Targeted covalent inhibitor for carbonic anhydrase

Abstract

To provide a composition for the prevention and / or treatment of diseases / disorders associated with carbonic anhydrase.SOLUTION: The present invention provides a pharmaceutical composition containing, as an active ingredient, fluorinated benzenesulfonamide compounds such as 2-((2-(cyclooctylamino)-3,5,6-trifluoro-4-sulfamoylphenyl)sulfonyl) ethyl acetate, 2-((2-(cyclododecylamino)-3,5,6-trifluoro-4-sulfamoylphenyl)sulfonyl) ethyl acetate. The composition has an irreversible inhibitory effect on carbonic anhydrase and is useful for the prevention and / or treatment of diseases / disorders associated with carbonic anhydrase.SELECTED DRAWING: None

Description

[Technical field]

[0001] The field of the invention relates to compounds that are precursors (designed / designated as prodrugs) of active compounds (designed / designated as pharmaceuticals), in particular compounds that are used as active ingredients in pharmaceutical formulations that irreversibly bind to and inhibit isoenzymes of carbonic anhydrase for the treatment of conditions responsive to the inhibition of carbonic anhydrase. [Background technology]

[0002] Carbonic anhydrase (CA) is present in all living organisms and acts as a catalyst for the reversible hydration of CO2. Fifteen carbonic anhydrase isozymes have been identified in humans, of which 12 are catalytically active and 3 are inactive forms of carbonic anhydrase. Carbonic anhydrase is involved in a wide range of physiological and pathological functions, and therefore several isozymes (e.g., CA II, IV, VA, VB, VII, IX, XII, XIII, and XIV) constitute targets for drug development. Carbonic anhydrase inhibitors (CAIs) are used as diuretics, systemic and local antiglaucoma agents, and are considered to be effective therapeutic agents for obesity, renal dysfunction, migraine, neuropathy, and epilepsy. In addition, several compounds are in clinical development for the treatment of hypoxic metastatic cancer. Recently, advances have been achieved in the treatment of conditions where there are few or no available therapeutic opportunities, such as neuropathic pain, cerebral ischemia, and some forms of arthritis.

[0003] The main classification of CAIs is aromatic and heterocyclic sulfonamides that are involved in reversible interactions with enzymes. The strong interaction of such compounds is based on the ability of the primary sulfonamide group to coordinate zinc at the binding site. Due to this feature, the irreversible inhibition mode of CAs has not been considered a priority or an inevitable necessity. However, irreversible covalent binding may be superior due to the sustained action of the active compounds, enhanced efficacy, the possibility of achieving complete target occupancy, and reduced competitiveness in an environment with high concentrations of natural substrates.

[0004] The development of covalent CA inhibitors began half a century ago with the brominated compounds bromoacetic acid, bromoacetazolamide, and N-bromoacetylacetazolamide, which may be involved in alkylation reactions. Unfortunately, the discovery of covalent inhibitors has pretty much stopped where it began, and covalent inhibitors have not been thoroughly explored among all CA isoenzymes. However, some progress has been made in protein labeling using CA as a model protein and attaching probes via a covalent mode. Although these investigations are not directly relevant to the expansion of the field of CA inhibitors, they may contribute to the development of covalent inhibitors.

[0005] For many years, it was believed that covalent inhibitors could cause too many side effects and were unlikely to be successful as pharmaceutical formulations. However, the rational design of covalent inhibitors, known as the design of targeted covalent inhibitors (TCIs), has opened a new era of covalent drug development. TCIs are generated from optimized reversible ligands and modified by the attachment of electrophilic reactive groups; warheads. Such warheads are predicted to act on proximal amino acids, most frequently cysteine, lysine, tyrosine, serine, threonine, or histidine. Thus, high affinity and selectivity compounds explored as reversible inhibitors can be repurposed into targeted covalent inhibitors.

[0006] In related publications (Dudutiene, V. et al. Bioorg. Med. Chem. 21, 2093-2106 (2013); EP2914583(B1)), fluorinated benzenesulfonamides were discovered as highly potent CA inhibitors. In other related publications (Dudutiene, V. et al. ChemMedChem, 10, 662-687 (2015); Dudutiene, V. et al. J. Med. Chem., 57, 9435-9446 (2014); EP2914583(B1)), it was shown that attachment of various substituents to the fluorinated benzenesulfonamide scaffold resulted in isoenzyme-selective inhibitors. Although the cited publications teach high affinity and selectivity compounds, they do not teach the use of TCIs to treat diseases by inhibiting the enzymatic activity of CA. Summary of the Invention

[0007] The present disclosure teaches compounds for the prevention and / or treatment of diseases / disorders associated with the inhibition of carbonic anhydrase. In the present disclosure, it has been observed that fluorinated benzenesulfonamides are useful in inhibiting carbonic anhydrase. These compounds are highly effective as inhibitors due to their irreversible mode of action. The pharmacological properties of these compounds make them useful in the treatment of conditions that respond to the inhibition of carbonic anhydrase; for example, glaucoma, macular edema, cataracts, retinopathy, infantile nystagmus syndrome (INS), retinal / cerebral edema, edema, acute mountain sickness, bipolar disorder, chronic obstructive pulmonary disease (COPD), gastric ulcer, obesity, epilepsy, sleep apnea syndrome, migraine, hemorrhagic infarction, diabetic injury, congestive heart failure, pulmonary hypertension, caries development, ischemic and hemorrhagic brain injury, osteoporosis, and cancer. [Brief description of the drawings]

[0008] [Figure 1]Binding to CAIX isoenzymes by FTSA and ITC. A, B: FTSA data of AV21-47 binding to CAIX. A: Raw data of CAIX unfolding in the presence of different compound concentrations. B: Dependence of CAIX melting temperature, Tm, on ligand concentration. C, D: Binding of AV19-37 to CAIX as determined by isothermal titration calorimetry. C: Raw ITC curve at 37°C in TRIS chloride buffer at pH 7.0. D: Integrated ITC curve.

[0009] [Diagram 2] CAIX-catalyzed CO2 hydration in the absence and presence of AV19-37 and AV19-36 measured by stopped-flow. A, CAIX was incubated with compounds for 2 h and CO2 hydration was measured. B, CAIX was incubated with compounds for 2 h and the complex was dialyzed in Tris buffer (pH 7.0) for 32 h. The black curve represents CAIX-catalyzed CO2 hydration. The grey curve is spontaneous CO2 hydration without CA enzyme. The dotted and dashed curves are CO2 hydration catalyzed by CAIX in the presence of compounds AV19-37 or AV19-36, respectively.

[0010] [Diagram 3] Figure 1 shows the mass spectra of native CAIX and the CAIX-AV19-37 complex. A, MS spectrum of native CAIX, corresponding to the molecular weight of the protein equal to 28060.32. B, spectrum of CAIX incubated with AV19-37 (protein / ligand molar ratio 1:2). The difference compared to the molecular weight of native CAIX is equal to 427.5 Da (corresponding to MW(AV19-37)-MW(acetic acid)=486.52-60.052=426.5). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Pharmaceutical compositions comprising fluorinated benzenesulfonamides are designed herein to covalently bind and inhibit carbonic anhydrase, and may be non-toxic, pharma- ceutical acceptable salts of fluorinated benzenesulfonamides that retain activity comparable to the parent compound and do not produce any harmful undesirable effects.

[0012] In the following description of pharmaceutical compositions, the use of such compositions may be for the treatment of diseases and disorders that respond to the inhibition of carbonic anhydrase.

[0013] Pharmaceutical compositions comprising fluorinated benzenesulfonamide compounds are designed to treat diseases related to the function of human carbonic anhydrase. The fluorinated benzenesulfonamide compounds have the general structure shown in Formula I: [ka] I Here, Y and X are F or NHR. 1 , N.R. 1 R 2 and Z is R 3 or NHR 3 ;R 1 , R 2 is R 4 , R 5 , R 6 , R 7 and R 4 is cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl, each of which is unfused or fused to benzene, and each of the rings is unsubstituted, or R 12 substituted on one or more carbon atoms with a substituent independently selected from 5 is alkyl, alkenyl, or alkynyl, each of which is unsubstituted; or R 12 substituted on one or more carbon atoms with a substituent independently selected from 6is phenyl, which is unfused or fused to benzene, a heteroarene, a cycloalkane, or a heterocycloalkane, each of which is unsubstituted, or R 12 substituted on one or more ring carbon atoms with a substituent independently selected from 7 is alkylphenyl, alkylheteroaryl, each of which is unsubstituted; or R 12 substituted on one or more carbon atoms with a substituent independently selected from 3 is R 8 , R 9 , R 10 , R 11 and R 8 is cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl, each of which is unfused or fused to benzene, and each of the rings is unsubstituted, or R 12 substituted on one or more carbon atoms with a substituent independently selected from 9 is alkyl, alkenyl, or alkynyl, each of which is unsubstituted; or R 12 substituted on one or more carbon atoms with a substituent independently selected from 10 is phenyl, which is unfused or fused to benzene, a heteroarene, a cycloalkane, or a heterocycloalkane, each of which is unsubstituted, or R 12 substituted on one or more ring carbon atoms with a substituent independently selected from 11 is alkylphenyl, alkylheteroaryl, each of which is unsubstituted; or R 12 substituted on one or more carbon atoms with a substituent independently selected from 12 is F, Cl, Br, I, OH, OR 13 , S.H., S.R. 13 , S(O)R 13 , SO2R 13 , C(O)R 13 , C(O)OR 13 , O.C.(O)R13 、C(O)N(R 13 )2、C(O)NHR 13 、C(O)N(CH3)R 13 、NHC(O)R 13 、NR 13 C(O)R 13 、NHC(O)OR 13 、NR 13 C(O)OR 13 、OC(O)N(R 13 )2、OC(O)NHR 13 、OC(O)NH2、NHC(O)NH2、NHC(O)NHR 13 、NHC(O)N(R 13 )2、NR 13 C(O)NHR 13 、NR 13 C(O)N(R 13 )2、SO2NH2、SO2NHR 13 、SO2N(R 13 )2、NR 13 SO2R 13 、NHSO2NHR 13 、NHSO2N(R 13 )2、NR 13 SO2NHR 13 、NR 13 SO2N(R 13 )2、C(O)NHNHOH、C(O)NHNHOR 13 、C(O)NHSO2R 13 、C(O)NR 13 SO2R 13 、C(NH)NH2、C(NH)NHR 13 、C(NH)N(R 13 )2、N(CH3)SO2NHR 13 、NHSO2N(CH3)R 13 、N(CH3)SO2N(CH3)R 13 、NH2、NHR 13 、N(R 13 )2、N(CH3)C(O)N(R 13 )2, CN, NO2, N3, C(O)H, CHNOH, CH(NOCH3), CF3, CF2CF3, OCF3, OCF2CF3, C(O)OH, C(O)NH2, R 13is alkyl, alkenyl, or alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl, alkylphenyl, alkylheteroaryl, phenyl, which are unfused or fused to benzene, heteroarene, cycloalkane, or heterocycloalkane.

