DBU, THF, 0oC, 30 min Step a: To a solution of (4-bromo-2-fluoro-phenyl)methanol 4e (2.00 g, 9.75 mmol, 1.00 eq.) in DCM (20 mL) was added SOCl2(4.64 g, 39.0 mmol, 2.83 mL, 4.00 eq.) and DMF (71.3 mg, 976 umol, 75.1 uL, 0.10 eq.) at 0 °C. The mixture was stirred at 30 °C for 2 hours. The reaction mixture was diluted with water (200 mL) and extracted with DCM (200 mL × 3). The combined organic layers were washed with water (100 mL) and brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-bromo-1- (chloromethyl)-2-fluoro-benzene 5e (1.96 g, 7.89 mmol, 81% yield, 90% purity) as a yellow oil,TSRI 2226.1PC which is used directly in next step.1H NMR (400 MHz, CDCl3) δ 7.26 - 7.15 (m, 3H), 4.50 (s, 2H). Step b: To a solution of 4-(methoxymethoxy)phenol 6 (1.10 g, 7.15 mmol, 1.60 eq.) and 4- bromo-1-(chloromethyl)-2-fluoro-benzene 5e (1.00 g, 4.47 mmol, 1.00 eq.) in DMF (10 mL) was added K2CO3(1.85 g, 13.4 mmol, 3.00 eq.). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with water (100 mL) and brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=15 / 1 to 2 / 1) to give 4-bromo-2-fluoro-1-[[4-(methoxymethoxy) phenoxy]methyl]benzene 7e (600 mg, 1.51 mmol, 34% yield, 86% purity) as a yellow oil. Step c: A mixture of 4-bromo-2-fluoro-1-[[4-(methoxymethoxy)phenoxy]methyl]benzene 7e (200 mg, 504 umol, 86% purity, 1.00 eq.), ditert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6-triisopropyl phenyl)phenyl]phosphane (48.5 mg, 101 umol, 0.20 eq.), 1H-1,2,4-triazole 8 (69.6 mg, 1.01 mmol, 2.00 eq.), Pd2(dba)3(46.2mg, 50.4 umol, 0.10 eq.) and Cs2CO3(329 mg, 1.01 mmol, 2.00 eq.) in toluene (2 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 5 hours under N2atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with water (20 mL) and brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters X bridge 150 × 25mm × 5 um; mobile phase: [water (10 mM NH4HCO3) - CAN]; B%: 40% - 70%, 8min). The desired fraction was collected and lyophilized to give 1-[3- fluoro-4-[[4-(methoxy methoxy)phenoxy]methyl]phenyl]-1,2,4- triazole 9e (90.0 mg, 265 umol, 53% yield, 97% purity) as a yellow oil. LCMS [ESI, M+1]: 330.1;1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.13 (s, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.55 - 7.48 (m, 2H), 7.05 - 6.98 (m, 2H), 6.95 - 6.88 (m, 2H), 5.14 (s, 2H), 5.13 (s, 2H), 3.49 (s, 3H). Step d: Formic acid (1.22 g, 26.5 mmol, 1.00 mL, 175 eq.) was added to a solution of 1-[3- fluoro-4-[[4-(methoxymethoxy)phenoxy]methyl]phenyl]-1,2,4-triazo le 9e (50.0 mg, 151 umol, 1.00 eq.). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted withTSRI 2226.1PC MeCN (5 mL) and concentrated under reduced pressure to give 4-[[2-fluoro-4-(1,2,4-triazol-1- yl)phenyl] methoxy]phenol 10e (20.0 mg, 56.1 umol, 37% yield, 80% purity) as a yellow oil. LCMS [ESI, M+1]: 286.0 Step e: To a solution of 4-[[2-fluoro-4-(1,2,4-triazol-1-yl) phenyl]methoxy]phenol 10e (20.0 mg, 56.1 umol, 80% purity, 1.00 eq.) in DCM (1 mL) was added TEA (22.7 mg, 224 umol, 31.2 uL, 4.00 eq.), sulfuryl fluoride (8.59 mg, 84.1 umol, 1.50 eq.) was bubbled into the mixture. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 × 40 mm × 15 um; mobile phase: [water (0.2%FA) - ACN]; B%: 48% - 78%, 10 min). The desired fraction was collected and lyophilized to give 1-[3-fluoro-4-[(4- fluorosulfonyloxyphenoxy)methyl]phenyl]-1,2,4-triazole Compound 187 (2.28 mg, 6.14 umol, 11% yield, 99% purity) as a gray solid. LCMS [ESI, M+1]: 367.9;1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.13 (s, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.59 - 7.48 (m, 2H), 7.30 (d, J = 9.2 Hz, 2H), 7.06 (d, J = 9.2 Hz, 2H), 5.19 (s, 2H);19F NMR (377 MHz, CDCl3) δ 36.62, -114.60. 4-((2,6-difluoro-4-(1H-1,2,4-triazol-3-yl)benzyl)oxy)phenylsulfurofluoridate (Compound 204)TSRI 2226.1PC F F(13)F HOBraClBrHO OH HOOBrcReagents and conditions: a) SOCl2, DMF / DCM, rt, 2 h; b) 13, K2CO3, DMF, rt, 5 h; c) Pin2B2, Pd(dppf)Cl2, KOAc, dioxane, 100oC, 2h; d) 16, Pd(dppf)Cl2, K3PO4, dioxane / H2O, 80oC, 2h); f) SEMCL, TEA, DCM, rt, 12h; g) AISF, DBU, THF, rt, 30 min; h) TFA, DCM, rt, 1h Step a: To a solution of (4-bromo-2,6-difluoro-phenyl)methanol 11 (15.0 g, 67.2 mmol, 1.00 eq.) in DCM (100 mL) was added SOCl2 (32.0 g, 269 mmol, 19.5 mL, 4.00 eq.) and DMF (491 mg, 6.73 mmol, 517 uL, 0.10 eq.). The mixture was stirred at 25 °C for 2 hrs. The pH of the mixture was adjusted with NaHCO3aqueous solution to 7. Then the solution was extracted with EA (300 mL × 3), and the combined organic layer was washed with brine (500 mL), dried over Na2SO4. The reaction mixture was concentrated under reduced pressure to give 5-bromo-2- (chloromethyl)-1,3-difluoro-benzene 12 (13.0 g, crude) as a yellow oil. Step b: To a solution of 5-bromo-2-(chloromethyl)-1,3-difluoro-benzene 12 (11.0 g, 45.5 mmol, 1.00 eq.) and benzene-1,4-diol 13 (7.52 g, 68.3 mmol, 10.1 mL, 1.50 eq.) in DMF (100 mL) wasTSRI 2226.1PC added K2CO3(18.8 g, 136 mmol, 3.00 eq.). The mixture was stirred at 20 °C for 5 hrs. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 30 / 1 to 3 / 1) to give compound 4-[(4-bromo-2,6-difluoro-phenyl)methoxy]phenol 14 (8.00 g, 22.8 mmol, 50% yield, 90% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 7.54 (d, J = 7.2 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H), 4.96 (s, 2H). Step c: A mixture of 4-[(4-bromo-2,6-difluoro-phenyl)methoxy]phenol 14 (7.50 g, 23.8 mmol, 1.00 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (9.07 g, 35.7 mmol, 1.50 eq.), Pd(dppf)Cl2(1.74 g, 2.38 mmol, 0.10 eq.) and AcOK (5.84 g, 59.5 mmol, 2.50 eq.) in dioxane (80.0 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 °C for 2 hrs under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 2 / 1) to give compound 4-[[2,6- difluoro- 4- (4,4,5,5- tetramethyl -1,3,2-dioxaborolan-2-yl) phenyl]methoxy]phenol 15 (9.0 g, 22.4 mmol, 93% yield, 90% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 7.28 (d, J = 7.2 Hz, 2H), 6.82 (d, J = 9.2 Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H), 5.01 (s, 2H), 1.30 (s, 12H). Step d: To a solution of 3-bromo-1H-1,2,4-triazole 16a (5.00 g, 33.8 mmol, 1.00 eq) and 2- (chloromethoxy)ethyl-trimethyl-silane (16.9 g, 101 mmol, 17.9 mL, 3.00 eq.) in DCM (50.0 mL) was added TEA (10.3 g, 101 mmol, 14.1 mL, 3.00 eq.). The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 30 / 1 to 3 / 1) to give compound 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole 16 (4.60 g, 14.8 mmol, 44% yield, 90% purity) as a yellow oil. LCMS [ESI, M+1]: 279.2. Step e: A mixture of 4-[[2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]methoxy]phenol 15 (3.51 g, 9.70 mmol, 1.00 eq.), 2-[(3-bromo-1,2,4-triazol-1- yl)methoxy]ethyl-trimethyl-silane 16 (5.4 g, 19.4 mmol, 2 eq.), K3PO4(6.18 g, 29.1 mmol, 3.00TSRI 2226.1PC eq.) and ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (632 mg, 970 umol, 0.10 eq.) in dioxane (70.0 mL) and H2O (14.0 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °C for 2 hrs under N2atmosphere (15 psi). The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (60 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 20 / 1 to 1 / 1) to give compound 4-[[2,6-difluoro-4-[1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3- yl]phenyl]methoxy]phenol 17 (3.00 g, 6.64 mmol, 68% yield, 96% purity) as a yellow oil. LCMS [ESI, M+1]: 434.3. Step f: To a solution of 4-[[2,6-difluoro-4-[1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3- yl]phenyl]methoxy]phenol 17 ( 2.80 g, 6.46 mmol, 1.00 eq.) in DCM (30.0 mL) was added TEA (2.61 g, 25.8 mmol, 3.60 mL, 4.00 eq.) under sulfuryl fluoride (659 mg, 6.46 mmol, 1.00 eq.) atmosphere (15 psi). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 1 / 1) to give 3-[3,5-difluoro-4-[(4- fluorosulfonyloxyphenoxy)methyl]phenyl]-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazole 18 (2.50 g, 4.61 mmol, 71% yield, 95% purity) as a yellow oil. LCMS [ESI, M+1]: 516.1. Step g: To a solution of 3-[3,5-difluoro-4-[(4-fluorosulfonyloxyphenoxy)methyl]phenyl]-1-(2- trimethylsilylethoxymethyl)-1,2,4-triazole 18 (2.30 g,4.46 mmol, 1.00 eq.) in DCM (30.0 mL) was added TFA (24.4 g, 214 mmol,15.8 mL, 48.0 eq.). The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 10 / 1 to 1 / 1) to give 3-[3,5-difluoro-4-[(4-fluorosulfonyloxyphenoxy)methyl]phenyl]-1H-1,2,4-triazole Compound 204 (950 mg, 2.44 mmol, 54% yield, 99% purity) as a white solid. LCMS [ESI, M+1]: 385.9;1H NMR (400 MHz, DMSO-d6) δ 14.43 (s, 1H), 8.65 (s, 1H), 7.72 (d, J = 8.0 Hz,TSRI 2226.1PC 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.25 - 7.22 (m, 2H), 5.21 (s, 2H);19F NMR (377 MHz, DMSO-d6) δ 37.54, -113.84. General Synthesis of 4-((2,6-difluoro-4-(3-(methylsulfonamido)-1H-1,2,4-triazol-1- yl)benzyl)oxy)phenyl sulfurofluoridate (Compound 95) OTBDMS OTBDMS OTBDMS OTBDMS 95)b) 24, Cu(OAc)2, pyridine, boric acid, CH3CN, 90oC, 4h; c) Pd / C, H2, THF; d) TABF, THF,0oC - rt, 1h; e) AISF, DBU, THF, 0oC, 30 min; f) MeSO2Cl, TEA, DCM, 0oC -rt, 1h; g) TBAF, THF, 0oC, 30 min Step a: A mixture of (4-((4-bromo-2,6-difluorobenzyl)oxy)phenoxy)(tert-butyl)dimethylsilane 22 (30 g, 69.87 mmol), bis(pinacolato)diboron (21.29 g, 83.84 mmol), potassium acetate (20.57 g, 209.61 mmol) in 1,4-dioxane (300 mL) was deoxygenated by purging argon over 15 min, then [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.11 g, 6.987 mmol) was added and the reaction mixture was stirred at 100 °C for 3 h. After completion, the reaction mixture was cooled