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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Bioorg Med Chem. Author manuscript; available in PMC 2010 May 1.
Published in final edited form as:
PMCID: PMC2730741
NIHMSID: NIHMS105754

Structure Activity Relationship Studies of a Novel Series of Anthrax Lethal Factor Inhibitors

Abstract

We report on the identification of a novel small molecule inhibitor of anthrax lethal factor using a high-throughput screening approach. Guided by molecular docking studies, we carried out structure activity relationship (SAR) studies and evaluated activity and selectivity of most promising compounds in in vitro enzyme inhibition assays and cellular assays. Selected compounds were further analyzed for their in vitro ADME properties, which allowed us to select two compounds for further preliminary in vivo efficacy studies. The data provided represents the basis for further pharmacology and medicinal chemistry optimizations that could result in novel anti-Anthrax therapies.

Introduction

Anthrax lethal factor has become an attractive drug target due to its relevance to the pathogenesis of Bacillus anthracis, a bioterrorism agent.1 B. anthracis, a rod shaped bacterium which infects humans through the respiratory system, skin, or digestive tract can be highly lethal depending upon its entry route into the human body. Although cutaneous anthrax is rarely lethal, inhalation anthrax is dangerous and usually fatal.2 The bacteria release a toxin that kills host macrophages, consisting of three virulence factors: protective antigen (PA, 83 kDa), edema factor (EF, 89 kDa) and lethal factor (LF, 90 kDa). It has been shown that bacterial strains lacking LF are not lethal in mice.36 Hence, lethal factor (LF), a Zn2+-metalloprotease, plays a critical role in the cleavage of several members of the MAPKK family near their N-terminus. This cleavage prevents interaction with, and phosphorylation of, downstream MAPK, thereby inhibiting one or more signaling pathways leading to cell death in macrophages. The MAPKK family has seven members, two MEKs (MAPK/ERK (extracelluar-signal-regulated kinase) Kinase) 1 and 2 (MEK1, MEK2) and five MKKs (MKK3, MKK4, MKK5, MKK6, and MKK7). MEK1 and MEK2 specifically phosphorylate and activate the ERK1 and ERK2 MAPKs. MKK3 and MKK6 are specific for the MAP kinase p38hog, where MKK4 and MKK7 phosphoactivate the stress-activated protein kinase JNK (c-Jun N-terminal kinase), although MKK4 can also phosphorylate p38hog. LF cleaves MEK1, MEK2, MKK3 and MKK6 at one site while MKK4 and MKK7 are cleaved at two different sites.7

With the threat of lethal anthrax spores being used as a biological weapon, the current treatment includes administration of appropriate antibiotics usually prior to the occurrence of symptoms. Although antibiotics such as ciprofloxacin are effective against B. anthracis, high levels of secreted toxin may remain in circulation for several days which continues to damage the host even after the bacteria may have been killed.6 Moreover, the current anthrax vaccine approved by the FDA for human use in the United States is AVA (anthrax vaccine adsorbed), which consists of a B. anthracis culture supernatant that has been adsorbed onto an aluminum adjuvant. By stimulating antibodies against PA, this vaccine has shown to provide protection in animal models of anthrax. However, humans treated with AVA requires six administered doses within an 18 month time period, along with annual booster immunizations, which is not an ideal dose regimen if there should be a need for rapid vaccination before or in response to bioterrorist events. Thus a combination of antibiotics and toxin inhibitors has been proposed as a rational approach for developing a more rapid response against anthrax. Since LF has been shown to act as the key virulence factor, much work has been focused on finding potent inhibitors of LF. Currently there are several potent LF inhibitors, in which some have been identified in our laboratory, however, only a few of these inhibitors are significantly effective in in vivo models. Therefore it is important that LF inhibitors not only inhibits the cleavage of MAPKK, but also are able to be bioavailable and to enter and remain active in cells since LF functions in the cytosol.

Results and Discussion

The LF inhibitors identified thus far contain key Zn2+-chelating moieties7 such as a hydroxymate813, polyphenols/catechol14,15, penicillin based16, rhodanine17,18,14,6,19, aminoglycoside2022, quinoline urea23, and hydrazone24,25. In this study, we present the identification of a novel scaffold shown to inhibit LF in vitro and in cell. This scaffold was identified via screening a diverse chemical library of 16,000 drug-like molecules (HitFinder, Maybridge, Morris Plains, NJ) utilizing high-throughput fluorescence microplate assays as previously described17,14,18. Kinetic studies of the most potent LF inhibitors with >50% inhibition at 20 μM, were performed and IC50 and Ki values were obtained by dose response measurements. A total of six compounds (Table 1) gave IC50 values ranging between 3 and 19 μM. Considering the ease of synthesis and guided by docking studies, we decided to focus on compound 5 (Table 1). Molecular modeling studies revealed that the docked geometry of compound 5 could fit well with the redocked molecular model of compound 7 from the previously published X-Ray crystal structure by Shoop et al.13 consisting of compound 7 in complex with LF (PDB: 1YQY) (Figure 2). Shoop et al. demonstrated in the X-Ray structure that compound 7 coordinated to the Zn2+ atom via the hydroxymate moiety, the thiophene group for compound 5 aligns similarly allowing us to preclude that the thiophene is coordinating the Zn2+ atom.

Figure 2
Molecular modeling studies; A). Chemical structure of Compound 5. B). Chemical structure of Compound 7. C). Detail of the redocked geometry of compound 7 from the X-Ray coordinates in complex with LF (PDB: 1YQY).13 Side chain residues His690 and His686 ...
Table 1
Chemical structure and inhibitory activity of 6 hit compounds from the HTS campaign against lethal factor (LF).

Initially, we synthesized compound 5, tested it to validate its kinetic activity and closely examined its predicted binding in the catalytic site of LF (Figure 2). In comparing the interactions of compounds 5 and 7 in the LF catalytic site, we observed that their mode of binding was similar, in which the hydroxymate of compound 7 chelating the zinc is represented by the thiophene moiety in compound 5, with the remaining sub-structures occupying similar subsites (Figure 2). Based on the proposed docking geometry, we decided to perform structure activity relationship studies in which we first explored changes amongst the sulfonylamide group to determine its relevance in binding to LF, (Table 2), with or without a methyl group at the fourth position of the thiophene ring (Table 3 and and4).4). We further dissected this scaffold by exchanging the thiophene ring with an isooxazole, a benzene ring, an ethyl group or completely eliminating the thiophene group (Table 5). The synthesis of analogues which lacked the benzothiazole moiety was also carried out (Table 6) as well as the synthesis of disubstituted sulfonamides (Table 7).