[0014] The compounds of formula I are precursors (designated as prodrugs) that can form compounds with active electrophilic groups to create active compounds that can be covalently bonded to carbonic anhydrase via Scheme A. The active compounds shown in Structure II are formed in the presence of nucleophilic amino acids. Compounds of Structure II are highly reactive and eager to interact with nucleophilic amino acids to form covalent bonds. The highly reactive vinyl sulfone group is known as a warhead used for the formation of covalent bonds between nucleophilic amino acids of small molecules and proteins such as cysteine, lysine, tyrosine, histidine, etc. [ka] Scheme A Scheme A: Conversion of a compound of structure I to a compound of structure II and reaction with a nucleophilic amino acid of carbonic anhydrase (CA) to form a covalent bond between compound II and the enzyme. The nucleophilic residue of the enzyme is designated as HB.

[0015] Compounds of structure II are highly reactive and unstable and are obtained in situ. Compounds of structure II can be one of the following: [ka] where X and Y are F and NHR 1 ;NR 1 R 2 and R 1 , R 2 is R 4 , R 5 , R 6 , R 7 and R 4is cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl, each of which is unfused or fused to benzene, and each of the rings is unsubstituted, or R 8 substituted on one or more carbon atoms with a substituent independently selected from:

[0016] R 5 is alkyl, alkenyl, or alkynyl, each of which is unsubstituted; or R 8 substituted on one or more carbon atoms with a substituent independently selected from:

[0017] R 6 is phenyl, which is unfused or fused to benzene, a heteroarene, a cycloalkane, or a heterocycloalkane, each of which is unsubstituted, or R 8 substituted on one or more ring carbon atoms with substituents independently selected from:

[0018] R 7 is alkylphenyl, alkylheteroaryl, each of which is unsubstituted; or R 8 substituted on one or more carbon atoms with a substituent independently selected from 8 is F, Cl, Br, I, OH, OR 9 , S.H., S.R. 9 , S(O)R 9 , SO2R 9 , C(O)R 9 , C(O)OR 9 , O.C.(O)R 9 , C(O)N(R 9 )2, C(O)NHR 9 , C(O)N(CH3)R 9 , NHC(O)R 9 , N.R. 9 C(O)R 9 , NHC(O)OR 9 , N.R. 9 C(O)OR 9 , O.C.(O)N(R 9)2, OC(O)NHR 9 , OC(O)NH2, NHC(O)NH2, NHC(O)NHR 9 , NHC(O)N(R 9 )2, NR 9 C(O)NHR 9 , N.R. 9 C(O)N(R 9 )2, SO2NH2, SO2NHR 9 , SO2N(R 9 )2, NR 9 SO2R 9 , NHSO2NHR 9 , NHSO2N(R 9 )2, NR 9 SO2NHR 9 , N.R. 9 SO2N(R 9 )2, C(O)NHNHOH, C(O)NHNHOR 9 , C(O)NHSO2R 9 , C(O)NR 9 SO2R 9 , C(NH)NH2, C(NH)NHR 9 , C(NH)N(R 9 )2, N(CH3)SO2NHR 9 , NHSO2N(CH3)R 9 , N(CH3)SO2N(CH3)R 9 , NH2, NHR 9 , N(R 9 )2, N(CH3)C(O)N(R 9 )2, CN, NO2, N3, C(O)H, CHNOH, CH(NOCH3), CF3, CF2CF3, OCF3, OCF2CF3, C(O)OH, C(O)NH2.

[0019] R 9 is alkyl, alkenyl or alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl or heterocycloalkynyl, phenyl, which is unfused or fused to benzene, heteroarene, cycloalkane or heterocycloalkane.

[0020] Exemplary uses of pharmaceutical compositions comprising compounds taught by structure I include the suppression of conditions in which irreversible inhibition of carbonic anhydrase is required, including ocular disorders such as glaucoma, macular edema, diabetic macular edema, retinitis pigmentosa, hereditary retinoschisis, cataracts, retinopathies (including chronic central serous chorioretinopathy, diabetic retinopathy, and hypertensive retinopathy), and the treatment of infantile nystagmus syndrome (INS), cerebral edema, edema, acute mountain sickness, bipolar disorder, chronic obstructive pulmonary disease (COPD), gastric ulcers, obesity, epilepsy, sleep apnea, migraine, diabetic injury, and the like. In one embodiment, the present invention relates to a cancer that is selected from the group consisting of cancers of the following types: brain injury, congestive heart failure, pulmonary hypertension, dental caries development, cerebral ischemia, diabetic brain injury, heart disease (including angina, myocardial infarction), idiopathic intracranial hypertension, other disorders including hydrocephalus, various brain pathologies such as traumatic brain injury and ischemic and hemorrhagic infarction, osteoporosis, pseudotumor cerebri, cancer, particularly kidney cancer, pancreatic cancer, esophageal cancer, head and neck cancer, thyroid cancer (including papillary / follicular carcinoma), nasopharyngeal cancer, breast cancer, ovarian cancer, vulvar cancer, cervical cancer, bladder cancer, skin cancer (including squamous cell / basal cell carcinoma), liver cancer, lung cancer, brain tumor, and mesothelioma.

[0021] General Reaction Scheme Compounds of structure I can be obtained according to general synthetic schemes B and C.

[0022] Compounds bearing an ester group were synthesized according to Scheme B. Pentafluorobenzenesulfonamide was synthesized from pentafluorobenzenesulfonyl chloride via an amination reaction using ammonia solution in THF according to the literature (Dudutiene, V. et al. Bioorg. Med. Chem. 21, 2093-2106 (2013)). Selective aromatic nucleophilic substitution at the para position was achieved using 2-mercaptoethanol in MeOH with Et3N, followed by oxidation of the sulfide to a sulfone group using H2O2 solution in acetic acid, as described in the literature (Dudutiene, V. et al. Bioorg. Med. Chem. 21, 2093-2106 (2013)). Compound 5 was synthesized using the well-known Fischer esterification method with the corresponding alkyl or phenyl carboxylic acid in toluene and a few drops of H2SO4 (conc.). Meta / para substituted sulfonamides bearing ester functionality were synthesized by aromatic nucleophilic substitution of compound 4 with appropriate cycloalkyl nucleophiles in DMSO according to known procedures (Dudutiene, V. et al. Chem Med Chem, 10, 662-687 (2015); US9725467) (B2); EP2914583 (B1)). The aromatic nucleophilic substitution reaction was carried out with primary cycloalkyl nucleophiles, but the use of other nucleophiles (primary / secondary alkylamines and secondary cycloalkylamines) is also possible. Furthermore, by increasing the reaction temperature, it is possible to synthesize dimeta substituted sulfonamides. Compound 7 was then synthesized by Fischer esterification reaction with either alkyl or phenyl carboxylic acids, respectively, in toluene and a few drops of H2SO4 (concentrated). [ka] Scheme Ba) NH3aq. (25%), THF; b) HSCH2CH2OH, MeOH, Et3N; c) H2O2 (30%), AcOH; d) R1COOH, H2SO4 (concentrated), toluene; e) NH2R2, DMSO.

[0023] Compounds bearing a carbamate group were synthesized according to Scheme C. To avoid sulfonylurea by-products during the proper carbamate synthesis, the sulfonamide group was protected by forming a sulfonimide, compound 8, using the methodology described in the literature (Dudutiene, V. et al. Bioorg. Med. Chem. 21, 2093-2106 (2013)). Para-substituted carbamates were synthesized either by refluxing compound 8 in toluene with various phenyl isocyanates or by carrying out the reaction in MeCN at room temperature with DBTDL as catalyst. The final step was the deprotection of the sulfonamide group by refluxing compound 9 in toluene with a few drops of HCl (conc.). Although only one example of a meta / para-substituted sulfonamide bearing a carbamate group was synthesized, other meta / para-substituted sulfonamides can be synthesized in the same manner. Compound 11 was synthesized similarly to compound 6 via aromatic nucleophilic substitution reaction with amines in DMSO at room temperature following the methodology ((Dudutiene, V. et al. Chem Med Chem, 10, 662-687 (2015)); US9725467 (B2); EP2914583 (B1)). Compound 11 was then refluxed with an isocyanate in toluene to give compound 12. Deprotection of the sulfonamide group was achieved by refluxing in MeOH with a few drops of HCl (conc.). [ka] Scheme Ca) (CH3O)2CHN(CH3)2, MeCN; b) OCNR3, toluene; c) OCNR3, DBTDL, MeCN; d) HCl (concentrated), toluene; e) NH2R4, DMSO; f) HCl (concentrated), MeOH.