to room temperature, filtered through a pad of celite, washed with ethylTSRI 2226.1PC acetate (150 mL) and the filtrate was concentrated to give crude product. The crude product was then purified by column chromatography over silica gel (230-400 mesh) using 0-10% ethyl acetate in pet-ether to afford tert-butyl(4-((2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzyl)oxy)phenoxy)dimethylsilane 23 (30 g, 90.12% yield) as an yellow gum. LCMS [ESI, M+1]: 477.3. Step b: A mixture of tert-butyl(4-((2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzyl)oxy)phenoxy)dimethylsilane 23 (30 g, 62.97 mmol), 3-nitro-1H-1,2,4-triazole 24 (14.36 g, 125.93 mmol), boric acid (7.79 g, 125.93 mmol), pyridine (19.92 g, 251.88 mmol) and molecular sieves (4 Å powder; 15 g) in acetonitrile (300 mL) was purged with oxygen for 15 min. Then copper(II) acetate (34.31 g, 188.91 mmol) was added and the mixture was stirred at 90 °C for 4 h. After completion, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (150 mL), filtered through a pad of celite, washed the celite pad with ethyl acetate (150 mL) and the filtrate was concentrated to give crude product. The crude product was then purified by column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in pet-ether to afford 1-(4-((4-((tert-butyldimethylsilyl)oxy)phenoxy)methyl)-3,5-difluorophenyl)- 3-nitro-1H-1,2,4-triazole 25 (15 g, 51.5% yield) as a pale yellow solid. LCMS [ESI, M+1]: 463.2. Step c: Zinc dust (10.6 g, 162.15 mmol) was added to a mixture of 1-(4-((4-((tert- butyldimethylsilyl)oxy)phenoxy)methyl)-3,5-difluorophenyl)-3-nitro-1H-1,2,4-triazole 25 (15 g, 32.43 mmol) in tetrahydrofuran (75 mL) and methanol (75 mL), was added ammonium chloride (34.7 g, 648.6 mmol) in water (75 mL) at 0 °C, the resultant mixture was stirred at room temperature for 3 h. After completion, the reaction mixture was diluted with ethyl acetate (150 mL) and water (100 mL), stirred for 15 min, then filtered through a pad of celite. The celite pad was washed with ethyl acetate (150 mL), and the layers were separated and the aqueous layer was extracted with ethyl acetate (2 X 200 mL). The combined organic layer was dried over anhydrous sodium sulphate and evaporated to give crude product. The crude product was stirred with 10% ethyl acetate in pet-ether (200 mL), the resultant solid was filtered and dried to afford 1-(4-((4-((tert-butyldimethylsilyl)oxy)phenoxy)methyl)-3,5-difluorophenyl)-1H-1,2,4-triazol-3- amine 26 (9.1 g, 64.3%) as a pale yellow solid. LCMS [ESI, M+1]: 433.3;1H NMR (400 MHz,TSRI 2226.1PC DMSO-d6) δ 8.93 (s, 1 H), 7.54 (d, J = 8.80 Hz, 2 H), 6.92-6.90 (m, 2 H), 6.78-6.76 (m, 2 H), 5.90 (s, 2 H), 5.00 (s, 2 H), 0.93 (s, 9 H), 0.15 (s, 6 H);19F NMR (400 MHz, DMSO-d6) δ - 112.81. Step d: Tetrabutylammonium fluoride 1.0 M tetrahydrofuran (29.4 mL, 24.5 mmol) was added to a suspension of 1-(4-((4-((tert-butyldimethylsilyl)oxy)phenoxy)methyl)-3,5-difluorophenyl)- 1H-1,2,4-triazol-3-amine 26 (10.6 g, 24.5 mmol) in tetrahydrofuran (53 mL) at 0 °C and the reaction mixture was stirred at room temperature for 1 h. After completion, the reaction mixture was diluted with water (100 mL) and resulting mixture was extracted with ethyl acetate (2 X 200 mL). The combined organic layer was dried over anhydrous sodium sulphate and evaporated to give crude product. The crude product was then stirred with 10% ethyl acetate in pet-ether (200 mL), resultant solid was filtered and dried under vacumm to afford 4-((4-(3-amino-1H-1,2,4- triazol-1-yl)-2,6-difluorobenzyl)oxy)phenol 27 (7.7 g, 98.7%) off-white solid. LCMS [ESI, M+1]: 319.1;1H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (s, 1 H), 8.93 (s, 1 H), 7.53 (d, J = 8.80 Hz, 2 H), 6.83 (d, J = 6.80 Hz, 2 H), 6.68 (d, J = 8.80 Hz, 2 H), 5.89 (s, 2 H), 4.97 (s, 2 H);19F NMR (400 MHz, DMSO-d6) δ = -112.81. Step e: To a stirred suspension of 4-((4-(3-amino-1H-1,2,4-triazol-1-yl)-2,6- difluorobenzyl)oxy)phenol 27 (7.7 g, 24.19 mmol) in tetrahydrofuran (77 mL) was added 1,8- diazabicyclo[5.4.0]undec-7-ene (11 g, 72.57 mmol) followed by 4- (acetylamino)phenyl]imidodisulfuryl difluoride (9.12 g, 29.03 mmol) at 0 °C and the resultant mixture was stirred at 0 °C for 30 min. After completion, the reaction mixture was diluted with ice-cold water (500 mL) and stirred for 10 min. After 10 min, precipitate was filtered, washed with n-pentane (100 mL) and dried under vaccumm to afford 4-((4-(3-amino-1H-1,2,4-triazol-1- yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate 28 (9.5 g, 98.1%) as a pale yellow solid. LCMS [ESI, M+1]: 401.2;1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1 H), 7.58-7.55 (m, 4 H), 7.22 (d, J = 9.20 Hz, 2 H), 5.91 (s, 2 H), 5.15 (s, 2 H);19F NMR (400 MHz, DMSO-d6): 37.51, - 112.67 Step f: To a stirred suspension of 4-((4-(3-amino-1H-1,2,4-triazol-1-yl)-2,6- difluorobenzyl)oxy)phenyl sulfurofluoridate 28 (9.5 g, 23.74 mmol) in dichloromethane (95 mL) was added triethylamine (16.54 mL, 118.68 mmol) followed by methanesulfonyl chloride (9.2TSRI 2226.1PC mL, 118.68 mmol) slowly at 0 °C and the resultant mixture was stirred at room temperature for 1 h. After completion, the mixture was diluted with ice cold water (200 mL) and extracted with dichloromethane (2 × 200 mL). The combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to give crude product. The crude product was then purified by column chromatography over silica gel (230-400 mesh) using 30-35% ethyl acetate in pet-ether as a gradient to afford 4-((2,6-difluoro-4-(3-(N- (methylsulfonyl)methylsulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate 29 (11.4 g, 86.4%) as an off-white solid. LCMS [ESI, M+1]: 557.0;1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1 H), 7.91 (d, J = 8.4 Hz, 2 H), 7.57 (d, J = 9.20 Hz, 2 H), 7.24 (d, J = 9.20 Hz, 2 H), 5.23 (s, 2 H), 3.68 (s, 6 H);19F NMR (400 MHz, DMSO-d6): 37.56, -111.44. Step g: Tetrabutylammonium fluoride (1.0 M in tetrahydrofuran; 24.58 mL, 24.58 mmol) was added to a solution of 4-((2,6-difluoro-4-(3-(N-(methylsulfonyl)methylsulfonamido)-1H-1,2,4- triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate 29 (11.4 g, 20.48 mmol) in tetrahydrofuran (57 mL) at 0 °C and the resultant mixture was stirred at 0 °C for 1 h. After completion, the reaction mixture was diluted with water (100 mL) and the reaction mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic layer was dried over sodium sulphate and evaporated to give crude product. The crude was then purified by column chromatography over silica gel using 65-70% ethyl acetate in pet-ether to afford 4-((2,6-difluoro-4-(3- (methylsulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate Compound 95 (4.6 g, 46.94%) as a white solid. LCMS [ESI, M+1]: 479.1;1H NMR (400 MHz, DMSO-d6) δ 11.2 (s, 1 H), 9.28 (s, 1 H), 7.73 (d, J = 8.4 Hz, 2 H), 7.57 (d, J = 9.20 Hz, 2 H), 7.23 (d, J = 9.20 Hz, 2 H), 5.20 (s, 2 H), 3.32 (s, 3 H);13C NMR (100 MHz, DMSO- d6) δ 163.30, 163.21, 160.82, 160.74, 158.33, 157.89, 144.09, 143.69, 139.04, 138.90, 138.76, 122.93, 116.87, 111.05, 110.86, 110.66, 103.18, 102.97, 102.88, 58.55, 41.72;19F NMR (400 MHz, DMSO- d6): δ 37.54, -112.00. Synthesis of 3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)benzoic acid Compound 145TSRI 2226.1PC OH OH F F Pd(dppf)Cl2, CO (50 psi)F O2.38 mmol, 1.00 eq.), TEA (723 mg, 7.14 mmol, 994 uL, 3.00 eq.) and Pd(dppf)Cl2(87.1 mg, 119 umol, 0.05 eq.) in MeOH (10.0 mL) was degassed and purged with CO for 3 times, and then the mixture was stirred at 80 °C for 12 hours under CO atmosphere (50 psi). The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 20 / 1 to 1 / 1) to give methyl 3,5-difluoro-4-[(4-hydroxyphenoxy)methyl]benzoate (670 mg, 2.3 mmol, 96% yield, 99% purity) as a white solid. LCMS [ESI, M+1]: 295.0.1H NMR (400 MHz, DMSO) δ = 9.02 (s, 1H), 7.64 (d, J = 7.6 Hz, 2H), 6.84 (br d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.8 Hz, 2H), 5.04 (s, 2H), 3.88 (s, 3H). Compound 3: To a solution of methyl 3,5-difluoro-4-[(4-hydroxyphenoxy)methyl] benzoate (670 mg, 2.28 mmol, 1.00 eq.) in THF (6.00 mL) was added a solution of LiOH•H2O (287 mg, 6.83 mmol, 3.00 eq.) in H2O (6.00 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour. HCl (1 N) was added to the mixture until pH = 7, the mixture was filtered and the filter cake was dried under reduced pressure to give 3,5-difluoro-4-[(4-hydroxyphenoxy)methyl]benzoic acid (540 mg, 1.9 mmol, 85% yield, 99% purity) as a white solid.1H NMR (400 MHz, DMSO) δ = 13.68 (br s, 1H), 9.01 (br s, 1H), 7.60 (d, J = 7.6 Hz, 2H), 6.90 - 6.77 (d, J = 8.8Hz, 2H), 6.69 - 6.58 (d, J = 8.8 Hz, 2H), 5.03 (s, 2H).TSRI 2226.1PC Compound 145: To a solution of 3,5-difluoro-4-[(4-hydroxyphenoxy) methyl]benzoic acid (500 mg, 1.78 mmol, 1.00 eq.) in DCM (1.00 mL) was added TEA (722 mg, 7.14 mmol, 993 uL, 4.00 eq.). The mixture was degassed and purged with sulfuryl difluoride for 3 times and stirred at 0 °C for 1 hour under sulfuryl difluoride atmosphere (15 psi). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18250*50mm*10 um;mobile phase: [water(0.225%FA)- ACN];B%: 40%-70%,15min) to give 3,5-difluoro-4-[(4- fluorosulfonyloxyphenoxy)methyl]benzoic acid Compound 145 (481 mg, 1.33 mmol, 74% yield, 99% purity) as a white solid.1H NMR (400 MHz, DMSO) δ = 13.72 (br s, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 9.2 Hz, 2H), 7.23 (d, J = 9.2 Hz, 2H), 5.23 (s, 2H).19F NMR (400 MHz, DMSO) δ = 37.55, -113.16. Intramacrophage activity of Compound 95 in THP-1 cells