Table 2
Benzothiazole-4-methylthiophene (BTMT) derivatives and IC50 values against lethal factor (LF).
Table 3
Benzothiazole thiophene (BTT) derivatives and IC50 values against lethal factor (LF).
Table 4
Benzothiazole thiophene (BTT) heterocyclic derivatives and IC50 values against lethal factor (LF).
Table 5
Benzothiazole derivatives and IC50 values against lethal factor (LF).
Table 6
Thiophene derivatives and IC50 values against lethal factor (LF).
Table 7
Disubstituted benzothiazole thiophene derivatives and IC50 values against lethal factor (LF).

The syntheses of these compounds were carried out under normal sulfonamide coupling conditions using pyridine as the solvent except for the disubstituted sulfonamides in which we used dichloromethane and triethylamine.26 The compounds were obtained with average yields of 65 – 80% and purity of at least 95% for key compounds. Once synthesized and characterized, we then performed an enzymatic assay to evaluate the inhibitory activity of the resulting compounds against LF. The fluorescence peptide cleavage assay was performed in a 96 well plate (100 μL/well) as we previously reported19. For a number of compounds, including the 6 original hits, a Lineweaver-Burk analysis was also carried out to verify that the compounds are competitive against the substrate (Figure 1).

Figure 1
Kinetics of inhibition of lethal factor (LF) for compounds 70 and 71. IC50 evaluation of (A) compound 70 and (B) compound 71 against LF; C) Ki evaluation of compound 70 at 10 μM; (red line; Ki = 1.01 μM); the black dashed line represents ...

From the data reported in Table 2 (Benzothiazole-4-methylthiophene derivatives, BTMT), we first compared the lead compound 5 (Table 1) with compounds 8 and 9 and observed a loss in activity for the molecules lacking a sulfonylaryl moiety or an electron withdrawing substituent on the sulfonylaryl group. However, it seems that the position of the substituents is crititcal for optimal binding. For instance, if we take compounds 10 and 11, which have a trifluoromethyl group in the meta or ortho position respectively, compound 10 is ten times more potent than compound 11. A similar trend was also observed with compounds which contained a substituent in the para position (compounds 12, 13, 14, 15), meta position (compounds 32 and 33) or disubstituted para/meta position (compounds 19, 20, 21, and 24). Here the meta or disubstituted analogues showed improved inhibitory properties with the exception of compounds 23 and 31. Overall, the most potent compounds of the BTMT series were compounds 21 and 10 which gave IC50 values of 8.9 and 9.4 μM, respectively.

As part of the evaluation of the SAR at the sulfonylamide moiety, replacement of BTMT with benzothiazole thiophene (BTT) retained enzyme potency while reducing the molecular weight of the compounds (Table 3 and and4).4). Initially, we showed that a compound lacking the sulfonylaryl moiety, (compound 42), was essentially inactive. However, reintroducing a sulfonylbenzene moiety (compound 43) leads to an activity with an IC50 value of 39 μM. Comparison of the IC50 values of compounds 43 and 9 (Table 2) revealed that the BTT series may lead to more potent inhibitors. Analysis of the IC50 values with the within the BTT series, did not reveal a clear trend regarding the role of the positioning of the substituents. However, compounds that were disubstituted in the para/meta position versus monosubstitution in the meta or para position appeared overall more potent (compounds 44, 48, 49, 65, 66, 67, 53, 54, 57, 63 and 64) with the exception of compounds 47 and 58. This observation resulted in the design and synthesis of compound 55 which indeed has an improved IC50 value of 6.6 μM. On the contrary, disubstitution at the ortho/meta or ortho/para position led to compounds that lost activity dramatically (compounds 56, 61, 62). Further, we synthesized compounds containing biphenylsufonyl groups that overall seem to be more potent. The most noticeable improvements were observed with compounds 70, 71, and 72, giving IC50 values of 3.8, 3.0 and 3.9 μM, respectively. Based on the SAR analysis discussed above, we subsequently synthesized the 3′,4′-disubstituted biphenyl derivatives that however led to compounds which are slightly less active (compounds 75 and 78). Within the BTT series we also observed that disubstitution at the meta/para position, where the meta position had a chlorine group, led to improved activity (compounds 49 versus 57, 48 versus 55, 65 versus 60, 68 versus 123). Based on these observations, we synthesized the 3-chloro-4-disubstituted biphenyl derivative 124, in which the inhibitory activity against LF was slightly improved when compared to the related compound 70. Moreover, the synthesis of BTT analogues with various heterocyclicsulfonyl moieties did not lead to compounds with increased affinity against LF (Table 4).

Finally, the substitution of the thiophene ring (Table 5) with various groups or its elimination resulted in compounds that lack significant inhibitory activity against LF. Similarly, compounds in which we eliminated the benzothiazole ring (Table 6), showed no inhibition at 50 μM, as well as the disubstituted sulfonylbenzene derivatives (Table 7). Overall, in comparing the BTT series with the BTMT series, we found that in most cases the binding affinity is significantly improved in the former series, with the exception of just a few compounds. Furthermore, we also found that most active compounds against LF did not inhibit (up to 100 μM) human matrix metalloproteases MMP-2 and MMP-9, the most closely related human proteases to LF.19,14,18

In order to assess the efficacy of the compounds in a cellular context, we measure the ability of most potent LF inhibitors to protect macrophages from LF/PA induced cell death.19 As shown in Table 8, compound 70 gave an IC50 value of 506 nM in this assay, while compounds 71, 93, and 55, and gave IC50 values of 251 nM, 1.6 μM and 1 μM, respectively. Hence we identified selective and potent LF inhibitors which are effective in protecting human macrophages from anthrax toxin. In order to evaluate whether these compounds are likely to be effective in vivo, we first measured critical in vitro parameters such as chemical stability, plasma stability, microsomal stability, solubility and cell permeability (Table 8). From these data, we concluded that except for solubility, compounds 70 and 55 were the most suited candidates for preliminary in vivo efficacy studies (Figure 3). Preliminarily, when administered via intraperitoneal injection (daily at 25 mg/kg), compound 70 seemed to be a little more effective in protecting the mice after 8 days of post infection compared to compound 55. While the observed protection with compound 70 is significant, further studies aimed at the determination of proper formulation of the compound (to increase solubility) and pharmacokinetics (to assess dose and regimen) must be conducted to improve the efficacy of the inhibitor.

Figure 3
In cell and in vivo mice studies of the inhibition of lethal factor (LF) for compounds 70 and 55. (A) Macrophage assay for the inhibition of LF for compound 70 (EC50 = 561 nM) (B) Effect of test compounds on LF cleavage of MEK1. (Left panel) HeLa cells ...
Table 8
In cell data along with in vitro ADME experiments for selected LF inhibitors. ADME experiments conducted according to the protocols at Asinex Corporation, Moscow, Russia, http://asinex.com).19

In conclusion, we have generated and validated a novel series of LF inhibitors with low- to sub-micromolar activity. By using SAR studies, we were able to design an inhibitor against LF, which shows to be effective in macrophages and lack cytotoxicity. We were also able to show selectivity amongst MMP-2 and -9 and show that with a single daily dose of LF inhibitor we were able to observe some protection using in vivo mice models of anthrax. Thus pharmacokinetic studies of compounds 55 and 70 are underway.