[0024] example All starting materials and reagents were commercially available or could be prepared according to known procedures. Melting points of compounds were determined in an open capillary on a Thermo Scientific 9100 series and are uncorrected. 1 H and 13C NMR spectra were analyzed using residual DMSO, CDCl3 signals ( 1 H and 13 C NMR spectra were recorded on a Bruker spectrometer (400 MHz and 100 MHz, respectively) in DMSO-D6 or CDCl3 with chromatic aberrations at 2.50 ppm, 7.26 ppm and 39.52 ppm, 77.16 ppm, respectively. 19 F NMR spectra were recorded on a Bruker spectrometer (376 MHz) with CFCl3 as an internal standard. TLC was performed with silica gel 60 F254 aluminum plates (Merck) and visualized with UV light. Column chromatography was performed with silica gel 60 (0.040-0.063 mm, Merck). High-resolution mass spectra (HRMS) were recorded on a Dual-ESI Q-TOF 6520 mass spectrometer (Agilent Technologies). IUPAC names of compounds were generated using Chemdraw Ultra12.0. [ka] 2,3,4,5,6-Pentafluorobenzenesulfonamide 2,3,4,5,6-Pentafluorobenzenesulfonamide was prepared according to a known procedure (Dudutiene, V. et al. Bioorg. Med. Chem. 21, 2093-2106 (2013)). A mixture of pentafluorobenzenesulfonyl chloride (1 g, 3.75 mmol) and THF (60 mL) was cooled to about -10 °C and aqueous ammonia (about 1.2 mL, 25%) was added dropwise with stirring. The progress of the reaction was monitored by TLC and the pH of the solution was maintained at about pH 7. THF was evaporated in vacuum and the resulting precipitate was washed with cold HO. Recrystallization was achieved from HO. Yield: 0.84 g (90%), melting point 156°C, close to the literature value (Dudutiene, V. et al. Bioorg. Med. Chem. 21, 2093-2106 (2013)) of 156-157°C. [ka] 2,3,5,6-Tetrafluoro-4-((2-hydroxyethyl)thio)benzenesulfonamide 2,3,5,6-Tetrafluoro-4-((2-hydroxyethyl)thio)benzenesulfonamide was prepared according to known procedures in the literature (Dudutiene, V. et al. Bioorg. Med. Chem. 21, 2093-2106 (2013). 2,3,4,5,6-Pentafluorobenzenesulfonamide (1.000 g; 4.05 mmol; 1 equiv.), 2-mercaptoethanol (0.341 ml; 4.86 mmol; 1.2 equiv.), EtN (0.677 ml; 4.86 mmol; 1.2 equiv.) were dissolved in MeOH (20 ml) and stirred at room temperature overnight. The mixture was left to stand. The next morning, an additional portion of 2-mercaptoethanol (0.085 ml; 1.21 mmol; 0.3 equiv.) and Et3N (0.169 ml; 1.21 mmol; 0.3 equiv.) was added and the reaction mixture was left to stir for 2 h. After completion of the reaction, the solvent was evaporated under reduced pressure and the resulting precipitate was washed with H2O. Recrystallization was achieved from H2O. Yield: 1.029 g; (83%). Melting point: (close to the value in the literature (Dudutiene, V. et al. Bioorg. Med. Chem. 21, 2093-2106 (2013)), melting point: 111-112 °C). [ka] 2-((2,3,5,6-Tetrafluoro-4-sulfamoylphenyl)thio)ethyl acetate (AV19-36) 2,3,5,6-Tetrafluoro-4-((2-hydroxyethyl)thio)benzenesulfonamide (0.104 g; 0.30 mmol; 1 equiv.), acetic acid (10 ml) and 2 drops of H2SO4 (concentrated) were dissolved in toluene (35 ml) and refluxed for 2 h. The resulting mixture was washed with brine (3x10 ml). The organic phase was dried with anhydrous Na2SO4 and evaporated under reduced pressure. The product was purified by column chromatography (silica gel, EtOAc / CHCl3 (1:1), Rf=0.76). Yield: 0.078 g; (65%). Melting point: 108-110°C. 1 H NMR (400MHz, DMSO-d6, δ): 1.90 (3H, s, CH3), 3.29 (2H, t, J=5.9Hz, SCH2), 4.16 (2H, t, J=5.3Hz, CH2O), 8.44 (2H, s, SO2NH2). 13 C NMR(100MHz, DMSO-d6, δ): 20.27(CH3), 32.56(SCH2, t, J( 19 F~ 13 C)=2.8Hz), 63.15(CH2O), 117.89(C4, t, J( 19 F~ 13 C)=20.5Hz), 122.94(C1, t, J( 19 F~ 13 C) = 15.6Hz), 142.48 (C3 and C5, ddt, 1 J( 19 F~ 13 C) = 253.7Hz, 2 J( 19 F~ 13 C) = 17.2Hz, 3 J( 19 F~ 13 C) = 4.4Hz), 146.72 (C2 and C6, dd, 1 J( 19 F~ 13 C) = 240.8Hz, 2 J( 19 F~ 13 C)=13.9Hz), 169.95(OC(O)). 19 F NMR (376MHz, DMSO-d6, δ): -132.44~-132.69 (2F, m), -139.10~-139.30 (2F, m). C10 H9F4NO4S2[(MH) - ]HRMS: calculated 345.9836, found 345.9838. [ka] 2,3,5,6-Tetrafluoro-4-((2-hydroxyethyl)sulfonyl)benzenesulfonamide (VD10-35-1) 2,3,5,6-Tetrafluoro-4-((2-hydroxyethyl)sulfonyl)benzenesulfonamide was prepared according to known procedures in the literature (Dudutiene, V. et al. Bioorg. Med. Chem. 21, 2093-2106 (2013)). 2,3,5,6-Tetrafluoro-4-((2-hydroxyethyl)thio)benzenesulfonamide (1.542 g; 5.06 mmol; 1 equiv.) was dissolved in acetic acid (30 ml) and heated at 75 °C for 18 h. H2O2 (30%) was added in portions (0.1 ml) every 30 min (3.6 ml in total) until the starting material was completely converted. Afterwards, the solvent was evaporated under reduced pressure and the product was purified by column chromatography (silica gel, EtOAc / CHCl3 (1:1), Rf = 0.13). Yield: 0.768 g; (45%). Melting point: 138-139°C (close to the value in the literature (Dudutiene, V. et al. Bioorg. Med. Chem. 21, 2093-2106 (2013)), melting point: 139-140°C). [ka] Ethyl 2-((2,3,5,6-tetrafluoro-4-sulfamoylphenyl)sulfonyl)propionate (AV21-03-2) 2,3,5,6-Tetrafluoro-4-((2-hydroxyethyl)sulfonyl)benzenesulfonamide (VD10-35-1) (0.152 g; 0.451 mmol), propionic acid (2 ml), and 3 drops of H2SO4 (concentrated) were dissolved in toluene (25 ml) and refluxed for 1 h. The resulting mixture was washed with brine (3x10 ml). The organic phase was dried with anhydrous Na2SO4 and evaporated under reduced pressure. The product was purified by column chromatography (silica gel, EtOAc / CHCl3 (1:1), Rf=0.74). Yield: 0.0448 g; (25%). Melting point: 109-111 °C. 1 H NMR (400MHz, DMSO-d6, δ): 0.93 (3H, t, J=7.5Hz, CH3), 2.08 (2H, q, J=7.5Hz, CH2CH3 ), 4.03 (2H, t, J=5.6Hz, SO2CH2), 4.42 (2H, t, J=5.6Hz, CH2O), 8.69 (2H, s, SO2NH2). 13 C NMR (100MHz, DMSO-d6, δ): 8.63(CH3), 26.36(CH2CH3), 56.00(SO2CH2), 57.22(CH2O), 121.32(C1, t, J( 19 F~ 13 C)=14.6Hz), 127.85(C4, t, J( 19 F~ 13 C) = 15.2Hz), 142.90 (C2 and C6, dd, 1 J( 19 F~ 13 C) = 256.1Hz, 2 J( 19 F~ 13 C) = 18.8Hz), 144.36 (C2 and C5, dd, 1 J( 19 F~ 13 C) = 259.1Hz, 2 J( 19 F~ 13 C)=20.4Hz), 172.82(OC(O)). 19 F NMR (376MHz, DMSO-d6, δ): -135.61~-135.83 (2F, m), -136.58~-136.79 (2F, m). C 11 H 11F4NO6S2[(MH) - ]HRMS: calculated 391.9891, found 391.9892. [ka] 2-((2,3,5,6-Tetrafluoro-4-sulfamoylphenyl)sulfonyl)ethyl pivalate (AV22-162) 2,3,5,6-Tetrafluoro-4-((2-hydroxyethyl)sulfonyl)benzenesulfonamide (VD10-35-1) (0.050 g; 0.015 mmol), pivalic acid (0.076 g; 0.074 mmol; 5 equiv.) and 3 drops of H2SO4 (concentrated) were dissolved in toluene (10 ml) and refluxed for 30 min. The resulting mixture was washed with brine (3x10 ml). The organic phase was dried with anhydrous Na2SO4 and evaporated under reduced pressure. The product was purified by column chromatography (silica gel, EtOAc / CHCl3 (1:1), Rf=0.62). Yield: 0.018 g; (29%). Melting point: 67-68°C. 1 H NMR (400MHz, DMSO-d6, δ): 1.02 (9H, s, C(CH3)3), 4.04 (2H, t, J=5.4Hz, SO2CH2), 4.42 (2H, t, J=5.5Hz, CH2O), 8.70 (2H, s, SO2NH2). 13 C NMR (100MHz, DMSO-d6, δ): 26.46(C(CH3)3), 38.00(C(CH3)3), 56.32(SO2CH2), 57.35(CH2O), 121.12(C1, t, J( 19 F~ 13 C)=14.9Hz), 127.94(C4, t, J( 19 F~ 13 C) = 15.4Hz), 143.01 (C2 and C6, dd, 1 J( 19 F~ 13 C) = 257.3Hz, 2 J( 19 F~ 13 C) = 13.4Hz), 144.35 (C3 and C5, dd, 1 J( 19 F~ 13 C) = 256.9Hz,2 J( 19 F~ 13 C)=16.7Hz), 176.84(OC(O)). 