[0121] THP-1 macrophages were obtained from ATCC TIB202 and maintained at 37 °C with 5% CO2. The Cells were passaged in RPMI 1640 supplemented with 10% fetal bovine serum (FBS) and 50 µM 2-Mercaptoethanol (Gibco).100 mL of 105cells / mL were differentiated by resuspending them in propagation media plus 50 nM of Phorbol myristate acetate (PMA) and incubating at 37 °C with 5% CO2overnight. The mid-log phase Mtb H37Rv strain carrying the lux-CDABE operon (Mtb-lux) was then diluted in propagation media and added to flask containing differentiated THP-1 at MOI of 1:1 for 24 h. The infected cells were washed twice with PBS and then resuspended in fresh media. The cells were then scrapped from the flask counted and added to drug spotted plates at final concentration of 105cells / well. Luminescence was recorded in CLARIOstar Plus (BMG Labtech) microplate reader at day 3 and data normalized to negative control (DMSO) minus inhibitor (Rifampicin 10 µM) on Genedata Screener Analyzer (v16.0.8.) Each drug concentration was tested in triplicates. MIC determination in Mtb H37Rv

[0122] The minimum inhibitory concentration (MIC) of the test compounds were determined using ten-point, two-fold serial dilutions in 7H9-OADC 20% tween 80 media either by itself or supplemented with 4% human serum albumin (HAS) using Microdilution Alamar Blue Assay (MABA) as previously described (Cho et al., 2015; VanderVen et al., 2015). Briefly,TSRI 2226.1PC Mycobacterial cells (H37Rv and Erdmann) at the mid-logarithmic phase of growth were diluted (1:1,000). Twenty µl of this dilution was added to each well containing 2-fold serially diluted test compounds and incubated for 7 days at 37 °C. Alamar Blue (Invitrogen) reagent (4 µL per well) was added along with 20% Tween 80 (2.5 µL per well, Sigma Aldrich) to evaluate bacterial cell viability. Plates were read 24 h after adding Alamar Blue at absorbance 570 nm with a reference wavelength of 600 nm. IC50 Determination in Mtb H37Ra