Methods and Materials

Reference Compounds and Reagents

Reference compounds 8 and 42 were purchased from Ryan Scientific. All common chemicals, reagents, and buffers were purchased from Sigma-Aldrich (St. Louis, MO), Acros Organics (Geel, Belgium) or Maybridge (Morris Plains, NJ). Recombinant LF and MAPKKide® were purchased from List Biological Laboratories (Campbell, CA). The MMP-2 and MMP-9 assay kits were purchased from Anaspec, Inc. (San Jose, CA). Synthetic details of the benzothiazole derivatives are described in the experimental section. Characterization of each benzothiazole derivative was obtained by means of NMR spectroscopy. Elemental analysis was performed for compounds 70, 72, 92 and HR/MS and HPLC purity was performed for compounds 10, 16, 17, 20, 21, 22, 30, 32, 33, 34, 35, 37, 38, 40, 44, 45, 46, 48, 49, 51, 53, 54, 55, 57, 59, 60, 63, 64, 65, 66, 67, 68, 71, 72, 73, 75, 77, 78, 79, 82, 83, 85, 87, 88, 89, 92, 98, 123, 124 (Table 9 and and1010).

Table 9
Elemental analysis of compounds 70, 72, 92.
Table 10
HRMS analysis and HPLC purity for compounds 10, 16, 17, 20, 21, 30, 33, 34, 35, 38, 40, 44, 45, 48, 51, 53, 55, 59, 60, 63, 64, 66, 67, 68, 71, 72, 75, 77, 78, 82, 85, 88, 89, 92, 123, 124.

Enzymatic Assays

MAPKKide® Assay

The fluorescence peptide cleavage assay was performed in a 96 well plates (100 μL/well) in which each reaction mixture contained MAPKKide® (4 μM) and LF (50 nM) (List Biological Laboratories) in 20 mM Hepes, pH 7.4, and the screening compounds (mixture of 20; each compound at 10 μM). Kinetics of the peptide cleavage was examined for 30 min by using a fluorescent plate reader (Victor V, Perkin Elmer, Waltham, MA) at excitation and emission wavelengths of 485 and 535 nm, respectively and IC50 values were obtained by dose response measurements. For selected compounds, Lineweaver-Burk analysis was also carried out to verify that the compounds are competitive against the substrate. The Km and Vmax values of the MAPKKide® cleavage by LF were determined at 25°C by using the same experimental condition described above for the fluorescence screening assay but with increasing MAPKKide® concentrations (10, 5, 2.5 μM). The Ki and Km(app) were calculated at 5 and/or 10 μM inhibitor concentration.

MMP-2 and -9 Assay

This assay was performed as outlined in the Anaspec MMP Assay kit (Cat. No. 71151/71155). The fluorescence peptide cleavage assay was performed in a 96 well plate (50 μL/well) in which each reaction mixture contained 5-FAM/QXLTM520 (60 μL; diluted 1:100 in assay buffer) and MMP-2 or MMP-9 (10 μg/mL; pro-MMP-2 and -9 are first activated with 1mM APMA for 20 min or 2 hrs respectively) in Enzolyte 520 MMP-2 assay buffer and the screening compounds at 20 μM. Kinetics of the peptide cleavage was examined every five minutes for 30 min by using a fluorescent plate reader (Victor V, Perkin Elmer, Waltham, MA) at excitation and emission wavelengths of 485 and 535 nm, respectively and % inhibition values were obtained.

ADME studies

In vitro ADME studies were conducted for selected compounds (Table 8) according to the protocols at Asinex Corporation (Moscow, Russia, www.asinex.com).19

Cell-Based Assay

Murine monocyte macrophage cells RAW 264.7 were seeded 45,000 cells per well in 96-well plates 24 hours prior to treatment. Cells were seeded and maintained in Hyclone DMEM (4500 mg/L Glucose, 110 g/L Sodium Pyruvate) supplemented with 5% fetal bovine serum, 2mM Glutamax (Invitrogen, Carlsbad, CA). Cells are replenished with fresh medium (0.1ml/well). Cells were treated with increasing concentrations of inhibitor (from 0.3 to 30 μM) for 2 hours. A hydroxamate inhibitor of the LF metalloproteinase activity, GM6001 (Ki = 5 μM) is included in the assay as a control. Anthrax protective-antigen-83 (PA83) and lethal factor (LF) are added to the final concentrations of 500ng/ml and 35ng/ml, respectively. After incubation for 4 hours, cell viability was assessed using ATPlite Assay from PerkinElmer (Waltham, MA). Each datum point represents triplicates of each concentration in one experiment. Viability was normalized to control cells which were treated with the vehicle, DMSO.

MEK1 Cleavage Assay

Reagents

Inhibitor 1 (GM6001, Ilomastat) purchased from United States Biological. (Swampscott, MA); Inhibitor 3 is a known LF inhibitor as described in our previously published paper.19 Inhibitors 2 and 4 have been synthesized in our laboratories and will be described in a proceeding manuscript. The N-terminal MEK1 antibody (anti-MEK1, N-terminal) was obtained from Calbiochem (San Diego, CA) and the β-actin antibody (Monoclonal-Anti-β-actin) was purchased from Sigma. Anti-rabbit and anti-mouse-horseradish peroxidases were purchased from GE Healthcare (UK).

Cell culture/Assay

HeLa (Human cervical carcinoma) cells were obtained from the American Type Culture Collection (Manassas, VA) and were cultured in Dulbecco’s Modified Eagle Medium (DMEM, Cellgro) supplemented with 10% fetal bovine serum (FBS, Omega Scientific; Tarzana, CA) and 1% penicillin/streptomycin (Omega Scientific, Tarzana, CA) at 37 °C in a humidified incubator containing 5% CO2.

Triplicate samples of approximately 2 × 104 HeLa cells were plated in individual wells of a 48-well plate and incubated for 48h. The cells were exposed, for 90 minutes at 37 °C, to a pre-incubated solution of 2.5 × 10−8 M PA83, 5 × 10−9 M LF and different concentrations of test compounds in serum-free DMEM medium. The analyzed inhibitors were dissolved in DMSO reaching a final DMSO concentration of 1%. Controls included untreated cells and LF-PA-only treated cells at different time points (45 and 90 minutes). Cells were later lysed and directly collected with reducing gel sample buffer and analyzed for MEK1 cleavage by immunoblotting as previously described.27

Animal Procedure

Mice (eight animals per group) were infected intranasally with 4 × 105 Bacillus anthracis Sterne spores. Treatment with compound 70 or 55 (25 mg/kg daily in DMSO administered via intraperitoneal injection) was started 24 h postexposure and continued for the next 8 days. Mice given DMSO alone were used as the control and all died on day 7 (blue line). The group treated with compound 70 had the best survival (p<0.01 compared to control group) while the group receiving compound 55 had slight improvement in comparison to the control (p<0.05).