19 F NMR (376MHz, DMSO-d6, δ): -135.72~-135.90 (2F, m), -136.46~-136.63 (2F, m). C 13 H 15 F4NO6S2[(MH) - ]HRMS: calculated 420.0204, found 420.0202. [ka] 2-((2,3,5,6-Tetrafluoro-4-sulfamoylphenyl)sulfonyl)ethyl 2-phenylacetate (AV21-25) 2,3,5,6-Tetrafluoro-4-((2-hydroxyethyl)sulfonyl)benzenesulfonamide (VD10-35-1) (0.041 g; 0.122 mmol; 1 equiv.), phenylacetic acid (0.075 g; 0.551 mmol; 5 equiv.) and 3 drops of H2SO4 (concentrated) were dissolved in toluene (15 ml) and refluxed for 1 h. The resulting mixture was washed with brine (3x10 ml). The organic phase was dried with anhydrous Na2SO4 and evaporated under reduced pressure. The product was purified by column chromatography (silica gel, EtOAc / CHCl3 (1:1), Rf=0.71). Yield: 0.0282 g; (51%). Melting point: 77-79°C. 1 H NMR (400 MHz, DMSO-d6, δ): 3.49 (2H, s, OC(O)CH2), 4.05 (2H, t, J = 5.5 Hz, SO2CH2), 4.46 (2H, t, J = 5.5 Hz, CHO), 7.19 (2H, d, J = 6.9 Hz, phenyl), 7.26 (1H, t, J = 7.2 Hz, phenyl), 7.31 (2H, t, J = 7.1 Hz, phenyl), 8.69 (2H, s, SO2NH2). 13 C NMR (100MHz, DMSO-d6, δ): 40.68(COCH2), 55.96(SO2CH2), 57.55(CH2O), 121.24(C1, t, J( 19 F~ 13C) = 14.8Hz), 126.95 (phenyl C4), 127.90 (C4, t, J( 19 F~ 13 C) = 15.7 Hz), 128.36 (phenyl), 142.96 (C2 and C6, dd, 1 J( 19 F~ 13 C) = 259.0Hz, 2 J( 19 F~ 13 C) = 17.7Hz), 144.33 (C3 and C5, dd, 1 J( 19 F~ 13 C) = 254.2Hz, 2 J( 19 F~ 13 C)=18.6Hz), 170.50(OC(O)). 19 F NMR (376MHz, DMSO-d6, δ): -135.53~-135.70 (2F, m), -136.43~-136.60 (2F, m). C 16 H 13 F4NO6S2[(MH) - HRMS for ]: calculated 454.0048, found 454.0044. [ka] 3-(Cyclooctylamino)-2,5,6-trifluoro-4-((2-hydroxyethyl)sulfonyl)benzenesulfonamide (VD11-4-2) 3-(Cyclooctylamino)-2,5,6-trifluoro-4-((2-hydroxyethyl)sulfonyl)benzenesulfonamide was prepared according to known procedures in the literature (Dudutiene, V. et al. J. Med. Chem. 57 9435-9446, (2014)). 2,3,5,6-Tetrafluoro-4-((2-hydroxyethyl)sulfonyl)benzenesulfonamide (VD10-35-1) (0.549 g; 1.63 mmol; 1 eq.) and cyclooctylamine (0.446 ml; 3.26 mmol; 2 eq.) were dissolved in DMSO (2 ml) and left under stirring at room temperature overnight. After complete conversion of the starting material, the reaction mixture was washed with brine (10 ml) and extracted with EtOAc (3 x 15 ml). The organic phase was dried with anhydrous Na2SO4 and evaporated under reduced pressure. The product was purified by column chromatography (silica gel, EtOAc / CHCl3 (1:1), Rf=0.52). Yield: 0.380 g (52%). Melting point: 90-91°C (close to the value in the literature (Dudutiene, V. et al. J. Med. Chem. 57, 9435-9446 (2014)), melting point: 89-90°C). [ka] Ethyl 2-((2-(cyclooctylamino)-3,5,6-trifluoro-4-sulfamoylphenyl)sulfonyl)propionate (AV21-08) 3-(Cyclooctylamino)-2,5,6-trifluoro-4-((2-hydroxyethyl)sulfonyl)benzenesulfonamide (VD11-4-2) (0.100 g; 0.225 mmol), propionic acid (3 ml) and 3 drops of H2SO4 (concentrated) were dissolved in toluene (25 ml) and refluxed for 3 h. The resulting mixture was washed with brine (3x10 ml). The organic phase was dried with anhydrous Na2SO4 and evaporated under reduced pressure. The product was purified by column chromatography (silica gel, EtOAc / CHCl3 (1:1), Rf=0.89) to give a yellow oil. Yield: 0.0313 g; (28%). 1H NMR (400 MHz, CDCl3, δ): 1.06 (3H, t, J = 7.6 Hz, CH3), 1.45-1.74 (12H, m, cyclooctane), 1.83-1.92 (2H, m, cyclooctane), 2.17 (2H, q, J = 7.6 Hz, CH2CH3), 3.66 (2H, t, J = 5.8 Hz, SO2CH2), 3.88 (1H, s, CH of cyclooctane), 4.49 (2H, t, J = 5.8 Hz, CHO), 5.55 (2H, s, SO2NH2), 6.85 (1H, d, J = 8.0 Hz, NH). 13 C NMR (100 MHz, CDCl3, δ): 8.88 (CH3), 23.40 (cyclooctane), 25.56 (cyclooctane), 27.19 (CH2CH3), 27.31 (cyclooctane), 33.06 (cyclooctane), 56.25 (CH of cyclooctane, d, J( 19 F~ 13 C)=11.7Hz), 56.58(SO2CH2, d, J( 19 F~ 13 C)=3.9Hz), 57.28(CH2O), 115.18(C1, dd, 1 J( 19 F~ 13 C) = 13.3Hz, 2 J( 19 F~ 13 C)=6.5Hz), 126.63(C4, dd, 1 J( 19 F~ 13 C) = 16.8Hz, 2 J( 19 F~ 13 C)=13.4Hz), 135.89(C3, d, J( 19 F~ 13 C)=12.9Hz), 136.59(C6, ddd, 1 J( 19 F~ 13 C) = 248.3Hz, 2 J( 19 F~ 13 C) = 17.4Hz, 3 J( 19 F~ 13 C) = 4.3Hz), 144.39 (C2, d, 1 J( 19 F~ 13C) = 253.3Hz, 2 J( 19 F~ 13 C)=3.7Hz), 146.30(C5, ddd, 1 J( 19 F~ 13 C) = 253.2Hz, 2 J( 19 F~ 13 C) = 16.5Hz, 3 J( 19 F~ 13 C) = 5.0 Hz), 173.73 (OC(O)). 19 F NMR(376MHz, CDCl3,δ):-125.61(1F,dd, 1 J=12.4Hz, 2 J=8.9Hz), -132.79(1F,dd, 1 J=25.8Hz, 2 J=12.5Hz), -151.60(1F, dd, 1 J=25.8Hz, 2 J=8.8Hz). 19 H 27 F3N2O6S2[(M+H) + ]HRMS: calculated 501.1335, found 501.1339. [ka] 2-((2-(cyclooctylamino)-3,5,6-trifluoro-4-sulfamoylphenyl)sulfonyl)ethyl acetate (AV19-37) 3-(Cyclooctylamino)-2,5,6-trifluoro-4-((2-hydroxyethyl)sulfonyl)benzenesulfonamide (VD11-4-2) (0.040 g; 0.090 mmol), acetic acid (1.2 ml) and 2 drops of H2SO4 (concentrated) were dissolved in toluene (10 ml) and refluxed for 1 h. The resulting mixture was washed with brine (3x10 ml). The organic phase was dried with anhydrous Na2SO4 and evaporated under reduced pressure. The product was purified by column chromatography (silica gel, EtOAc / CHCl3 (1:1), Rf=0.78). Yield: 0.0203 g; (46%). Melting point: 96°C. 1H NMR (400 MHz, CDCl3, δ): 1.45–1.73 (12H, m, cyclooctane), 1.83–1.91 (2H, m, cyclooctane), 1.93 (3H, s, CH3), 3.66 (2H, t, J = 5.7 Hz, SO2CH2), 3.88 (1H, s, CH of cyclooctane), 4.48 (2H, t, J = 5.7 Hz, CHO), 5.65 (2H, s, SO2NH2), 6.84 (2H, d, J = 6.7 Hz, NH). 13 C NMR (100 MHz, CDCl3, δ): 20.46 (CH3), 23.38 (cyclooctane), 25.54 (cyclooctane), 27.31 (cyclooctane), 33.04 (cyclooctane), 56.24 (CH of cyclooctane, d, J( 19 F~ 13 C)=11.7Hz), 56.43(SO2CH2, d, J( 19 F~ 13 C)=4.0Hz), 57.39(CH2O), 115.10(C1, dd, 1 J( 19 F~ 13 C) = 12.7Hz, 2 J( 19 F~ 13 C)=5.9Hz), 126.63(C4, dd, 1 J( 19 F~ 13 C) = 17.1Hz, 2 J( 19 F~ 13 C)=13.3Hz), 135.85(C3, d, J( 19 F~ 13 C)=13.6Hz), 136.57(C6, ddd, 1 J( 19 F~ 13 C) = 248.33Hz, 2 J( 19 F~ 13 C) = 17.8Hz, 3 J( 19 F~ 13 C) = 3.9Hz), 144.36(C2,d, 1 J( 19 F~ 13 C)=252.7Hz), 146.28(C5, dd, 1 J(19 F~ 13 C) = 252.8Hz, 2 J( 19 F~ 13 C) = 15.8Hz, 3 J( 19 F~ 13 C)=4.5Hz), 170.29(OC(O)). 19 F NMR(376MHz, CDCl3, δ):-125.63(1F, dd, 1 J=12.4Hz, 2 J=8.8Hz), -132.86(1F,dd, 1 J=25.7Hz, 2 J=12.5Hz),-151.63(1F,dd, 1 J=25.8Hz, 2 J=8.8Hz). 18 H 25 F3N2O6S2[(M+H) + ]HRMS: calculated 487.1179, found 487.1179. [ka] 3-(Cyclododecylamino)-2,5,6-trifluoro-4-((2-hydroxyethyl)sulfonyl)benzenesulfonamide (AV19-51) 3-(Cyclododecylamino)-2,5,6-trifluoro-4-((2-hydroxyethyl)sulfonyl)benzenesulfonamide was prepared according to a known procedure in the literature (Dudutiene, V. et al. Chem Med Chem, 10, 662-687 (2015)). 2,3,5,6-Tetrafluoro-4-((2-hydroxyethyl)sulfonyl)benzenesulfonamide (VD10-35-1) (0.300 g; 0.89 mmol; 1 eq.) and cyclododecylamine (0.326 g; 1.78 mmol; 2 eq.) were dissolved in DMSO (2 ml) and left under stirring at room temperature for 2 h. After complete conversion of the starting material, the reaction mixture was washed with brine (10 ml) and extracted with EtOAc (3 x 15 ml). The organic phase was dried with anhydrous Na2SO4 and evaporated under reduced pressure. The product was purified by column chromatography (silica gel, EtOAc / CHCl3 (1:1), Rf=0.60). Yield: 0.278 g (62%). Melting point: 143-145°C (close to the value in the literature (Dudutiene, V. et al. Chem Med Chem, 10, 662-687 (2015)), melting point: 143-144°C). [ka] 2-((2-(cyclododecylamino)-3,5,6-trifluoro-4-sulfamoylphenyl)sulfonyl)ethyl acetate (AV21-47) 3-(Cyclododecylamino)-2,5,6-trifluoro-4-((2-hydroxyethyl)sulfonyl)benzenesulfonamide (AV19-51) (0.102 g; 0.204 mmol), acetic acid (4 ml) and 3 drops of H2SO4 (concentrated) were dissolved in toluene (25 ml) and refluxed for 4 h. The resulting mixture was washed with brine (3x10 ml). The organic phase was dried with anhydrous Na2SO4 and evaporated under reduced pressure. The product was purified by column chromatography (silica gel, EtOAc / CHCl3 (1:1), Rf=0.86). Yield: 0.052 g; (47%). Melting point: 138-140°C. 1H NMR (400 MHz, DMSO-d6, δ): 1.21–1.46 (20H, m, cyclododecane), 1.55–1.65 (2H, m, cyclododecane), 1.81 (3H, s, OC(O)CH3), 3.78 (1H, s, CH of cyclododecane), 3.92 (2H, t, J = 4.9 Hz, SO2CH2), 4.36 (2H, t, J = 4.9 Hz, CHO), 6.52 (1H, d, J = 8.6 Hz, NH), 8.38 (2H, s, SO2NH2). 