[0123] Inhibition concentration of 50 was determined against Mtb H37Ra in liquid culture using an Alamar Blue reduction assay was used as described (VanderVen et al., 2015). For inhibition assays in Mtb was first cultured to an (OD600 of 0.4) in 7H9 media (7H9 base supplemented with 10% OADC and glycerol) and 0.05% tyloxapol.1.0´106 bacteria were added to 384-well microplates containing 7H9 media to a final volume of 20 μL containing the experimental compounds or controls. Compounds were tested in a 9-point dose-titration, serially diluted 1:3 starting at 30 μM. The microplates were incubated for 7 days in humidified, sealed plastic bags at 37°C. To quantify bacterial proliferation 10 μL of an Alamar Blue solution 50% was added to each well and the plates were re-incubated at 37°C for 16 hr. Alamar Blue reduction was quantified using a PHERAstar plate reader (BMG Labtech) with λex = 492 nm and λem = 595 nm. All assay plates contained DMSO and 10 μM rifampicin control wells and percent inhibition for the experimental compounds was calculated. IC50 and IC90 values were determined by using the Smart Fit function in Genedata Screener Analyzer (v16.0.8) with the maximum % activity and the minimum % activity fixed at 100% and 0%, respectively.^ HEK293T cytotoxicity assay

[0124] HEK293T (ATCC) were grown in DMEM (Gibco Cat # 11965-092) supplemented with 10% heat-inactivated FBS, Pen Strep (Gibco) 1X in a 5% CO2humidified atmosphere at 37 ◦C. Cells were washed once with DPBS 1X (Gibco), incubated for less than 5 minutes at room temperature in TrypLE solution (Gibco), washed once in propagation medium to remove trypsin, and counted with Trypan Blue.5 µL of cell suspension (7.5x104cells / well) was dispensed into 1536-well plates containing serial 3-fold drug dilution ranging from 40 µM to 2 nM and incubated for 3 days in a 5% CO2humidified atmosphere at 37 ◦C. Cell Titer-Glo® LuminescentTSRI 2226.1PC Cell Viability Assay (Promega) reagent was diluted 1:1 with water and then 2 µL were added to plates. Luminescence was measured in a PHERAStar plate reader (BMG Labtech) and data normalized to negative control (DMSO) minus inhibitor (Puromycin 10 µM). Dose-response curves were fit using the Smart Fit function in Genedata Screener Analyzer (v16.0.8). HEPG2 CYTOTOXICITY ASSAY

[0125] HepG2 (ATCC) were grown in DMEM (Gibco Cat # 31053-028) supplemented with 10% heat-inactivated FBS, Pen Strep (Gibco) 1×, Glutamax 1× (Gibco), Sodium pyruvate 1 mM (Gibco) in a 5% CO2humidified atmosphere at 37 ◦C. Cells were washed twice with DPBS 1× (Gibco), incubated ten minutes at 37 ◦C in TrypLE solution (Gibco), washed once in propagation medium to remove trypsin and counted with Trypan Blue.5 µL of cell suspension (5.0×104cells / well) was dispensed into 1536-well plates, containing serial 3-fold drug dilution ranging from 40µM to 2 nM and incubated for 3 days in a 5% CO2humidified atmosphere at 37 ◦C. Cell Titer-Glo® Luminescent Cell Viability Assay (Promega) reagent was diluted 1:1 with water and then 2 µL were added to plates. Luminescence was measured in a PHERAStar plate reader (BMG Labtech) and data normalized to negative control (DMSO) minus inhibitor (Puromycin 10µM). Dose-response curves were fit using the Smart Fit function in Genedata Screener Analyzer (v16.0.8).

[0126] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the disclosure should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

[0127] This application refers to various issued patents, published patent applications, journal articles, and other publications, each of which are incorporated herein by reference.

