Modulators of intracellular chloride concentration

Abstract

The present invention relates to compounds of Formula Ia, Formula Ib, and Formula Ic (Formula Ia), pharmaceutical compositions containing said compounds, and their use in the treatment or prevention of conditions associated with depolarization of GABAergic transmission, including, for example, Down's syndrome and autism. TIFF2022528271000026.tif49170

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This patent application claims priority to Italian Patent Application No. 102019000004929, filed April 2, 2019, the entire disclosure of which is hereby incorporated by reference.

[0002] The present invention relates to compounds of formula Ia, Ib, and Ic that inhibit the sodium-potassium-chloride cotransporter (hereinafter also referred to as NKCC1). [ka]

[0003] Pharmacological inhibition of NKCC1 can be used to treat various pathophysiological conditions, especially brain disorders. 2-Aminobenzenesulfonamide derivatives are potent NKCC1 inhibitors and show promising efficacy in restoring GABAergic transmission and associated cognitive behaviors in rodent models of Down's syndrome and autism. [Background technology]

[0004] Down's syndrome is the most common genetic form of intellectual disability (approximately 10 per 10,000 and 14 per 10,000 live births in European countries and the United States, respectively). Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of a third copy of chromosome 21, either in whole or in part. The most prominent clinical feature of Down's syndrome is intellectual disability, characterized by low intelligence quotient (IQ), learning disabilities, and memory impairments, especially in hippocampus-related functions. Although educational methods and integrated education have led to improved cognitive development in individuals with Down's syndrome, there are still constitutional disabilities that cannot be fully addressed by the above methodologies. Indeed, although there are several clinical candidates to treat Down's syndrome (i.e., piracetam, memantine and donepezil, rivastigmine, epigallocatechin gallate and antioxidants, pentylenetrazol, ACI-24), there is still no approved pharmacological drug to improve the cognitive symptoms of Down's syndrome. Thus, there is an urgent need to work towards discovering drugs that enhance cognitive function in subjects with Down's syndrome.

[0005] Over the past few years, a large body of literature has documented Cl-1 in Down syndrome and many other neurodevelopmental disorders. - It has been shown that inhibitory GABAergic transmission via permeable GABAA receptors is defective (Non-Patent Document 1, Non-Patent Document 2). Nevertheless, the use of general GABAA receptor inhibitors to restore defective GABAergic transmission is dangerous because of the high risk of epileptic seizures in patients.

[0006] Brain disorders characterized by alterations in GABAergic transmission include Down's syndrome, neuropathic pain, stroke, cerebral ischemia, cerebral edema, hydrocephalus, traumatic brain injury, brain trauma-induced depression-like behavior, autism spectrum disorder (i.e., autism, fragile X syndrome, Rett syndrome, Asperger syndrome, and DiGeorge syndrome), epilepsy, seizures, status epilepticus, infantile spasms, gliomas, glioblastomas, anaplastic astrocytomas, Parkinson's disease, Huntington's disease, schizophrenia, anxiety disorders, tuberous sclerosis and related behavioral disorders, and Dravet syndrome. + ·K + ·Cl - NKCCs belong to a family of transporters that mediate electroneutral transport of sodium, potassium, and chloride ions across the plasma membrane. They move each solute in the same direction and maintain electroneutrality by moving two positively charged solutes (sodium and potassium) together with two negatively charged solutes (chloride ions).

[0007] NKCC1 is widely distributed, especially in exocrine glands and the brain. NKCC2 is found in the kidney, where it functions to remove sodium, potassium, and chloride ions from the urine so they can be reabsorbed into the blood.

[0008] In neurons, Cl - Importer NKCC1 and Cl - The exporter KCC2 mainly transports intracellular Cl - Control the concentration.

[0009] Importantly, in several animal models of Down's syndrome and brain disease, the expression ratio of NKCC1 / KCC2 is defective. Targeting NKCC1 with inhibitors provides therapeutic benefits for several diseases, including, but not limited to, Down's syndrome, neuropathic pain, stroke, cerebral ischemia, cerebral edema, hydrocephalus, traumatic brain injury, brain trauma-induced depression-like behavior, autism spectrum disorder (i.e., autism, fragile X syndrome, Rett syndrome, Asperger syndrome, and DiGeorge syndrome), epilepsy, seizures, status epilepticus, infantile spasms, glioma, glioblastoma, anaplastic astrocytoma, Parkinson's disease, Huntington's disease, schizophrenia, anxiety, tuberous sclerosis and related behavioral disorders, and Dravet syndrome. In animal models, NKCC1 inhibition with the FDA-approved diuretic bumetanide rescues behavioral defects. In particular, bumetanide inhibits GABAAR-driven Cl-2 activation in adult Down syndrome mouse models. - NKCC1 inhibitors restored electrical currents, synaptic plasticity, and hippocampal-dependent memory, and thus may have therapeutic activity in diseases in which GABAergic transmission is defective.

[0010] Furthermore, in five independent clinical studies (including a Phase II clinical trial), bumetanide treatment impaired childhood assessment of autism and emotional facial expression perception.

[0011] Nevertheless, bumetanide has been shown to inhibit renal-specific Cl - It also inhibits the transporter NKCC2, which has a diuretic effect that can cause ionic imbalance and severely threaten compliance during chronic treatment.

[0012] Diseases for which bumetanide has been shown to have an ameliorating effect include Down's syndrome, neuropathic pain, stroke, cerebral ischemia, cerebral edema, hydrocephalus, traumatic brain injury, brain trauma-induced depressive-like behavior, autism spectrum disorders (i.e., autism, fragile X syndrome, Rett syndrome, Asperger's syndrome, and DiGeorge syndrome), epilepsy, seizures, status epilepticus, infantile spasms, glioma, glioblastoma, anaplastic astrocytoma, Parkinson's disease, Huntington's disease, schizophrenia, anxiety disorders, tuberous sclerosis and related behavioral disorders, and Dravet syndrome.

[0013] Patent Document 1 describes the use of NKCC1 modulators to improve cognitive performance in subjects in need of cognitive improvement. It is also said that these compounds can be used for long-term treatment because the undesirable diuretic effect is reduced. The most promising compound, 3-aminosulfonyl-5-N,N-dibutylamino-4-phenoxybenzoic acid, is described to interact with GABAA receptors, and therefore, it is neither an NKCC1 nor an NKCC2 inhibitor, which may cause the risk of undesirable side effects, including epileptic seizures.

[0014] WO 02 / 06336 describes compounds for the treatment of fragile X syndrome. In a preferred embodiment, the chloride ion modulator is a selective inhibitor of NKCC1.

[0015] In a publication by Huang et al. (Non-Patent Document 3), the efficacy of STS66, 3-(butylamino)-2-phenoxy-benzenesulfonamide, is investigated, which is a close analogue and derivative of bumetanide and therefore acts as an NKCC1 inhibitor.

[0016] Lykke et al., in Non-Patent Document 4, investigated bumetanide derivatives as selective inhibitors of NKCC1. The tested derivatives were selected during screening for compounds with high diuretic potency from about 5000 3-amino-5-sulfamoylbenzoic acid derivatives synthesized by Peter W. Feit and colleagues at Leo Pharma in the 1960s and 1970s, which ultimately led to the discovery of bumetanide. According to the authors, none of the compounds exhibited significantly higher NKCC2 / NKCC1 selectivity. The authors conclude that it would be difficult, if not impossible, to develop bumetanide derivatives with higher selectivity for NKCC1 versus NKCC2 than bumetanide.

[0017] Thus, there is a need for alternative therapeutic approaches for Down's syndrome and other brain disorders that would allow restoration of defective GABAergic transmission through inhibition of NKCC1.

[0018] Therefore, bumetanide is not a viable treatment strategy, and the same can be said for the analogues described. Alternative compounds are still greatly needed. [Prior art documents] [Patent documents]

[0019] [Patent Document 1] International Publication No. 2010 / 085352 [Patent Document 2] International Publication No. 2014 / 076235 [Non-patent literature]

[0020] [Non-Patent Document 1] Deidda, G. et al. Modulation of GABAergic transmission in development and neurodevelopmental disorders: investigating physiology and pathology to gain therapeutic perspectives. Front Cell Neurosci 2014, 8, 119.3 [Non-Patent Document 2] Contestabile, A. et al. The GABAergic Hypothesis for Cognitive Disabilities in Down syndrome. Frontiers in Cellular Neurosciences 2017, 11.54 [Non-Patent Document 3] "Novel NKCC1 Inhibitors Reduces Stroke Damages";Stroke, April, 2019 [Non-Patent Document 4] "The search for NKCC1-selective drugs for the treatment of epilepsy: Structure-function relationship of bumetanide and various bumetanide derivatives in inhibiting the human cation-chloride cotransporter NKCC1A." Epilepsy & Behavior 59 (2016) 42-49 Summary of the Invention

[0021] The present invention relates to novel 2-aminobenzenesulfonamide derivatives that inhibit the sodium-potassium-chloride cotransporter (herein also referred to as NKCC1). Pharmacological inhibition of NKCC1 can be used to treat various pathophysiological conditions, especially brain disorders. Since modulation of NKCC1 leads to fine-tuning of GABAergic transmission, NKCC1 inhibitors can improve the function of NKCC1 / KCC2 expression ratio and / or Cl-expression. - The present invention has beneficial effects on diseases characterized by defective GABAergic transmission via permeable GABA A receptors. The aim of the present invention is to treat diseases involving the involvement of GABA A and / or chloride ion homeostasis.

[0022] (Subject of the invention) According to a first object, the present invention provides new 2-aminobenzenesulfonamide derivatives capable of inhibiting the sodium-potassium-chloride cotransporter (also called, for brevity, NKCC1).

[0023] The present invention also discloses methods for making the disclosed compounds.

[0024] In a second subject, the use of the compounds of the invention for the treatment or prevention of pathologies associated with depolarization of GABAergic transmission is disclosed.

[0025] Medicaments containing the compounds of the invention represent a third subject of the present invention.

[0026] In a fourth aspect, a method for treating or preventing a condition associated with depolarization of GABAergic transmission is disclosed, comprising administering to a patient in need thereof a compound of the invention. [Brief description of the drawings]

[0027] [Figure 1]Figure 2: In vitro testing of NKCC1 inhibitors in chloride ion kinetic assay. a) Example traces obtained in chloride ion kinetic assay on HEK cells transfected with YFP (mock) or YFP and NKCC1. Arrows indicate the addition of NaCl (final concentration 74 mM) used to start the flux assay. b) Quantification of the effect of bumetanide (10 μM and 100 μM) or furosemide (10 μM and 100 μM) in chloride ion kinetic assay on HEK293 cells transfected with mock or NKCC1. Data represent the mean ± sem from 5 independent experiments. c) Quantification of the effect of bumetanide and frusemide and two selected compounds (3.8, 3.17) in chloride ion kinetic assay on HEK293 cells transfected with NKCC1. Data represent the mean ± sem from 5 independent experiments and are expressed as % of control. *P<0.05, **P<0.01, ***P<0.001 Kruskal-Wallis Anova (Dunn's post-hoc test); ###P<0.001 unpaired two-tailed Student's t test. [Diagram 2] Figure 2: In vitro testing of NKCC1 inhibitors in calcium mobilization assay. a) Example traces of fluorescence levels upon application of GABA (100 μM) and KCl (90 mM) used to induce calcium influx in primary neuronal cultures treated with vehicle, bumetanide, furosemide, and compound 3.8, compound 3.13, and compound 3.17 in calcium mobilization assay after 3 days in culture (3DIV). b) Quantification of the mean fluorescence increase upon application of GABA normalized to the increase upon application of KCl in neurons treated with bumetanide, furosemide, and three exemplary compounds (3.8, 3.13, 3.17) (10 μM, 100 μM). Data represent the mean ± sem from five independent experiments and are expressed as % of control. *P<0.05, **P<0.01, ***P<0.001 Kruskal-Wallis Anova (Dunn's post-hoc test). [Diagram 3]Figure 1: Evaluation of drug-likeness of selected compound Compound 3.17. a) Chemical-physical properties of bumetanide and Compound 3.17 by LC-MS analysis. b) Comparison between urine volume of WT mice (C57Bl / 6N) after 2 hours of treatment with bumetanide (0.2 mg / kg) and Compound 3.17 (0.2 mg / kg). c) Evaluation of urine volume of Ts65Dn mouse model of Down's syndrome and WT littermates after 2 hours of treatment with Compound 3.17 (0.2 mg / kg). Numbers in brackets: number of animals analyzed. Data represent mean ± sem and are expressed as % of the respective vehicle. [Figure 4] Figure 1 shows in vivo evaluation of efficacy of selected NKCC1 inhibitors in Ts65Dn mice. (a) Quantification of discrimination index in mice treated with vehicle (WT, n=14, Ts65Dn, n=10) or 3.17 (WT, n=14, Ts65Dn, n=11). ***P<0.001; two-way ANOVA Tukey's post-hoc test. (b) Quantification of discrimination index in mice treated with vehicle (WT, n=14, Ts65Dn, n=10) or 3.17 (WT, n=14, Ts65Dn, n=11). *P<0.05, **P<0.01; two-way ANOVA Tukey's post-hoc test. (c) Quantification of correct choices in mice treated with vehicle (WT, n=14; Ts65Dn, n=10) or 3.17 (WT, n=14; Ts65Dn, n=11). ***P<0.001; two-way ANOVA with Tukey's post-hoc test. (d) Quantification of freezing responses in mice treated with vehicle (WT, n=14; Ts65Dn, n=10) or 3.17 (WT, n=14; Ts65Dn, n=11). *P<0.05, **P<0.01; two-way ANOVA with Tukey's post-hoc test. [Diagram 5] FIG. 1 reports a synthetic procedure, Scheme 1, for preparing compounds of the invention. [Figure 6] FIG. 2 reports a synthetic procedure, Scheme 2, for preparing compounds of the invention. [Figure 7] FIG. 3 reports a synthetic procedure, Scheme 3, for preparing compounds of the invention. [Figure 8]FIG. 1 reports synthetic procedure Scheme 4 and synthetic procedure Scheme 5 for producing compounds of the present invention. [Figure 9] FIG. 1 reports synthetic procedure Scheme 6 and synthetic procedure Scheme 7 for producing compounds of the present invention. [Figure 10] FIG. 1 reports a synthetic procedure, Scheme 8, for preparing compounds of the invention. [Figure 11] FIG. 9 reports a synthetic procedure, Scheme 9, for preparing compounds of the invention. [Figure 12] FIG. 1 reports a synthetic procedure, Scheme 10, for preparing compounds of the invention. [Figure 13] FIG. 1 reports a synthetic procedure, Scheme 12, for preparing compounds of the invention. [Figure 14] FIG. 1 reports a synthetic procedure, Scheme 13, for preparing compounds of the invention. [Figure 15] FIG. 1 reports a synthetic procedure, Scheme 14, for preparing compounds of the invention. [Figure 16] FIG. 1 reports a synthetic procedure, Scheme 15, for preparing compounds of the invention. [Figure 17] FIG. 1 shows the results of in vitro testing of selective NKCC1 inhibitors in a thallium-based assay on NKCC2-transfected HEK cells. [Figure 18]Figures 18a-d show the results of an in vivo evaluation of the efficacy of compound 3.17 in a VPA-induced mouse model of autism. (a) Left panel, quantification of the sociality index in mice treated with vehicle (WT, n=15, VPA, n=10) or 3.17 (WT, n=9, VPA, n=12); two-way ANOVA based on ranks, Tukey's post-hoc test, **P<0.01. Right panel, quantification of the social novelty index in mice treated with vehicle (WT, n=15, VPA, n=10) or 3.17 (WT, n=9, VPA, n=12); two-way ANOVA, Tukey's post-hoc test, *P<0.05, **P<0.01. (b) Quantification of interaction time in mice treated with vehicle (WT, n=15, VPA, n=10) or 3.17 (WT, n=10, VPA, n=11); Two-way ANOVA, Tukey's post-hoc test, **P<0.01. (c) Quantification of the number of marbles buried by mice treated with vehicle (WT, n=17, VPA, n=17) or 3.17 (WT, n=13, VPA, n=13); Two-way ANOVA, Tukey's post-hoc test, *P<0.05, **P<0.01. (d) Quantification of grooming time for mice treated with vehicle (WT, n=20; VPA, n=17) or 3.17 (WT, n=13; VPA, n=13); two-way ANOVA based on ranks, Tukey's post-hoc test, *P<0.05, **P<0.01. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] The present invention provides 2-aminobenzenesulfonamide derivatives according to formula Ia, Ib, and Ic that are NKCC1 inhibitors and address the need for alternative compounds to bumetanide, particularly compounds that can restore GABA A signaling through NKCC1 inhibition.

[0029] In one embodiment, the present invention provides a compound of formula Ia: [ka] (In the formula, R1 and R2 are independently hydrogen, Optionally containing one or more unsaturations, and halogen, -OH, -C 3~8 Cycloalkyl, non-aromatic heterocycle, aromatic heterocycle, -C 1~6 A linear or branched C optionally substituted with a group selected from the group consisting of alkoxyalkyl, -NH2, -NO2, amide, carboxylic acid, ketone, ether, ester, aldehyde, or sulfonamide. 1~10 Alkyl, Linear or branched, substituted or unsubstituted C 3~8 Cycloalkyl, Linear or branched, substituted or unsubstituted C 4~10 Cycloalkylalkyl, C 3~8 Heterocycloalkyl, optionally substituted phenyl, and or R1 and R2 together with the nitrogen atom to which they are attached form a substituted or unsubstituted saturated heterocycle; R3 and R4 are independently hydrogen, Optionally containing one or more unsaturations, and halogen, -OH, -C 3~8 Cycloalkyl, non-aromatic heterocycle, aromatic heterocycle, -C 1~6 A linear or branched C optionally substituted with a group selected from the group consisting of alkoxyalkyl, -NH2, -NO2, amide, carboxylic acid, ketone, ether, ester, aldehyde, or sulfonamide. 1~10 Alkyl, C 3~10 Cycloalkyl, C 4~10 Cycloalkylalkyl, C 2~8 Haloalkyl, Substituted or unsubstituted linear or branched C 2~8 Heteroalkyl, optionally substituted phenyl, with the proviso that at least one of R3 and R4 is other than hydrogen; or R3 and R4 together with the nitrogen atom to which they are attached form a substituted or unsubstituted saturated heterocycle; R5 is, hydrogen, halogen, Hydroxyl, -OC 1~10 Alkyl, -OC 3~10 Cycloalkyl, -OC 3~8 Heterocycloalkyl, C 1~10 Alkoxyalkyl, C 3~10 Alkoxycycloalkyl, optionally substituted phenoxyl; -NH2, C 1~8 Alkylamines, C2~C 16 Dialkylamines, Aniline, -SH, C 1~8 Alkyl thioethers, Thiophenol, -NO2, and R6 is, Nitro, Nitrile, -CHOH, Carboxylic acids, C 1~4 Alkyl esters, C 2~8 Heteroalkyl esters, C 3~6 Cycloalkyl esters, Phenyl esters, Carboxamides, Cyclic amides, Tetrazole, with the proviso that when R6 is nitro, R1 is other than H, R2 is a linear or branched unsubstituted C 2~6 is other than alkyl, R3 is other than H; R4 is linear and unsubstituted C 1~3 is other than alkyl, R5 is other than H; and The compound of formula Ia is [Table 1] or a pharma- ceutically acceptable salt thereof, or a stereoisomeric form thereof, or individual geometric isomers, enantiomers, diastereoisomers, tautomers, zwitterions, and pharma- ceutically acceptable salts thereof, which is not one of

[0030] In one embodiment, R1 and R2 are independently hydrogen, Optionally containing one or more unsaturations, and halogen, -OH, -C 3~8 Cycloalkyl, non-aromatic heterocycle, aromatic heterocycle, -C 1~6 A linear or branched C optionally substituted with a group selected from the group consisting of alkoxyalkyl, -NH2, -NO2, amide, carboxylic acid, ketone, ether, ester, aldehyde, or sulfonamide. 1~10 Alkyl, Linear or branched, substituted or unsubstituted C 3~8 Cycloalkyl, Linear or branched, substituted or unsubstituted C 4~10 Cycloalkylalkyl, optionally substituted phenyl, and or R1 and R2 together with the nitrogen atom to which they are attached form a substituted or unsubstituted saturated heterocycle; R3 and R4 are independently hydrogen, Optionally containing one or more unsaturations, and halogen, -OH, -C 3~8 Cycloalkyl, non-aromatic heterocycle, aromatic heterocycle, -C 1~6A linear or branched C optionally substituted with a group selected from the group consisting of alkoxyalkyl, -NH2, -NO2, amide, carboxylic acid, ketone, ether, ester, aldehyde, or sulfonamide. 1~10 Alkyl, C 3~10 Cycloalkyl, C 4~10 Cycloalkylalkyl, C 2~8 Haloalkyl, Substituted or unsubstituted linear or branched C 2~8 Heteroalkyl, optionally substituted phenyl, with the proviso that at least one of R3 and R4 is other than hydrogen; or R3 and R4 together with the nitrogen atom to which they are attached form a substituted or unsubstituted saturated heterocycle; R5 is, hydrogen, halogen, Hydroxyl, C 1~10 Alkoxyalkyl, C 3~10 Alkoxycycloalkyl, optionally substituted phenoxyl; -NH2, C 1~8 Alkylamines, C2~C 16 Dialkylamines, Aniline, -SH, C 1~8 Alkyl thioethers, Thiophenol, -NO2, and R6 is, Nitro, Nitrile, -CHOH, Carboxylic acids, C 1~4 Alkyl esters, C 2~8 Heteroalkyl esters, C3~6 Cycloalkyl esters, Phenyl esters, Carboxamides, Cyclic amides, Tetrazole, It is.