Molecular Modeling

Docking studies were performed with GOLD2830 and analyzed with Sybyl and Benchware 3D Explorer (Tripos, St. Louis). The X-ray coordinates of Lethal Factor PDB code 1YQY13 and 1PWQ10 were used to dock the compounds. For each compound, 20 solutions were generated and subsequently ranked according to Chemscore.30 Top solutions were used to represent the docked geometry of the compounds and compared with the X-ray coordinates of compounds previously reported.

HPLC Purity Analysis

Reverse-phase high performance liquid chromatography (RP-HPLC) was performed on a HPLC Breeze from Waters Inc. (Milford, MA) using a Symmetry C18 (5 μM; 4.6 mm × 150 mm) reverse phase column (Waters Inc.). Mobile phase A was 0.1% trifluoroacetic acid/H2O and mobile phase B was 0.1% trifluoroacetic acid/acetonitrile in which the flow rate was 1ml/min for 20 min. A linear gradient program was used from 50% A and 50% B to 5% A and 95% B in 15 min followed by 5 min at 100% B. Results were analyzed using the Breeze software (Waters Inc.).

Synthetic Chemistry

General procedure for the synthesis of monosubstituted benzothiazole sufonylamides

To a solution of the amine (0.812 mmol) in pyridine (10 mL) was added the sulfonyl chloride (1.22 mmol) dropwise and the mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 (20 mL) and extracted with 3N HCl (3X) and the aqueous portion was extracted with CH2Cl2 once. The organic layer was dried with Na2SO4 and concentrated. Purification was done via column chromatography using ethyl acetate and hexane to give the desired compound. Note: In some cases, purification had to be done twice

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl) benzenesulfonamide (9).

1H NMR (300 MHz, d-CDCl3) δ 8.09 (d, 1H, J = 8.1 Hz), 7.89 (d, 2H, J = 7.8 Hz), 7.57 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.45 (d, 1H, J = 8.4 Hz), 7.34 (dist. t, 2H, J = 7.8, 7.2 Hz), 6.51 (s, 1H), 2.51 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-3-(trifluoromethyl) benzenesulfonamide (10).

1H NMR (300 MHz, d-CDCl3) δ 8.10 (dist. t, 2H, J = 9.3, 2.1 Hz), 8.00 (d, 1H, J = 8.1 Hz), 7.89 (d, 1H, J = 7.8 Hz), 7.69 (d, 1H, J = 7.8 Hz), 7.58 (t, 1H, J = 8.1 Hz), 7.45 (t, 2H, J = 8.1 Hz), 6.58 (s, 1H), 2.51 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-2-(trifluoromethyl)benzenesulfonamide (11).

1H NMR (300 MHz, d-CDCl3) δ 8.38 (d, 1H, J = 9.0 Hz), 8.08 (d, 1H, J = 8.4 Hz), 7.89 (d, 1H, J = 7.8 Hz), 7.80 (d, 2H, J = 9.0 Hz), 7.66 (dist. t, 1H, J = 3.6 Hz), 7.59 (dist. t, 1H, J = 6.9 Hz) 7.45 (dist. t, 1H, J = 6.9 Hz), 6.47 (s, 1H), 2.53 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-4-(trifluoromethoxy)benzenesulfonamide (12).

1H NMR (300 MHz, d-CDCl3) δ 8.08 (d, 1H, J = 8.1Hz), 7.89 (dist. t, 3H, J = 9.3, 9.0 Hz), 7.58 (d, 1H, J = 8.1 Hz), 7.45 (t, 1H, J = 8.1 Hz), 7.12 (d, 2H, J = 8.1 Hz), 6.56 (s, 1H), 2.52 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-4-methoxybenzenesulfonamide (13).

1H NMR (300 MHz, d-CDCl3) δ 8.08 (d, 1H, J = 7.8Hz), 7.90 (d, 3H, J = 7.8 Hz), 7.81 (d, 1H, J = 9.0 Hz), 7.57 (dist. t, 1H, J = 7.2 Hz), 6.99 (dist. t, 2H, J = 7.2 Hz), 6.79 (d, 1H, J = 9.0 Hz), 6.52 (s, 1H), 3.77 (s, 3H), 2.52 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-4-methylbenzenesulfonamide (14).

1H NMR (300 MHz, d-CDCl3) δ 8.09 (d, 1H, J = 8.1 Hz), 7.90 (d, 1H, J = 8.1 Hz), 7.75 (d, 2H, J = 8.1 Hz), 7.57 (t,1H, J = 7.2 Hz), 7.43 (dist. t,1H, J = 7.2 Hz), 7.13 (d,1H, J = 7.8 Hz), 6.50 (s, 1H), 2.51 (s, 3H), 2.32 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-4-fluorobenzenesulfonamide (15).

1H NMR (300 MHz, d-CDCl3) δ 8.08 (d, 1H, J = 8.4Hz), 7.89 (m, 3H), 7.58 (t, 1H, J = 8.1 Hz), 7.47 (t, 1H, J = 8.1 Hz), 6.99 (t, 2H, J = 8.4 Hz), 6.54 (s, 1H), 2.52 (s, 3H).

N-(4-(N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)sulfamoyl)phenyl)acetamide (16).

1H NMR (300 MHz, d-CDCl3) δ 8.06 (d, 1H, J = 8.1 Hz), 7.89 (d, 1H, J = 7.8 Hz), 7.80 (d, 2H, J = 8.7 Hz), 7.59-7.40 (m, 4H), 6.49 (s, 1H), 2.50 (s, 3H), 2.16(s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-4-nitrobenzenesulfonamide (17).

1H NMR (300 MHz, d-CDCl3) δ 8.13 (q, 4H, J = 9.0 Hz), 8.07 (d, 1H, J = 8.1 Hz), 7.91 (d, 1H, J = 8.1 Hz), 7.61 (dist. t, 1H, J = 8.1 Hz), 7.49 (dist. t, 1H, J = 8.1 Hz), 6.59 (s, 1H), 2.52 (s, 3H); HRMS (ESI), m/z Calcd. For C18H13N3O4S3 [M – H]+ 432.0141 Found 432.0137.

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-4-chloro-2-fluorobenzenesulfonamide (18).

1H NMR (300 MHz, d-CDCl3) δ 8.11 (d, 1H, J = 8.4 Hz), 7.92 (d, 1H, J = 7.8 Hz), 7.89 (s, 1H), 7.59 (t, 1H, J = 8.4 Hz), 7.46 (dist. t, 1H, J = 8.4 Hz), 7.20 (d, 1H, J = 9.6 Hz), 7.03 (d, 1H, J = 9.6 Hz), 6.49 (s, 1H), 2.53 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-3-fluoro-4-methylbenzenesulfonamide (19).