Claims

TSRI 2226.1PC WHAT IS CLAIMED IS:

1. A compound having the Formula (I) R1mQ is O, NH, CH2, or absent; ---- represents a single or double bond; X1is O, CH, CH2, NH, N(C1-C6) alkyl, C(=O), N, NHC(=O), or S(=O)2; X2is CH,CH2, C(=O), N, O, -CH2S(=O)2-, or -CH2C(=O)NH-; wherein if X1is O, then X2is CH2, and ---- represents a single bond; if X1is CH, then X2is CH, and ---- represents a double bond; if X1is N, then X2is N, and ---- represents a double bond; if X1is NH or N(C1-C6) alkyl, then X2is C(=O), and ---- represents a single bond; if X1is C(=O), then X2is NH, and ---- represents a single bond; if X1is NHC(=O), then X2is - CH2S(=O)2-, and ---- represents a single bond; if X1is S(=O)2, then X2is -CH2C(=O)NH-, and -- -- represents a single bond; if X1is CH2, then X2is O, and ---- represents a single bond; if X2is O, then X1is CH2, and ---- represents a single bond; and if Q is absent, then X1is O, X2is CH2, and ---- represents a single bond; Y is absent, -C(=O)-, -C(=O)N(Y’)-, -(CH2)rC(=O)O-, -S(=O)2-, -C(=O)NHS(=O)2-, - NHC(=O)O-, -NHC(=O)NH-, -NHC(=O)-, -NH-, -NHS(=O)2-, -OCH2C(=O)NH-; or - S(=O)2NH-; Y’ is H or (C1-C6) alkyl; each Z is independently CH or N; A is H, halo, CN, NO2, (C1-C20) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, hetero (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C7) cycloalkyl, 3- to 7-membered heterocycloalkyl, (C6-C10) aryl, (C1-C6)TSRI 2226.1PC alkyl (C6-C10) aryl, 5- to 10-membered heteroaryl, or (C1-C6) alkyl 5- to 10-membered heteroaryl, optionally substituted with one or more A’; each A’ is independently OH, halo, CN, oxo, -C(=O)(C1-C6) alkyl, -C(=O)OH, (C1-C6) alkyl, (C1-C6) alkoxy, -S(=O)2(C1-C6) alkyl, -NHS(=O)2(C1-C6) alkyl, -N((C1-C6) alkyl)S(=O)2(C1-C6) alkyl, halo (C1-C6) alkyl, -NH2, -NH(C1-C6) alkyl, -N((C1-C6) alkyl)2,- C(=O)O(C1-C6) alkyl, -C(=O)NH2, -C(=O)NH(C1-C6) alkyl, -C(=O)N((C1-C6) alkyl)2, - NHC(=O)(C1-C6) alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, hydroxy (C1-C6) alkyl, (C1-C6) heteroalkyl, (C6-C10) aryl, (C1-C6) alkyl (C6-C10) aryl, or 5- to 10- membered heteroaryl, wherein 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, (C6-C10) aryl, and 5- to 10-membered heteroaryl are each optionally substituted with one or more A’’; each A’’ is independently OH, halo, (C1-C6) alkyl, hetero (C1-C6) alkyl, or halo (C1-C6) alkyl, each R1is independently halo, OH, CN, (C1-C6) alkyl, or halo (C1-C6) alkyl; each R2is independently halo, OH, NH2, CN, -C(=O)OH, (C1-C6) alkyl, halo (C1-C6) alkyl, or hetero (C1-C6) alkyl; or A and R2together form a fused (C6-C10) aryl; or two R2together form a fused (C6-C10) aryl or 3- to 7-membered heterocycloalkyl, optionally substituted with one or more OH, halo, NH2, NHC(=O)O(C1-C6) alkyl, CN, oxo, (C1- C6) alkyl, hetero (C1-C6) alkyl, hydroxy (C1-C6) alkyl, halo (C1-C6) alkyl, or (C3-C7) cycloalkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; r is 0, 1, or 2; with the proviso that Formula (I) is not 1) 4-(benzyloxy)phenyl sulfurofluoridate, 2) (E)-4- (phenyldiazenyl)phenyl sulfurofluoridate; 3) 3-(phenylcarbamoyl)phenyl sulfurofluoridate; 4) (E)-4-(3,5-dihydroxystyryl)phenyl sulfurofluoridate; 5) (E)-4-(3,5-dimethoxystyryl)phenyl sulfurofluoridate; 6) 4-(p-tolylcarbamoyl)phenyl sulfurofluoridate; 7) 4-((2- iodobenzyl)oxy)phenyl sulfurofluoridate; 8) (E)-3-hydroxy-5-(4-hydroxystyryl)phenyl sulfurofluoridate; 9) (Z)-2-methoxy-5-(3,4,5-trimethoxystyryl)phenyl sulfurofluoridate; 10) ((E)- 2-((4-((fluorosulfonyl)oxy)phenyl)diazenyl)benzoic acid); 11) (E)-4-((3,5-dichloro-4-TSRI 2226.1PC hydroxyphenyl)diazenyl)phenyl sulfurofluoridate; 12) (E)-3-((3,5-dichloro-4- hydroxyphenyl)diazenyl)phenyl sulfurofluoridate; 13) (E)-4-((4-hydroxy-3,5- dimethylphenyl)diazenyl)phenyl sulfurofluoridate; 14) (E)-3-((4-hydroxy-3,5- dimethylphenyl)diazenyl)phenyl sulfurofluoridate; 15) (E)-4-((4-hydroxyphenyl)diazenyl)phenyl sulfurofluoridate; 16) (E)-4-((4-aminophenyl)diazenyl)phenyl sulfurofluoridate; 17) (E)-4-((4- amino-3-chlorophenyl)diazenyl)-2-chlorophenyl sulfurofluoridate; 18) (E)-4-((4- chlorophenyl)diazenyl)phenyl sulfurofluoridate; 19) (E)-4-((4-bromophenyl)diazenyl)phenyl sulfurofluoridate; 20) (E)-4-(p-tolyldiazenyl)phenyl sulfurofluoridate; 21) (E)-2-chloro-4-((3- chlorophenyl)diazenyl)phenyl sulfurofluoridate; 22) 2-[4-[(fluorosulfonyl)oxy]phenyl]-5,6,7- trimethoxy-4H-1-benzopyran-4-one; 23) N-[4-[(fluorosulfonyl)oxy]phenyl]-3,4-dihydro-2- methyl-3-oxo-2H-1,4-benzothiazine-6-carboxamide; 24) N-[3-[(fluorosulfonyl)oxy]phenyl]-3,4- dihydro-2-methyl-3-oxo-2H-1,4-benzothiazine-6-carboxamide; 25) 4-[[4- [(fluorosulfonyl)oxy]phenyl]methoxy]-1,3-Benzenedicarboxaldehyde; 26) 4-[[4- [(fluorosulfonyl)oxy]phenyl]methoxy]-1,3-Benzenedimethanol; 27) N-[3-[[3- [(fluorosulfonyl)oxy]phenyl]methoxy]phenyl]-3,4-dihydro-2-methyl-3-oxo2H-1,4- benzothiazine-6-carboxamide; 28) N-[3-[[4-[(fluorosulfonyl)oxy]phenyl]methoxy]phenyl]-3,4- dihydro-2-methyl-3-oxo-2H-1,4-Benzothiazine-6-carboxamide; 29) 4-((3- aminophenoxy)methyl)phenyl sulfurofluoridate; 30) 3-((3-aminophenoxy)methyl)phenyl sulfurofluoridate; 31) methyl 4-((4-((fluorosulfonyl)oxy)benzyl)oxy)-3,5- bis(hydroxymethyl)benzoate; 32) 4-((2,4,6-tris(hydroxymethyl)phenoxy)methyl)phenyl sulfurofluoridate; 33) 4-((2,4-bis(bromomethyl)phenoxy)methyl)phenyl sulfurofluoridate; 34) 4- (((2-amino-4-((tert-butoxycarbonyl)amino)quinazolin-5-yl)oxy)methyl)phenyl sulfurofluoridate; or 35) 4-(((2,4-diaminoquinazolin-5-yl)oxy)methyl)phenyl sulfurofluoridate; 36) 3-chloro-4- (pyridin-2-ylmethoxy)benzenesulfonyl fluoride; 37) 4-(benzyloxy)benzenesulfonyl fluoride; 38) 3-chloro-4-((3-fluorobenzyl)oxy)benzenesulfonyl fluoride; or 39) 4-((4- nitrobenzyl)oxy)benzenesulfonyl fluoride; including any enantiomers, scalemic or racemic mixtures, or pharmaceutically acceptable salts thereof.