[0031] In preferred embodiments, R1 and R2 are independently H, -CH3, cyclopentane, cyclohexane, 4-tetrahydropyran, or together with the nitrogen atom to which they are attached, morpholine, piperidine optionally substituted with at least one halogen, pyrrolidine.

[0032] Even more preferably, R1 and R2 are independently -CH3, -C2H5, -C3H7, -C4H9. In a preferred embodiment, R1 and R2 are both -CH3.

[0033] In a preferred embodiment, R and R are independently selected from hydrogen, at least one C 1~6 Linear or branched -C optionally substituted with alkoxyalkyl 1~8 Alkyl, -C 2~8 haloalkyl, or R3 and R4 together with the nitrogen atom to which they are attached are a substituted or unsubstituted saturated heterocycle.

[0034] Even more preferably, R3 and R4 are independently H, -C4H9, -C6H 13 , -C8H 17 , -C2H4C(CH3)3, -C7H 14 CF3, -C3H6CF3, -C5H 10 CF3, -C2H4OCH3, -C4H8OCH3, -C6H 12 or, together with the nitrogen atom to which they are attached, a piperazine, preferably a substituted piperazine, even more preferably -N(C4H8CF3)piperazine.

[0035] Even more preferably, R3 and R4 are independently -CH3, -C2H5, -C3H7, -C4H9, -C5H11 , -CH 13 , -CH 15 , -C8H 17 , or -C 1~8 In a preferred embodiment, R3 is H and R4 is -CH 14 It is CF3.

[0036] For purposes of the present invention, one or more of the hydrogen atoms of the compounds detailed above may be replaced with deuterium.

[0037] In a preferred embodiment, R5 is hydrogen, halogen, or hydroxyl, more preferably hydrogen.

[0038] In a preferred embodiment, R6 is a carboxylic acid, C 1~4 It is preferably an alkyl ester, nitro, or nitrile, and more preferably a carboxylic acid.

[0039] In one embodiment, the claimed compounds have the formula as reported herein below: [ka] Compound 3.17 has the formula:

[0040] definition Unless otherwise specified herein, terms used herein should be understood to have the following meanings:

[0041] The term "alkyl" as used herein, as an individual substituent or as part of a larger substituent, refers to a saturated monovalent or divalent hydrocarbon moiety having linear or branched moieties or combinations thereof and having 1 to 10, preferably 1 to 8, and even more preferably 1 to 4 carbon atoms. Suitable examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2-methylpropyl, and the like. Hydrogen atoms on an alkyl group can be, but are not limited to, deuterium, halogen, -OH, -C 3~8 Cycloalkyl, non-aromatic heterocycle, aromatic heterocycle, -C 1~6 It may be substituted with groups including alkoxyalkyl, -NH2, -NO2, amide, carboxylic acid, ketone, ether, ester, aldehyde, or sulfonamide.

[0042] For purposes of this invention, alkyl substituents may contain one or more unsaturations.

[0043] The term "cycloalkyl" as used herein refers to a monovalent or divalent ring of 3 to 10 carbon atoms or 3 to 8 carbon atoms derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic. Cycloalkyl includes, but is not limited to, halogen groups, -OH groups, -C ... 3~8 Cycloalkyl groups, non-aromatic heterocyclic groups, aromatic heterocyclic groups, -C 1~6 It may be substituted with groups including alkoxyalkyl groups, -NH2 groups, -NO2 groups, amide groups, ether groups, ester groups, carboxylic acid groups, aldehyde groups, ketone groups, and sulfonamide groups.

[0044] Examples of cycloalkylalkyl groups include cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, and cycloheptylethyl groups.

[0045] The term "haloalkyl," as used herein, refers to an alkyl group that is partially or fully substituted with halogen atoms, which may be the same or different. Examples of "haloalkyl" include -CH2CF3 and -CCl2CF3.

[0046] In the present invention, the "alkoxy" includes, for example, the above-mentioned alkyl-O- group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, etc., the "alkoxyalkyl" includes, for example, methoxymethyl, etc., and the "aminoalkyl" includes, for example, 2-aminoethyl, etc.

[0047] In the present invention, "halogen" refers to any halogen element, for example fluorine, chlorine, bromine, or iodine.

[0048] The term "heterocycle" as used herein refers to a 3- to 8-membered ring that may be aromatic or non-aromatic, containing at least one heteroatom selected from O or N or S, or a combination of at least two thereof, interrupting a carbocyclic structure. The heterocyclic ring may contain C=O, and the S heteroatom may be oxidized. The heterocycle may be monocyclic or polycyclic. Heterocyclic ring moieties include, but are not limited to, halogen groups, -OH groups, -C 1~10 Alkyl group, -C 3~8 Cycloalkyl groups, non-aromatic heterocyclic groups, aromatic heterocyclic groups, -C 1~6It may be substituted with groups including alkoxyalkyl groups, -NH2 groups, -NO2 groups, amide groups, ether groups, ester groups, aldehyde groups, carboxylic acid groups, ketone groups, and sulfonamide groups.Preferred heterocycles are aziridine, azetidine, pyrrolidine, imidazoline, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, azepane, and azocane.

[0049] As used herein, the term "substituted heterocycle" refers to any group that is substituted with halogen, -C 1~5 Alkyl, -C 1~5 Alkenyl, -C 1~5 It refers to a heterocycle optionally substituted with haloalkyl.

[0050] The term "alkenyl" as used herein refers to a monovalent or divalent hydrocarbon group having 2 to 6 carbon atoms derived from a saturated alkyl having at least one double bond. 2~6 Alkenyl can be in the E or Z configuration. The alkenyl group is -C 1~6 It may be substituted by alkyl.

[0051] As used herein, the term "substituted phenyl" or "substituted phenoxyl" refers to any of the C 1~8 Alkyl, preferably methyl, C 1~8 Alkoxy refers to a phenyl group substituted with a substituent selected from the group consisting of methoxy, hydroxyl, trifluoromethyl, nitro, amine, halogen.

[0052] The term "pharmaceutically acceptable salts" refers to salts or complexes that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. "Pharmaceutically acceptable salts" according to the present invention include the therapeutically active non-toxic base salts or acid salt forms that the compounds of formula I are able to form.

[0053] The compounds of formula Ia and their salts may exist in the form of solvates which are included within the scope of the present invention. Such solvates include, for example, hydrates, alcoholates, and the like.

[0054] In relation to the present invention, reference to one or more compounds is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof, unless a particular isomeric form is specifically mentioned.

[0055] The compounds according to the present invention may exist in different polymorphic forms. Although not explicitly shown in the above formula, such forms are intended to be included within the scope of the present invention.

[0056] In one embodiment, the compound of formula Ia is 1.6 2-(butylamino)-5-nitro-benzenesulfonamide, 1.7 2-(hexylamino)-5-nitro-benzenesulfonamide, 1.8 5-nitro-2-(octylamino)benzenesulfonamide, 1.9 2-(3,3-dimethylbutylamino)-5-nitro-benzenesulfonamide, 1.10 2-(butylamino)-N-methyl-5-nitro-benzenesulfonamide, 1.11 2-(hexylamino)-N-methyl-5-nitro-benzenesulfonamide, 1.12 N-methyl-5-nitro-2-(octylamino)benzenesulfonamide, 1.13 2-(3,3-dimethylbutylamino)-N-methyl-5-nitro-benzenesulfonamide, 1.14 2-(Butylamino)-N,N-dimethyl-5-nitro-benzenesulfonamide, 1.15 2-(hexylamino)-N,N-dimethyl-5-nitro-benzenesulfonamide, 1.16 N,N-Dimethyl-5-nitro-2-(octylamino)benzenesulfonamide, 1.17 2-(3,3-dimethylbutylamino)-N,N-dimethyl-5-nitro-benzenesulfonamide, 2.2 4-(Butylamino)-2-chloro-5-sulfamoyl-benzoic acid, 2.3 2-Chloro-4-(hexylamino)-5-sulfamoyl-benzoic acid, 2.4 2-Chloro-4-(octylamino)-5-sulfamoyl-benzoic acid, 2.5 2-chloro-4-(3,3-dimethylbutylamino)-5-sulfamoyl-benzoic acid, 2.6 4-(Butylamino)-3-sulfamoyl-benzoic acid, 2.7 4-(hexylamino)-3-sulfamoyl-benzoic acid, 2.8 4-(octylamino)-3-sulfamoyl-benzoic acid, 2.9 4-(3,3-dimethylbutylamino)-3-sulfamoyl-benzoic acid, 3.6 4-(butylamino)-3-(methylsulfamoyl)benzoic acid, 3.7 4-(hexylamino)-3-(methylsulfamoyl)benzoic acid, 3.8 3-(methylsulfamoyl)-4-(octylamino)benzoic acid, 3.9 4-(3,3-dimethylbutylamino)-3-(methylsulfamoyl)benzoic acid, 3.10 3-(Methylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.11 4-(butylamino)-3-(dimethylsulfamoyl)benzoic acid, 3.12 3-(Dimethylsulfamoyl)-4-(hexylamino)benzoic acid, 3.13 3-(dimethylsulfamoyl)-4-(octylamino)benzoic acid, 3.14 4-(3,3-dimethylbutylamino)-3-(dimethylsulfamoyl)benzoic acid, 3.15 3-(dimethylsulfamoyl)-4-(4,4,4-trifluorobutylamino)benzoic acid, 3.16 3-(dimethylsulfamoyl)-4-(6,6,6-trifluorohexylamino)benzoic acid, 3.17 3-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.18 3-(dimethylsulfamoyl)-4-(2-methoxyethylamino)benzoic acid, 3.19 3-(dimethylsulfamoyl)-4-(4-methoxybutylamino)benzoic acid, 3.20 3-(dimethylsulfamoyl)-4-(6-methoxyhexylamino)benzoic acid, 3.21 3-(cyclopentylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.22 3-(cyclohexylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.5 3-Pyrrolidin-1-ylsulfonyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.6 3-(1-piperidylsulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.7 3-Morpholinosulfonyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 6.3 5-cyano-N,N-dimethyl-2-(8,8,8-trifluorooctylamino)benzenesulfonamide, 7.4 2-Hydroxy-5-sulfamoyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 9.1 3-(Dimethylsulfamoyl)-4-[4-(5,5,5-trifluoropentyl)piperazin-1-yl]benzoic acid, 10.1 N,N-Dimethyl-5-(1H-tetrazol-5-yl)-2-(8,8,8-trifluorooctylamino)benzenesulfonamide, 12.3 Methyl 5-(N,N-dimethylsulfamoyl)-2-methoxy-4-((8,8,8-trifluorooctyl)amino)benzoate, 12.4 Methyl 5-(N,N-dimethylsulfamoyl)-2-hydroxy-4-((8,8,8-trifluorooctyl)amino)benzoate, 12.5 Methyl 5-(N,N-dimethylsulfamoyl)-2-ethoxy-4-((8,8,8-trifluorooctyl)amino)benzoate, 12.6 Methyl 2-(cyclopentyloxy)-5-(N,N-dimethylsulfamoyl)-4-((8,8,8-trifluorooctyl)amino)benzoate, 12.7 5-(N,N-dimethylsulfamoyl)-2-ethoxy-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 12.8 2-(Cyclopentyloxy)-5-(N,N-dimethylsulfamoyl)-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 13.1 5-(N,N-dimethylsulfamoyl)-2-methoxy-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 14.3 3-Morpholinosulfonyl-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 14.4 3-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 15.1 3-(Dimethylsulfamoyl)-4-(hept-6-enylamino)benzoic acid, 15.2 Methyl 3-(N,N-dimethylsulfamoyl)-4-(hept-6-en-1-ylamino)benzoate, 15.3 Methyl 4-((8-bromo-8,8-difluorooctyl)amino)-3-(N,N-dimethylsulfamoyl)benzoate, 15.4 4-[(8-bromo-8,8-difluorooctyl)amino]-3-(dimethylsulfamoyl)benzoic acid, 16.1 5-(Dimethylsulfamoyl)-2-isopropoxy-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.2 2-(cyclohexoxy)-5-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.3 5-(Dimethylsulfamoyl)-2-tetrahydropyran-4-yloxy-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.4 2-(Cyclobutoxy)-5-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.5 5-(dimethylsulfamoyl)-2-(oxetan-3-yloxy)-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.6 5-(Dimethylsulfamoyl)-2-(4-piperidyloxy)-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.7 5-(Dimethylsulfamoyl)-2-phenoxy-4-(8,8,8-trifluorooctylamino)benzoic acid, is selected from the group consisting of:

[0057] Preferably, the compound of formula Ia is 1.7 2-(hexylamino)-5-nitro-benzenesulfonamide, 1.17 2-(3,3-dimethylbutylamino)-N,N-dimethyl-5-nitro-benzenesulfonamide, 2.2 4-(Butylamino)-2-chloro-5-sulfamoyl-benzoic acid, 2.6 4-(Butylamino)-3-sulfamoyl-benzoic acid, 2.7 4-(hexylamino)-3-sulfamoyl-benzoic acid, 2.8 4-(octylamino)-3-sulfamoyl-benzoic acid, 2.9 4-(3,3-dimethylbutylamino)-3-sulfamoyl-benzoic acid, 3.6 4-(butylamino)-3-(methylsulfamoyl)benzoic acid, 3.7 4-(hexylamino)-3-(methylsulfamoyl)benzoic acid, 3.8 3-(methylsulfamoyl)-4-(octylamino)benzoic acid, 3.9 4-(3,3-dimethylbutylamino)-3-(methylsulfamoyl)benzoic acid, 3.10 3-(Methylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.11 4-(butylamino)-3-(dimethylsulfamoyl)benzoic acid, 3.12 3-(Dimethylsulfamoyl)-4-(hexylamino)benzoic acid, 3.13 3-(dimethylsulfamoyl)-4-(octylamino)benzoic acid, 3.14 4-(3,3-dimethylbutylamino)-3-(dimethylsulfamoyl)benzoic acid, 3.17 3-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.20 3-(dimethylsulfamoyl)-4-(6-methoxyhexylamino)benzoic acid, 3.21 3-(cyclopentylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.22 3-(cyclohexylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.5 3-Pyrrolidin-1-ylsulfonyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.6 3-(1-piperidylsulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.7 3-Morpholinosulfonyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 13.1 5-(N,N-dimethylsulfamoyl)-2-methoxy-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 14.4 3-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 15.1 3-(Dimethylsulfamoyl)-4-(hept-6-enylamino)benzoic acid, is selected from the group consisting of:

[0058] In a further embodiment, the compound of formula Ia is 1.7 2-(hexylamino)-5-nitro-benzenesulfonamide, 1.15 2-(hexylamino)-N,N-dimethyl-5-nitro-benzenesulfonamide, 2.2 4-(Butylamino)-2-chloro-5-sulfamoyl-benzoic acid, 2.6 4-(Butylamino)-3-sulfamoyl-benzoic acid, 2.7 4-(hexylamino)-3-sulfamoyl-benzoic acid, 2.8 4-(octylamino)-3-sulfamoyl-benzoic acid, 3.8 3-(methylsulfamoyl)-4-(octylamino)benzoic acid, 3.13 3-(dimethylsulfamoyl)-4-(octylamino)benzoic acid, 3.14 4-(3,3-dimethylbutylamino)-3-(dimethylsulfamoyl)benzoic acid, and 3.17 3-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, is selected from the group consisting of:

[0059] According to a second aspect of the present invention, there is provided a compound of formula Ib: [ka] (In the formula, R1 and R2 are independently hydrogen, Linear or branched, unsubstituted or substituted, optionally containing one or more unsaturations 1~10 Alkyl, Linear or branched, substituted or unsubstituted C 3~8 Cycloalkyl, Linear or branched, substituted or unsubstituted C 4~10 Cycloalkylalkyl, C3~8 Heterocycloalkyl, optionally substituted phenyl, and or R1 and R2 together with the nitrogen atom to which they are attached form a substituted or unsubstituted saturated heterocycle; R3 and R4 are independently hydrogen, Unsubstituted or substituted C, optionally containing one or more unsaturations 1~10 Alkyl, C 3~10 Cycloalkyl, C 4~10 Cycloalkylalkyl, C 2~8 Haloalkyl, Substituted or unsubstituted linear or branched C 2~8 Heteroalkyl, optionally substituted phenyl, with the proviso that at least one of R3 and R4 is other than hydrogen; or R3 and R4 together with the nitrogen atom to which they are attached form a substituted or unsubstituted saturated heterocycle; R5 is, hydrogen, halogen, Hydroxyl, -OC 1~10 Alkyl, -OC 3~10 Cycloalkyl, -OC 3~8 Heterocycloalkyl, C 1~10 Alkoxyalkyl, C 3~10 Alkoxycycloalkyl, optionally substituted phenoxyl; -NH2, C 1~8 Alkylamines, C2~C 16 Dialkylamines, Aniline, -SH, C 1~8 Alkyl thioethers, Thiophenol, -NO2, and R6 is, Nitro, Nitrile, -CHOH, Carboxylic acids, C 1~4 Alkyl esters, C 2~8 Heteroalkyl esters, C 3~6 Cycloalkyl esters, Phenyl esters, Carboxamides, C 1~4 Alkyl amides, C 2~8 Dialkylamides, Cycloalkylamides, Cyclic amides, Tetrazole, or a pharma- ceutically acceptable salt thereof, or a stereoisomeric form thereof, or individual geometric isomers, enantiomers, diastereoisomers, tautomers, zwitterions, and pharma-ceutically acceptable salts thereof are provided.

[0060] In a further embodiment, the compound of formula Ic: [ka] (In the formula, R1 and R2 are independently hydrogen, Linear or branched, unsubstituted or substituted, optionally containing one or more unsaturations 1~10 Alkyl, Linear or branched, substituted or unsubstituted C 3~8 Cycloalkyl, Linear or branched, substituted or unsubstituted C 4~10 Cycloalkylalkyl, optionally substituted phenyl, and or R1 and R2 together with the nitrogen atom to which they are attached form a substituted or unsubstituted saturated heterocycle; R3 and R4 are independently hydrogen, Substituted or unsubstituted C, optionally containing one or more unsaturations 1~10 Alkyl, C 3~10 Cycloalkyl, C 4~10 Cycloalkylalkyl, C 2~8 Haloalkyl, Substituted or unsubstituted linear or branched C 2~8 Heteroalkyl, optionally substituted phenyl, with the proviso that at least one of R3 and R4 is other than hydrogen; or R3 and R4 together with the nitrogen atom to which they are attached form a substituted or unsubstituted saturated heterocycle; R5 is, hydrogen, halogen, Hydroxyl, C 1~10 Alkoxyalkyl, C 3~10 Alkoxycycloalkyl, optionally substituted phenoxyl; -NH2, C 1~8 Alkylamines, C2~C 16 Dialkylamines, Aniline, -SH, C 1~8 Alkyl thioethers, Thiophenol, -NO2, and R6 is, Nitro, Nitrile, -CHOH, Carboxylic acids, C 1~4 Alkyl esters, C 2~8 Heteroalkyl esters, C 3~6 Cycloalkyl esters, Phenyl esters, Carboxamides, C 1~4 Alkyl amides, C 2~8 Dialkylamides, Cycloalkylamides, Cyclic amides, Tetrazole, or a pharma- ceutically acceptable salt thereof, or a stereoisomeric form thereof, or individual geometric isomers, enantiomers, diastereoisomers, tautomers, zwitterions, and pharma-ceutically acceptable salts thereof are provided.

[0061] The compounds of Formula Ib and Formula Ic are indicated for use in the treatment or prevention of conditions likely to have a component associated with depolarization of GABAergic transmission due to increased expression levels or function of NKCC1 or decreased expression levels or function of KCC2.

[0062] In one embodiment of the present invention, there is provided a pharmaceutical composition comprising at least one compound of Formula Ib or Formula Ic in a pharma- ceutically acceptable carrier.

[0063] In a further embodiment, there is provided a method for treating a disorder associated with depolarization of GABAergic transmission due to an increase in the expression level or function of NKCC1 or a decrease in the expression level or function of KCC2, which may be carried out, for example, by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula Ib or formula Ic.

[0064] Advantageously, the method has been shown to have no diuretic side effects.

[0065] These compounds are useful in the treatment of mammals, including humans.

[0066] The actual amount of compound to be administered in any given case will be determined by the physician taking into account relevant circumstances such as the severity of the condition, the age and weight of the patient, the general health of the patient, the cause of the condition, and the route of administration.

[0067] Further, the formulations can be designed to provide sustained release of the active compound over a given period of time or to carefully control the amount of drug released at a given time during the course of treatment.