13 C NMR (100 MHz, DMSO-d6, δ): 20.04 (CH3), 20.45 (cyclododecane), 22.60 (cyclododecane), 22.71 (cyclododecane), 23.73 (cyclododecane), 23.89 (cyclododecane), 30.08 (cyclododecane), 52.84 (CH of cyclododecane, d, J = 11.6 Hz), 55.66 (SO2CH2, d, J = 2.3 Hz), 57.65 (CHO), 115.34 (C1, dd, 1 J( 19 F~ 13 C) = 13.2Hz, 2 J( 19 F~ 13 C)=5.1Hz), 127.71(C4, dd, 1 J( 19 F~ 13 C) = 18.1Hz, 2 J( 19 F~ 13 C) = 13.9Hz), 135.13 (C3, d, 1 J( 19 F~ 13 C)=15.3Hz), 136.67(C6,d, 1 J( 19 F~ 13 C)=253.6Hz), 143.95(C2,d, 1 J( 19 F~ 13 C)=252.9Hz), 145.58(C5, dd, 1 J( 19 F~ 13 C) = 246.4Hz, 2 J( 19 F~ 13 C)=13.7Hz), 169.54(OC(O)). 19F NMR (376MHz, DMSO-d6, δ): -124.88 (1F, s), -134.22 (1F, dd, 1 J=26.8Hz, 2 J=12.5Hz), -150.76(1F, dd, 1 J=26.8Hz, 2 J=6.7Hz). 22 H 33 F3N2O6S2[(M+H) + ]HRMS: calculated 543.1805, found 543.1803. [ka] Ethyl 2-((2-(cyclododecylamino)-3,5,6-trifluoro-4-sulfamoylphenyl)sulfonyl)propionate (AV22-132) 3-(Cyclododecylamino)-2,5,6-trifluoro-4-((2-hydroxyethyl)sulfonyl)benzenesulfonamide (AV19-51) (0.0377 g; 0.075 mmol), propionic acid (2 ml) and 3 drops of H2SO4 (concentrated) were dissolved in toluene (10 ml) and refluxed for 1 h. The resulting mixture was washed with brine (2x5 ml). The organic phase was dried with anhydrous Na2SO4 and evaporated under reduced pressure. The product was purified by column chromatography (silica gel, CHCl3, Rf=0.20). Yield: 0.0248 g; (59%). Melting point: 110-112°C. 1 H NMR (400 MHz, DMSO-d6, δ): 0.91 (3H, t, J = 7.5 Hz, CH3), 1.23-1.44 (20H, m, cyclododecane), 1.54-1.64 (2H, m, cyclododecane), 2.05 (2H, q, J = 7.6 Hz, CH2CH3), 3.78 (1H, s, CH of cyclododecane), 3.94 (2H, t, J = 5.2 Hz, SO2CH2), 4.37 (2H, t, J = 5.0 Hz, CHO), 6.52 (1H, d, J = 8.2 Hz, NH), 8.40 (2H, s, SO2NH2). 13C NMR (100 MHz, DMSO-d6, δ): 8.56 (CH3), 20.44 (cyclododecane), 22.58 (cyclododecane), 22.70 (cyclododecane), 23.71 (cyclododecane), 23.87 (cyclododecane), 26.36 (CH2CH3), 30.08 (cyclododecane), 52.82 (CH of cyclododecane, d, J = 11.6 Hz), 55.76 (SO2CH2), 57.59 (CH2O), 115.32 (C1, t, J( 19 F~ 13 C)=7.0Hz), 127.67(C4, t, J( 19 F~ 13 C)=14.2Hz), 135.11(dd, 1 J( 19 F~ 13 C) = 13.9Hz, 2 J( 19 F~ 13 C)=2.4Hz), 136.65(C6,d, 1 J( 19 F~ 13 C)=252.8Hz), 143.98(C2,d, 1 J( 19 F~ 13 C)253.0Hz), 145.56(C5, dd, 1 J( 19 F~ 13 C) = 249.8Hz, 2 J( 19 F~ 13 C)=15.4Hz), 172.82(OC(O)). 19 F NMR (376MHz, DMSO-d6, δ): -124.86 (1F, s), -134.21 (1F, dd, 1 J=26.9Hz, 2 J=12.4Hz), -150.79(1F, dd, 1 J=26.9Hz, 2 J=6.6Hz). 23 H 35 F3N2O6S2[(M+H) + HRMS for ]: calculated 557.1961, found 557.1966. [ka] 2,3,5,6-Tetrafluoro-4-(vinylsulfonyl)benzenesulfonamide (AV22-48) 2,3,5,6-Tetrafluoro-4-((2-hydroxyethyl)sulfonyl)benzenesulfonamide (0.200 g; 0.592 mmol; 1 equiv.), thionyl chloride (0.064 ml; 0.85 mmol; 1.5 equiv.), Et3N (0.006 ml; 0.43 mmol; 0.75 equiv.) were dissolved in MeCN (2 ml) and left under stirring at room temperature for 52 h. The resulting mixture was washed with brine (3x10 ml). The organic phase was dried with anhydrous Na2SO4 and evaporated under reduced pressure. The product was purified by column chromatography (silica gel, EtOAc / CHCl3 (1:1), Rf=0.64). Yield: 0.173 g; (92%). Melting point: 174-176°C. 1 H NMR (400MHz, DMSO-d6, δ): 6.54 (1H, d, J=17.0Hz, CH2), 6.57 (1H, d, J=23.6Hz, CH2), 7.36 (1H, dd, 1 J=16.3Hz, 2 J=9.8Hz, CH), 8.63(2H, s, SO2NH2). 13 C NMR (100MHz, DMSO-d6, δ): 121.79 (C1, t, J( 19 F~ 13 C)=14.2Hz), 128.17(C4, t, J( 19 F~ 13 C)=15.7Hz), 133.34(CH2), 138.12(CH), 143.45(C3 and C5, dd, 1 J( 19 F~ 13 C) = 259.0Hz, 2 J( 19 F~ 13 C) = 11.1Hz) 144.49 (C2 and C6, dd, 1 J( 19 F~ 13 C) = 256.0Hz, 2 J( 19 F~ 13 C)=14.8Hz). 19F NMR (376MHz, DMSO-d6, δ): -135.89~-136.11 (2F, m), -136.43~-136.72 (2F, m). C8H5F4NO4S2[(MH) - HRMS for ]: calculated 317.9523, found 317.9524. [ka] N,N-Dimethyl-N'-((2,3,5,6-tetrafluoro-4-((2-hydroxyethyl)sulfonyl)phenyl)sulfonyl)formimidamide (AV21-56) 2,3,5,6-Tetrafluoro-4-((2-hydroxyethyl)sulfonyl)benzenesulfonamide (0.160 g; 0.047 mmol) and N,N-dimethyl-formamide dimethyl acetal (0.076 g; 0.074 mmol; 5 equiv.) were dissolved in acetonitrile (10 ml) and left stirring at room temperature for 1 h. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (silica gel, EtOAc, Rf=0.65). Yield: 0.155 g; (83%). Melting point: 188-189° C. 1 H NMR (400MHz, DMSO-d6, δ): 2.99 (3H, s, NCH3), 3.23 (3H, s, NCH3), 3.71 (2H, t, J=5.3Hz , SO2CH2), 3.85 (2H, q, J=5.3Hz, CH2OH), 4.98 (1H, t, J=5.2Hz, OH), 8.30 (1H, s, NCHN). 13 C NMR (100MHz, DMSO-d6, δ): 35.64(NCH3), 41.36(NCH3), 55.07(SO2CH2), 59.53(CH2OH), 122.46(C1, t, J( 19 F~ 13 C)=15.1Hz), 126.45(C4, t, J( 19 F~ 13 C) = 15.2Hz), 143.00 (C2 and C6, dd, 1 J( 19 F~ 13 C) = 253.7Hz, 2 J( 19 F~ 13C) = 17.8Hz), 144.23 (C3 and C5, dd, 1 J( 19 F~ 13 C) = 252.2Hz, 2 J( 19 F~ 13 C)=16.3Hz), 160.93(NCHN). 19 F NMR (376MHz, DMSO-d6, δ): -136.20~-136.38 (2F, m), -136.72~-136.91 (2F, m). C 11 H 12 F4N2O5S2[(M+H) + ]HRMS: calculated 393.0197, found 393.0199. [ka] 2-((4-(N-((dimethylamino)methylene)sulfamoyl)-2,3,5,6-tetrafluorophenyl)sulfonyl)ethyl phenylcarbamate (AV22-137) N,N-Dimethyl-N'-((2,3,5,6-tetrafluoro-4-((2-hydroxyethyl)sulfonyl)phenyl)sulfonyl)formimidamide (0.068 g; 0.17 mmol; 1 equiv.) and phenyl isocyanate (0.028 ml; 0.26 mmol; 1.5 equiv.) were dissolved in toluene (10 ml) and refluxed at boiling temperature for 14 h. Additional portions of phenyl isocyanate (0.057 ml; 0.052 mmol; 3 equiv.) were added after 2 and 7 h, respectively. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (silica gel, EtOAc / CHCl3 (1:1), Rf=0.43). Yield: 0.072 g; (81%). Melting point: 177-178°C. 1H NMR (400 MHz, DMSO-d6, δ): 2.96 (3H, s, NCH3), 3.22 (3H, s, NCH3), 4.04 (2H, t, J = 5.3 Hz, SO2CH2), 4.51 (2H, t, J = 5.4 Hz, CHO), 7.00 (1H, t, J = 7.3 Hz, phenyl CH(C4)), 7.27 (2H, t, J = 7.8 Hz, phenyl CH(C3 and C5)), 7.39 (2H, d, J = 7.6 Hz, phenyl CH(C2 and C6)), 8.27 (1H, s, NCHN), 9.62 (1H, s, OC(O)NH). 13 C NMR (100 MHz, DMSO-d6, δ): 35.61 (NCH3), 41.34 (NCH3), 56.36 (SO2CH2), 57.38 (CH2O), 118.54 (phenyl C4), 121.10 (C1, t, J( 19 F~ 13 C) = 14.9 Hz), 122.75 (phenyl C3 and C5), 126.95 (C4, t, J( 19 F~ 13 C) = 15.1 Hz), 128.70 (phenyl C2 and C6), 138.54 (phenyl C1), 143.29 (C2 and C6, dd, 1 J( 19 F~ 13 C) = 262.1Hz, 2 J( 19 F~ 13 C) = 22.0Hz), 144.25 (C5 and C3, dd, 1 J( 19 F~ 13 C) = 247.2Hz, 2 J( 19 F~ 13 C)=13.0Hz), 152.64(OC(O)NH), 160.89(NCHN). 19 F NMR (376MHz, DMSO-d6, δ): -135.99~-136.16 (2F, m), -136.28~-136.47 (2F, m). C 18 H 17 F4N3O6S2[(M+H) + HRMS for ]: calculated 512.0568, found 512.0571. [ka] 2-((2,3,5,6-Tetrafluoro-4-sulfamoylphenyl)sulfonyl)ethyl phenylcarbamate (AV22-138-1) 2-((4-(N-((dimethylamino)methylene)sulfamoyl)-2,3,5,6-tetrafluorophenyl)sulfonyl)ethyl phenylcarbamate (0.030 g; 0.059 mmol; 1 equiv.) and 3 drops of HCl (conc.) were dissolved in toluene (3 ml) and refluxed at boiling point for 18 h. After 5 h, an additional 10 drops of HCl (conc.) were added. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (silica gel, EtOAc / CHCl3 (1:1), Rf=0.59). Yield: 0.007 g; (26%). Melting point: 64-66° C. 1 H NMR (400 MHz, DMSO-d6, δ): 4.06 (2H, t, J = 5.4 Hz, SO2CH2), 4.52 (2H, t, J = 5.5 Hz, CHO), 7.00 (1H, t, J = 7.3 Hz, phenyl CH(C4)), 7.26 (2H, t, J = 7.9 Hz, phenyl CH(C3 and C5)), 7.41 (2H, d, J = 7.9 Hz, phenyl CH(C2 and C6)), 8.60 (2H, s, SO2NH2), 9.65 (1H, s, OC(O)NH). 