1H NMR (300 MHz, d-CDCl3) δ 8.08 (d, 1H, J = 8.1 Hz), 7.91 (d, 1H, J = 7.8 Hz), 7.60-7.50 (m, 3H), 7.44 (dist. t, 1H, J = 7.2 Hz), 7.15 (dist. t, 1H, J = 7.2 Hz), 6.53 (s, 1H), 2.52 (s, 3H), 2.23(s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-4-fluoro-3-methylbenzenesulfonamide (20).

1H NMR (300 MHz, d-CDCl3) δ 8.08 (d, 1H, J = 8.1Hz), 7.91 (d, 1H, J = 8.1 Hz), 7.69-7.62 (m, 2H), 7.60 (dist. t, 1H, J = 7.2 Hz), 7.44 (dist. t, 2H, J = 7.2 Hz) 6.92 (t, 1H, J = 9.0 Hz), 6.55 (s, 1H), 2.52 (s, 3H), 2.08 (s, 3H); HRMS (ESI), m/z Calcd. For C19H15FN2O2S3 [M – H]+ 419.0352 Found 419.0356.

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-3-chloro-4-methylbenzenesulfonamide (21).

1H NMR (300 MHz, d-CDCl3) δ 8.08 (d, 1H, J = 8.4 Hz), 7.90 (d, 1H, J = 7.8 Hz), 7.83 (s, 1H), 7.63-7.54 (m, 2H), 7.43 (dist. t, 1H, J = 8.4 Hz), 7.16 (d, 1H, J = 7.8 Hz), 6.54 (s, 1H), 2.50 (s, 3H), 2.31 (s, 3H);

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-2,4,5-trichlorobenzenesulfonamide (22).

1H NMR (300 MHz, d-CDCl3) δ 8.32 (s, 1H), 8.05 (d, 1H, J = 8.1Hz), 7.93 (d, 1H, J = 8.1 Hz), 7.57 (dist. t, 1H, J = 7.5 Hz), 7.48 (s, 1H), 7.31 (dist. t, 1H, J = 6.99), 6.49 (s, 1H), 2.55 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-3-chloro-4-fluorobenzenesulfonamide (23).

1H NMR (300 MHz, d-CDCl3) δ 8.09 (d, 1H, J = 8.4 Hz), 7.93 (d, 2H, J = 8.1 Hz), 7.76 -7.71 (m, 1H), 7.60 (dist. t, 1H, J = 8.1, 7.5 Hz), 7.46 (dist. t, 1H, J = 7.8, 7.5 Hz), 7.07 (t, 1H, J = 8.4 Hz), 6.59 (s, 1H), 2.53 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-3,4-dimethoxybenzenesulfonamide (24).

1H NMR (300 MHz, d-CDCl3) δ 8.08 (d, 1H, J = 8.1 Hz), 7.90 (d, 1H, J = 7.8 Hz), 7.55 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.46 – 7.39 (m, 2H), 7.20 (s, 1H), 6.71 (d, 1H, J = 8.4 Hz), 6.54 (s, 1H), 3.82 (s, 3H), 3.57 (s, 3H), 2.50 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-4-tert-butylbenzenesulfonamide (25).

1H NMR (300 MHz, d-CDCl3) δ 8.09 (d, 1H, J = 8.1 Hz), 7.89 (d, 1H, J = 8.1 Hz), 7.74 (d, 2H, J = 8.1 Hz), 7.58 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.44 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.32 (s, 2H), 6.55 (s, 1H), 2.52 (s, 3H), 1.24 (s, 9H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-3,4-dichlorobenzenesulfonamide (26).

1H NMR (300 MHz, d-CDCl3) δ 8.08 (d, 1H, J = 8.1 Hz), 7.94 – 7.91 (m, 2H), 7.63 (dist. t, 2H, J = 9.0, 8.1 Hz), 7.46 (dist. t, 1H, J = 7.8, 7.2 Hz), 7.37 (d, 1H, J = 9.0 Hz), 6.59 (s, 1H), 2.53 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-3-chloro-2-fluorobenzenesulfonamide (27).

1H NMR (300 MHz, d-CDCl3) δ 8.14 (d, 1H, J = 8.1 Hz), 8.00 – 7.11 (m, 2H), 7.62 – 7.52 (m, 2H), 7.46 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.18 (t, 1H, J = 8.1 Hz), 6.49 (s, 1H), 2.54 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-3-chloro-2-methylbenzenesulfonamide (28).

1H NMR (300 MHz, d-CDCl3) δ 8.06 (t, 2H, J = 8.7 Hz), 7.94 (d, 1H, J = 8.1 Hz), 7.59 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.54 (d, 1H, J = 8.1 Hz), 7.46 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.23 (t, 1H, J = 8.1 Hz), 6.44 (s, 1H), 2.76 (s, 3H), 2.54 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-3-nitrobenzenesulfonamide (29).

1H NMR (300 MHz, d-CDCl3) δ 8.43 (s, 1H), 8.09 (d, 1H, J = 8.4 Hz), 7.94 – 7.89 (m, 2H), 7.59 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.46 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.30 (d, 1H, J = 8.1 Hz), 6.60 (s, 1H), 2.56 (s, 3H), 2.52 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide (30).

1H NMR (300 MHz, d-CDCl3) δ 8.12 (s, 1H), 8.08 (d, 1H, J = 7.8 Hz), 7.91 (dist. t, 1H, J = 7.8, 6.9 Hz), 7.60 (dist. t, 1H, J = 8.1, 7.5 Hz), 7.48 (d, 1H, J = 7.5 Hz), 7.43 (d, 1H, J = 8.1 Hz), 6.61 (s, 1H), 2.53 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-3-chlorobenzenesulfonamide (31).

1H NMR (300 MHz, d-CDCl3) δ 8.08 (d, 1H, J = 8.4 Hz), 7.90 (d, 1H, J = 7.8 Hz), 7.84 (s, 1H), 7.72 (d, 2H, J = 7.8 Hz), 7.58 (dist. t, 1H, J = 8.4, 8.1 Hz), 7.44 (t, 1H, J = 8.1 Hz), 7.42 (d,1H, J = 7.8 Hz), 7.28 (d, 1H, J = 8.4), 6.55 (s, 1H), 2.51 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-3-(trifluoromethoxy)benzenesulfonamide (32).

1H NMR (300 MHz, d-CDCl3) δ 8.07 (d, 1H, J = 8.4 Hz), 7.89 (d, 1H, J = 8.1 Hz), 7.77 (d, 1H, J = 7.8 Hz), 7.71 (s, 1H), 7.58 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.44 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.36-7.22 (m, 1H), 6.57 (s, 1H), 2.51 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-3-methoxybenzenesulfonamide (33).