[0068] Taking into account the chemical structure of the compound of the present invention, a suitable formulation can be prepared to allow an effective amount of the drug to pass through the blood-brain barrier. As an example, a nanoformulation can be prepared.

[0069] Because individual subjects may experience wide variations in the severity of their symptoms, and because each drug has its own unique therapeutic characteristics, the precise mode of administration and dosage used for each subject is left to the discretion of the physician.

[0070] 2-Aminobenzenesulfonamide derivatives have been demonstrated to be potent inhibitors of the NKCC1 transporter, showing good inhibition percentages at 10 and 100 micromolar concentrations in cell-based assays. Furthermore, these compounds showed significant activity in a Down's syndrome mouse model (Ts65Dn mice), rescuing hippocampus-dependent cognitive behaviors at a dose of 0.2 mg / kg. Notably, in vivo treatment with these compounds had no statistically significant diuretic effect at 0.2 mg / kg in C57Bl6N mice, Ts65Dn mice, and their wild-type littermates when compared to vehicle-treated animals. Furthermore, these compounds showed remarkable efficacy in restoring sociality in a rodent model of drug-induced autism.

[0071] In a second aspect, the present invention relates to a compound of formula Ib or formula Ic for use in treating a disease or disorder associated with depolarization of GABAergic transmission due to an increase in NKCC1 or a decrease in KCC2 expression or function levels (relative to physiological or desired levels). In particular, the compounds described herein are used in the treatment of Down's syndrome, neuropathic pain, stroke, cerebral ischemia, cerebral edema, hydrocephalus, traumatic brain injury, brain trauma-induced depression-like behavior, autism spectrum disorder (i.e., autism, fragile X syndrome, Rett syndrome, Asperger syndrome, and DiGeorge syndrome), epilepsy, seizures, status epilepticus, West syndrome, glioma, glioblastoma, anaplastic astrocytoma, Parkinson's disease, Huntington's disease, schizophrenia, anxiety, tuberous sclerosis and related behavioral disorders, Dravet syndrome.

[0072] The present invention may be useful either as a sole therapeutic agent or in combination with other psychotropic drugs including, but not limited to, fluoxetine, memantine, donepezil, DAPT, anti-inflammatory drugs including, but not limited to, acetaminophen and other COX inhibitors, antioxidants and psychoactive dietary supplements including, but not limited to, melatonin, EGCG, resveratrol, omega-3, folinic acid, selenium, zinc, vitamin A, vitamin E, and vitamin C. Additionally, the present invention may be useful in combination with early education therapies.

[0073] The compounds described herein are characterized in preferred embodiments by the presence of an amino substituent at the ortho position of the benzenesulfonamide skeleton, a carboxylic acid substituent at the meta position of the benzenesulfonamide skeleton, an amino group having at least one substituent different from hydrogen, and the absence of aromatic substituents on the benzenesulfonamide skeleton.

[0074] Surprisingly, the compounds described herein demonstrated effective inhibition of NKCC1 when compared to bumetanide.

[0075] As an additional advantage, the compounds of the present invention exhibit particular NKCC1 / NKCC2 selectivity making them highly desirable.

[0076] The compound of the present invention is also characterized by having no diuretic effect.

[0077] In yet a further advantage, the compounds of the present invention exhibit NKCC1 / NKCC2 selectivity and are free of diuretic effects.

[0078] In particular, compound 3.17 of the present invention disclosed below showed the highest NKCC1 / NKCC2 selectivity. EXAMPLES

[0079] Example 1: Chemical synthesis and characterization All commercially available reagents and solvents were used without further purification when purchased from the supplier. Dry solvents were purchased from Sigma-Aldrich. Automated column chromatographic purifications were performed using a Teledyne ISCO instrument (CombiFlash® Rf) with pre-packed silica gel or basic alumina columns of different sizes (from 4 g up to 120 g) and mixtures of increasing polarity of cyclohexane and ethyl acetate (EtOAc), cyclohexane and tert-butyl methyl ether (TBME) or dichloromethane (DCM) and methanol (MeOH). A Bruker Avance III 400 system ( 1 NMR experiments were carried out at 400.13 MHz for H and 100.62 MHz for 13C. Spectra were acquired at 300 K using deuterated dimethylsulfoxide (DMSO-d6) or deuterated chloroform (CDCl3) as solvent. 1For H-NMR, data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, dd = double of doublet, t = triplet, q = quartet, m = multiplet), coupling constant (Hz) and integral. UPLC / MS analysis was performed on a Waters ACQUITY UPLC / MS system consisting of a SQD (single quadrupole detector) mass spectrometer equipped with an electrospray ionization interface and a photodiode array detector. The PDA range was 210 nm to 400 nm. The analysis was performed on an ACQUITY UPLC BEH C18 column (100 x 2.1 mm ID, 1.7 μm particle size) with a VanGuard BEH C18 precolumn (5 x 2.1 mm ID, 1.7 μm particle size). The mobile phases were 10 mM NH4OAc in H2O at pH 5 adjusted with CH3COOH (A) and 10 mM NH4OAc in CH3CN-H2O (95:5) at pH 5.0. Depending on the analysis, three gradients were applied: gradient 1 (5% to 100% mobile phase B in 3 min), gradient 2 (5% to 50% mobile phase B in 3 min), or gradient 3 (50% to 100% mobile phase B in 3 min). Positive and negative mode electrospray ionization was applied. Positive and negative mode electrospray ionization was applied. ESI was applied in positive and negative mode. All tested compounds showed purity of 90% or higher by NMR and UPLC / MS analysis.

[0080] Schemes and synthetic procedures for preparing some of the compounds of the invention are shown in Figures 5A-5D.

[0081] Synthesis: 2-Chloro-5-nitro-benzenesulfonyl chloride (Compound 1.2, Scheme 1) 1-Chloro-4-nitrobenzene 1.1 (500 mg, 3.14 mmol) was stirred in chlorosulfonic acid (1.05 ml, 15.71 mmol) at 120° C. for 16 h. Upon completion of the reaction, the mixture was slowly poured into ice-cold water (30 ml) and extracted twice with DCM (2×30 ml). The combined organic layers were dried over Na2SO4 and concentrated to dryness under reduced pressure to give 374.1 mg (46% yield) of the title compound. Characteristic evaluation: Rt=2.14 min; MS(ESI) m / z: 253.7 [MH]-, [MH]- Calculated value: 254.9. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 2.9 Hz, 1H), 8.16 (dd, J = 8.7, 2.9 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H).

[0082] 2-Chloro-5-nitro-benzenesulfonamide (Compound 1.3, Scheme 1) To an ice-cold solution of 5 ml of tetrahydrofuran and 4 ml of 20% aqueous NH4OH was added compound 1.2 (374.1, 1.47 mmol) dissolved in THF, and the reaction mixture was stirred at room temperature for 1 h. The reaction crude was then evaporated to dryness at low pressure, and the residue was suspended in water (20 ml) and extracted twice with EtOAc (2 x 20 ml). The combined organic layers were dried over Na2SO4 and concentrated to dryness at low pressure. Purification by silica gel flash chromatography (cyclohexane / EtOAc from 90:10 to 70:30) afforded the pure title compound (166.2 g, 48% yield). Characterization: Rt = 1.42 min; MS (ESI) m / z: 235.3 [MH]-, [MH]- Calculated value: 236. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 2.7 Hz, 1H), 8.42 (dd, J = 8.7, 2.8 Hz, 1H), 7.98 (s, 2H), 7.96 (m, J = 8.7 Hz, 1H).

[0083] General procedure C for the synthesis of sulfonamides 1.4 to 1.5 (Reaction C, Scheme 1) To an ice-cold solution of the appropriate amine hydrochloride (1.0 mmol) and triethylamine (2 mmol) in DCM (1.0 ml) was added compound 1.2 (1 mmol) dissolved in DCM (1.5 ml) and the reaction mixture was stirred at room temperature for 1 h. The reaction crude was diluted with DCM (20 ml), washed with saturated NH4Cl solution (20 ml) and the aqueous layer was extracted twice with DCM (2 x 20 ml). The combined organic layers were dried over Na2SO4 and concentrated to dryness under reduced pressure. Purification by silica gel flash chromatography finally afforded the pure title compound.

[0084] 2-Chloro-N-methyl-5-nitro-benzenesulfonamide (Compound 1.4, Scheme 1) The title compound was synthesized following general procedure C above using intermediate 1.2 (347 mg, 1.46 mmol) and methylamine hydrochloride (100.7 mg, 1.46 mmol). Purification by silica gel flash chromatography (95:05 cyclohexane / TBME) afforded the pure title compound (204.9 mg, 56% yield). Characterization: Rt = 1.62 min; MS (ESI) m / z: 249.3 [MH]-. [MH]- Calculated value: 250. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 2.7 Hz, 1H), 8.45 (dd, J = 8.7, 2.8 Hz, 1H), 8.11 (q, J = 4.4 Hz, 1H), 2.53 (d, J = 4.7 Hz, 3H).

[0085] 2-Chloro-N,N-dimethyl-5-nitro-benzenesulfonamide (Compound 1.5, Scheme 1) The title compound was synthesized following general procedure C above using intermediate 1.2 (190.3 mg, 0.8 mmol) and dimethylamine hydrochloride (163.7 mg, 1.60 mmol). Purification by silica gel flash chromatography (80:20 cyclohexane / EtOAc) afforded the pure title compound (156.32 mg, 74% yield). Characterization: Rt = 1.98 min; MS (ESI) m / z: 265.3 [MH] +. [MH]- calculated: 264. 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.7 Hz, 1H), 8.46 (dd, J = 8.7, 2.8 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H), 2.87 (s, 6H).

[0086] General Procedure D for the Synthesis of Compounds 1.6 to 1.17 (Reaction D, Scheme 1) A suspension of intermediate 1.3, intermediate 1.4, or intermediate 1.5 (1 mmol) and the appropriate amine (5 mmol) in dry toluene (0.7 mL) was stirred at 100° C. for 1 h under argon atmosphere. After completion of the reaction, the mixture was evaporated to dryness at low pressure, and the residue was treated with water (10 mL) and extracted with EtOAc (10 mL). The organic layer was dried over Na2SO4 and concentrated to dryness at low pressure. Purification by silica gel flash chromatography finally afforded the pure title compound.

[0087] 2-(Butylamino)-5-nitro-benzenesulfonamide (Compound 1.6, Scheme 1) The title compound was synthesized following general procedure D above using intermediate 1.3 (50 mg, 0.21 mmol) and butylamine (0.1 ml, 1.05 mmol). The compound was obtained pure without silica gel purification (55.96 mg, 97% yield). Characterization: Rt = 2.03 min; MS (ESI) m / z: 274.4 [MH]+. [MH]- Calculated value: 273.1; 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 2.7 Hz, 1H), 8.19 (dd, J = 9.4, 2.7 Hz, 1H), 6.95 (d, J = 9.4 Hz, 1H), 3.35 (m, 2H), 1.65 - 1.55 (m, 2H), 1.44 - 1.32 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H).

[0088] 2-(Hexylamino)-5-nitro-benzenesulfonamide (Compound 1.7, Scheme 1) The title compound was synthesized following general procedure D above using intermediate 1.3 (50 mg, 0.21 mmol) and hexylamine (0.14 ml, 1.05 mmol). Purification by silica gel flash chromatography (90:10 to 70:30 cyclohexane / EtOAc) afforded the pure title compound (59.81 mg, 94% yield). Characterization: Rt = 2.34 min; MS (ESI) m / z: 302.5 [MH] +. [MH]- Calculated value: 301.1; 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 2.7 Hz, 1H), 8.19 (ddd, J = 9.4, 2.8, 0.5 Hz, 1H), 7.72 (s, 2H), 6.95 (d, J = 9.4 Hz, 1H), 6.85 (t, J = 5.6 Hz, 1H), 3.37 - 3.28 (m, 2H), 1.66 - 1.56 (m, 2H), 1.41 - 1.25 (m, 6H), 0.90 - 0.83 (m, 3H).

[0089] 5-Nitro-2-(octylamino)benzenesulfonamide (Compound 1.8, Scheme 1) The title compound was synthesized following general procedure D above using intermediate 1.3 (50 mg, 0.21 mmol) and octylamine (0.175 ml, 1.05 mmol). Purification by silica gel flash chromatography (80:20 cyclohexane / EtOAc) afforded the pure title compound (64.27 mg, 93% yield). Characterization: Rt = 2.61 min; MS (ESI) m / z: 330.5 [MH]+. [MH]- Calculated value: 329.1; 1H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 2.8 Hz, 1H), 8.20 (dd, J = 9.4, 2.8 Hz, 1H), 7.73 (s, 2H), 6.95 (d, J = 9.4 Hz, 1H), 6.86 (s, 1H), 3.34 - 3.29 (m, 2H), 1.62 (p, J = 7.2 Hz, 2H), 1.41 - 1.20 (m, 10H), 0.90 - 0.81 (m, 3H).

[0090] 2-(3,3-Dimethylbutylamino)-5-nitro-benzenesulfonamide (Compound 1.9, Scheme 1) The title compound was synthesized following general procedure D above using intermediate 1.3 (50 mg, 0.21 mmol) and 3,3-dimethylbutan-1-amine (0.148 ml, 1.05 mmol). Purification by silica gel flash chromatography (cyclohexane / EtOAc from 95:05 to 75:25) afforded the pure title compound (55.6 mg, 88% yield). Characterization: Rt = 2.29 min; MS (ESI) m / z: 265.3 [MH]+. [MH]- Calculated value: 264; 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 2.7 Hz, 1H), 8.21 (dd, J = 9.4, 2.8 Hz, 1H), 7.70 (s, 2H), 6.93 (d, J = 9.4 Hz, 1H), 6.78 (t, J = 4.7 Hz, 1H), 3.38 - 3.30 (m, 2H), 1.59 - 1.51 (m, 2H), 0.96 (s, 9H).

[0091] 2-(Butylamino)-N-methyl-5-nitro-benzenesulfonamide (Compound 1.10, Scheme 1) The title compound was synthesized following general procedure D above using intermediate 1.4 (40 mg, 0.16 mmol) and butylamine (80 μl, 0.79 mmol). Purification by silica gel flash chromatography (80:20 cyclohexane / EtOAc) afforded the pure title compound (38.65 mg, 84% yield). Characterization: Rt = 2.27 min; MS (ESI) m / z: 288.4 [MH]+. [MH]- Calculated: 287.1; 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 2.8 Hz, 1H), 8.21 (dd, J = 9.4, 2.7 Hz, 1H), 7.89 (s, 1H), 6.98 (d, J = 9.4 Hz, 1H), 6.88 (t, J = 5.6 Hz, 1H), 3.38 - 3.33 (m, 2H), 2.44 (s, 3H), 1.66 - 1.54 (m, 2H), 1.43 - 1.32 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H).

[0092] 2-(Hexylamino)-N-methyl-5-nitro-benzenesulfonamide (Compound 1.11, Scheme 1) The title compound was synthesized following general procedure D above using intermediate 1.4 (40 mg, 0.16 mmol) and hexylamine (0.1 ml, 0.79 mmol). Purification by silica gel flash chromatography (80:20 cyclohexane / EtOAc) afforded the pure title compound (40.38 mg, 80% yield). Characterization: Rt = 2.56 min; MS (ESI) m / z: 316.4 [MH]+. [MH]- Calculated value: 315.1; 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 2.8 Hz, 1H), 8.21 (dd, J = 9.4, 2.8 Hz, 1H), 7.88 (s, 1H), 6.97 (d, J = 9.5 Hz, 1H), 6.92 (t, J = 5.6 Hz, 1H), 3.38 - 3.27 (m, 2H), 2.44 (s, 3H), 1.66 - 1.54 (m, 2H), 1.40 - 1.24 (m, 6H), 0.90 - 0.82 (m, 3H).

[0093] N-Methyl-5-nitro-2-(octylamino)benzenesulfonamide (Compound 1.12, Scheme 1) The title compound was synthesized following general procedure D above using intermediate 1.4 (40 mg, 0.16 mmol) and octylamine (0.13 ml, 0.79 mmol). Purification by silica gel flash chromatography (80:20 cyclohexane / EtOAc) afforded the pure title compound (39.56 mg, 72% yield). Characterization: Rt = 1.99 min; MS (ESI) m / z: 344.4 [MH]+. [MH]- Calculated value: 343.1; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 2.8 Hz, 1H), 8.22 (dd, J = 9.4, 2.8 Hz, 1H), 7.89 (s, 1H), 6.98 (d, J = 9.4 Hz, 1H), 6.89 (t, J = 5.5 Hz, 1H), 3.36 - 3.30 (m, 2H), 2.45 (s, 3H), 1.65 - 1.56 (m, 2H), 1.40 - 1.20 (m, 10H), 0.89 - 0.82 (m, 3H).

[0094] 2-(3,3-Dimethylbutylamino)-N-methyl-5-nitro-benzenesulfonamide (Compound 1.13, Scheme 1) The title compound was synthesized following general procedure D above using intermediate 1.4 (40 mg, 0.16 mmol) and 3,3-dimethylbutan-1-amine (0.11 ml, 0.79 mmol). Purification by silica gel flash chromatography (80:20 cyclohexane / EtOAc) afforded the pure title compound (42.26 mg, 84% yield). Characterization: Rt = 2.15 min; MS (ESI) m / z: 316.4 [MH]+. [MH]- Calculated value: 315.1; 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 2.7 Hz, 1H), 8.23 ​​(dd, J = 9.3, 2.8 Hz, 1H), 6.96 (d, J = 9.4 Hz, 1H), 6.81 (t, J = 5.4 Hz, 1H), 3.36 - 3.30 (m, 2H), 2.43 (s, 3H), 1.57 - 1.51 (m, 2H), 0.96 (s, 9H).

[0095] 2-(Butylamino)-N,N-dimethyl-5-nitro-benzenesulfonamide (Compound 1.14, Scheme 1) The title compound was synthesized following general procedure D above using intermediate 1.5 (50 mg, 0.19 mmol) and butylamine (93 μl, 0.94 mmol). Purification by silica gel flash chromatography (75:25 cyclohexane / EtOAc) afforded the pure title compound (41.45 mg, 72% yield). Characterization: Rt = 2.47 min; MS (ESI) m / z: 302.4 [MH]+. [MH]- Calculated value: 301.1; 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 2.8 Hz, 1H), 8.25 (ddd, J = 9.4, 2.7, 0.6 Hz, 1H), 7.21 (t, J = 5.6 Hz, 1H), 7.03 (d, J = 9.5 Hz, 1H), 3.38 - 3.32 (m, 2H), 2.72 (s, 6H), 1.63 - 1.53 (m, 2H), 1.42 - 1.32 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).

[0096] 2-(Hexylamino)-N,N-dimethyl-5-nitro-benzenesulfonamide (Compound 1.15, Scheme 1) The title compound was synthesized following general procedure D above using intermediate 1.5 (65 mg, 0.24 mmol) and hexylamine (0.16 ml, 1.21 mmol). Purification by silica gel flash chromatography (80:20 cyclohexane / EtOAc) afforded the pure title compound (68.42 mg, 87% yield). Characterization: Rt = 1.80 min; MS (ESI) m / z: 328.5 [MH]-. [MH]- Calculated value: 329.1; 1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 2.7 Hz, 1H), 8.24 (ddd, J = 9.4, 2.8, 0.6 Hz, 1H), 7.21 (t, J = 5.6 Hz, 1H), 7.01 (d, J = 9.4 Hz, 1H), 3.36 - 3.30 (m, 2H), 2.71 (s, 6H), 1.62 - 1.53 (m, 2H), 1.38 - 1.24 (m, 6H), 0.90 - 0.82 (m, 3H).

[0097] N,N-Dimethyl-5-nitro-2-(octylamino)benzenesulfonamide (Compound 1.16, Scheme 1) The title compound was synthesized following general procedure D above using intermediate 1.5 (50 mg, 0.19 mmol) and octylamine (0.15 ml, 0.94 mmol). Purification by silica gel flash chromatography (85:15 cyclohexane / EtOAc) afforded the pure title compound (57.52 mg, 85% yield). Characterization: Rt = 2.30 min; MS (ESI) m / z: 358.4 [MH]+. [MH]- Calculated value: 357.2; 1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 2.8 Hz, 1H), 8.23 ​​(ddd, J = 9.4, 2.8, 0.6 Hz, 1H), 7.20 (t, J = 5.6 Hz, 1H), 7.01 (d, J = 9.5 Hz, 1H), 3.38 - 3.31 (m, 2H), 2.71 (s, 6H), 1.62 - 1.53 (m, 2H), 1.37 - 1.20 (m, 10H), 0.87 - 0.82 (m, 3H).