2. The compound of Claim 1, wherein the compound has any one of Formulae (Ia)-(Id):TSRI 2226.1PC O FR1O1SmR2F RmnSR2Y A Y A .wherein: each Z is independently CH or N; Y is absent, -C(=O)-, -C(=O)N(Y’)-, -(CH2)rC(=O)O-, -S(=O)2-, -C(=O)NHS(=O)2-, - NHC(=O)O-, -NHC(=O)NH-, -NHC(=O)-, -NH-, -NHS(=O)2-, -OCH2C(=O)NH-; or - S(=O)2NH-; Y’ is H or (C1-C6) alkyl; each Z is independently CH or N;TSRI 2226.1PC A is H, halo, CN, NO2, (C1-C20) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, hetero (C1-C6) alkyl, halo (C1-C6) alkyl, (C3-C7) cycloalkyl, 3- to 7-membered heterocycloalkyl, (C6-C10) aryl, (C1-C6) alkyl (C6-C10) aryl, 5- to 10-membered heteroaryl, or (C1-C6) alkyl 5- to 10-membered heteroaryl, optionally substituted with one or more A’; each A’ is independently OH, halo, CN, oxo, -C(=O)(C1-C6) alkyl, -C(=O)OH, (C1-C6) alkyl, (C1-C6) alkoxy, -S(=O)2(C1-C6) alkyl, -NHS(=O)2(C1-C6) alkyl, -N((C1-C6) alkyl)S(=O)2(C1-C6) alkyl, halo (C1-C6) alkyl, -NH2, -NH(C1-C6) alkyl, -N((C1-C6) alkyl)2,- C(=O)O(C1-C6) alkyl, -C(=O)NH2, -C(=O)NH(C1-C6) alkyl, -C(=O)N((C1-C6) alkyl)2, - NHC(=O)(C1-C6) alkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, hydroxy (C1-C6) alkyl, (C1-C6) heteroalkyl, (C6-C10) aryl, (C1-C6) alkyl (C6-C10) aryl, or 5- to 10- membered heteroaryl, wherein 3- to 7-membered cycloalkyl, 3- to 7-membered heterocycloalkyl, (C6-C10) aryl, and 5- to 10-membered heteroaryl are each optionally substituted with one or more A’’; each A’’ is independently OH, halo, (C1-C6) alkyl, hetero (C1-C6) alkyl, or halo (C1-C6) alkyl, each R1is independently halo, OH, CN, (C1-C6) alkyl, or halo (C1-C6) alkyl; each R2is independently halo, OH, NH2, CN, -C(=O)OH, (C1-C6) alkyl, halo (C1-C6) alkyl, or hetero (C1-C6) alkyl; or A and R2together form a fused (C6-C10) aryl; or two R2together form a fused (C6-C10) aryl or 3- to 7-membered heterocycloalkyl, optionally substituted with one or more OH, halo, NH2, NHC(=O)O(C1-C6) alkyl, CN, oxo, (C1- C6) alkyl, hetero (C1-C6) alkyl, hydroxy (C1-C6) alkyl, halo (C1-C6) alkyl, or (C3-C7) cycloalkyl; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; r is 0, 1, or 2; with the proviso that Formula (II) is not 1) 3-bromo-5-(1-phenyl-1H-1,2,3-triazol-4-yl)phenyl sulfurofluoridate; 2) 3-((fluorosulfonyl)oxy)-5-(1-(4-methoxyphenyl)-1H-1,2,3-triazol-4- yl)benzoic acid; or 3) 3-((fluorosulfonyl)oxy)-5-(1-(p-tolyl)-1H-1,2,3-triazol-4-yl)benzoic acid;TSRI 2226.1PC including any enantiomers, scalemic or racemic mixtures, or pharmaceutically acceptable salts thereof.