1H NMR (300 MHz, d-CDCl3) δ 8.07 (d, 1H, J = 8.1 Hz), 7.89 (d, 1H, J = 8.1 Hz), 7.55 (t, 1H, J = 8.1 Hz), 7.43 (d, 1H, J = 7.8 Hz), 7.34 (s, 1H), 7.22 (t, 1H, J = 8.1 Hz), 6.95 (d,1H, J = 8.1 Hz), 6.51 (s, 1H), 3.60 (s, 3H), 2.48 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)naphthalene-2-sulfonamide (34).

1H NMR (300 MHz, d-CDCl3) δ 8.46 (s, 1H), 8.13 (d, 1H, J = 8.1 Hz), 7.86-7.72 (m, 5H), 7.61-7.50 (m, 3H), 7.43 (dist. t, 1H, J = 7.8 Hz), 7.16 (d, 1H, J = 7.8 Hz), 6.49 (s, 1H), 2.44 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)biphenyl-4-sulfonamide (35).

1H NMR (300 MHz, d-CDCl3) δ 8.11 (d, 1H, J = 8.1 Hz), 7.91-7.87 (m, 3H), 7.59 (dist. t, 1H, J = 7.2 Hz), 7.59 (m, 8H, J = 6.9 Hz), 6.55 (s, 1H), 2.51 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-4′-methoxybiphenyl-4-sulfonamide (36).

1H NMR (300 MHz, d-CDCl3) δ 8.11 (d, 1H, J = 8.1 Hz), 7.90-7.85 (m, 3H), 7.58 (dist. t, 2H, J = 7.2, 6.9 Hz), 7.49 – 7.41 (m, 5H), 7.96 (d, 2H, J = 9.0 Hz), 6.54 (s, 1H), 3.86 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-4′-chlorobiphenyl-4-sulfonamide (37).

1H NMR (300 MHz, d-CDCl3) δ 8.11 (d, 1H, J = 7.5 Hz), 7.92-7.86 (m, 3H), 7.57 (d, 1H, J = 8.7 Hz), 7.49 – 7.40 (m, 8H), 6.55 (s, 1H), 2.51 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiopen-2-yl)-4′-methoxybiphenyl-3-sulfonamide (38).

1H NMR (300 MHz, d-CDCl3) δ 8.10 (d, 1H, J = 7.8 Hz), 7.98 (s, 1H), 7.87 (d, 1H, J = 7.2 Hz), 7.76 (d, 1H, J = 7.8 Hz), 7.59 (d, 1H, J = 7.2 Hz), 7.55 (d, 1H, J = 7.2 Hz), 7.42 (t, 1H, J = 8.1 Hz), 7.35 (t, 1H, J = 7.8 Hz), 7.22 (d, 2H, J = 8.7 Hz), 6.82 (d, 1H, J = 8.7 Hz), 6.53 (s, 1H), 3.84 (s, 3H), 2.48 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiopen-2-yl)-4′-chlorobiphenyl-3-sulfonamide (39).

1H NMR (300 MHz, d-CDCl3) δ 8.10 (d, 1H, J = 8.1 Hz), 7.95 (s, 1H), 7.88 (d, 1H, J = 8.1 Hz), 7.80 (d, 1H, J = 7.8 Hz), 7.60 (d, 1H, J = 7.0 Hz), 7.56 (d, 1H, J = 7.0 Hz), 7.50 – 7.36 (m, 3H), 7.19 (d, 3H, J = 8.1 Hz), 6.57 (s, 1H), 2.50 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiopen-2-yl)-3′,5′-bis(trifluoromethyl)biphenyl-3-sulfonamide (40).

1H NMR (300 MHz, d-CDCl3) δ 8.10 (d, 1H, J = 8.1 Hz), 7.96 – 7.87 (m, 6H), 7.60 (t, 1H, J = 8.1 Hz), 7.52 – 7.42 (m, 3H), 6.59 (s, 1H), 2.51 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiopen-2-yl)biphenyl-3-sulfonamide (41).

1H NMR (300 MHz, d-CDCl3) δ 8.10 (d, 1H, J = 8.1 Hz), 8.04 (s, 1H), 7.87 (d, 1H, J = 8.1 Hz), 7.81 (d, 1H, J = 7.8 Hz), 7.64 (d, 1H, J = 8.1 Hz), 7.55 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.45 – 7.35 (m, 2H), 7.30 (br s, 5H), 6.54 (s, 1H), 2.49 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)benzenesulfonamide (43).

1H NMR (300 MHz, d-CDCl3) δ 8.04 (d, 1H, J = 8.1 Hz), 7.94 (d, 2H, J = 7.5 Hz), 7.85 (d, 1H, J = 7.8 Hz), 7.56 – 7.38 (m, 5H), 7.09 (d, 1H, J = 5.7 Hz), 6.83 (d, 2H, J = 5.7).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-3-(trifluoromethyl)benzenesulfonamide (44).

1H NMR (300 MHz, d-CDCl3) δ 8.18 (s, 1H), 8.06 (dist. t, 2H, J = 7.8 Hz), 7.87 (d, 1H, J = 7.8 Hz), 7.72 (d, 1H, J = 7.8 Hz), 7.59-7.42 (m, 4H), 7.12 (d, 1H, J = 5.7 Hz), 6.91 (d, 2H, J = 5.7 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-2-(trifluoromethyl)benzenesulfonamide (45).

1H NMR (300 MHz, d-CDCl3) δ 8.36 (dd, 1H, J = 4.8, 2.7 Hz), 8.05 (d, 1H, J = 8.1 Hz), 7.85 (t, 2H, J = 7.5 Hz), 7.87 – 7.81 (m, 2H), 7.52 (t, 1H, J = 8.1 Hz), 7.42 (t, 2H, J = 8.1 Hz), 7.12 (d, 1H, J = 5.7 Hz), 6.81 (d, 1H, J = 5.7 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-4-(trifluoromethoxy)benzenesulfonamide (46).

1H NMR (300 MHz, d-CDCl3) δ 8.04 (dd, 1H, J = 8.7, 2.7 Hz), 7.96 (d, 2H, J = 8.7 Hz), 7.88 (d, 1H, J = 7.8 Hz), 7.57 (dist. t, 1H, J = 8.1, 7.5 Hz), 7.42 (dist. t, 1H, J = 7.8, 7.5 Hz), 7.18 (d, 2H, J = 7.8 Hz), 7.13 (d, 1H, J = 5.7 Hz), 6.88 (d, 1H, J = 5.7 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-4-methoxybenzenesulfonamide (47).