[0098] 2-(3,3-Dimethylbutylamino)-N,N-dimethyl-5-nitro-benzenesulfonamide (Compound 1.17, Scheme 1) The title compound was synthesized following general procedure D above using intermediate 1.5 (50 mg, 0.19 mmol) and 3,3-dimethylbutan-1-amine (0.13 ml, 0.94 mmol). Purification by silica gel flash chromatography (85:15 cyclohexane / EtOAc) afforded the pure title compound (51.11 mg, 82% yield). Characterization: Rt = 2.70 min; MS (ESI) m / z: 330.4 [MH]+. [MH]- Calculated value: 329.1; 1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 2.7 Hz, 1H), 8.25 (ddd, J = 9.3, 2.8, 0.6 Hz, 1H), 7.16 (t, J = 5.6 Hz, 1H), 6.98 (d, J = 9.3 Hz, 1H), 3.38 - 3.32 (m, 2H), 2.71 (s, 6H), 1.52 - 1.47 (m, 2H), 0.95 (s, 9H).

[0099] General Procedure E for the Synthesis of Compounds 2.2 to 2.5 (Scheme 2) A suspension of commercially available 2-chloro-4-fluoro-5-sulfamoyl-benzoic acid 2.1 (1 mmol) and the appropriate amine (5 mmol) in dry toluene (0.7 ml) was stirred at 100° C. for 1 h under argon atmosphere. After completion of the reaction, the mixture was evaporated to dryness at low pressure and the residue was treated with saturated aqueous NH4Cl (15 ml) and extracted with EtOAc (15 ml). The combined organic layers were dried over Na2SO4 and concentrated to dryness at low pressure. Trituration in cyclohexane finally afforded the pure title compound.

[0100] 4-(Butylamino)-2-chloro-5-sulfamoyl-benzoic acid (Compound 2.2, Scheme 2) The title compound was synthesized following general procedure E above using intermediate 2.1 (70 mg, 0.26 mmol) and butylamine (0.13 ml, 1.32 mmol). Trituration with cyclohexane (1 ml) afforded pure title compound (40.84 mg, 51% yield). Characterization: Rt = 1.52 min; MS (ESI) m / z: 305.3 [MH]-. [MH]- Calculated value: 306.04; 1H NMR (400 MHz, DMSO-d6) δ 12.80 (bs, 1H), 8.26 (s, 1H), 7.57 (s, 2H), 6.84 (s, 1H), 6.39 (t, J = 5.3 Hz, 1H), 3.31 - 3.21 (m, 2H), 1.64 - 1.53 (m, 2H), 1.44 - 1.33 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).

[0101] 2-Chloro-4-(hexylamino)-5-sulfamoyl-benzoic acid (Compound 2.3, Scheme 2) The title compound was synthesized following general procedure E above using intermediate 2.1 (50 mg, 0.19 mmol) and hexylamine (0.12 ml, 0.95 mmol). Trituration with cyclohexane (1 ml) afforded the pure title compound (52.82 mg, 83% yield). Characterization: Rt = 1.78 min; MS (ESI) m / z: 333.4 [MH]-. [MH]- Calculated value: 334.1; 1H NMR (400 MHz, DMSO-d6) δ 12.77 (bs, 1H), 8.25 (s, 1H), 7.55 (s, 2H), 6.83 (s, 1H), 6.39 (t, J = 5.4 Hz, 1H), 3.27 - 3.20 (m, 2H), 1.59 (p, J = 7.1 Hz, 2H), 1.41 - 1.24 (m, 6H), 0.90 - 0.84 (m, 3H).

[0102] 2-Chloro-4-(octylamino)-5-sulfamoyl-benzoic acid (Compound 2.4, Scheme 2) The title compound was synthesized following general procedure E above using intermediate 2.1 (50 mg, 0.19 mmol) and octylamine (0.16 ml, 0.95 mmol). Trituration with cyclohexane (1 ml) afforded pure title compound (48.89 mg, 71% yield). Characterization: Rt = 2.01 min; MS (ESI) m / z: 361.4 [MH]-. [MH]- Calculated value: 362.1; 1H NMR (400 MHz, DMSO-d6) δ 12.78 (bs, 1H), 8.26 (s, 1H), 7.56 (s, 2H), 6.84 (s, 1H), 6.40 (t, J = 5.3 Hz, 1H), 3.28 - 3.21 (m, 2H), 1.65 - 1.55 (m, 2H), 1.41 - 1.20 (m, 10H), 0.90 - 0.83 (m, 3H).

[0103] 2-Chloro-4-(3,3-dimethylbutylamino)-5-sulfamoyl-benzoic acid (Compound 2.5, Scheme 2) The title compound was synthesized following general procedure E above using intermediate 2.1 (50 mg, 0.19 mmol) and 3,3-dimethylbutan-1-amine (0.13 ml, 0.95 mmol). Trituration with cyclohexane (1 ml) afforded the pure title compound (52.82 mg, 83% yield). Characterization: Rt = 1.66 min; MS (ESI) m / z: 333.4 [MH]-. [MH]- Calculated value: 334.1; 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.54 (s, 2H), 6.83 (s, 1H), 6.29 (t, J = 5.1 Hz, 1H), 3.27 - 3.20 (m, 2H), 1.56 - 1.50 (m, 2H), 0.96 (s, 9H).

[0104] General Procedure F for the Synthesis of Compounds 2.6 to 2.9 (Reaction F, Scheme 2) To a suspension of the appropriate 4-amino-2-chloro-5-sulfamoyl-benzoic acid intermediate 2.2-intermediate 2.5 (1 mmol) and palladium hydroxide on carbon (20 wt%) in dry methanol (20 ml) under Ar atmosphere, ammonium formate (4 mmol) was added and the reaction mixture was stirred at reflux temperature for 1 h. After completion of the reaction, the crude was filtered through a coarse patch of Celite and the filtrate was concentrated to dryness at reduced pressure. The dried residue was diluted in EtOAc (10 ml) and washed with saturated NH4Cl solution (10 ml). The organic layer was dried over Na2SO4 and concentrated to dryness at reduced pressure. Trituration in cyclohexane finally afforded the pure title compound.

[0105] 4-(Butylamino)-3-sulfamoyl-benzoic acid (Compound 2.6, Scheme 2) The title compound was synthesized following general procedure F above using intermediate 2.2 (30 mg, 0.1 mmol). Trituration with cyclohexane (1 ml) afforded the pure title compound (11.71 mg, 43% yield). Characterization: Rt = 1.53 min; MS (ESI) m / z: 273.4 [MH]+. [MH]- Calculated value: 272.1; 1H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(d, J = 2.1 Hz, 1H), 7.87 (dd, J = 8.8, 2.2 Hz, 1H), 7.46 (s, 2H), 6.83 (d, J = 8.9 Hz, 1H), 6.37 (t, J = 5.4 Hz, 1H), 3.28 - 3.21 (m, 2H), 1.64 - 1.55 (m, 2H), 1.44 - 1.34 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H).

[0106] 4-(Hexylamino)-3-sulfamoyl-benzoic acid (Compound 2.7, Scheme 2) The title compound was synthesized following general procedure F above using intermediate 2.3 (30.7 mg, 0.09 mmol). Trituration with cyclohexane (1 ml) afforded the pure title compound (11.71 mg, 43% yield). Characterization: Rt = 1.81 min; MS (ESI) m / z: 301.4 [MH]+. [MH]- Calculated: 300.1; 1H NMR (400 MHz, DMSO-d6) δ 12.45 (bs, 1H), 8.23 ​​(d, J = 2.1 Hz, 1H), 7.87 (dd, J = 8.8, 2.2 Hz, 1H), 7.46 (s, 2H), 6.82 (d, J = 8.9 Hz, 1H), 6.38 (t, J = 5.4 Hz, 1H), 3.27 - 3.20 (m, 2H), 1.60 (h, J = 6.6 Hz, 2H), 1.42 - 1.25 (m, 8H), 0.92 - 0.80 (m, 3H).

[0107] 4-(Octylamino)-3-sulfamoyl-benzoic acid (Compound 2.8, Scheme 2) The title compound was synthesized following general procedure F above using intermediate 2.4 (35.7 mg, 0.1 mmol). Trituration with cyclohexane (1 ml) afforded the pure title compound (9.68 mg, 36% yield). Characterization: Rt = 2.16 min; MS (ESI) m / z: 329.4 [MH]+. [MH]- Calculated: 328.1; 1H NMR (400 MHz, DMSO-d6) δ 12.43 (bs, 1H), 8.23 ​​(d, J = 2.1 Hz, 1H), 7.86 (dd, J = 8.7, 2.1 Hz, 1H), 7.46 (s, 2H), 6.82 (d, J = 8.9 Hz, 1H), 6.38 (t, J = 5.3 Hz, 1H), 3.27 - 3.19 (m, 2H), 1.65 - 1.56 (m, 2H), 1.42 - 1.15 (m, 12H), 0.92 - 0.80 (m, 3H).

[0108] 4-(3,3-Dimethylbutylamino)-3-sulfamoyl-benzoic acid (Compound 2.9, Scheme 2) The title compound was synthesized following general procedure F above using intermediate 2.5 (29.6 mg, 0.09 mmol). Trituration with cyclohexane (1 ml) afforded the pure title compound (15.13 mg, 56% yield). Characterization: Rt = 1.80 min; MS (ESI) m / z: 301.4 [MH]+. [MH]- Calculated value: 300.1; 1H NMR (400 MHz, DMSO-d6) δ 12.48 (bs, 1H), 8.24 (d, J = 2.1 Hz, 1H), 7.89 (dd, J = 8.8, 2.1 Hz, 1H), 7.46 (s, 2H), 6.83 (d, J = 8.9 Hz, 1H), 3.28 - 3.21 (m, 2H), 1.59 - 1.52 (m, 2H), 0.97 (s, 9H).

[0109] General Procedure G for the Synthesis of Compounds 3.2 to 3.3 (Reaction G, Scheme 3) 4-Fluoro-3-chlorosulfonyl-benzoic acid 3.1 (1 mmol) dissolved in 1.5 mL of THF was added dropwise to 3 mL of an ice-cold 2 M solution of the appropriate amine in THF and stirred at RT for 1 h. Upon completion of the reaction, the reaction mixture was evaporated to dryness and the residue was treated with water and HCl. The precipitated product was filtered and rinsed with water to give the pure title compound.

[0110] 4-Fluoro-3-(methylsulfamoyl)benzoic acid (Compound 3.2, Scheme 3) The title compound was synthesized following general procedure G above using intermediate 3.1 (500 mg, 2.07 mmol) and a 2M solution of methylamine in THF (2.07 ml, 4.15 mmol). The work-up described afforded the pure title compound (313.8 mg, 64% yield). Characterization: Rt = 1.26 min; MS (ESI) m / z: 232.3 [MH]-. [MH]- Calculated value:233.02 1H NMR (400 MHz, DMSO-d6) δ 8.30 (dd, J = 7.0, 2.2 Hz, 1H), 8.25 - 8.19 (m, 1H), 7.89 (q, J = 4.8 Hz, 1H), 7.62 - 7.54 (m, 1H), 2.52 (d, J = 4.8 Hz, 3H).

[0111] 3-(Dimethylsulfamoyl)-4-fluoro-benzoic acid (Compound 3.3, Scheme 3) The title compound was synthesized following general procedure G above using intermediate 3.1 (1 g, 4.15 mmol) and a 2M solution of dimethylamine in THF (4.15 ml, 8.30 mmol). The work-up described afforded the pure title compound (749 mg, 73% yield). Characterization: Rt = 1.11 min; MS (ESI) m / z: 246.3 [MH]-. [MH]- calculated: 247.03. 1H NMR (400 MHz, DMSO-d6) δ 8.29 - 8.24 (m, 2H), 7.67 - 7.58 (m, 1H), 2.75 (d, J = 1.9 Hz, 6H).

[0112] 3-(Cyclopentylsulfamoyl)-4-fluoro-benzoic acid (Compound 3.4, Scheme 3) The title compound was synthesized following general procedure G above using intermediate 3.1 (250 mg, 1.04 mmol) and cyclopentylamine (0.21 ml, 2.07 mmol) in THF (8.5 ml). The work-up described afforded the pure title compound (261.4 mg, 88% yield). Characterization: Rt = 1.25 min; MS (ESI) m / z: 286.4 [MH]-. [MH]- Calculated value: 287.06. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (dd, J = 7.1, 2.3 Hz, 1H), 8.21 (ddd, J = 8.6, 4.7, 2.3 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.56 (dd, J = 10.0, 8.6 Hz, 1H), 3.58 - 3.48 (m, 1H), 1.68 - 1.48 (m, 4H), 1.45 - 1.28 (m, 4H).

[0113] 3-(Cyclohexylsulfamoyl)-4-fluoro-benzoic acid (Compound 3.5, Scheme 3) The title compound was synthesized following general procedure G above using intermediate 3.1 (250 mg, 1.04 mmol) and cyclohexylamine (0.24 ml, 2.07 mmol) in THF (8.5 ml). After work-up as described and trituration with a 9:1 mixture of cyclohexane / ethyl acetate (2 ml), pure title compound (185.6 mg, 59% yield) was obtained. Characterization: Rt = 1.37 min; MS (ESI) m / z: 286.4 [MH]-. [MH]- Calculated value: 287.06. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (dd, J = 7.1, 2.3 Hz, 1H), 8.21 (ddd, J = 8.6, 4.7, 2.3 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.56 (dd, J = 10.0, 8.6 Hz, 1H), 3.58 - 3.48 (m, 1H), 1.68 - 1.48 (m, 4H), 1.45 - 1.28 (m, 4H).

[0114] General Procedure H for the Synthesis of Compounds 3.6 to 3.22, Compounds 5.5 to 5.7, Compound 6.3, and Compound 7.4 (Reaction H, Scheme 3, Scheme 5, Scheme 6, Scheme 7) A suspension of the appropriate intermediate (1 mmol) and the appropriate amine (2 mmol) in dry 1,4-dioxane (3 ml) was stirred at 100° C. for 4 h under argon atmosphere. After completion of the reaction, the mixture was evaporated to dryness at low pressure and the residue was treated with saturated aqueous NH4Cl (15 ml) and extracted twice with EtOAc (2×15 ml). The combined organic layers were dried over Na2SO4 and concentrated to dryness at low pressure. Trituration in cyclohexane finally afforded the pure title compound.

[0115] 4-(Butylamino)-3-(methylsulfamoyl)benzoic acid (Compound 3.6, Scheme 3) The title compound was synthesized following general procedure H above using intermediate 3.2 (50 mg, 0.21 mmol) and butylamine (42 μl, 0.42 mmol) in dry 1,4-dioxane (0.7 ml). Trituration with cyclohexane (1 ml) afforded pure title compound (47.10 mg, 78% yield). Characterization: Rt = 1.66 min; MS (ESI) m / z: 285.4 [MH]-. [MH]- Calculated value: 286.1. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 2.1 Hz, 1H), 7.90 (dd, J = 8.8, 2.1 Hz, 1H), 7.66 (s, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.44 (t, J = 5.4 Hz, 1H), 3.24 (q, J = 6.6 Hz, 2H), 2.39 (s, 3H), 1.58 (p, J = 7.2 Hz, 2H), 1.43 - 1.32 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H).

[0116] 4-(Hexylamino)-3-(methylsulfamoyl)benzoic acid (Compound 3.7, Scheme 3) The title compound was synthesized following general procedure H above using intermediate 3.2 (50 mg, 0.21 mmol) and hexylamine (57 μl, 0.42 mmol) in dry 1,4-dioxane (0.7 ml). Trituration with cyclohexane (1 ml) afforded pure title compound (51.69 mg, 78% yield). Characterization: Rt = 2.00 min; MS (ESI) m / z: 313.4 [MH]-. [MH]- Calculated value: 314.1. 1H NMR (400 MHz, DMSO-d6) δ 12.53 (bs, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.90 (dd, J = 8.8, 2.1 Hz, 1H), 7.63 (q, J = 5.0 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.44 (t, J = 5.3 Hz, 1H), 3.23 (q, J = 6.6 Hz, 2H), 1.60 (p, J = 7.1 Hz, 2H), 1.40 - 1.25 (m, 6H), 0.90 - 0.83 (m, 3H).

[0117] 3-(Methylsulfamoyl)-4-(octylamino)benzoic acid (Compound 3.8, Scheme 3) The title compound was synthesized following general procedure H above using intermediate 3.2 (50 mg, 0.21 mmol) and octylamine (71 μl, 0.42 mmol) in dry 1,4-dioxane (0.7 ml). Trituration with cyclohexane (1 ml) afforded pure title compound (69.51 mg, 97% yield). Characterization: Rt = 2.28 min; MS (ESI) m / z: 341.4 [MH]-. [MH]- Calculated value: 342.2. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 2.1 Hz, 1H), 7.89 (dd, J = 8.8, 2.1 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.44 (t, J = 5.4 Hz, 1H), 3.23 (q, J = 6.6 Hz, 2H), 2.38 (s, 3H), 1.59 (p, J = 7.1 Hz, 2H), 1.40 - 1.20 (m, 9H), 0.89 - 0.82 (m, 3H).

[0118] 4-(3,3-Dimethylbutylamino)-3-(methylsulfamoyl)benzoic acid (Compound 3.9, Scheme 3) The title compound was synthesized following general procedure H above using intermediate 3.2 (50 mg, 0.21 mmol) and 3,3-dimethylbutan-1-amine (60 μl, 0.42 mmol) in dry 1,4-dioxane (0.7 ml). Trituration with cyclohexane (1 ml) afforded pure title compound (50.56 mg, 84% yield). Characterization: Rt = 1.93 min; MS (ESI) m / z: 313.4 [MH]-. [MH]- Calculated value: 314.1. 1H NMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.91 (dd, J = 8.8, 2.1 Hz, 1H), 7.62 (q, J = 5.0 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.35 (t, J = 5.2 Hz, 1H), 3.27 - 3.20 (m, 2H), 2.38 (d, J = 5.0 Hz, 3H), 1.57 - 1.50 (m, 2H), 0.96 (s, 9H).

[0119] 3-(Methylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid (Compound 3.10, Scheme 3) The title compound was synthesized following general procedure H above using intermediate 3.2 (100 mg, 0.42 mmol) and intermediate 4.5 (86.4 mg, 0.47 mmol) in dry 1,4-dioxane (1.4 ml). Trituration with cyclohexane (2 ml) afforded the pure title compound (111.5 mg, 67% yield). Characterization: Rt = 2.11 min; MS (ESI) m / z: 395.2 [MH]-. [MH]- Calculated value: 396.1. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 2.1 Hz, 1H), 7.90 (dd, J = 8.8, 2.1 Hz, 1H), 7.63 (q, J = 5.0 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.44 (t, J = 5.4 Hz, 1H), 3.24 (q, J = 6.7 Hz, 2H), 2.39 (d, J = 4.8 Hz, 3H), 2.28 - 2.15 (m, 2H), 1.64 - 1.55 (m, 2H), 1.51 - 1.42 (m, 2H), 1.39 - 1.30 (m, 6H).

[0120] 4-(Butylamino)-3-(dimethylsulfamoyl)benzoic acid (Compound 3.11, Scheme 3) The title compound was synthesized following general procedure H above using intermediate 3.3 (50 mg, 0.20 mmol) and butylamine (40 μl, 0.40 mmol) in dry 1,4-dioxane (0.7 ml). Trituration with cyclohexane (1 ml) afforded pure title compound (41.45 mg, 69% yield). Characterization: Rt = 1.90 min; MS (ESI) m / z: 299.4 [MH]-. [MH]- Calculated value: 300.1. 1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 8.9, 2.1 Hz, 1H), 6.91 (d, J = 9.0 Hz, 1H), 6.74 (t, J = 5.4 Hz, 1H), 3.29 - 3.19 (m, 2H), 2.66 (s, 6H), 1.61 - 1.52 (m, 2H), 1.42 - 1.31 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H).

[0121] 3-(Dimethylsulfamoyl)-4-(hexylamino)benzoic acid (Compound 3.12, Scheme 3) The title compound was synthesized following general procedure H above using intermediate 3.3 (50 mg, 0.20 mmol) and hexylamine (53 μl, 0.40 mmol) in dry 1,4-dioxane (0.7 ml). Trituration with cyclohexane (1 ml) afforded pure title compound (53.20 mg, 81% yield). Characterization: Rt = 2.17 min; MS (ESI) m / z: 327.4 [MH]-. [MH]- Calculated value: 328.1. 1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 8.8, 2.1 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 6.74 (t, J = 5.4 Hz, 1H), 3.28 - 3.18 (m, 2H), 2.65 (s, 6H), 1.57 (p, J = 7.0 Hz, 2H), 1.39 - 1.24 (m, 6H), 0.89 - 0.84 (m, 3H).

[0122] 3-(Dimethylsulfamoyl)-4-(octylamino)benzoic acid (Compound 3.13, Scheme 3) The title compound was synthesized following general procedure H above using intermediate 3.3 (50 mg, 0.20 mmol) and octylamine (67 μl, 0.40 mmol) in dry 1,4-dioxane (0.7 ml). Trituration with cyclohexane (1 ml) afforded pure title compound (59.9 mg, 84% yield). Characterization: Rt = 2.44 min; MS (ESI) m / z: 355.4 [MH]-. [MH]- Calculated value: 356.2. 1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 8.9, 2.1 Hz, 1H), 6.91 (d, J = 9.0 Hz, 1H), 6.75 (t, J = 5.4 Hz, 1H), 3.23 (q, J = 6.6 Hz, 2H), 2.65 (s, 6H), 1.57 (p, J = 6.9 Hz, 2H), 1.39 - 1.19 (m, 10H), 0.90 - 0.80 (m, 3H).