19 F NMR (376MHz, DMSO-d6, δ): -136.18~-136.49 (4F, m). C 15 H 12 F4N2O6S2[(MH) - ]HRMS: calculated 455.0000, found 455.0001. [ka] N'-((3-(cyclooctylamino)-2,5,6-trifluoro-4-((2-hydroxyethyl)sulfonyl)phenyl)sulfonyl)-N,N-dimethylformimidamide (AV22-141) N,N-Dimethyl-N'-((2,3,5,6-tetrafluoro-4-((2-hydroxyethyl)sulfonyl)phenyl)sulfonyl)formimidamide (0.100 g; 0.25 mmol; 1 eq.) and cyclooctylamine (0.070 ml; 0.51 mmol; 2 eq.) were dissolved in DMSO (1 ml) and left under stirring at room temperature for 1.5 h. The reaction mixture was washed with brine (5 ml) and extracted with EtOAc (3 x 10 ml). The collected organic phase was dried with anhydrous Na2SO4 and evaporated under reduced pressure. The product was purified by column chromatography (silica gel, EtOAc, Rf = 0.64) to give a yellow oil. Yield: 0.062 g; (49%). 1 H NMR (400 MHz, DMSO-d6, δ): 1.40–1.70 (12H, m, cyclooctane), 1.76–1.87 (2H, m, cyclooctane), 2.97 (3H, s, NCH3), 3.21 (3H, s, NCH3), 3.64 (2H, t, J = 5.4 Hz, SO2CH2), 3.73 (1H, br.s, CH of cyclooctane), 3.81 (2H, q, J = 5.4 Hz, CH2OH), 4.98 (1H, t, J = 5.2 Hz, OH), 6.60 (1H, d, J = 8.2 Hz, NH), 8.28 (1H, s, NCHN). 13 C NMR (100 MHz, DMSO-d6, δ): 22.89 (cyclooctane), 25.11 (cyclooctane), 26.65 (cyclooctane), 32.27 (cyclooctane), 35.48 (NCH3), 41.20 (NCH3), 55.02 (CH2OH), 55.31 (CH of cyclooctane, d, J( 19 F~ 13 C)=11.1Hz), 59.52(SO2CH2, d, J( 19 F~ 13 C)=2.5Hz), 116.70(C1,dd, 1 J( 19 F~ 13 C) = 12.8Hz, 2 J( 19 F~ 13 C)=5.5Hz), 126.05(C4, dd, 1 J( 19 F~ 13 C) = 18.2Hz,2 J( 19 F~ 13 C)=13.9Hz), 134.49(C3, d, J( 19 F~ 13 C)=16.1Hz), 136.97(C6, d, J( 19 F~ 13 C)=246.7Hz), 144.26(C2, d, 1 J( 19 F~ 13 C)=252.5Hz), 145.62(C5, dd, 1 J( 19 F~ 13 C) = 246.0Hz, 2 J( 19 F~ 13 C)=12.4Hz), 160.75(NCHN). 19 F NMR (376MHz, DMSO-d6, δ): -124.67 (1F, br.s), -134.26 (1F, dd, 1 J=27.3Hz, 2 J=12.2Hz), -150.64(1F, dd, 1 J=27.3Hz, 2 J=6.7Hz). 19 H 28 F3N3O5S2[(M+H) + ]HRMS: calculated 500.1495, found 500.1493. [ka] 2-((2-(cyclooctylamino)-4-(N-((dimethylamino)methylene)sulfamoyl)-3,5,6-trifluorophenyl)sulfonyl)ethyl phenylcarbamate (AV22-143) N'-((3-(cyclooctylamino)-2,5,6-trifluoro-4-((2-hydroxyethyl)sulfonyl)phenyl)sulfonyl)-N,N-dimethylformimidamide (0.038 g; 0.08 mmol; 1 equiv.) and phenyl isocyanate (0.025 ml; 0.23 mmol; 3 equiv.) were dissolved in toluene (7 ml) and refluxed at boiling temperature for 28 h. Additional portions of phenyl isocyanate (0.025 ml; 0.023 mmol; 3 equiv.) were added after 10 and 24 h, respectively. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (silica gel, EtOAc / CHCl3 (1:1), Rf=0.65). Yield: 0.018 g; (38%). Melting point: 177-178°C. 1 H NMR (400 MHz, DMSO-d6, δ): 1.33–1.63 (12H, m, cyclooctane), 1.71–1.82 (2H, m, cyclooctane), 2.95 (3H, s, NCH3), 3.20 (3H, s, NCH3), 3.69 (1H, br.s, CH of cyclooctane), 3.95 (2H, t, J = 5.0 Hz, SO2CH2), 4.46 (2H, t, J = 5.2 Hz, CHO), 6.58 (1H, d, J = 8.2 Hz, NHCH(CH2)2), 6.99 (1H, t, J = 7.3 Hz, phenylCH(C4)), 7.26 (2H, t, J = 7.8 Hz, phenylCH(C3 and C5)), 7.42 (2H, d, J = 6.6 Hz, phenylCH(C2 and C6)), 8.27 (1H, s, NCHN), 9.66 (1H, s, OC(O)NH). 13 C NMR (100 MHz, DMSO-d6, δ): 22.83 (cyclooctane), 25.03 (cyclooctane), 26.54 (cyclooctane), 32.31 (cyclooctane), 35.46 (NCH3), 41.20 (NCH3), 55.27 (CH of cyclooctane, d, J = 11.3 Hz), 56.14 (SO2CH2, d, J = 2.4 Hz), 57.50 (CHO), 115.03 (C1, dd, 1 J( 19 F~ 13 C) = 13.2Hz, 2 J( 19 F~ 13C) = 5.9 Hz), 118.48 (phenyl C4), 122.64 (phenyl C3 and C5), 126.57 (C4, dd, 1 J( 19 F~ 13 C) = 18.2Hz, 2 J( 19 F~ 13 C) = 14.1 Hz), 128.62 (phenyl C2 and C6), 134.55 (C3, d, J( 19 F~ 13 C)=14.5Hz), 137.09(C6, ddd, 1 J( 19 F~ 13 C) = 241.5Hz, 2 J( 19 F~ 13 C) = 17.6Hz, 3 J( 19 F~ 13 C) = 5.0 Hz), 138.68 (phenyl C1), 144.29 (C2, dd, 1 J( 19 F~ 13 C) = 253.2Hz, 2 J( 19 F~ 13 C)=21.3Hz), 145.66(C5, ddd, 1 J( 19 F~ 13 C) = 250.5Hz, 2 J( 19 F~ 13 C) = 17.2Hz, 3 J( 19 F~ 13 C)=4.0Hz), 152.75(OC(O)NH), 160.76(NCHN). 19 F NMR (376MHz, DMSO-d6, δ): -124.61 (1F, s), -134.25 (1F, dd, 1 J=27.4Hz, 2 J=12.3Hz), 150.25(1F,dd, 1 J=27.7Hz, 2 J=6.7Hz). 26 H 33 F3N4O6S2[(MH) -HRMS for ]: calculated 617.1721, found 617.1723. [ka] 2-((2-(cyclooctylamino)-3,5,6-trifluoro-4-sulfamoylphenyl)sulfonyl)ethyl phenylcarbamate (AV22-149) 2-((2-(cyclooctylamino)-4-(N-((dimethylamino)methylene)sulfamoyl)-3,5,6-trifluorophenyl)sulfonyl)ethylphenylcarbamate (0.015 g; 0.024; 1 eq.) and 3 drops of HCl (concentrated) were dissolved in MeOH (3 ml) and refluxed at boiling point for 29 h. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (silica gel, EtOAc / CHCl3 (1:1), Rf=0.88). Yield: 0.004 g; (29%). Melting point: 158-160° C. 1 H NMR (400 MHz, DMSO-d6, δ): 1.36–1.63 (12H, m, cyclooctane), 1.75–1.85 (2H, m, cyclooctane), 3.72 (1H, br.s, CH of cyclooctane), 3.97 (2H, t, J = 5.3 Hz, SO2CH2), 4.46 (2H, t, J = 5.4 Hz, CHO), 6.62 ( 1H, d, J = 8.3 Hz, NHCH(CH2)2), 6.99 (1H, t, J = 7.3 Hz, C4 of phenyl), 7.26 (2H, t, J = 7.8 Hz, C3 and C5 of phenyl), 7.43 (2H, d, J = 8.0 Hz, C2 and C6 of phenyl), 8.32 (2H, s, SO2NH2), 9.67 (1H, s, OC(O)NH). 19 F NMR (376MHz, DMSO-d6, δ): -124.89 (1F, s), -134.36 (1F, dd, 1 J=27.0Hz, 2 J=12.2Hz), -150.47(1F, dd, 1 J=27.0Hz, 2 J=6.4Hz). 23 H 28 F3N3O6S2[(M+H) + HRMS for ]: calculated 564.1444, found 564.1444. [ka] 2-((4-(N-((dimethylamino)methylene)sulfamoyl)-2,3,5,6-tetrafluorophenyl)sulfonyl)ethyl(4-methoxyphenyl)carbamate (AV22-166) N,N-Dimethyl-N'-((2,3,5,6-tetrafluoro-4-((2-hydroxyethyl)sulfonyl)phenyl)sulfonyl)formimidamide (0.050 g; 0.13 mmol; 1 eq.), 4-methoxyphenyl isocyanate (0.025 ml; 0.19 mmol; 1.5 eq.) and dibutyltin dilaurate (0.015 ml; 0.026 mmol; 0.2 eq.) were dissolved in acetonitrile (3 ml). The mixture was stirred at room temperature for 5 days. An additional portion of 4-methoxyphenyl isocyanate (0.025 ml; 0.19 mmol; 1.5 eq.) was added after 2 days. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (silica gel, EtOAc / CHCl3 (1:1), Rf=0.41). Yield: 0.008 g; (12%). Melting point: 167-168℃. 1 H NMR (400 MHz, DMSO-d6, δ): 2.96 (3H, s, NCH3), 3.21 (3H, s, NCH3), 3.70 (3H, s, OCH3), 4.03 (2H, t, J = 5.4 Hz, SO2CH2), 4.49 (2H, t, J = 5.3 Hz, C2O), 6.85 (2H, d, J = 8.8 Hz, phenyl C2 and C6), 7.28 (2H, d, J = 7.2 Hz, phenyl C3 and C6), 8.27 (1H, s, NCHN), 9.41 (1H, s, OC(O)NH). 13 C NMR (100 MHz, DMSO-d6, δ): 35.58 (NCH3), 41.34 (NCH3), 55.14 (OCH3), 56.40 (SO2CH2), 57.31 (CH2O), 113.91 (phenyl C3 and C5), 120.25 (phenyl C2 and C6), 121.13 (C1, t, J = 14.7 Hz), 126.91 (C4), 128.63 (phenyl C1), 131.52 (phenyl C4), 143.34 (C2 and C6, dd, 1 J(19 F~ 13 C) = 250.0Hz, 2 J( 19 F~ 13 C) = 11.2Hz), 144.16 (C3 and C5, dd, 1 J( 19 F~ 13 C) = 242.7Hz, 2 J( 19 F~ 13 C) = 10.3 Hz), 152.79 (OC(O)NH), 155.03 (phenyl C4), 160.90 (NCHN). 19 F NMR (376MHz, DMSO-d6, δ): -135.95~-136.16 (2F, m), -136.30~-136.55 (2F, m). C 19 H 19 F4N3O7S2[(M+Na) + HRMS for ]: calculated 564.0493, found 564.0501. [ka] 2-((2,3,5,6-Tetrafluoro-4-sulfamoylphenyl)sulfonyl)ethyl(4-methoxyphenyl)carbamate (AV23-04) 2-((4-(N-((dimethylamino)methylene)sulfamoyl)-2,3,5,6-tetrafluorophenyl)sulfonyl)ethyl(4-methoxyphenyl)carbamate (0.006 g; 0.011 mmol; 1 eq.) and 3 drops of HCl (concentrated) were dissolved in MeOH (3 ml) and refluxed for 31 h. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (silica gel, EtOAc / CHCl3 (1:1), Rf=0.57). Yield: 0.002 g; (37%). Melting point: 188-189° C. 1H NMR (400MHz, DMSO-d6, δ): 3.70 (3H, s, OCH3), 4.05 (2H, t, J=5.4Hz, SO2CH2), 4.49 (2H, t, J=5.4Hz, CH2O ), 6.85 (2H, d, J=8.9Hz, phenyl), 7.30 (2H, d, J=7.5Hz, phenyl), 8.61 (2H, s, SO2NH2), 9.45 (1H, s, OC(O)NH). 19 F NMR (376MHz, DMSO-d6, δ): -136.22~-136.49 (4F, m). C 16 H 14 F4N2O7S2[(MH) - ]HRMS: calculated 485.0106, found 485.0105.