1H NMR (300 MHz, d-CDCl3) δ 8.04 (d, 1H, J = 8.1 Hz), 7.88 – 7.83 (m, 3H), 7.54 (t, 1H, J = 8.1 Hz), 7.40 (t, 1H, J = 8.1 Hz), 7.01 (d, 1H, J = 5.7 Hz), 6.85 – 6.80 (m, 3H), 3.77 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-4-methylbenzenesulfonamide (48).

1H NMR (300 MHz, d-CDCl3) δ 8.04 (d, 1H, J = 8.1 Hz), 7.86 (d, 1H, J = 7.8 Hz), 7.82 (d, 2H, J = 8.7 Hz), 7.54 (dist. t, 1H, J = 8.7, 8.1 Hz), 7.41 (dist. t, 1H, J = 8.4, 7.8 Hz), 7.16 (d, 2H, J = 8.7 Hz), 7.09 (d, 1H, J = 5.7 Hz), 6.82 (d, 1H, J = 5.7 Hz), 2.32 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-4-fluorobenzenesulfonamide (49).

1H NMR (300 MHz, d-CDCl3) δ 8.04 (d, 1H, J = 8.1 Hz), 7.96 – 7.91 (m, 2H), 7.88 (d, 1H, J = 8.1 Hz), 7.55 (t, 1H, J = 8.4 Hz), 7.42 (t, 1H, J = 8.4 Hz), 7.12 (d, 1H, J = 6.0 Hz), 7.04 (t, 2H, J = 8.7 Hz), 6.86 (d, 1H, J = 6.0 Hz).

N-(4-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)sulfamoyl)phenyl)acetamide (50).

1H NMR (300 MHz, d-CDCl3) δ 7.99 (d, 1H, J = 8.1 Hz), 7.82 (d, 1H, J = 7.5 Hz), 7.56 – 7.48 (m, 3H), 7.38 (dist. t, 1H, J = 8.1, 7.5 Hz), 7.06 (d, 1H, J = 5.7 Hz), 6.79 (d, 1H, J = 5.7 Hz), 2.13 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-4-(trifluoromethyl)benzenesulfonamide (51).

1H NMR (300 MHz, d-CDCl3) δ 8.04 (m, 3H), 7.88 (d, 1H, J = 7.8 Hz), 7.64 – 7.53 (m, 3H), 7.43 (dist. t, 1H, J = 7.8, 7.2 Hz), 7.13 (d, 2H, J = 5.4 Hz), 6.89 (d, 1H, J = 5.4 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-4-chloro-2-fluorobenzenesulfonamide (52).

1H NMR (300 MHz, d-CDCl3) δ 8.08 (d, 1H, J = 8.1 Hz), 7.96 – 7.88 (m, 2H), 7.56 (dist. t, 1H, J = 8.4, 6.9 Hz), 7.44 (dist. t, 1H, J = 8.4, 6.9 Hz), 7.23 (d, 1H, J = 8.4 Hz), 7.14 (d, 1H, J = 5.7 Hz), 7.08 (d, 1H, J = 9.0 Hz), 6.83 (d, 1H, J = 5.7 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-3-fluoro-4-methylbenzenesulfonamide (53).

1H NMR (300 MHz, d-CDCl3) δ 8.05 (d, 1H, J = 8.1 Hz), 7.87 (d, 1H, J = 8.1 Hz), 7.62 – 7.52 (m, 2H), 7.42 (t, 1H, J = 8.1 Hz), 7.20 (t, 1H, J = 7.5 Hz), 7.13 (d, 1H, J = 5.4 Hz), 6.86 (d, 1H, J = 5.4 Hz), 2.24 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-4-fluoro-3-methylbenzenesulfonamide (54).

1H NMR (300 MHz, d-CDCl3) δ 8.05 (d, 1H, J = 8.1 Hz), 7.87 (d, 1H, J = 8.1 Hz), 7.76 (dist. t, 1H, J = 7.8, 7.0 Hz), 7.72 – 7.69 (m, 1H), 7.68 - 7.52 (m, 1H), 7.41 (dist. t, 1H, J = 8.1, 7.0 Hz), 7.11 (d, 1H, J = 5.7 Hz), 7.00-6.88 (m, 1H), 6.86 (d, 1H, J = 5.7 Hz), 2.13 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-3-chloro-4-methylbenzenesulfonamide (55).

1H NMR (300 MHz, d-CDCl3) δ 8.05 (d, 1H, J = 8.1 Hz), 7.90 (s, 1H), 7.87 (d, 1H, J = 8.1 Hz), 7.67 (d, 1H, J = 8.1 Hz), 7.55 (t, 1H, J = 7.8 Hz), 7.42 (t, 1H, J = 7.8 Hz), 7.21 (d, 1H, J = 8.1 Hz), 7.13 (d, 1H, J = 6.0 Hz), 6.87 (d, 1H, J = 6.0 Hz), 2.33 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-2,5-bis(2,2,2-trifluoroethoxy)benzenesulfonamide (56).

1H NMR (300 MHz, d-CDCl3) δ 8.04 (d, 1H, J = 8.1 Hz), 7.88 (d, 1H, J = 8.1 Hz), 7.66 (d, 1H, J = 3.0 Hz), 7.54 (dist. t, 1H, J = 8.4, 7.2 Hz), 7.41 (dist. t, 2H J = 8.1, 7.2 Hz), 7.15 (d, 1H, J = 3.0 Hz), 7.13 (d, 1H, J = 6.0 Hz), 6.99 (d, 1H, J = 8.4 Hz), 6.77 (d, 1H, J = 6.0 Hz), 4.46 – 4.33 (m, 4H).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-3-chloro-4-fluorobenzenesulfonamide (57).

1H NMR (300 MHz, d-CDCl3) δ 8.05 (d, 1H, J = 8.7 Hz), 8.00 (d, 1H, J = 7.0 Hz), 7.88 (d, 1H, J = 8.1 Hz), 7.81 – 7.76 (m, 1H), 7.56 (dist. t, 1H, J = 8.1, 7.0 Hz), 7.42 (dist. t, 1H, J = 8.1, 7.0 Hz), 7.13 (d, 1H, J = 5.7 Hz), 7.11 (br s, 1H), 6.90 (d, 1H, J = 5.7 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-3,4-dimethoxybenzenesulfonamide (58).

1H NMR (300 MHz, d-CDCl3) δ 8.03 (d, 1H, J = 7.8 Hz), 7.85 (d, 1H, J = 7.8 Hz), 7.55 – 7.49 (m, 2H), 7.39 (t, 1H, J = 8.1 Hz), 7.29 (s, 1H), 7.08 (d, 1H, J = 6.0 Hz), 6.85 (d, 1H, J = 6.0 Hz), 6.75 (d, 1H, J = 8.7 Hz), 3.82 (s, 3H), 3.64 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-4-tert-butylbenzenesulfonamide (59).