[0123] 4-(3,3-Dimethylbutylamino)-3-(dimethylsulfamoyl)benzoic acid (Compound 3.14, Scheme 3) The title compound was synthesized following general procedure H above using intermediate 3.3 (50 mg, 0.20 mmol) and 3,3-dimethylbutan-1-amine (57 μl, 0.40 mmol) in dry 1,4-dioxane (0.7 ml). Trituration with cyclohexane (1 ml) afforded the pure title compound (42 mg, 63% yield). Characterization: Rt = 2.13 min; MS (ESI) m / z: 327.4 [MH]-. [MH]- Calculated value: 328.1. 1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.95 (dd, J = 8.9, 2.1 Hz, 1H), 6.90 (d, J = 8.9 Hz, 1H), 6.69 (t, J = 5.3 Hz, 1H), 3.29 - 3.22 (m, 2H), 2.66 (s, 6H), 1.54 - 1.46 (m, 2H), 0.96 (s, 9H).

[0124] 3-(Dimethylsulfamoyl)-4-(4,4,4-trifluorobutylamino)benzoic acid (Compound 3.15, Scheme 3) The title compound was synthesized following general procedure H above using intermediate 3.3 (50 mg, 0.20 mmol) and 4,4,4-trifluorobutylamine (48 μl, 0.40 mmol) in dry 1,4-dioxane (0.7 ml). Trituration with cyclohexane (1 ml) afforded the pure title compound (40.13 mg, 57% yield). Characterization: Rt = 1.78 min; MS (ESI) m / z: 353.4 [MH]-. [MH]- Calculated value: 354.1. 1H NMR (400 MHz, DMSO-d6) δ 12.64 (bs, 1H), 8.07 (d, J = 2.1 Hz, 1H), 7.95 (dd, J = 8.8, 2.1 Hz, 1H), 6.98 (d, J = 9.0 Hz, 1H), 6.88 (t, J = 5.9 Hz, 1H), 3.38 (q, J = 6.8 Hz, 2H), 2.67 (s, 6H), 2.40 - 2.25 (m, 2H), 1.83 - 1.73 (m, 2H).

[0125] 3-(Dimethylsulfamoyl)-4-(6,6,6-trifluorohexylamino)benzoic acid (Compound 3.16, Scheme 3) The title compound was synthesized following general procedure H above using intermediate 3.3 (50 mg, 0.20 mmol) and 6,6,6-trifluorohexylamine (60 μl, 0.40 mmol) in dry 1,4-dioxane (0.7 ml). Trituration with cyclohexane (1 ml) afforded the pure title compound (57.32 mg, 75% yield). Characterization: Rt = 2.02 min; MS (ESI) m / z: 381.4 [MH]-. [MH]- Calculated value: 382.1. 1H NMR (400 MHz, DMSO-d6) δ 12.64 (bs, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.94 (dd, J = 8.8, 2.1 Hz, 1H), 6.93 (d, J = 9.0 Hz, 1H), 6.77 (t, J = 5.4 Hz, 1H), 3.26 (q, J = 6.8 Hz, 2H), 2.66 (s, 6H), 2.32 - 2.18 (m, 2H), 1.62 (p, J = 7.4 Hz, 3H), 1.58 - 1.48 (m, 2H), 1.47 - 1.37 (m, 2H).

[0126] 3-(Dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid (Compound 3.17, Scheme 3) The title compound was synthesized following general procedure H above using intermediate 3.3 (50 mg, 0.20 mmol) and intermediate 4.5 (89 mg, 0.40 mmol) in dry 1,4-dioxane (0.7 ml). Trituration with cyclohexane (1 ml) afforded pure title compound (44.34 mg, 54% yield). Characterization: Rt = 2.28 min; MS (ESI) m / z: 409.4 [MH]-. [MH]- Calculated value: 410.1. 1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 8.8, 2.1 Hz, 1H), 6.91 (d, J = 9.0 Hz, 1H), 6.75 (t, J = 5.4 Hz, 1H), 3.24 (q, J = 6.6 Hz, 2H), 2.29 - 2.14 (m, 2H), 1.64 - 1.52 (m, 2H), 1.52 - 1.39 (m, 2H), 1.40 - 1.25 (m, 6H).

[0127] 3-(Dimethylsulfamoyl)-4-(2-methoxyethylamino)benzoic acid (Compound 3.18, Scheme 3) The title compound was synthesized following general procedure H above using intermediate 3.3 (50 mg, 0.20 mmol) and 2-methoxyethylamine (36 μl, 0.40 mmol) in dry 1,4-dioxane (0.7 ml). Trituration with cyclohexane (1 ml) afforded pure title compound (53.96 mg, 89% yield). Characterization: Rt = 1.40 min; MS (ESI) m / z: 301.4 [MH]-. [MH]- Calculated value: 302.1. 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 8.8, 2.1 Hz, 1H), 6.95 (d, J = 9.0 Hz, 1H), 6.89 (t, J = 5.3 Hz, 1H), 3.55 (t, J = 5.2 Hz, 2H), 3.40 (q, J = 5.3 Hz, 2H), 3.29 (s, 3H), 2.65 (s, 6H).

[0128] 3-(Dimethylsulfamoyl)-4-(4-methoxybutylamino)benzoic acid (Compound 3.19, Scheme 3) The title compound was synthesized following general procedure H above using intermediate 3.3 (50 mg, 0.20 mmol) and 4-methoxybutan-1-amine (51 μl, 0.40 mmol) in dry 1,4-dioxane (0.7 ml). Trituration with cyclohexane (1 ml) afforded the pure title compound (56.08 mg, 85% yield). Characterization: Rt = 1.59 min; MS (ESI) m / z: 329.4 [MH]-. [MH]- Calculated value: 330.1. 1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 8.8, 2.1 Hz, 1H), 6.91 (d, J = 8.9 Hz, 1H), 6.77 (t, J = 5.5 Hz, 1H), 3.38 - 3.32 (m, 2H), 3.26 (q, J = 6.5 Hz, 2H), 3.22 (s, 3H), 2.65 (s, 6H), 1.65 - 1.51 (m, 4H).

[0129] 3-(Dimethylsulfamoyl)-4-(6-methoxyhexylamino)benzoic acid (Compound 3.20, Scheme 3) The title compound was synthesized following general procedure H above using Intermediate 3.3 (50 mg, 0.20 mmol) and Intermediate 4.4 (53.1, 0.40 mmol) in dry 1,4-dioxane (0.7 ml). Trituration with cyclohexane (1 ml) afforded the pure title compound (23.17 mg, 32% yield). Characterization: Rt = 1.84 min; MS (ESI) m / z: 357.5 [MH]-. [MH]- Calculated value: 358.2. 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 8.8, 2.1 Hz, 1H), 6.90 (d, J = 8.9 Hz, 1H), 6.73 (t, J = 5.3 Hz, 1H), 3.31 - 3.26 (m, 2H), 3.26 - 3.21 (m, 2H), 3.20 (s, 3H), 1.62 - 1.53 (m, 2H), 1.52 - 1.43 (m, 2H), 1.39 - 1.27 (m, 4H).

[0130] 3-(Cyclopentylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid (Compound 3.21, Scheme 3) The title compound was synthesized following general procedure H above using intermediate 3.4 (50 mg, 0.17 mmol) and intermediate 4.5 (35.1 mg, 0.19 mmol) in dry 1,4-dioxane (0.6 ml). Trituration with diethyl ether (1 ml) afforded the pure title compound (31.7 mg, 41% yield). Characterization: Rt = 2.33 min; MS (ESI) m / z: 449.5 [MH]-. [MH]- Calculated value: 450.2. 1H NMR (400 MHz, chloroform-d) δ 8.49 (d, J = 2.1 Hz, 1H), 8.08 (dd, J = 8.8, 2.1 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 6.53 (s, 1H), 4.63 - 4.51 (m, 1H), 3.63 - 3.53 (m, 1H), 3.25 (t, J = 7.1 Hz, 2H), 2.14 - 2.00 (m, 2H), 1.85 - 1.75 (m, 2H), 1.74 - 1.65 (m, 2H), 1.65 - 1.54 (m, 4H), 1.53 - 1.47 (m, 2H), 1.46 - 1.36 (m, 6H), 1.36 - 1.27 (m, 2H).

[0131] 3-(Cyclohexylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid (Compound 3.22, Scheme 3) The title compound was synthesized following general procedure H above using intermediate 3.5 (50 mg, 0.16 mmol) and intermediate 4.5 (33.4 mg, 0.18 mmol) in dry 1,4-dioxane (0.55 ml). Trituration with diethyl ether (1 ml) afforded pure title compound (25.3 mg, 34% yield). Characterization: Rt = 2.40 min; MS (ESI) m / z: 463.5 [MH]-. [MH]- Calculated value: 464.2. 1H NMR (400 MHz, chloroform-d) δ 8.49 (d, J = 2.1 Hz, 1H), 8.07 (dd, J = 8.8, 2.1 Hz, 1H), 6.74 (d, J = 8.9 Hz, 1H), 6.50 (s, 1H), 4.49 (d, J = 7.9 Hz, 1H), 3.25 (t, J = 7.1 Hz, 2H), 3.18 - 3.07 (m, 1H), 2.14 - 2.00 (m, 2H), 1.79 - 1.66 (m, 4H), 1.66 - 1.49 (m, 6H), 1.48 - 1.34 (m, 6H), 1.30 - 1.19 (m, 3H), 1.18 - 1.07 (m, 2H).

[0132] General Procedure I for the Synthesis of Intermediate 4.2 to Intermediate 4.3 (Reaction I, Scheme 3) A suspension of potassium phthalimide 4.1 (1 mmol) and the appropriate alkyl bromide (1.2 mmol) in dry N,N-dimethylformamide (3.5 ml) was stirred at room temperature for 16 h. After completion of the reaction, the mixture was diluted with water (35 ml) containing EtOAc (35 ml). The organic layer was dried over Na2SO4 and concentrated to dryness under reduced pressure. Purification by silica gel flash chromatography finally gave the pure title compound.

[0133] 2-(6-Methoxyhexyl)isoindoline-1,3-dione (Compound 4.2, Scheme 4) The title compound was synthesized following general procedure I above using potassium phthalimide 4.1 (300 mg, 1.60 mmol) and 1-bromo-6-methoxyhexane (0.36 ml, 2.08 mmol) in dry N,N-dimethylformamide (5.5 ml). Purification by silica gel flash chromatography (70:30 cyclohexane / EtOAc) afforded the pure title compound (355.72 mg, 84% yield). Characterization: Rt = 2.23 min; MS (ESI) m / z: 262.5 [MH]+. [MH]- Calculated: 261.1. 1H NMR (400 MHz, Chloroform-d) δ 7.86 - 7.79(m, 2H), 7.73 - 7.66 (m, 2H), 3.67 (t, J = 7.4 Hz, 2H), 3.34 (t, J = 6.5 Hz, 2H), 3.30 (s, 3H), 1.68 (p, J = 6.1, 5.6 Hz, 2H), 1.56 (p, J = 6.6 Hz, 2H), 1.43 - 1.31 (m, 4H).

[0134] 2-(8,8,8-Trifluorooctyl)isoindoline-1,3-dione (Compound 4.3, Scheme 4) The title compound was synthesized following general procedure I above using potassium phthalimide 4.1 (300 mg, 1.60 mmol) and intermediate 8-bromo-1,1,1-trifluorooctane (0.4 ml, 2.08 mmol) in dry N,N-dimethylformamide (5.5 ml). Purification by silica gel flash chromatography (85:15 cyclohexane / EtOAc) afforded the pure title compound (392.63 mg, 75% yield). Characterization: Rt = 1.76 min; MS (ESI) m / z: 314.4 [MH]+. [MH]- Calculated: 313.1. 1H NMR (400 MHz, Chloroform-d) δ 7.86 - 7.81 (m, 2H), 7.73 - 7.67 (m, 2H), 3.70 - 3.65 (m, 2H), 2.11 - 1.97 (m, 2H), 1.68 (p, J = 7.2 Hz, 2H), 1.58 - 1.47 (m, 2H), 1.39 - 1.30 (m, 6H).

[0135] General Procedure J for the Synthesis of Compounds 4.4 to 4.5 (Reaction J, Scheme 4) The corresponding intermediate 4.2 or intermediate 4.3 (1 mmol) was refluxed in absolute ethanol (1.2 mmol) containing hydrazine hydrate (1.5 mmol) for 4 h. Upon completion of the reaction, the mixture was cooled at room temperature and the resulting precipitated solid was filtered. The solid was washed with ethanol and the filtrate was concentrated to dryness under reduced pressure. Purification by flash chromatography on basic alumina finally afforded the pure title amine.

[0136] 6-Methoxyhexan-1-amine (Compound 4.4, Scheme 4) The title compound was synthesized following general procedure J above using intermediate 4.2 (356 mg, 1.35 mmol) and hydrazine hydrate (0.15 ml, 2.02 mmol) in absolute ethanol (5.5 ml). Purification by basic alumina flash chromatography (90:10 dichloromethane / methanol) afforded the pure title compound (127.55 mg, 7% yield). Characterization: Rt = 1.00 min; MS (ESI) m / z: 132.4 [MH]+. [MH]- Calculated value: 131.1. 1H NMR (400 MHz, DMSO-d6) δ 3.29 (t, J = 6.5 Hz, 2H), 3.20 (s, 3H), 1.51 - 1.43 (m, 2H), 2.68 (p, J = 6.2 Hz, 2H), 1.37 - 1.21 (m, 6H)

[0137] 8,8,8-Trifluorooctan-1-amine (Compound 4.5, Scheme 4) The title compound was synthesized following general procedure J above using intermediate 4.3 (393 mg, 1.24 mmol) and hydrazine hydrate (0.14 ml, 1.86 mmol) in absolute ethanol (5.5 ml). Purification by basic alumina flash chromatography (95:5 dichloromethane / methanol) afforded the pure title compound (136.31 mg, 60% yield). Characterization: Rt = 1.59 min; MS (ESI) m / z: 184.4 [MH]+. [MH]- Calculated value: 183.1. 1H NMR (400 MHz, DMSO-d6) δ 2.78 - 2.68 (m, 2H), 2.30 - 2.15 (m, 2H), 1.61 - 1.41 (m, 4H), 1.38 - 1.21 (m, 6H).

[0138] General Procedure K for the Synthesis of Compounds 5.2 to 5.4 (Scheme 5) 4-Fluoro-3-chlorosulfonyl-benzoic acid 3.1 (1 mmol) dissolved in 2 mL of THF was added dropwise to 8 mL of an ice-cold solution of the appropriate cyclic amine (3 mmol) in THF and stirred at room temperature for 1 h. Upon completion of the reaction, the reaction mixture was evaporated to dryness and the residue was treated with water and HCl. The precipitated product was filtered and rinsed with water to give the pure title compound.

[0139] 4-Fluoro-3-pyrrolidin-1-ylsulfonyl-benzoic acid (Compound 5.2, Scheme 5) The title compound was synthesized following general procedure K above using intermediate 3.1 (250 mg, 1.04 mmol) and pyrrolidine (0.26 ml, 3.11 mmol) in THF (8 ml). The work-up described afforded the pure title compound (243.2 mg, 85% yield). Characterization: Rt = 1.17 min; MS (ESI) m / z: 272.4 [MH]-. [MH]- Calculated value: 273.05. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (dd, J = 6.8, 2.3 Hz, 1H), 8.25 (ddd, J = 8.6, 4.8, 2.3 Hz, 1H), 7.62 (dd, J = 10.1, 8.6 Hz, 1H), 3.28 - 3.21 (m, 4H), 1.81 - 1.73 (m, 4H).

[0140] 4-Fluoro-3-(1-piperidylsulfonyl)benzoic acid (Compound 5.3, Scheme 5) The title compound was synthesized following general procedure K above using intermediate 3.1 (250 mg, 1.04 mmol) and piperidine (0.31 ml, 3.11 mmol) in THF (8 ml). The described work-up afforded the pure title compound (257.3 mg, 86% yield). Characterization: Rt = 1.34 min; MS (ESI) m / z: 286.4 [MH]-. [MH]- calculated: 287.06. 1H NMR (400 MHz, DMSO-d6) δ 8.28 - 8.23 ​​(m, 2H), 7.65 - 7.58 (m, 1H), 3.08 (t, J = 5.4 Hz, 4H), 1.58 - 1.49 (m, 4H), 1.46 - 1.39 (m, 2H).

[0141] 4-Fluoro-3-morpholinosulfonyl-benzoic acid (Compound 5.4, Scheme 5) The title compound was synthesized following general procedure K above using intermediate 3.1 (250 mg, 1.04 mmol) and morpholine (0.27 ml, 3.11 mmol) in THF (8 ml). The described work-up afforded the pure title compound (248.1 mg, 83% yield). Characterization: Rt = 1.03 min; MS (ESI) m / z: 288.4 [MH]-. [MH]- calculated: 289.04. 1H NMR (400 MHz, DMSO-d6) δ 8.32 - 8.24 (m, 2H), 7.64 (dd, J = 10.1, 8.5 Hz, 1H), 3.67 - 3.60 (m, 4H), 3.10 - 3.04 (m, 4H).

[0142] 3-Pyrrolidin-1-ylsulfonyl-4-(8,8,8-trifluorooctylamino)benzoic acid (Compound 5.5, Scheme 5) The title compound was synthesized following general procedure H above using intermediate 5.2 (50 mg, 0.17 mmol) and intermediate 4.5 (34.8 mg, 0.19 mmol) in dry 1,4-dioxane (0.55 ml). Trituration with diethyl ether (1 ml) afforded the pure title compound (17.3 mg, 23% yield). Characterization: Rt = 2.30 min; MS (ESI) m / z: 435.5 [MH]-. [MH]- Calculated value: 436.2. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 2.1 Hz, 1H), 7.92 (dd, J = 8.8, 2.1 Hz, 1H), 6.89 (d, J = 8.9 Hz, 1H), 6.74 (t, J = 5.3 Hz, 1H), 3.24 (q, J = 6.7 Hz, 2H), 3.18 - 3.11 (m, 4H), 2.29 - 2.14 (m, 2H), 1.79 - 1.68 (m, 4H), 1.57 (m, 2H), 1.46 (m =, 2H), 1.33 (s, 6H).

[0143] 3-(1-Piperidylsulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid (Compound 5.6, Scheme 5) The title compound was synthesized following general procedure H above using intermediate 5.3 (50 mg, 0.17 mmol) and intermediate 4.5 (34.8 mg, 0.19 mmol) in dry 1,4-dioxane (0.55 ml). Trituration with diethyl ether (1 ml) afforded the pure title compound (13 mg, 17% yield). Characterization: Rt = 2.40 min; MS (ESI) m / z: 449.5 [MH]-. [MH]- Calculated value: 450.2. 1H NMR (400 MHz, DMSO-d6) δ 8.04 (d, J = 2.1 Hz, 1H), 7.92 (dd, J = 8.8, 2.1 Hz, 1H), 6.89 (d, J = 9.0 Hz, 1H), 6.69 (t, J = 5.4 Hz, 1H), 3.24 (q, J = 6.7 Hz, 2H), 2.98 (t, J = 5.4 Hz, 4H), 2.29 - 2.15 (m, 2H), 1.62 - 1.55 (m, 2H), 1.55 - 1.43 (m, 6H), 1.42 - 1.37 (m, 2H), 1.37 - 1.30 (m, 6H).

[0144] 3-Morpholinosulfonyl-4-(8,8,8-trifluorooctylamino)benzoic acid (Compound 5.7, Scheme 5) The title compound was synthesized following general procedure H above using intermediate 5.4 (50 mg, 0.17 mmol) and intermediate 4.5 (34.8 mg, 0.19 mmol) in dry 1,4-dioxane (0.55 ml). Trituration with diethyl ether (1 ml) afforded pure title compound (28.4 mg, 37% yield). Characterization: Rt = 2.21 min; MS (ESI) m / z: 451.2 [MH]-. [MH]- Calculated value: 452.16. 1H NMR (400 MHz, chloroform-d) δ 8.33 (d, J = 2.1 Hz, 1H), 8.07 (dd, J = 8.9, 2.1 Hz, 1H), 6.87 (t, J = 5.0 Hz, 1H), 6.74 (d, J = 9.0 Hz, 1H), 3.77 - 3.70 (m, 4H), 3.21 (q, J = 7.0 Hz, 2H), 3.12 - 3.06 (m, 4H), 2.14 - 1.99 (m, 2H), 1.73 - 1.63 (m, 2H), 1.61 - 1.50 (m, 2H), 1.48 - 1.32 (m, 6H).