[0025] Evaluation of the binding and inhibitory properties of target compounds Compound binding to CA isoenzymes The interaction of synthetic fluorine compounds with catalytically active recombinant human CA isoenzymes was tested by a Fluorescent Thermal Shift Assay (FTSA). The assay is based on the thermostabilizing effect of the compounds on proteins. Compounds binding to proteins shift the unfolding transition towards higher temperatures. The protein melting temperature (T m The shift in apparent dissociation constant (K) depends on the concentration and binding strength of the compound. FTSA experiments were performed as previously described (Zubriene, A. et al. Chem Med Chem, 12(2), 161-176 (2017)). d_app ) is determined by analyzing ligand dosing curves as described in Gedgaudas, M. et al. Drug Discovery Today, 27(8), 2076-2079 (2022).

[0026] The para-substituted compounds bind to CA isoenzyme I (CAI) with the highest affinity; dWhile the affinity ranges from 0.0024 to 0.0084 nM, substitution with a cyclooctyl or cyclododecyl group at the meta position reduces affinity by more than 1000-fold (Table 1). In contrast, cancer-associated CAIX isoenzymes bind para-substituted compounds with one-tenth the affinity of meta-substituted compounds. Para, meta-substituted fluorinated benzenesulfonamides bind with extremely high picomolar affinity (K d s0.0022-0.0091 nM) and is selective for this isoenzyme.