4. The compound of any one of Claims 1-3, wherein m is 0.

5. The compound of any one of Claims 1-4, wherein n is 0.

6. The compound any one of Claims 1-4, wherein n is 1.

7. The compound of any one of Claims 1-4, wherein n is 2.

8. The compound of any one of Claims 1-4 or 6-7, wherein R2is halo.

9. The compound of Claim 8, wherein halo is F.

10. The compound of any one of Claims 1-9, wherein Y is absent.

11. The compound of any one of Claims 1-9, wherein Y is -C(=O)-.

12. The compound of any one of Claims 1-9, wherein Y is -C(=O)O-.

13. The compound of any one of Claims 1-9, wherein Y is -NHC(=O)-.

14. The compound of any one of Claims 1-9, wherein Y is -C(=O)NH-.

15. The compound of any one of Claims 1-14, wherein A is H.

16. The compound of any one of Claims 1-14, wherein A is (C1-C12) alkyl.

17. The compound of any one of Claims 1-14, wherein A is 5- to 10-membered heteroaryl.

18. The compound of any one of Claims 1-14, wherein A is (C6-C10) aryl.

19. The compound of any one of Claims 1-14, wherein A is 3- to 7-membered heterocycloalkyl.

20. The compound of any one of Claims 1-19, wherein X1is O, X2is CH2, and ---- represents a single bond.

21. The compound of any one of Claims 1-19, wherein X1is CH, X2is CH, and ---- represents a double bond.

22. The compound of any one of Claims 1-19, wherein X1is N, X2is N, and ---- represents a double bond.

23. The compound of any one of Claims 1-19, wherein X1is NH or N(C1-C6) alkyl, X2is C(=O), and ---- represents a single bond; 24. A compound having the structure of Compound 95:TSRI 2226.1PC O F F S O O N O NOOS N N mixtures, or pharmaceutically acceptable salts25. A compound having the structure of Compound 94: F O F S O or racemic mixtures, or pharmaceutically acceptable salts26. A compound having any one of the formulae selected from the group consisting of: methyl 3-fluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)benzoate; methyl 4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)benzoate; 4-((4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-carbamoylbenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(pyridin-3-ylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(but-3-en-1-ylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; (E)-4-(4-acetamidostyryl)phenyl sulfurofluoridate; (E)-4-((4-acetamidophenyl)diazenyl)phenyl sulfurofluoridate; (E)-4-((4-(pyridin-3-ylcarbamoyl)phenyl)diazenyl)phenyl sulfurofluoridate; 4-((4-(nicotinamido)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate;TSRI 2226.1PC 4-((4-(cyclopropylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(ethylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; methyl 2-(4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)acetate; 4-((4-(morpholine-4-carbonyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(methylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(propylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(pyrrolidine-1-carbonyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(phenethylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-cyanobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-acetamidobenzyl)oxy)phenyl sulfurofluoridate; (E)-3-chloro-4-(4-(fluorocarbonyl)styryl)phenyl sulfurofluoridate; 4-((2-chlorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-acetamidobenzyl)oxy)-3-fluorophenyl sulfurofluoridate; (E)-4-((4-acetamidophenyl)diazenyl)-3-fluorophenyl sulfurofluoridate; 4-((4-(isopropylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)benzoic acid; 4-((4-(benzylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(dimethylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-((4-phenylbutyl)carbamoyl)benzyl)oxy)phenyl sulfurofluoridate;TSRI 2226.1PC 4-((4-(piperidine-1-carbonyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(phenylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(phenylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(butylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(heptan-2-ylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(1-methyl-1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-acetamidobenzyl)oxy)-3-chlorophenyl sulfurofluoridate; 4-((4-propionamidobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(methylsulfonyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(pyrazin-2-yl)benzyl)oxy)phenyl sulfurofluoridate; (E)-4-((4-(pyridin-4-ylcarbamoyl)phenyl)diazenyl)phenyl sulfurofluoridate; 4-((4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(cyclohexylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; (E)-4-((4-acetamidophenyl)diazenyl)-3-methylphenyl sulfurofluoridate; 4-((4-(4-methylpiperidine-1-carbonyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-acetamidobenzyl)oxy)-3-methylphenyl sulfurofluoridate; 4-((4-(4-methylpiperazine-1-carbonyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-ethynylbenzyl)oxy)phenyl sulfurofluoridate; (E)-4-((4-(4-oxopiperidine-1-carbonyl)phenyl)diazenyl)phenyl sulfurofluoridate; (E)-4-((4-(diethylcarbamoyl)phenyl)diazenyl)phenyl sulfurofluoridate; 4-((2-fluoro-5-(trifluoromethyl)benzyl)oxy)phenyl sulfurofluoridate;TSRI 2226.1PC 4-((4-(undecylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(quinolin-3-ylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; (E)-4-((4-((fluorosulfonyl)oxy)phenyl)diazenyl)benzoic acid; 4-((4-chlorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(octadec-9-en-1-ylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((3-chlorobenzyl)oxy)phenyl sulfurofluoridate; (E)-4-((4-(morpholine-4-carbonyl)phenyl)diazenyl)phenyl sulfurofluoridate; 4-((4-(trifluoromethyl)benzyl)oxy)phenyl sulfurofluoridate; 3-((4-acetamidophenyl)carbamoyl)phenyl sulfurofluoridate; 2-(4-((fluorosulfonyl)oxy)phenyl)benzo[d]thiazole-6-carboxylic acid; 2-((4-acetamidophenyl)carbamoyl)pyridin-4-yl sulfurofluoridate; 4-(1-(4-aminophenyl)-1H-1,2,3-triazol-4-yl)phenyl sulfurofluoridate; 4-((4-(benzyl(methyl)carbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(hexadecylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 3-(1-(4-aminophenyl)-1H-1,2,3-triazol-4-yl)phenyl sulfurofluoridate; 3-(1-(4-acetamidophenyl)-1H-1,2,3-triazol-4-yl)phenyl sulfurofluoridate; N-(4-((4-hydroxyphenoxy)methyl)phenyl)acetamide; 4-(4-acetamidobenzamido)phenyl sulfurofluoridate; 3-(4-acetamido-N-methylbenzamido)phenyl sulfurofluoridate; 2-(pyrrolidin-1-yl)benzo[d]thiazol-6-yl sulfurofluoridate;TSRI 2226.1PC 4-(2-((4-fluorophenyl)sulfonyl)acetamido)phenyl sulfurofluoridate; 4-((2-((5-chloropyridin-2-yl)amino)-2-oxoethyl)sulfonyl)phenyl sulfurofluoridate; methyl 2-(4-((fluorosulfonyl)oxy)phenyl)-4-oxo-4H-chromene-6-carboxylate; (E)-4-(4-aminostyryl)phenyl sulfurofluoridate; methyl (E)-4-(2-chloro-4-((fluorosulfonyl)oxy)styryl)benzoate; 4-(3-(4-acetamidophenoxy)oxetan-3-yl)phenyl sulfurofluoridate; 4-((4-methylbenzyl)oxy)phenyl sulfurofluoridate; 4-(naphthalen-2-ylmethoxy)phenyl sulfurofluoridate; 4-([1,1'-biphenyl]-4-ylmethoxy)phenyl sulfurofluoridate; 4-((4-(2H-tetrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-((fluorosulfonyl)carbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)benzenesulfonyl fluoride; (4-((4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl)sulfamoyl fluoride; methyl 4-((4-((fluorosulfonyl)methyl)phenoxy)methyl)benzoate; 3-((4-acetamidophenoxy)methyl)phenyl sulfurofluoridate; 4-((4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenol; methyl 3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)benzoate; ethyl 1-(3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)-5-(trifluoromethyl)-1H-1,2,3- triazole-4-carboxylate; 4-((2,6-difluoro-4-(5-methyl-3-(methylsulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-3-(3-(methylsulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(methylsulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-(ethylsulfonamido)-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate;TSRI 2226.1PC 4-((4-(1-(4-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-(methylsulfonamido)-1H-1,2,3-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-hydroxypyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(4-carbamoyl-1H-imidazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-(methylcarbamoyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-acetamido-1H-pyrazol-5-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(hydroxymethyl)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(4-carbamoyl-1H-1,2,3-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1H-1,2,3-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(methoxymethyl)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-acetamido-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-carbamoyl-1-methyl-1H-pyrazol-5-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-carbamoyl-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(6-hydroxypyridin-2-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4H-1,2,4-triazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(4-carbamoyl-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(4-cyano-5-methyl-1H-imidazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-hydroxy-6-methylpyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(pyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(pyridazin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(pyridin-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-methyl-1H-imidazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-(difluoromethyl)-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(4-acetamido-1H-1,2,3-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate;TSRI 2226.1PC 4-((2,6-difluoro-4-(1H-imidazol-2-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-methyl-1H-imidazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(6-oxo-1,6-dihydropyridin-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(pyrimidin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-3-(methylcarbamoyl)-1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2-fluoro-4-(2-hydroxy-6-methylpyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-((methoxycarbonyl)amino)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-((1-methylethyl)sulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(2-chloropyridin-4-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-(dimethylamino)-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; methyl 5-(3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)-1-methyl-1H-pyrazole-3- carboxylate; 4-((4-(2,4-dimethyl-1H-imidazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-3-(methylsulfonamido)-1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(2-carbamoylpyridin-4-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(N-methylmethylsulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(methylsulfonamido)-1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1H-imidazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(5-hydroxypyrazin-2-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((3-((1H-1,2,4-triazol-1-yl)methyl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(hydroxymethyl)-5-methyl-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)benzoic acid; 4-((2,6-difluoro-4-(3-(methylsulfonyl)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1H-tetrazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-carbamoyl-5-methyl-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-cyano-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate;TSRI 2226.1PC 4-((2,6-difluoro-4-(2-(methylamino)-2-oxoethoxy)benzyl)oxy)phenyl sulfurofluoridate; 4-((3-fluoro-5-(3-(methylsulfonamido)-1H-1,2,4-triazol-1-yl)pyridin-2-yl)methoxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-sulfamoyl-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-methyl-1H-1,2,3-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-1H-1,2,4-triazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(methylcarbamoyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-methyl-1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-3-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,4-difluoro-5-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 1-(3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)-5-(trifluoromethyl)-1H-1,2,3- triazole-4-carboxylic acid; 4-((2,6-difluoro-4-(2-methylpyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-ethyl-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-isopropyl-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(4-cyano-1H-1,2,3-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-(trifluoromethyl)pyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2-chloro-6-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-cyano-1H-pyrazol-5-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-amino-1H-pyrazol-5-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-1H-imidazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-methoxy-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(pyrazin-2-yl)benzyl)oxy)phenyl sulfurofluoridate; methyl 4-(3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)picolinate; 4-((4-(2-aminopyridin-4-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(2-cyanopyridin-4-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate;TSRI 2226.1PC 4-((2,6-difluoro-4-(pyridin-2-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-methyl-4H-1,2,4-triazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-methoxypyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(5-methyl-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-fluoro-2-methylpyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-hydroxypyridin-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(2-acetamidopyridin-4-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(5-fluoro-2-methylpyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-morpholino-1H-imidazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2-fluoro-4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-((3-(methylsulfonamido)-1H-1,2,4-triazol-1-yl)methyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(5-(methylsulfonyl)-1H-1,2,4-triazol-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(2-(difluoromethyl)pyridin-4-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-(trifluoromethyl)-1H-imidazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-hydroxy-2-oxo-1,2-dihydropyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(methylsulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)-3-fluorophenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-morpholino-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-((1H-1,2,4-triazol-1-yl)methyl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(isoxazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-fluoro-3-((4-((fluorosulfonyl)oxy)phenoxy)methyl)benzoic acid; 4-((2,6-difluoro-4-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-chloro-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate;TSRI 2226.1PC 4-((2,6-difluoro-4-(3-(methylsulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)-2-methylphenyl sulfurofluoridate; 4-((4-((4H-1,2,4-triazol-4-yl)methyl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(methylsulfonamido)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(pyrimidin-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(trifluoromethyl)-1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-nitro-1H-1,2,3-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2-cyano-6-fluoro-4-(1H-1,2,3-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1H-imidazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(4-amino-1H-1,2,3-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-(tert-butyl)-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 3-cyano-5-fluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)benzoic acid; 4-((2-cyano-6-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 1-(3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid; 4-((4-(1-(l1-oxidaneyl)-1l4-pyridin-4-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(2-(dimethylamino)pyridin-4-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2H-1,2,3-triazol-2-yl)benzyl)oxy)phenyl sulfurofluoridate; 6-((2,6-difluoro-4-(3-(methylsulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)pyridin-3-yl sulfurofluoridate; 4-((4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; isopropyl 3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)benzoate; 4-((2,3-difluoro-4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,5-difluoro-4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(pyrimidin-2-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(pyridazin-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 1-(3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)-1H-1,2,4-triazole-3-carboxylic acid; 4-((2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-amino-1-methyl-1H-pyrazol-5-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-acetamido-1-methyl-1H-pyrazol-5-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate;TSRI 2226.1PC 4-((2,6-difluoro-4-(1-methyl-1H-imidazol-2-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-oxo-2,3-dihydropyridazin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-((3-methyl-1H-1,2,4-triazol-1-yl)methyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-((5-methyl-1H-1,2,4-triazol-1-yl)methyl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-((1H-1,2,3-triazol-1-yl)methyl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-((2H-1,2,3-triazol-2-yl)methyl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-(hydroxymethyl)-6-methylpyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(5-fluoro-2-hydroxypyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-1H-1,2,4-triazol-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(2-chloro-6-hydroxypyridin-4-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-2-fluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,3-difluoro-5-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(methylsulfonamido)isoxazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-(methylsulfonamido)-1H-1,2,4-triazol-1-yl)benzyl)oxy)-3-methylphenyl sulfurofluoridate; 4-((3-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((3-fluoro-4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; ethyl 1-(3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)-4-(trifluoromethyl)-1H-1,2,3- triazole-5-carboxylate; 4-((3,4-difluoro-5-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,4-difluoro-3-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2-cyano-5-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-(methylsulfonamido)pyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1-methyl-1H-pyrazol-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(6-hydroxypyrimidin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-((3,5-dimethyl-1H-1,2,4-triazol-1-yl)methyl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(3-methylureido)benzyl)oxy)phenyl sulfurofluoridate;TSRI 2226.1PC 4-((5-((1H-1,2,4-triazol-1-yl)methyl)-2,4-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(4-cyano-1H-imidazol-1-yl)-2-fluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2-fluoro-4-(2-hydroxy-6-methylpyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(1-acetyl-3-amino-1H-pyrazol-5-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-3-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(2-hydroxy-6-(trifluoromethyl)pyridin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-(3-((1,1-dimethylethyl)sulfonamido)-1H-1,2,4-triazol-1-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-acetamidobenzyl)oxy)phenyl sulfurofluoridate; 4-((4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((3-fluoro-5-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methoxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1H-tetrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(1H-pyrazol-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2-cyano-6-fluoro-4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-morpholinobenzyl)oxy)phenyl sulfurofluoridate; 4-((3-cyano-5-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((3-fluoropyridin-2-yl)methoxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(5-hydroxyisoxazol-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(6-oxo-1,6-dihydropyridazin-4-yl)benzyl)oxy)phenyl sulfurofluoridate; 5-(3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid; 4-((2,5-difluoro-3-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2-fluoro-5-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,4-difluoro-5-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,3-difluoro-5-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2-fluoro-4-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-((4-cyano-1H-imidazol-1-yl)methyl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate; 4-((2,5-difluoro-3-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((3,5-difluoro-4-(1H-1,2,4-triazol-1-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-(1-(2,6-difluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)ethoxy)phenyl sulfurofluoridate;TSRI 2226.1PC 4-(3,5-difluoro-4-((4-((fluorosulfonyl)oxy)phenoxy)methyl)phenyl)picolinic acid; 4-((2,6-difluoro-4-(3-methoxy-1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2,6-difluoro-4-(4-hydroxy-1,2,5-oxadiazol-3-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((2-fluoro-3-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((3-fluoro-5-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-fluoro-3-(1H-pyrazol-5-yl)benzyl)oxy)phenyl sulfurofluoridate; 4-((4-((4-cyano-5-methyl-1H-imidazol-1-yl)methyl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate 4-((2,6-difluoro-4-(1H-pyrazol-5-yl)benzyl)oxy)phenol; and 4-((4-(3-carbamoyl-1H-pyrazol-5-yl)-2,6-difluorobenzyl)oxy)phenyl sulfurofluoridate.