[0145] 5-Cyano-2-fluoro-N,N-dimethyl-benzenesulfonamide (Compound 6.2, Reaction L, Scheme 6) 5-Cyano-2-fluorobenzene-1-sulfonyl chloride 6.1 (300 mg, 1.35 mmol) dissolved in 3.5 mL of THF was added dropwise to an ice-cold solution of 2 M dimethylamine in THF (0.74 ml, 1.49 mmol) and N,N-diisopropylethylamine (0.48 ml, 2.70 mmol) in 10 ml of THF, followed by stirring at room temperature for 30 min. Upon completion of the reaction, the reaction mixture was evaporated to dryness, the residue was partitioned between ethyl acetate (50 ml) and water (50 ml), and the layers were separated. The organic layer was dried over Na2SO4 and concentrated to dryness under reduced pressure. Purification by silica gel flash chromatography (70:30 to 30:70 cyclohexane / DCM+1% EtOAc) afforded the pure title compound (194.2 mg, 63% yield). Characterization: 1H NMR (400 MHz, chloroform-d) δ 8.20 (dd, J = 6.2, 2.2 Hz, 1H), 7.87 (ddd, J = 8.6, 4.4, 2.2 Hz, 1H), 7.36 (t, J = 8.9 Hz, 1H), 2.89 (d, J = 1.9 Hz, 6H).

[0146] 5-Cyano-N,N-dimethyl-2-(8,8,8-trifluorooctylamino)benzenesulfonamide (Compound 6.3, Scheme 6) The title compound was synthesized following general procedure H above using intermediate 6.2 (194 mg, 0.84 mmol) and intermediate 4.5 (311.5 mg, 1.64 mmol) in dry 1,4-dioxane (4.2 ml). Trituration with diethyl ether (3 ml) afforded the pure title compound (317.2 mg, 97% yield). Characterization: Rt = 1.82 min; MS (ESI) m / z: 390.3 [MH]-. [MH]- Calculated value: 391.15. 1H NMR (400 MHz, chloroform-d) δ 7.87 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 8.8, 2.1 Hz, 1H), 6.85 (s, 1H), 6.72 (d, J = 8.8 Hz, 1H), 3.23 - 3.13 (m, 2H), 2.77 (s, 6H), 2.14 - 1.98 (m, 2H), 1.73 - 1.61 (m, 2H), 1.60 - 1.48 (m, 4H), 1.46 - 1.33 (m, 6H).

[0147] 4-Fluoro-2-hydroxy-5-sulfamoyl-benzoic acid (Compound 7.3, Reaction M, Scheme 7) 4-Fluoro-2-hydroxy-benzoic acid 7.1 (2 g, 12.81 mmol) was stirred in chlorosulfonic acid (4.30 ml, 64.06 mmol) at 120° C. for 4 hours. After completion of the reaction, the mixture was slowly poured into ice-cold water (50 ml) and the resulting precipitated solid was collected by filtration to give intermediate 7.2. This intermediate (1.12 g, 4.35 mmol) was quickly dissolved in 10 ml of THF and added to an ice-cold solution of 0.83 ml of 20% aqueous NH4OH (4.35 mmol) and trimethylamine (0.61 ml, 4.34 mmol) in 30 ml of tetrahydrofuran. The reaction mixture was stirred at 0° C. for 8 hours. After completion of the reaction, the mixture was evaporated to dryness under low pressure and the residue was treated with saturated aqueous NH4Cl (50 ml) and extracted twice with EtOAc (2×50 ml). The combined organic layers were dried over Na2SO4 and concentrated to dryness under reduced pressure to give the pure title compound (915.9 mg, 30% yield over two steps). Characterization: Rt = 1.15 min; MS (ESI) m / z: 234.3 [MH]-. [MH]- calculated: 235. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 8.5 Hz, 1H), 7.61 (s, 2H), 7.03 (d, J = 11.7 Hz, 1H).

[0148] 2-Hydroxy-5-sulfamoyl-4-(8,8,8-trifluorooctylamino)benzoic acid (Compound 7.4, Scheme 7) The title compound was synthesized following general procedure H above using intermediate 7.3 (250 mg, 1.02 mmol) and intermediate 4.5 (377.7 mg, 2.04 mmol) in dry 1,4-dioxane (3.4 ml). Trituration with cyclohexane (3 ml) afforded the pure title compound (286 mg, 69% yield). Characterization: Rt = 1.81 min; MS (ESI) m / z: 397.3 [MH]-. [MH]- Calculated value: 398.1. 1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.32 (s, 2H), 6.36 (t, J = 5.3 Hz, 1H), 6.12 (s, 1H), 3.18 (q, J = 6.8 Hz, 2H), 2.29 - 2.15 (m, 2H), 1.64 - 1.54 (m, 2H), 1.52 - 1.42 (m, 2H), 1.41 - 1.29 (m, 6H).

[0149] tert-Butyl 4-(5,5,5-trifluoropentyl)piperazine-1-carboxylate (Compound 8.2, Reaction N, Scheme 8) To a solution of 1-boc-piperazine 8.1 (400 mg, 2.15 mmol) in acetonitrile (5 mL) cooled to 0° C., 5-iodo-1,1,1-trifluoropentane (0.25 mL, 3.22 mmol) and N,N-diisopropylethylamine (0.57 mL, 3.22 mmol) were added and the reaction mixture was stirred at room temperature for 24 h. Upon completion of the reaction, the reaction crude was concentrated to dryness at reduced pressure. The residue was dissolved in EtOAc (25 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over Na2SO4 and concentrated to dryness at reduced pressure. Purification by silica gel flash chromatography (98:2 dichloromethane / methanol) afforded the pure title compound (378.9 mg, 92% yield). Characterization: Rt = 2.02; MS (ESI) m / z: 311.5 [MH]+. [MH]- Calculated: 310.2. 1H NMR (400 MHz, Chloroform-d) δ 3.42 (t, J = 4.7 Hz, 4H), 2.41 - 2.31 (m, 6H), 2.16 - 2.02 (m, 2H), 1.63 - 1.50 (m, 4H), 1.45 (s, 9H).

[0150] 1-(5,5,5-Trifluoropentyl)piperazine ditrifluoroacetate (Compound 8.3, Reaction O, Scheme 8) Intermediate 8.2 (378.9 mg, 2.01 mmol) was stirred in neat trifluoroacetic acid (1.5 mL) at room temperature for 1.5 h. Upon completion of the reaction, the reaction crude was diluted with DCM and concentrated to dryness three times (3×10 ml) and once (10 ml) with MeOH at low pressure to give the pure title compound (717.5 mg, 81% yield). Characterization: 1H NMR (400 MHz, Methanol-d4) δ 3.59 - 3.48 (m, 8H), 3.31 - 3.28 (m, 2H), 3.22 - 3.15 (m, 2H), 2.30 - 2.17 (m, 2H), 1.87 - 1.78 (m, 2H), 1.68 - 1.59 (m, 2H).

[0151] 3-(Dimethylsulfamoyl)-4-[4-(5,5,5-trifluoropentyl)piperazin-1-yl]benzoic acid (Compound 9.1, Reaction P, Scheme 9) To a solution of intermediate 8.3 (106.4 mg, 0.24 mmol) and triethylamine (0.14 ml, 1.00 mmol) in dry 1,4-dioxane (1 ml) under argon atmosphere, intermediate 3.3 (50 mg, 0.20 mmol) dissolved in 1,4-dioxane (1 ml) was added and the reaction mixture was stirred at 100° C. for 24 hours. Upon completion of the reaction, the reaction crude was partitioned between ethyl acetate (25 ml) and saturated NH4Cl solution (25 ml) and the pH was adjusted to 3 with concentrated hydrochloric acid. The layers were separated and the aqueous layer was washed with diethyl ether (25 ml). The aqueous layer was then neutralized to pH 7 and extracted with ethyl acetate (3×25 ml) and DCM (25 ml). The combined organic layers were dried over Na2SO4 and concentrated to dryness under reduced pressure. Trituration with diethyl ether (2 ml) gave the pure title compound (26.7 mg, 30% yield). Characterization: Rt = 1.31; MS (ESI) m / z: 436.5 [MH]-. [MH]- Calculated value: 437.2. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 2.1 Hz, 1H), 8.12 (dd, J = 8.3, 2.2 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 3.08 - 2.99 (m, 4H), 2.67 (s, 6H), 2.57 - 2.53 (m, 4H), 2.40 - 2.34 (m, 2H), 2.34 - 2.18 (m, 2H), 1.58 - 1.46 (m, 4H).

[0152] N,N-Dimethyl-5-(1H-tetrazol-5-yl)-2-(8,8,8-trifluorooctylamino)benzenesulfonamide (Compound 10.1, Scheme 10, Figure 12) A mixture of intermediate 6.3 (317.2 mg, 0.8 mmol), sodium azide (63.2 mg, 0.96 mmol), and zinc chloride (132.6 mg, 0.96 mmol) was stirred in 4 ml of n-butanol at 110° C. for 10 h. Upon completion of the reaction, the reaction mixture was evaporated to dryness under reduced pressure. Then, 5% NaOH (20 mL) was added and the mixture was stirred for 20 min. The resulting suspension was filtered and the solid was washed with 5% NaOH (10 mL). The pH of the filtrate was adjusted to 1.0 with concentrated hydrochloric acid and extracted three times with EtOAc (3×25 ml). The combined organic layers were dried over Na2SO4 and concentrated to dryness under reduced pressure. Purification by silica gel flash chromatography (98:2 dichloromethane / methanol) finally afforded the pure title compound (110.93 mg, 32% yield). Characterization: Rt = 0.77; MS (ESI) m / z: 433.3 [MH]-. [MH]- Calculated value: 434.2. 1H NMR (400 MHz, chloroform-d) δ 8.25 (d, J = 2.1 Hz, 1H), 8.19 (dd, J = 8.8, 2.2 Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H), 6.61 (s, 1H), 3.19 (t, J = 7.1 Hz, 2H), 2.76 (s, 6H), 2.14 - 1.98 (m, 2H), 1.73 - 1.62 (m, 2H), 1.61 - 1.49 (m, 2H), 1.49 - 1.30 (m, 6H).

[0153] 5-(N,N-Dimethylsulfamoyl)-4-fluoro-2-hydroxybenzoic acid (Compound 12.1, Scheme 12) 4-Fluoro-2-hydroxy-benzoic acid 7.1 (2 g, 12.81 mmol) was stirred in chlorosulfonic acid (4.30 ml, 64.06 mmol) at 120° C. for 4 h. Once the reaction was complete, the mixture was slowly poured into ice-cold water (50 ml) and the resulting precipitated solid was collected by filtration. The collected solid (1.141 g) was dissolved in 10 ml of THF and added dropwise to an ice-cold solution of 2 M dimethylamine in THF (3 ml) and DIPEA (3 ml) in 35 ml of tetrahydrofuran. The reaction mixture was stirred at 0° C. for 8 h. Once the reaction was complete, the mixture was evaporated to dryness at low pressure and the residue was treated with saturated aqueous NH4Cl (50 ml) and extracted twice with EtOAc (2×50 ml). The combined organic layers were dried over Na2SO4 and concentrated to dryness at low pressure to give the pure title compound (823.9 mg, 70% yield). UPLC / MS: Rt = 1.19 min (gradient 1); MS (ESI) m / z: 262.0 [MH] - [MH] - Calculated: 262.0. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 8.2 Hz, 1H), 7.13 - 7.03 (m, 1H), 2.71 (d, J = 1.7 Hz, 6H).

[0154] Methyl 5-(N,N-dimethylsulfamoyl)-4-fluoro-2-methoxybenzoate (Compound 12.2, Scheme 12) To an ice-cold solution of intermediate 12.1 (200 mg, 0.75 mmol) in 8:2 DCM / MeOH (9 ml), trimethylsilyldiazomethane (2M in hexane, 1.13 ml, 2.26 mmol) was carefully added and the reaction mixture was stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was quenched with 2 ml of 1M acetic acid solution in methanol and evaporated to dryness. The dried residue was suspended in saturated aqueous NaHCO3 (15 ml) and extracted twice with EtOAc (2 x 15 ml). Purification by silica gel flash chromatography (cyclohexane / EtOAc from 85:15 to 70:30) afforded the pure title compound (201 mg, 92% yield) as a white solid. UPLC / MS: Rt = 1.75 min (gradient 1); MS (ESI) m / z: 292.1 [M+H] + . [M+H] + Calculated: 292.0. 1H NMR (600 MHz, chloroform-d) δ 8.35 (d, J = 5.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 2.72 (s, 6H).

[0155] Methyl 5-(N,N-dimethylsulfamoyl)-2-methoxy-4-((8,8,8-trifluorooctyl)amino)benzoate (Compound 12.3, Scheme 12) Compound 12.3 was synthesized following general procedure H above using intermediate 12.2 (50 mg, 0.17 mmol) and intermediate 4.5 (75.4 mg, 0.34 mmol) in dry 1,4-dioxane (0.85 ml). Purification by silica gel flash chromatography (cyclohexane / EtOAc from 80:15 to 75:25) afforded the pure title compound (64.9 mg, 84% yield) as a white solid. UPLC / MS: Rt = 2.65 min (gradient 1); MS (ESI) m / z: 455.3 [M+H] + . [M+H] +Calculated value: 455.2. 1H NMR (400 MHz, chloroform-d) δ 8.23 ​​(s, 1H), 6.77 (t, J = 4.8 Hz, 1H), 6.10 (s, 1H), 3.97 (s, 3H), 3.84 (s, 3H), 3.22 - 3.16 (m, 2H), 2.75 (s, 6H), 2.14 - 2.04 (m, 2H), 1.72 (p, J = 7.1 Hz, 2H), 1.60 - 1.55 (m, 4H), 1.45 (dd, J = 5.0, 2.0 Hz, 2H), 1.41 (dd, J = 3.9, 2.6 Hz, 4H).

[0156] Methyl 5-(N,N-dimethylsulfamoyl)-2-hydroxy-4-((8,8,8-trifluorooctyl)amino)benzoate (Compound 12.4, Scheme 12) Under argon atmosphere, BBr3 (1M in DCM, 0.55 ml, 0.55 mmol) was added dropwise to an ice-cold solution of intermediate 12.3 (50 mg, 0.11 mmol) in DCM (1.2 mL) and the mixture was stirred at room temperature for 6 h. Upon completion of the reaction, the reaction mixture was cooled to 0° C., quenched with 2 ml of methanol and evaporated to dryness. The dried crude residue was then partitioned between EtOAc (10 ml) and saturated NH4Cl solution (10 ml) and the layers were separated. The organic layer was dried over Na2SO4 and concentrated to dryness under reduced pressure. Purification by silica gel flash chromatography (95:05 cyclohexane / EtOAc) afforded the pure title compound (40.2 mg, 83% yield) as a white solid. UPLC / MS: Rt = 2.10 min (gradient 1); MS (ESI) m / z: 441.3 [MH] + . [M+H] +Calculated value: 441.1. 1H NMR (400 MHz, chloroform-d) δ 11.26 (s, 1H), 8.17 (s, 1H), 6.73 (t, J = 4.6 Hz, 1H), 6.16 (s, 1H), 3.92 (s, 3H), 3.16 (q, J = 7.1, 5.0 Hz, 2H), 2.75 (s, 6H), 2.15 - 1.99 (m, 2H), 1.74 - 1.63 (m, 2H), 1.62 - 1.54 (m, 2H), 1.48 - 1.35 (m, 6H).

[0157] Methyl 5-(N,N-dimethylsulfamoyl)-2-ethoxy-4-((8,8,8-trifluorooctyl)amino)benzoate (Compound 12.5, Scheme 12) To a solution of intermediate 12.4 (31.8 mg, 0.07 mmol) in acetonitrile (0.7 mL) was added ethyl iodide (10 μl, 0.11 mmol) and potassium carbonate (15 mg, 0.11 mmol) and the reaction mixture was stirred at 80° C. for 10 h. Upon completion of the reaction, the crude was partitioned between EtOAc (10 ml) and water (10 ml) and the layers were separated. The organic layer was dried over Na2SO4 and concentrated to dryness under reduced pressure. Purification by silica gel flash chromatography (cyclohexane / EtOAc from 100:00 to 80:20) afforded the pure title compound (25.6 mg, 78% yield) as a white solid. UPLC / MS: Rt = 1.85 min (gradient 1); MS (ESI) m / z: 469.3 [M+H] + . [M+H] +Calculated value: 469.2. 1H NMR (400 MHz, chloroform-d) δ 8.20 (s, 1H), 6.71 (t, J = 4.8 Hz, 1H), 6.07 (s, 1H), 4.14 (q, J = 7.0 Hz, 2H), 3.82 (s, 3H), 3.18 - 3.11 (m, 2H), 2.72 (s, 6H), 2.13 - 1.99 (m, 2H), 1.73 - 1.64 (m, 2H), 1.61 - 1.53 (m, 2H), 1.51 (t, J = 6.9 Hz, 3H), 1.48 - 1.35 (m, 6H).

[0158] 5-(N,N-Dimethylsulfamoyl)-2-ethoxy-4-((8,8,8-trifluorooctyl)amino)benzoic acid (Compound 12.7, Scheme 12) To a solution of compound 12.5 (25.6 mg, 0.05 mmol) in tetrahydrofuran (0.5 mL) was added 1M aqueous LiOH (0.27 ml, 0.27 mmol) and the reaction mixture was stirred at room temperature for 16 h. Upon completion of the reaction, the crude was partitioned between EtOAc (10 ml) and saturated NH4Cl solution (10 ml) and the layers were separated. The organic layer was dried over Na2SO4 and concentrated to dryness under reduced pressure. Trituration with cyclohexane afforded the pure title compound (19.54 mg, 86% yield) as a white solid. UPLC / MS: Rt = 1.32 min (gradient 1); MS (ESI) m / z: 453.3 [MH]-. [MH] - Calculated value: 453.2. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 6.62 (t, J = 5.2 Hz, 1H), 6.23 (s, 1H), 4.15 (q, J = 6.9 Hz, 2H), 3.23 (q, J= 6.5 Hz, 2H), 2.60 (s, 6H), 2.29 - 2.14 (m, 2H), 1.63 - 1.52 (m, 2H), 1.51 - 1.42 (m, 2H), 1.40 - 1.25 (m, 9H).

[0159] Methyl 2-(cyclopentyloxy)-5-(N,N-dimethylsulfamoyl)-4-((8,8,8-trifluorooctyl)amino)benzoate (Compound 12.6, Scheme 12) To a solution of intermediate 12.4 (30.0 mg, 0.07 mmol) in acetonitrile (0.7 mL) was added cyclopentyl bromide (15 μl, 0.13 mmol) and potassium carbonate (28.3 mg, 0.20 mmol) and the reaction mixture was stirred at 80° C. for 4 h. Upon completion of the reaction, the crude was partitioned between EtOAc (10 mL) and water (10 mL) and the layers were separated. The organic layer was dried over Na2SO4 and concentrated to dryness under reduced pressure. Purification by silica gel flash chromatography (cyclohexane / EtOAc 100:00 to 90:10) afforded the pure title compound (25.6 mg, 72% yield) as a white solid. UPLC / MS: Rt = 2.30 min (gradient 2); MS (ESI) m / z: 509.2 [M+H] + . [M+H] + Calculated value: 509.6. 1H NMR (400 MHz, chloroform-d) δ 8.19 (s, 1H), 6.69 (t, J = 4.8 Hz, 1H), 6.07 (s, 1H), 4.88 - 4.81 (m, 1H), 3.80 (s, 3H), 3.19 - 3.10 (m, 2H), 2.72 (s, 6H), 2.13 - 1.99 (m, 2H), 1.99 - 1.92 (m, 4H), 1.91 - 1.81 (m, 2H), 1.73 - 1.62 (m, 2H), 1.61 - 1.51 (m, 2H), 1.49 - 1.34 (m, 6H).

[0160] 2-(Cyclopentyloxy)-5-(N,N-dimethylsulfamoyl)-4-((8,8,8-trifluorooctyl)amino)benzoic acid (Compound 12.8, Scheme 12) To a solution of intermediate 12.6 (25.6 mg, 0.05 mmol) in tetrahydrofuran (0.25 mL) was added 1M aqueous LiOH (0.5 ml, 0.25 mmol) and the mixture was stirred at room temperature for 16 h. Upon completion of the reaction, the crude was partitioned between EtOAc (10 ml) and saturated NH4Cl solution (10 ml) and the layers were separated. The organic layer was dried over Na2SO4 and concentrated to dryness under reduced pressure. Trituration with cyclohexane afforded the pure title compound (16.3 mg, 66% yield) as a white solid. UPLC / MS: Rt = 1.80 min (gradient 1); MS (ESI) m / z: 493.3 [MH]-. [MH] - Calculated: 493.2. 1H NMR (400 MHz, chloroform-d) 1 H NMR (400 MHz, chloroform-d) δ 8.40 (s, 1H), 6.94 (s, 1H), 6.12 (s, 1H), 5.09 - 5.03 (m, 1H), 3.20 - 3.13 (m, 2H), 2.75 (s, 6H), 2.14 - 1.97 (m, 5H), 1.93 - 1.81 (m, 2H), 1.81 - 1.65 (m, 4H), 1.61 - 1.51 (m, 4H), 1.50 - 1.33 (m, 6H).