[0027] Most para-substituted compounds bound more strongly to CAIII, CAVA, and CAVB than to para- and meta-substituted compounds. CAXII, CAXIII, and CAXIV bound all compounds with low nanomolar affinity.

[0028] The compound AV19-36, which has S instead of SO2 at the para position and is therefore unable to form covalent bonds with nucleophilic amino acids, bound to all CAs tested with affinities at least 60- to 1300-fold lower than the similar compound AV21-03-2.

[0029] FIG. 1 shows representative binding data of CAIX with covalently bound compounds by FTSA and Isothermal Titration Calorimetry (ITC). Binding of AV21-47 to CAIX was observed at K d,app The binding activity was very strong at 2.5 pM (Fig. 1B). The ITC curve of AV19-37 binding to CAIX showed that the compound binding stoichiometry was close to 1, which corresponds to one molecule of AV19-37 binding in the active site of CAIX (Fig. 1D).

[0030] To determine whether the mechanism of irreversible enzyme-inactivating compound binding involves covalent modification of the enzyme, we measured the enzymatic activity of CAIX isoenzymes in the absence and presence of compounds before and after dialysis. CAIX 1.5 μM was incubated with 15 μM of compounds AV19-37 (covalent ligand) and 100 μM of AV19-36 (non-covalent ligand) for 2 h. Solutions of CAIX without test compounds and CAIX-complexed compounds were then dialyzed in 25 mM Tris buffer (pH=7) containing 50 mM NaCl. The CO2 hydration rate was measured by recording the absorbance of phenol red (final concentration 50 μM) at 557 nm by using an Applied Photophysics SX.18MV-R stopped-flow spectrophotometer. Experiments were performed at 25 °C with 25 mM Hepes containing 50 mM NaCl, pH 7.5.

[0031] CAIX lost its catalytic activity after 2 h of incubation with AV19-37 (Fig. 2A), and the activity was not restored after 32 h of dialysis (Fig. 2B). In contrast, CAIX incubated with AV19-36 partially restored its catalytic activity after dialysis, indicating reversible binding of this compound to CAIX.

[0032] To demonstrate the covalent binding of the compounds to the CA isoenzymes, mass spectrometry experiments were performed using an electrospray ionization time-of-flight mass spectrometer (Q-TOF). Except for the CAIII isoenzyme, which showed no covalent modification in the presence of ligand, the covalent binding of AV19-37 to 11 catalytically active CA isoenzymes was confirmed through MS experiments. Representative mass spectrometry data are shown in Figure 3. Compound AV19-37 incubated with CAIX isoenzyme showed a major peak associated with a protein-compound adduct with a mass shift equal to the compound molecular weight without acetate (ΔMW=427.5, respectively) and a set of minor peaks associated with two or three bound inhibitor molecules to CAIX. [Table 1]

Claims

1. 1. A composition as part of a pharmaceutical formulation comprising an effective amount of a fluorinated benzenesulfonamide compound that irreversibly binds to a carbonic anhydrase target, said fluorinated benzenesulfonamide compound having the structure I, or a pharma- ceutical acceptable salt thereof: 【Chemistry 28】 I Here, X and Y are F or NHR. １ , N.R. １ R ２ and Z is R ３ or N.H.R. ３ and R １ , R ２ is R ４ , R ５ , R ６ , R ７ and R ４ is cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl, each of which is unfused or fused to benzene, and each of the rings is unsubstituted, or R １２ substituted on one or more carbon atoms with substituents independently selected from: R ５ is alkyl, alkenyl, or alkynyl, each of which is unsubstituted; or R １２ substituted on one or more carbon atoms with substituents independently selected from: R ６ is phenyl, which is unfused or fused to benzene, a heteroarene, a cycloalkane, or a heterocycloalkane, each of which is unsubstituted, or R １２ substituted on one or more ring carbon atoms with substituents independently selected from: R ７ is alkylphenyl, alkylheteroaryl, each of which is unsubstituted, or R １２ substituted on one or more carbon atoms with substituents independently selected from: R ３ is R ８ , R ９ , R １０ , R １１ and R ８ is cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl, each of which is unfused or fused to benzene, and each of the rings is unsubstituted, or R １２ substituted on one or more carbon atoms with substituents independently selected from: R ９ is alkyl, alkenyl, or alkynyl, each of which is unsubstituted; or R １２ substituted on one or more carbon atoms with substituents independently selected from: R １０ is phenyl, which is unfused or fused to benzene, a heteroarene, a cycloalkane, or a heterocycloalkane, each of which is unsubstituted, or R １２ substituted on one or more ring carbon atoms with substituents independently selected from: R １１ is alkylphenyl, alkylheteroaryl, each of which is unsubstituted, or R １２ substituted on one or more carbon atoms with substituents independently selected from: R １２ は、F、&-、Br、I、OH、OR １３ ,SH,SR １３ ,S(O)R １３ 、SO ２ R １３ , C (O) R １３ ,C(O)OR １３ ,OC(O)R １３ , C (O) N (R １３ ) ２ ,C(O)NHR １３ , C (O) N (CH) ３ )R １３ ,NHC (O)R １３ ,NR １３ C(O)R １３ ,NHC (O)O １３ ,NR １３ C(O)OR １３ ,OC(O)N(R) １３ ) ２ ,OC(O)NHR １３ ,OC(O)NH ２ ,NHC(O)NH ２ 、NXC(O)NXR １３ 、NFC(O)N(R １３ ) ２ ,NR １３ C(O)NHR １３ ,NR １３ C(O)N(R １３ ) ２ 、SO ２ NH ２ 、SO ２ NHR １３ 、SO ２ N (R) １３ ) ２ ,NR １３ SO ２ R １３ 、NHSO ２ NHR １３ 、NHSO ２ N (R) １３ ) ２ ,NR １３ SO ２ NHR １３ ,NR １３ SO ２ N (R) １３ ) ２ 、C(O)NXNXOH、C(O)NXNXOR １３ 、C(O)NHSO ２ R １３ 、C(O)NR １３ SO ２ R １３ 、C(NH)NH ２ 、C(NH)NHR １３ 、C(NH)N(R １３ ) ２ 、N(CH ３ )SO ２ NHR １３ 、NHSO ２ N(CH ３ )R １３ 、N(CH ３ )SO ２ N(CH ３ )R １３ 、NH ２ 、NHR １３ 、N(R １３ ) ２ 、N(CH ３ )C(O)N(R １３ ) ２ 、CN、NO ２ 、N ３ 、C(O)H、CHNOH、CH(NOCH ３ )、CF ３ 、CF ２ CF ３ 、OCF ３ 、OCF ２ CF ３ 、C(O)OH、C(O)NH ２ であり; R １３ is alkyl, alkenyl or alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl or heterocycloalkynyl, phenyl, which is unfused or fused with benzene, heteroarene, cycloalkane or heterocycloalkane; composition.

2. The fluorinated benzenesulfonamide compound is: Ethyl 2-((2,3,5,6-tetrafluoro-4-sulfamoylphenyl)sulfonyl)propionate, 2-((2,3,5,6-tetrafluoro-4-sulfamoylphenyl)sulfonyl)ethyl 2-phenylacetate, 2-((2,3,5,6-tetrafluoro-4-sulfamoylphenyl)sulfonyl)ethyl pivalate, 2-((2-(cyclooctylamino)-3,5,6-trifluoro-4-sulfamoylphenyl)sulfonyl)ethyl acetate, Ethyl 2-((2-(cyclooctylamino)-3,5,6-trifluoro-4-sulfamoylphenyl)sulfonyl)propionate, 2-((2-(cyclododecylamino)-3,5,6-trifluoro-4-sulfamoylphenyl)sulfonyl)ethyl acetate, Ethyl 2-((2-(cyclododecylamino)-3,5,6-trifluoro-4-sulfamoylphenyl)sulfonyl)propionate, 2,3,5,6-tetrafluoro-4-(vinylsulfonyl)benzenesulfonamide, 2-((2,3,5,6-tetrafluoro-4-sulfamoylphenyl)sulfonyl)ethyl phenylcarbamate, 2-((2,3,5,6-tetrafluoro-4-sulfamoylphenyl)sulfonyl)ethyl(4-methoxyphenyl)carbamate, and 2-((2-(cyclooctylamino)-3,5,6-trifluoro-4-sulfamoylphenyl)sulfonyl)ethylphenylcarbamate The composition of claim 1 selected from the group consisting of:

3. 2. The composition of claim 1, wherein the fluorinated benzenesulfonamide compound forms a vinyl sulfone group in the presence of a nucleophilic amino acid of the carbonic anhydrase target, and the vinyl sulfone group covalently bonds to the nucleophilic amino acid of the carbonic anhydrase target.

4. 10. The pharmaceutical composition of claim 1 comprising a pharma- ceutically acceptable diluent, excipient, or carrier.

5. A pharmaceutical composition as part of a pharmaceutical formulation for use in the treatment of conditions where irreversible inhibition of carbonic anhydrase is indicated, said conditions including eye disorders such as glaucoma, macular edema, diabetic macular edema, retinitis pigmentosa, hereditary retinoschisis, cataracts, retinopathies (including chronic central serous chorioretinopathy, diabetic retinopathy, hypertensive retinopathy), and conditions including infantile nystagmus syndrome (INS), cerebral edema, edema, acute mountain sickness, bipolar disorder, chronic obstructive pulmonary disease (COPD), gastric ulcers, obesity, epilepsy, sleep apnea, migraine, diabetes, diabetes mellitus, and the like.

2. The pharmaceutical composition of claim 1, wherein the therapeutic agent is selected from diabetic injury, congestive heart failure, pulmonary hypertension, cariogenesis, cerebral ischemia, diabetic brain injury, angina, myocardial infarction, idiopathic intracranial hypertension, other disorders including hydrocephalus, various brain pathologies such as traumatic brain injury and ischemic and hemorrhagic infarction, osteoporosis, pseudotumor cerebri, cancer, especially kidney cancer, pancreatic cancer, esophageal cancer, head and neck cancer, thyroid cancer, papillary / follicular carcinoma, nasopharyngeal cancer, breast cancer, ovarian cancer, vulvar cancer, cervical cancer, bladder cancer, skin cancer, squamous / basal cell carcinoma, liver cancer, lung cancer, brain tumor, and mesothelioma.

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