27. A composition comprising the compound of any one of Claims 1-26, admixed with a pharmaceutically acceptable carrier, diluent, or excipient.

28. The composition of Claim 27, further comprising one or more therapeutic compounds or compositions used for the treatment of a mycobacterial disease.

29. The composition of Claim 27, further comprising one or more therapeutic compounds or compositions used for the treatment of a TB infection.

30. The composition of Claim 29, wherein the one or more therapeutic compounds or compositions is selected from bedaquiline, pretomanid and linezolid.

31. The composition of Claim 29, wherein the one or more therapeutic compounds or compositions is Nix-TB.

32. The composition of Claim 29, wherein the one or more therapeutic compounds or compositions is selected from bedaquiline, pretomanid, linezolid, isoniazid, rifampin, rifabutin, rifapentine, pyrazinamide, ethambutol, ethionamide, moxifloxacin, tedizolid, radezolid, sutezolid, posizolid clofazimine, gatifloxacin, kanamycin, nitroimidazo-oxazine, delamanid, OPC-167832, streptomycin, prednisolone, an oxazolidinone, a fluoroquinolone, a corticosteroid, EMB analogue SQ109, a benzothiazinone, a dinitrobenzamide, and an antiviral agent including an antiretroviral agent.

33. The composition of any one of Claims 27-31, wherein the composition is suitable for oral administration.TSRI 2226.1PC 34. A method of preventing, ameliorating, or treating a bacterial infection, comprising administering to a subject in need thereof a therapeutically effective amount the compound of any one of Claims 1-26 or the composition of any one of Claims 27-33.

35. A method of covalently targeting Mycobacterium tuberculosis (Mtb) acyltransferase domain of Polyketide synthase 13, comprising treating intracellular and / or extracellular Mtb with the compound of any one of Claims 1-26 or the composition of any one of Claims 27-33.

36. A method of preventing, ameliorating, or treating a mycobacterial disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of Claims 1-26 or the composition of any one of Claims 27-33.

37. A method of preventing, ameliorating, or treating a TB infection, comprising administering to a subject in need thereof a therapeutically effective amount the compound of any one of Claims 1-26 or the composition of any one of Claims 27-33.

38. Any compound, composition, or method as described herein.

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