[0161] 5-(N,N-Dimethylsulfamoyl)-2-methoxy-4-((8,8,8-trifluorooctyl)amino)benzoic acid (Compound 13.1, Scheme 13) To a solution of intermediate 12.3 (59 mg, 0.13 mmol) in tetrahydrofuran (1.3 mL) was added 1M aqueous LiOH (0.26 ml, 0.26 mmol) and the mixture was stirred at room temperature for 16 h. Upon completion of the reaction, the crude was partitioned between EtOAc (10 ml) and saturated NH4Cl solution (10 ml) and the layers were separated. The organic layer was dried over Na2SO4 and concentrated to dryness under reduced pressure. Trituration with cyclohexane afforded the pure title compound (41.2 mg, 72% yield) as a white solid. UPLC / MS: Rt = 1.16 min (gradient 1); MS (ESI) m / z: 439.5 [MH]-. [MH] - Calculated value: 439.2. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 6.65 (t, J = 5.2 Hz, 1H), 6.26 (s, 1H), 3.88 (s, 3H), 3.29 - 3.22 (m, 2H), 2.61 (s, 6H), 1.65 - 1.55 (m, 2H), 1.52 - 1.42 (m, 4H), 1.39 - 1.29 (m, 6H).

[0162] 4-Fluoro-3-(N-(tetrahydro-2H-pyran-4-yl)sulfamoyl)benzoic acid (Compound 14.1, Scheme 14) The title compound was synthesized following general procedure G above using intermediate 3.1 (250 mg, 1.04 mmol) and tetrahydro-2H-pyran-4-amine (0.32 ml, 2.07 mmol) in THF (8.5 ml). The work-up described afforded the pure title compound (160.9 mg, 51% yield) as a white solid. UPLC / MS: Rt = 0.93 min (gradient 1); MS (ESI) m / z: 302.1 [MH]-. [MH] Calculated value: 302.06. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (dd, J = 7.1, 2.3 Hz, 1H), 8.27 (d, J = 7.8 Hz, 1H), 8.24 - 8.18 (m, 1H), 7.57 (t, J = 9.3 Hz, 1H), 3.77 - 3.68 (m, 2H), 3.27 - 3.19 (m, 3H), 1.58 - 1.49 (m, 2H), 1.49 - 1.37 (m, 2H).

[0163] 3-((4,4-Difluoropiperidin-1-yl)sulfonyl)-4-fluorobenzoic acid (Compound 14.2, Scheme 14) The title compound was synthesized following general procedure K above using intermediate 3.1 (150 mg, 0.62 mmol) and 4,4-difluoropiperidine hydrochloride (198.1 mg, 1.24 mmol) and DIPEA (0.33 ml, 1.87 mmol) in THF (5.0 ml). Upon completion of the reaction, the reaction mixture was evaporated to dryness. The work-up described afforded the pure title compound (176.4 mg, 88% yield) as a white solid. UPLC / MS: Rt = 1.38 min (gradient 1); MS (ESI) m / z: 322.0 [MH]-. [MH] Calculated value: 322.04. 1H NMR (400 MHz, DMSO-d6) δ 8.31 - 8.25 (m, 2H), 7.67 - 7.60 (m, 1H), 3.29 (t, J = 5.8 Hz, 4H), 2.07 (ddd, J = 19.7, 13.7, 5.8Hz, 4H).

[0164] 3-Morpholinosulfonyl-4-((8,8,8-trifluorooctyl)amino)benzoic acid (Compound 14.3, Scheme 14) The title compound was synthesized following general procedure H above using Intermediate 14.2 (50 mg, 0.17 mmol) and Intermediate 4.5 (34.8 mg, 0.19 mmol) in dry 1,4-dioxane (0.55 ml). Purification by silica gel flash chromatography (CH2Cl2 / MeOH 100:0 to 98:02) followed by trituration with diethyl ether (1 ml) afforded the pure title compound (28.4 mg, 37% yield) as a white solid. UPLC / MS: Rt = 2.21 min (gradient 1); MS (ESI) m / z: 451.2 [MH]-. [MH] - Calculated value: 451.2. 1H NMR (400 MHz, chloroform-d) δ 8.33 (d, J = 2.1 Hz, 1H), 8.07 (dd, J = 8.9, 2.1 Hz, 1H), 6.87 (t, J = 5.0 Hz, 1H), 6.74 (d, J = 9.0 Hz, 1H), 3.77 - 3.70 (m, 4H), 3.21 (q, J= 7.0 Hz, 2H), 3.12 - 3.06 (m, 4H), 2.14 - 1.99 (m, 2H), 1.73 - 1.63 (m, 2H), 1.61 - 1.50 (m, 2H), 1.48 - 1.32 (m, 6H).

[0165] 3-((4,4-Difluoropiperidin-1-yl)sulfonyl)-4-((8,8,8-trifluorooctyl)amino)benzoic acid (Compound 14.4, Scheme 14) The title compound was synthesized following general procedure H above using Intermediate 14.1 (50 mg, 0.15 mmol) and Intermediate 4.5 (34.8 mg, 0.19 mmol) in dry 1,4-dioxane (0.55 ml). Purification by silica gel flash chromatography (CH2Cl2 / MeOH 100:0 to 98:02) followed by trituration with petroleum ether (1 ml) afforded the pure title compound (22.6 mg, 31% yield) as a white solid. UPLC / MS: Rt = 2.39 min (gradient 1); MS (ESI) m / z: 485.2 [MH]-. [MH] - Calculated value: 485.2. 1H NMR (400 MHz, chloroform-d) δ 8.35 (d, J = 2.0 Hz, 1H), 8.08 (dd, J = 8.9, 2.1 Hz, 1H), 6.78 (t, J = 5.0 Hz, 1H), 6.74 (d, J = 9.0 Hz, 1H), 3.31 (t, J = 5.8 Hz, 4H), 3.25 - 3.18 (m, 2H), 2.14 - 2.00 (m, 6H), 1.69 (p, J = 7.0 Hz, 2H), 1.62 - 1.52 (m, 2H), 1.49 - 1.35 (m, 6H).

[0166] 3-(Dimethylsulfamoyl)-4-(hept-6-enylamino)benzoic acid (Compound 15.1, Scheme 15) The title compound was synthesized following general procedure H above using intermediate 3.3 (420 mg, 1.68 mmol) and hept-6-en-1-amine hydrochloride (335.6 mg, 1.68 mmol) in dry 1,4-dioxane (16.5 ml). Purification by silica gel flash chromatography (CH2Cl2 / MeOH 100:0 to 98:02) followed by trituration with diethyl ether (3 ml) afforded the pure title compound (409.6 mg, 72% yield) as a white solid. UPLC / MS: Rt = 2.13 min (gradient 1); MS (ESI) m / z: 439.2 [MH]-. [MH] -Calculated value: 339.1. 1H NMR (400 MHz, chloroform-d) δ 8.34 (d, J = 2.0 Hz, 1H), 8.06 (dd, J = 8.9, 2.1 Hz, 1H), 6.91 (t, J = 5.0 Hz, 1H), 6.72 (d, J = 9.0 Hz, 1H), 5.80 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.04 - 4.91 (m, 2H), 3.24 - 3.18 (m, 2H), 2.77 (s, 6H), 2.13 - 2.02 (m, 2H), 1.69 (p, J = 7.0 Hz, 2H), 1.49 - 1.39 (m, 4H).

[0167] Methyl 3-(N,N-dimethylsulfamoyl)-4-(hept-6-en-1-ylamino)benzoate (Compound 15.2, Scheme 12) To an ice-cold solution of intermediate 15.1 (220 mg, 0.64 mmol) in 8:2 DCM / MeOH (8 ml), trimethylsilyldiazomethane (2M in hexane, 0.48 ml, 0.96 mmol) was carefully added and the reaction mixture was stirred at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was quenched with 2 ml of 1M acetic acid solution in methanol and evaporated to dryness. The dried residue was suspended in saturated aqueous NaHCO3 (15 ml) and extracted twice with EtOAc (2 x 15 ml). Purification by silica gel flash chromatography (100:00 to 90:10 cyclohexane / EtOAc) afforded the pure title compound (213.2 mg, 94% yield) as a white solid. UPLC / MS: Rt = 1.81 min (gradient 1); MS (ESI) m / z: 355.2 [M+H] + . [M+H] + Calculated: 355.2. 1H NMR (600 MHz, chloroform-d) 1H NMR (400 MHz, chloroform-d) δ 8.28 (d, J = 2.1 Hz, 1H), 8.01 (dd, J = 8.9, 2.1 Hz, 1H), 6.83 - 6.74 (m, 1H), 6.70 (d, J = 8.9 Hz, 1H), 5.79 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.04 - 4.92 (m, 2H), 3.87 (s, 3H), 3.23 - 3.15 (m, 2H), 2.75 (s, 6H), 2.12 - 2.03 (m, 2H), 1.74 - 1.63 (m, 2H), 1.49 - 1.38 (m, 4H).

[0168] Methyl 4-((8-bromo-8,8-difluorooctyl)amino)-3-(N,N-dimethylsulfamoyl)benzoate (Compound 15.3, Scheme 15) In a sealed glass tube, to a solution of intermediate 15.2 (213.2 mg, 0.62 mmol) in THF (6.2 ml) was added potassium bicarbonate (62.7 mg, 0.62 mmol), eosin salt (23.8 mg, 0.03 mmol), and dibromodifluoromethane (0.12 ml, 1.24 mmol). The reaction mixture was then stirred at room temperature under blue LED irradiation (λ=460 nm-470 nm) for 16 h. Upon completion of the reaction, the reaction mixture was evaporated to dryness. The dried residue was suspended in aqueous water (25 ml) and extracted twice with EtOAc (2×25 ml). Purification by silica gel flash chromatography (petroleum ether / TBME from 100:00 to 80:20) afforded the pure title compound (144.5 mg, 48% yield) as a white solid. 15).UPLC / MS: Rt = 2.13 min (gradient 2); MS (ESI) m / z: 485.0 [M+H] + . [M+H] + Calculated value: 485.08 1 H NMR (600 MHz, chloroform-d) 1H NMR (400 MHz, chloroform-d) 1H NMR (400 MHz, chloroform-d) δ 8.27 (d, J = 2.1 Hz, 1H), 8.02 (dd, J = 8.9, 2.1 Hz, 1H), 6.79 (t, J = 5.0 Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H), 3.87 (s, 3H), 3.23 - 3.16 (m, 2H), 2.76 (s, 6H), 2.40 - 2.26 (m, 2H), 1.72 - 1.55 (m, 6H), 1.48 - 1.35 (m, 6H).

[0169] 4-[(8-Bromo-8,8-difluoro-octyl)amino]-3-(dimethylsulfamoyl)benzoic acid (Compound 15.4, Scheme 15) To a solution of intermediate 15.3 (50 mg, 0.10 mmol) in tetrahydrofuran (1.0 mL) was added 1M aqueous LiOH (0.42 ml, 0.2 mmol) and the mixture was stirred at room temperature for 16 h. Upon completion of the reaction, the crude was partitioned between EtOAc (10 ml) and saturated NH4Cl solution (10 ml) and the layers were separated. The organic layer was dried over Na2SO4 and concentrated to dryness under reduced pressure. Trituration with cyclohexane afforded the pure title compound (40.1 mg, 85% yield) as a white solid. UPLC / MS: Rt = 1.22 min (gradient 2); MS (ESI) m / z: 469.1 [MH]-. [MH] - Calculated: 469.1. 1H NMR (400 MHz, chloroform-d) 1H NMR (400 MHz, chloroform-d) δ 8.29 (d, J = 2.1 Hz, 1H), 8.05 (dd, J = 8.9, 2.1 Hz, 1H), 6.83 (t, J = 5.0 Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H), 3.25 - 3.18 (m, 2H), 2.77 (s, 6H), 2.42 - 2.28 (m, 2H), 1.76 - 1.59 (m, 6H), 1.51 - 1.38 (m, 6H).

[0170] Example 2: Activity Data The data obtained are reported in Table 1 below.

[0171] [Table 2] TIFF0007676317000008.tif233170TIFF0007676317000009.tif233170TIFF00076763170 00010.tif221170TIFF0007676317000011.tif235170TIFF0007676317000012.tif231170 TIFF0007676317000013.tif216170TIFF0007676317000014.tif234170TIFF00076763170 00015.tif197170TIFF0007676317000016.tif245170TIFF0007676317000017.tif200170

[0172] According to one embodiment of the present invention, the most active compounds are: Compound 1.7, Compound 1.17, Compound 2.2, Compound 2.6, Compound 2.7, Compound 2.8, Compound 2.9, Compound 3.6, Compound 3.7, Compound 3.8, Compound 3.9, Compound 3.10, Compound 3.11, Compound 3.12, Compound 3.13, Compound 3.14, Compound 3.17, Compound 3.20, Compound 3.21, Compound 3.22, Compound 5.5, Compound 5.6, Compound 5.7, Compound 13.1, Compound 14.4, Compound 15.1.

[0173] Chloride ion dynamics assay To screen the efficacy of compounds in blocking NKCC1 in vitro, Cl - Intracellular Cl-mediated signal transduction via membrane-tagged yellow fluorescent protein (mbYFPQS, Addgene) - A functional NKCC1 transporter assay was performed by measuring fluctuations in ion concentration. The fluorescence of mbYFPQS was correlated with the intracellular Cl - Since it is inversely proportional to the concentration of Cl- This allows for indirect estimation of transporter activity. In particular, HEK293 cells were incubated with Cl2+ or mock constructs (control). - After 2 DIV, cells were transfected with Cl - Cells were treated with bumetanide and furosemide (as positive controls) or the respective test compounds of the present invention in free medium. After 30 min, the inhibitory activity of the compounds was tested by monitoring the fluorescence upon application of NaCl (FIG. 1a). Transported by NKCC1, Cl binds to YFP, causing a decrease in fluorescence. NKCC1 - Cells transfected with 3.17 showed a strong decrease in fluorescence levels upon application of NaCl compared to mock-transfected cells (Fig. 1b). This effect was significantly reduced by preincubation with bumetanide at 10 μM and 100 μM, whereas preincubation with furosemide was effective only at 100 μM (Fig. 1b). Furthermore, data were normalized again due to the decrease in fluorescence observed in mock-transfected cells upon application of bumetanide or furosemide. The NKCC1 inhibitory activity of selected compounds was tested using a Cl kinetics assay (Fig. 1c). Notably, at 100 μM, compound 3.17 inhibited NKCC1 better than bumetanide and furosemide.

[0174] Calcium mobilization assay Next, compounds of the invention were tested for their ability to restore depolarizing GABAergic signaling in immature neurons. This effect was indirectly measured as calcium influx into cells using an in vitro calcium mobilization assay in primary cultures of hippocampal neurons. The calcium mobilization assay takes advantage of the physiological endogenous high expression of NKCC1 in immature neurons, which causes the depolarizing action of GABA and inhibits voltage-dependent Ca 2+ Thus, in immature neurons, compounds that block NKCC1 may increase the Ca 2+Immature neurons were cultured for 3 days in vitro (3DIV) and loaded with a calcium-sensitive dye (Fluo4) for 15 min. Neurons were then treated with bumetanide and furosemide (as positive controls) or each selected compound for 15 min. As a functional readout, fluorescence levels were monitored in these cultures before and after application of GABA (100 μM, 20 s). To test for neuronal viability at the end of the experiment, neurons were strongly depolarized to detect voltage-dependent Ca in living cells. 2+ KCl was applied (90 mM, 40 s), which causes high activation of the channel. To quantify how bumetanide, furosemide, and the selected compounds affect NKCC1 inhibition, the fluorescence values ​​upon application of GABA were normalized to the fluorescence levels upon KCl application in treated neurons. Bumetanide, furosemide, and each of the selected compounds significantly reduced the increase in fluorescence upon GABA application compared to vehicle (DMSO)-treated controls. They did not affect the fluorescence levels upon KCl application (Figure 2a). The selected compounds significantly reduced Ca2+ upregulation upon GABA stimulation. 2+ It showed optimal potency in inhibiting the response (FIG. 2b), with fluorescence values ​​comparable to bumetanide at 10 μM and even better than bumetanide at 100 μM, consistent with the chloride ion (YFP) assay.

[0175] Pharmacodynamic research The selected NKCC1 inhibitor, compound 3.17, was evaluated for solubility in aqueous buffers, and in vitro plasma stability and phase I metabolism (Figure 3a). The compound was highly soluble (>250 μM in PBS (pH 7.4)) and highly resistant to hydrolysis and phase I metabolism (t1 / 2>120 min in plasma, t1 / 2>60 min in liver microsomes). The data show that the compound has promising solubility and in vitro metabolic stability.

[0176] Cognitive impairment test The efficacy of compound 3.17 in rescuing cognitive impairment in four different cognitive tests in Ts65Dn mice (FIG. 4) was evaluated. Adult Ts65Dn mice and their WT littermates (2 months old) were treated with 3.17 (0.2 mg / kg i.p.) or its vehicle for one week. During the next three weeks, animals were tested in four different tasks assessing memory and cognition: a) a novel object location task (Deidda, G. et al. Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome. Nat Med 2015, 21 (4), 318-26; Contestabile, A. et al. Lithium rescues synaptic plasticity and memory in Down syndrome mice. J Clin Invest 2013, 123 (1), 348-61); b) a novel object recognition test (Deidda G. 2015; Fernandez, F., Garner, CC, Object recognition memory is conserved in Ts1Cje, a mouse model of Down syndrome. Neuroscience letters 2007, 421, 137-141); c) a T-maze task (Belichenko, NP et al. The "Down syndrome critical region" is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of Down syndrome. J Neurosci 2009, 29 (18), 5938-48) (spontaneous alternation protocol, 11 trials), and d) fear conditioning test (Deidda G. 2015; Costa, AC et al.Acute injections of the NMDA receptor antagonist memantine rescue performance deficits of the Ts65Dn mouse model of Down syndrome on a fear conditioning test. Neuropsychopharmacology 2008, 33 (7), 1624-32). As expected, vehicle-treated Ts65Dn mice showed impaired performance compared to WT. Treatment with 3.17 improved the cognitive performance of Ts65Dn mice (Figure 4).

[0177] Example 3: NKCC1 vs. NKCC2 selectivity data Compounds of the invention were tested for selective inhibition of NKCC1 compared to NKCC2, as reported in Table 2 below.

[0178] [Table 3]

[0179] According to the exemplary data reported in Table 2 above, some compounds show better NKCC1 / NKCC2 selectivity.

[0180] As an advantage, these compounds do not have diuretic side effects.

[0181] In particular, the above advantages are demonstrated for Compounds 1.7, 1.15, 2.2, 2.6, 2.7, 2.8, 3.8, 3.13, 3.14, and 3.17, which are particularly preferred within the present invention.

[0182] In vitro thallium-based assay in HEK cells Thallium-based assays are the standard assays used to measure the activity of potassium transporters, such as the sodium-potassium-chloride cotransporter NKCC2.

[0183] This assay detects thallium (K + The assay consists of monitoring cells upon application of NKCC2 (simulating K) and thus NaCl entering the cells by NKCC2 activated by the presence of chloride ions binds to the fluorescent dye and thus an increase in fluorescence is measured. The assay involves parallel testing in 96 wells for fast and easy drug screening. In detail, kidney epithelial cells (HEK293) were transfected with NKCC2 transporter or mock constructs (control). After 2 days, cells were loaded with thallium-sensitive fluorescent dye in Cl-free medium. After 1 hour of incubation, the inhibitory activity of bumetanide and furosemide (as positive controls) as well as new compounds were tested by monitoring the fluorescence upon application of thallium (simulating K) and subsequent NaCl. Upon entry into the cells by NKCC2 (activated by the presence of Cl), thallium binds to the fluorescent dye and increases the fluorescence. Upon application of thallium, cells transfected with NKCC2 showed a strong increase in the fluorescence level compared to mock-transfected cells. Preincubation with bumetanide (10 μM) significantly reduced ion flux, resulting in an increase in fluorescence of NKCC2-transfected cells. A decrease in fluorescence was observed in mock-transfected cells treated with bumetanide and furosemide, indicating that HEK293 cells express endogenous transporters that are sensitive to bumetanide / furosemide. This latter result was used to normalize the fluorescence measurements obtained in the assay. In particular, the ΔF / F0 values ​​of mock-transfected cells (both control and treated) were subtracted from the respective ΔF / F0 values ​​of Cl-transporter-transfected cells. This assay allowed testing novel chemical entities for their ability to block NKCC2 (results in Table 2).

[0184] Figure 17 shows the results of the thallium assay. a) Example traces obtained in a thallium-based assay on non-transfected (mock) or NKCC2-transfected kidney epithelial (HEK293) cells. Arrows indicate the addition of thallium (final concentration 2 mM) and NaCl stimulation (135 mM) used to initiate the flux assay. b) Quantification of the effects of bumetanide, frusemide, and three example compounds (3.8, 3.13, 3.17) in a thallium-based assay on NKCC2-transfected HEK293 cells. Data represent the mean ± sem from five independent experiments and are expressed as % of control. * P < 0.05, ** P < 0.01, *** P < 0.001 Kruskal-Wallis anova (Dunn's post hoc test); ### P<0.001 unpaired two-tailed Student's t test.

[0185] VPA autism model In vivo evaluation of the efficacy of selected NKCC1 inhibitors in a valproic acid (VPA)-induced mouse model of autism, assessing their ability to rescue alterations in social interactions. The VPA model was obtained by treating pregnant C57bl / 6j dams at day 12.5 of gestation with 600 mg / kg (i.p.) VPA in PBS. VPA-treated dams produce offspring that exhibit behaviors related to the core symptoms of autism (Nicolini and Fahnestock, 2018). As a control, offspring of C57bl / 6j dams treated with PBS at day 12.5 were used. To evaluate the efficacy of compounds in restoring social deficits, juvenile male offspring of both VPA- and PBS-treated dams were treated for 7 days with 0.2 mg / kg compound 3.17 in PBS or with 2% DMSO in PBS as a control (i.p. injection). Mice were then tested in various tests for social competence and repetitive behaviors. Social competence was tested in a three-chamber test (Silverman et al., 2010). In the three-chamber test, mice are placed alone in a three-chamber box with an opening between the chambers. After 10 min of free exploration, a strange intruder was placed under one pencil cup in one chamber and an empty pencil cup was placed in the other chamber. The sociability index consisted of the time the animal explored the strange intruder relative to the time it explored the pencil cup, as defined below: [(time spent with intruder-time spent with empty cup) / (time spent with intruder+time spent with empty cup)%]. In a second phase, a new intruder was placed under the previously empty pencil case to measure the social novelty index, i.e. the exploration time of the new intruder compared to the object already encountered in the past 10 min. The social novelty index was measured as follows: [(time spent with new intruder-time spent with previous intruder) / (time spent with new intruder+time spent with previous intruder)%].

[0186] As reported in Figure 18A, vehicle-treated VPA mice exhibited significantly lower social index and social novelty when compared to vehicle-treated naive mice. Treatment with compound 3.17 in VPA mice completely restored the social index and social novelty index to control levels.

[0187] Sociality during male-female interactions was then assessed (Drapeau et al., 2018). In this test, test mice are assessed for their approach to a female intruder mouse that is placed in the same cage for 5 min after 5 min of habituation. The time spent interacting is calculated as a measure of social interaction between males and females. As shown in Figure 18B, vehicle-treated VPA mice showed a significantly lower male-female interaction index than vehicle-treated naive mice. Treatment with compound 3.17 in VPA mice fully restored the interaction. Finally, repetitive behavior was assessed in two different tests. In the marble burying test (Eissa et al., 2018), mice are placed in a cage with a 4 cm bedding on which 15 (5 × 3) balls are arranged in an orderly fashion. Repetitive behavior is assessed as the number of marbles buried in the bedding. The grooming test consists of the assessment of grooming behavior, i.e. licking the head or other parts of the body or scratching with the front paws, which are typical behaviors of rodents (Campolongo et al., 2018). During this test, mice are placed in a cylindrical support and repetitive grooming activity is measured for 5 min after 10 min of habituation. As shown in Figure 18C and Figure 18D, vehicle-treated VPA mice showed more repetitive behavior (more marbles buried and more time spent grooming) than vehicle-treated naive mice. Compound 3.17 treatment restored repetitive behavior to control levels in VPA mice.

Claims

1. 2.2 4-(butylamino)-2-chloro-5-sulfamoyl-benzoic acid, 2.3 2-chloro-4-(hexylamino)-5-sulfamoyl-benzoic acid, 2.4 2-Chloro-4-(octylamino)-5-sulfamoyl-benzoic acid, 2.5 2-chloro-4-(3,3-dimethylbutylamino)-5-sulfamoyl-benzoic acid, 2.7 4-(hexylamino)-3-sulfamoyl-benzoic acid, 2.8 4-(octylamino)-3-sulfamoyl-benzoic acid, 2.9 4-(3,3-dimethylbutylamino)-3-sulfamoyl-benzoic acid, 3.7 4-(hexylamino)-3-(methylsulfamoyl)benzoic acid, 3.8 3-(methylsulfamoyl)-4-(octylamino)benzoic acid, 3.9 4-(3,3-dimethylbutylamino)-3-(methylsulfamoyl)benzoic acid, 3.10 3-(methylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.11 4-(butylamino)-3-(dimethylsulfamoyl)benzoic acid, 3.12 3-(dimethylsulfamoyl)-4-(hexylamino)benzoic acid, 3.13 3-(dimethylsulfamoyl)-4-(octylamino)benzoic acid, 3.14 4-(3,3-dimethylbutylamino)-3-(dimethylsulfamoyl)benzoic acid, 3.15 3-(dimethylsulfamoyl)-4-(4,4,4-trifluorobutylamino)benzoic acid, 3.16 3-(dimethylsulfamoyl)-4-(6,6,6-trifluorohexylamino)benzoic acid, 3.17 3-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.18 3-(dimethylsulfamoyl)-4-(2-methoxyethylamino)benzoic acid, 3.19 3-(dimethylsulfamoyl)-4-(4-methoxybutylamino)benzoic acid, 3.20 3-(dimethylsulfamoyl)-4-(6-methoxyhexylamino)benzoic acid, 3.21 3-(cyclopentylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.22 3-(cyclohexylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.5 3-Pyrrolidin-1-ylsulfonyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.6 3-(1-piperidylsulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.7 3-morpholinosulfonyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 6.3 5-cyano-N,N-dimethyl-2-(8,8,8-trifluorooctylamino)benzenesulfonamide, 7.4 2-Hydroxy-5-sulfamoyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 9.1 3-(dimethylsulfamoyl)-4-[4-(5,5,5-trifluoropentyl)piperazin-1-yl]benzoic acid, 12.7 5-(N,N-dimethylsulfamoyl)-2-ethoxy-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 12.8 2-(cyclopentyloxy)-5-(N,N-dimethylsulfamoyl)-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 13.1 5-(N,N-dimethylsulfamoyl)-2-methoxy-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 14.3 3-Morpholinosulfonyl-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 14.4 3-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 15.4 4-[(8-bromo-8,8-difluorooctyl)amino]-3-(dimethylsulfamoyl)benzoic acid, 16.1 5-(dimethylsulfamoyl)-2-isopropoxy-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.2 2-(cyclohexoxy)-5-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.3 5-(dimethylsulfamoyl)-2-tetrahydropyran-4-yloxy-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.4 2-(cyclobutoxy)-5-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.5 5-(dimethylsulfamoyl)-2-(oxetan-3-yloxy)-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.6 5-(Dimethylsulfamoyl)-2-(4-piperidyloxy)-4-(8,8,8-trifluorooctylamino)benzoic acid, and 16.7 5-(dimethylsulfamoyl)-2-phenoxy-4-(8,8,8-trifluorooctylamino)benzoic acid, or a stereoisomeric form thereof, or an individual geometric isomer, enantiomer, diastereoisomer, tautomer, zwitterion, and pharma- ceutically acceptable salt thereof, selected from the group comprising:

2. 2.2 4-(butylamino)-2-chloro-5-sulfamoyl-benzoic acid, 2.7 4-(hexylamino)-3-sulfamoyl-benzoic acid, 2.8 4-(octylamino)-3-sulfamoyl-benzoic acid, 2.9 4-(3,3-dimethylbutylamino)-3-sulfamoyl-benzoic acid, 3.7 4-(hexylamino)-3-(methylsulfamoyl)benzoic acid, 3.8 3-(methylsulfamoyl)-4-(octylamino)benzoic acid, 3.9 4-(3,3-dimethylbutylamino)-3-(methylsulfamoyl)benzoic acid, 3.10 3-(methylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.11 4-(butylamino)-3-(dimethylsulfamoyl)benzoic acid, 3.12 3-(dimethylsulfamoyl)-4-(hexylamino)benzoic acid, 3.13 3-(dimethylsulfamoyl)-4-(octylamino)benzoic acid, 3.14 4-(3,3-dimethylbutylamino)-3-(dimethylsulfamoyl)benzoic acid, 3.17 3-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.20 3-(dimethylsulfamoyl)-4-(6-methoxyhexylamino)benzoic acid, 3.21 3-(cyclopentylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.22 3-(cyclohexylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.5 3-Pyrrolidin-1-ylsulfonyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.6 3-(1-piperidylsulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.7 3-morpholinosulfonyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 13.1 5-(N,N-dimethylsulfamoyl)-2-methoxy-4-((8,8,8-trifluorooctyl)amino)benzoic acid, and 14.4 3-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 2. The compound of claim 1 selected from the group comprising:

3. 2.2 4-(butylamino)-2-chloro-5-sulfamoyl-benzoic acid, 2.7 4-(hexylamino)-3-sulfamoyl-benzoic acid, 2.8 4-(octylamino)-3-sulfamoyl-benzoic acid, 3.8 3-(methylsulfamoyl)-4-(octylamino)benzoic acid, 3.13 3-(dimethylsulfamoyl)-4-(octylamino)benzoic acid, 3.14 4-(3,3-dimethylbutylamino)-3-(dimethylsulfamoyl)benzoic acid, and 3.17 3-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 2. The compound of claim 1 selected from the group consisting of:

4. For use as a medicine, 2.2 4-(butylamino)-2-chloro-5-sulfamoyl-benzoic acid, 2.3 2-chloro-4-(hexylamino)-5-sulfamoyl-benzoic acid, 2.4 2-Chloro-4-(octylamino)-5-sulfamoyl-benzoic acid, 2.5 2-chloro-4-(3,3-dimethylbutylamino)-5-sulfamoyl-benzoic acid, 2.7 4-(hexylamino)-3-sulfamoyl-benzoic acid, 2.8 4-(octylamino)-3-sulfamoyl-benzoic acid, 2.9 4-(3,3-dimethylbutylamino)-3-sulfamoyl-benzoic acid, 3.7 4-(hexylamino)-3-(methylsulfamoyl)benzoic acid, 3.8 3-(methylsulfamoyl)-4-(octylamino)benzoic acid, 3.9 4-(3,3-dimethylbutylamino)-3-(methylsulfamoyl)benzoic acid, 3.10 3-(methylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.11 4-(butylamino)-3-(dimethylsulfamoyl)benzoic acid, 3.12 3-(dimethylsulfamoyl)-4-(hexylamino)benzoic acid, 3.13 3-(dimethylsulfamoyl)-4-(octylamino)benzoic acid, 3.14 4-(3,3-dimethylbutylamino)-3-(dimethylsulfamoyl)benzoic acid, 3.15 3-(dimethylsulfamoyl)-4-(4,4,4-trifluorobutylamino)benzoic acid, 3.16 3-(dimethylsulfamoyl)-4-(6,6,6-trifluorohexylamino)benzoic acid, 3.17 3-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.18 3-(dimethylsulfamoyl)-4-(2-methoxyethylamino)benzoic acid, 3.19 3-(dimethylsulfamoyl)-4-(4-methoxybutylamino)benzoic acid, 3.20 3-(dimethylsulfamoyl)-4-(6-methoxyhexylamino)benzoic acid, 3.21 3-(cyclopentylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.22 3-(cyclohexylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.5 3-Pyrrolidin-1-ylsulfonyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.6 3-(1-piperidylsulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.7 3-morpholinosulfonyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 6.3 5-cyano-N,N-dimethyl-2-(8,8,8-trifluorooctylamino)benzenesulfonamide, 7.4 2-Hydroxy-5-sulfamoyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 9.1 3-(dimethylsulfamoyl)-4-[4-(5,5,5-trifluoropentyl)piperazin-1-yl]benzoic acid, 12.7 5-(N,N-dimethylsulfamoyl)-2-ethoxy-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 12.8 2-(cyclopentyloxy)-5-(N,N-dimethylsulfamoyl)-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 13.1 5-(N,N-dimethylsulfamoyl)-2-methoxy-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 14.3 3-Morpholinosulfonyl-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 14.4 3-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 15.4 4-[(8-bromo-8,8-difluorooctyl)amino]-3-(dimethylsulfamoyl)benzoic acid, 16.1 5-(dimethylsulfamoyl)-2-isopropoxy-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.2 2-(cyclohexoxy)-5-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.3 5-(dimethylsulfamoyl)-2-tetrahydropyran-4-yloxy-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.4 2-(cyclobutoxy)-5-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.5 5-(dimethylsulfamoyl)-2-(oxetan-3-yloxy)-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.6 5-(Dimethylsulfamoyl)-2-(4-piperidyloxy)-4-(8,8,8-trifluorooctylamino)benzoic acid, and 16.7 5-(dimethylsulfamoyl)-2-phenoxy-4-(8,8,8-trifluorooctylamino)benzoic acid, or a stereoisomeric form thereof, or an individual geometric isomer, enantiomer, diastereoisomer, tautomer, zwitterion, and pharma- ceutically acceptable salt thereof, selected from the group comprising:

5. A compound as described in claim 4 for use in the treatment or prevention of a pathology associated with depolarization of GABAergic transmission.

6. The compound of claim 5, wherein the pathology is selected from the group consisting of Down's syndrome, neuropathic pain, stroke, cerebral ischemia, cerebral edema, hydrocephalus, traumatic brain injury, brain trauma-induced depressive-like behavior, autism spectrum disorder, autism, fragile X syndrome, Rett syndrome, Asperger syndrome, and DiGeorge syndrome, epilepsy, seizures, status epilepticus, West syndrome, glioma, glioblastoma, anaplastic astrocytoma, Parkinson's disease, Huntington's disease, schizophrenia, anxiety, tuberous sclerosis and related behavioral disorders, Dravet syndrome. 2.2 4-(butylamino)-2-chloro-5-sulfamoyl-benzoic acid, 2.3 2-chloro-4-(hexylamino)-5-sulfamoyl-benzoic acid, 2.4 2-Chloro-4-(octylamino)-5-sulfamoyl-benzoic acid, 2.5 2-chloro-4-(3,3-dimethylbutylamino)-5-sulfamoyl-benzoic acid, 2.7 4-(hexylamino)-3-sulfamoyl-benzoic acid, 2.8 4-(octylamino)-3-sulfamoyl-benzoic acid, 2.9 4-(3,3-dimethylbutylamino)-3-sulfamoyl-benzoic acid, 3.7 4-(hexylamino)-3-(methylsulfamoyl)benzoic acid, 3.8 3-(methylsulfamoyl)-4-(octylamino)benzoic acid, 3.9 4-(3,3-dimethylbutylamino)-3-(methylsulfamoyl)benzoic acid, 3.10 3-(methylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.11 4-(butylamino)-3-(dimethylsulfamoyl)benzoic acid, 3.12 3-(dimethylsulfamoyl)-4-(hexylamino)benzoic acid, 3.13 3-(dimethylsulfamoyl)-4-(octylamino)benzoic acid, 3.14 4-(3,3-dimethylbutylamino)-3-(dimethylsulfamoyl)benzoic acid, 3.15 3-(dimethylsulfamoyl)-4-(4,4,4-trifluorobutylamino)benzoic acid, 3.16 3-(dimethylsulfamoyl)-4-(6,6,6-trifluorohexylamino)benzoic acid, 3.17 3-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.18 3-(dimethylsulfamoyl)-4-(2-methoxyethylamino)benzoic acid, 3.19 3-(dimethylsulfamoyl)-4-(4-methoxybutylamino)benzoic acid, 3.20 3-(dimethylsulfamoyl)-4-(6-methoxyhexylamino)benzoic acid, 3.21 3-(cyclopentylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.22 3-(cyclohexylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.5 3-Pyrrolidin-1-ylsulfonyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.6 3-(1-piperidylsulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.7 3-morpholinosulfonyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 6.3 5-cyano-N,N-dimethyl-2-(8,8,8-trifluorooctylamino)benzenesulfonamide, 7.4 2-Hydroxy-5-sulfamoyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 9.1 3-(dimethylsulfamoyl)-4-[4-(5,5,5-trifluoropentyl)piperazin-1-yl]benzoic acid, 12.7 5-(N,N-dimethylsulfamoyl)-2-ethoxy-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 12.8 2-(cyclopentyloxy)-5-(N,N-dimethylsulfamoyl)-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 13.1 5-(N,N-dimethylsulfamoyl)-2-methoxy-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 14.3 3-Morpholinosulfonyl-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 14.4 3-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 15.4 4-[(8-bromo-8,8-difluorooctyl)amino]-3-(dimethylsulfamoyl)benzoic acid, 16.1 5-(dimethylsulfamoyl)-2-isopropoxy-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.2 2-(cyclohexoxy)-5-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.3 5-(dimethylsulfamoyl)-2-tetrahydropyran-4-yloxy-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.4 2-(cyclobutoxy)-5-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.5 5-(dimethylsulfamoyl)-2-(oxetan-3-yloxy)-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.6 5-(Dimethylsulfamoyl)-2-(4-piperidyloxy)-4-(8,8,8-trifluorooctylamino)benzoic acid, and 16.7 5-(dimethylsulfamoyl)-2-phenoxy-4-(8,8,8-trifluorooctylamino)benzoic acid, or a stereoisomeric form thereof, or an individual geometric isomer, enantiomer, diastereoisomer, tautomer, zwitterion, and pharma- ceutically acceptable salt thereof, selected from the group comprising: A pharmaceutical composition comprising a pharma- ceutically acceptable excipient and, optionally, one or more psychotropic and / or anti-inflammatory drugs. 2.2 4-(butylamino)-2-chloro-5-sulfamoyl-benzoic acid, 2.3 2-chloro-4-(hexylamino)-5-sulfamoyl-benzoic acid, 2.4 2-Chloro-4-(octylamino)-5-sulfamoyl-benzoic acid, 2.5 2-chloro-4-(3,3-dimethylbutylamino)-5-sulfamoyl-benzoic acid, 2.7 4-(hexylamino)-3-sulfamoyl-benzoic acid, 2.8 4-(octylamino)-3-sulfamoyl-benzoic acid, 2.9 4-(3,3-dimethylbutylamino)-3-sulfamoyl-benzoic acid, 3.7 4-(hexylamino)-3-(methylsulfamoyl)benzoic acid, 3.8 3-(methylsulfamoyl)-4-(octylamino)benzoic acid, 3.9 4-(3,3-dimethylbutylamino)-3-(methylsulfamoyl)benzoic acid, 3.10 3-(methylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.11 4-(butylamino)-3-(dimethylsulfamoyl)benzoic acid, 3.12 3-(dimethylsulfamoyl)-4-(hexylamino)benzoic acid, 3.13 3-(dimethylsulfamoyl)-4-(octylamino)benzoic acid, 3.14 4-(3,3-dimethylbutylamino)-3-(dimethylsulfamoyl)benzoic acid, 3.15 3-(dimethylsulfamoyl)-4-(4,4,4-trifluorobutylamino)benzoic acid, 3.16 3-(dimethylsulfamoyl)-4-(6,6,6-trifluorohexylamino)benzoic acid, 3.17 3-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.18 3-(dimethylsulfamoyl)-4-(2-methoxyethylamino)benzoic acid, 3.19 3-(dimethylsulfamoyl)-4-(4-methoxybutylamino)benzoic acid, 3.20 3-(dimethylsulfamoyl)-4-(6-methoxyhexylamino)benzoic acid, 3.21 3-(cyclopentylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 3.22 3-(cyclohexylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.5 3-Pyrrolidin-1-ylsulfonyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.6 3-(1-piperidylsulfonyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 5.7 3-morpholinosulfonyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 6.3 5-cyano-N,N-dimethyl-2-(8,8,8-trifluorooctylamino)benzenesulfonamide, 7.4 2-Hydroxy-5-sulfamoyl-4-(8,8,8-trifluorooctylamino)benzoic acid, 9.1 3-(dimethylsulfamoyl)-4-[4-(5,5,5-trifluoropentyl)piperazin-1-yl]benzoic acid, 12.7 5-(N,N-dimethylsulfamoyl)-2-ethoxy-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 12.8 2-(cyclopentyloxy)-5-(N,N-dimethylsulfamoyl)-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 13.1 5-(N,N-dimethylsulfamoyl)-2-methoxy-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 14.3 3-Morpholinosulfonyl-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 14.4 3-((4,4-difluoropiperidin-1-yl)sulfonyl)-4-((8,8,8-trifluorooctyl)amino)benzoic acid, 15.4 4-[(8-bromo-8,8-difluorooctyl)amino]-3-(dimethylsulfamoyl)benzoic acid, 16.1 5-(dimethylsulfamoyl)-2-isopropoxy-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.2 2-(cyclohexoxy)-5-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.3 5-(dimethylsulfamoyl)-2-tetrahydropyran-4-yloxy-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.4 2-(cyclobutoxy)-5-(dimethylsulfamoyl)-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.5 5-(dimethylsulfamoyl)-2-(oxetan-3-yloxy)-4-(8,8,8-trifluorooctylamino)benzoic acid, 16.6 5-(Dimethylsulfamoyl)-2-(4-piperidyloxy)-4-(8,8,8-trifluorooctylamino)benzoic acid, and 16.7 5-(dimethylsulfamoyl)-2-phenoxy-4-(8,8,8-trifluorooctylamino)benzoic acid, or a stereoisomeric form thereof, or an individual geometric isomer, enantiomer, diastereoisomer, tautomer, zwitterion, and a pharma- ceutically acceptable salt thereof, selected from the group comprising:

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