1H NMR (300 MHz, d-CDCl3) δ 8.06 (d, 1H, J = 8.1 Hz), 7.87 (d, 1H, J = 8.4 Hz), 7.82 (d, 1H, J = 8.4 Hz), 7.56 (dist. t, 1H, J = 8.4, 7.2 Hz), 7.43 (d, 1H, J = 7.2 Hz), 7.37 (d, 1H, J = 8.4 Hz), 7.13 (d, 1H, J = 6.0 Hz), 6.87 (d, 1H, J = 6.0 Hz), 1.25 (s, 9H).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-3,4-dichlorobenzenesulfonamide (60).

1H NMR (300 MHz, d-CDCl3) δ 8.06 (d, 1H, J = 8.1 Hz), 8.00 (s, 1H), 7.89 (d, 1H, J = 8.1 Hz), 7.71 (d, 1H, J = 8.4 Hz), 7.57 (dist. t, 1H, J = 7.8, 7.5 Hz), 7.44 (dist. t, 1H, J = 8.1, 6.0 Hz), 7.15 (d, 1H, J = 5.7 Hz), 6.91 (d, 1H, J = 5.7 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-3-chloro-2-fluorobenzenesulfonamide (61).

1H NMR (300 MHz, d-CDCl3) δ8.11 (d, 1H, J = 8.0 Hz), 7.89 (d, 1H, J = 6.0 Hz), 7.57 (t, 1H, J = 7.0 Hz), 7.44 (t, 1H, J = 7.0 Hz), 7.21 (d, 1H, J = 8.0 Hz), 7.15 (d, 1H, J = 5.7 Hz), 6.84 (d, 1H, J = 5.7 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-3-chloro-2-methylbenzenesulfonamide (62).

1H NMR (300 MHz, d-CDCl3) δ8.07 (d, 1H, J = 8.1 Hz), 8.02 (d, 1H, J = 8.4 Hz), 7.90 (d, 1H, J = 8.1 Hz), 7.56 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.43 (dist. t, 1H, J = 7.8, 7.2 Hz), 7.24 (t, 1H, J = 8.1 Hz), 7.13 (d, 1H, J = 5.7 Hz), 6.78 (d, 1H, J = 5.7 Hz), 2.81 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-4-methyl-3-nitrobenzenesulfonamide (63).

1H NMR (300 MHz, d-CDCl3) δ8.51 (s, 1H), 8.04 (d, 1H, J = 8.1 Hz), 7.97 (d, 1H, J = 8.1 Hz), 7.86 (d, 1H, J = 7.8 Hz), 7.55 (t, 1H, J = 7.8 Hz), 7.42 (t, 1H, J = 7.8 Hz), 7.33 (d, 1H, J = 8.1 Hz), 7.12 (d, 1H, J = 5.7 Hz), 6.91 (d, 1H, J = 5.7 Hz), 2.55 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide (64).

1H NMR (300 MHz, d-CDCl3) δ8.22 (s, 1H), 8.05 (d, 1H, J = 8.1 Hz), 7.97 (d, 1H, J = 8.4 Hz), 7.89 (d, 1H, J = 8.1 Hz), 7.58 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.51 – 7.42 (m, 2H), 7.15 (d, 1H, J = 6.0 Hz), 6.94 (d, 1H, J = 6.0 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-4-chlorobenzenesulfonamide (65).

1H NMR (300 MHz, d-CDCl3) δ8.05 (d, 1H, J = 7.5 Hz), 7.90 – 7.82 (m, 3H), 7.55 (t, 1H, J = 7.2 Hz), 7.44 (t, 1H J = 7.5 Hz), 7.40 – 7.31 (m, 2H), 7.12 (d, 1H, J = 6.3 Hz), 6.86 (d, 1H, J = 6.3 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-6-chloronaphthalene-2-sulfonamide (66).

1H NMR (300 MHz, d-CDCl3) δ8.47 (s, 1H), 8.08 (d, 1H, J = 8.4 Hz), 7.89 – 7.67 (m, 5H), 7.56 (dist. t, 1H, J = 8.1, 7.2), 7.50 – 7.39 (m, 2H), 7.07 (d, 1H, J = 5.7 Hz), 6.82 (d, 1H, J = 5.7 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-6-chloronaphthalene-2-sulfonamide (67).

1H NMR (300 MHz, d-CDCl3) δ8.47 (s, 1H), 8.08 (d, 1H, J = 8.4 Hz), 7.89 – 7.67 (m, 5H), 7.56 (dist. t, 1H, J = 8.1, 7.2), 7.50 – 7.39 (m, 2H), 7.07 (d, 1H, J = 5.7 Hz), 6.82 (d, 1H, J = 5.7 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide (68).

1H NMR (300 MHz, d-CDCl3) δ8.04 (d, 1H, J = 8.7 Hz), 7.90 (d, 1H, J = 7.8 Hz), 7.77 (d, 1H, J = 9.0 Hz), 7.56 (dist. t, 1H, J = 7.8, 7.5 Hz), 7.50 (d, 2H, J = 9.0 Hz), 7.44 (dist. t, 1H, J = 8.7, 8.1 Hz), 7.13 (d, 1H, J = 5.7 Hz), 6.88 (d, 1H, J = 5.7 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-4′-methylbiphenyl-4-sulfonamide (69).

1H NMR (300 MHz, d-CDCl3) δ8.07 (d, 1H, J = 8.1 Hz), 7.95 (d, 1H, J = 8.1 Hz), 7.92 (d, 2H, J = 8.1 Hz), 7.85 (d, 2H, J = 8.1 Hz), 7.54 (d, 1H, J = 8.7 Hz), 7.50 – 7.20 (m, 7H), 7.10 (d, 1H, J = 5.7 Hz), 6.85 (d, 1H, J = 5.7 Hz).

N-(3-(benzo[d]thiazol-2-yl)isoxazol-5-yl)-4′-methoxybiphenyl-4-sulfonamide (70).

1H NMR (300 MHz, d-CDCl3) δ8.27 (s, 1H), 8.00 (d, 2H, J = 8.4 Hz), 7.97 – 7.89 (m, 2H), 7.72 (d, 2H, J = 7.0 Hz), 7.58 (d, 2H, J = 7.0 Hz), 7.49 (t, 1H, J = 7.0 Hz), 7.40 (d, 1H, J = 8.4 Hz), 7.04 (d, 1H, J = 7.5 Hz), 3.90 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)isoxazol-5-yl)-4′-chlorobiphenyl-4-sulfonamide (71).

1H NMR (300 MHz, d-CDCl3) δ8.22 (s, 1H), 8.02 (d, 1H, J = 8.1 Hz), 7.94 – 7.86 (m, 2H), 7.71 (d, 1H, J = 8.4 Hz), 7.57 – 7.40 (m, 5H), 7.37 (d, 2H, J = 7.8 Hz).

N-(3-(benzo[d]thiazol-2-yl)isoxazol-5-yl)-4′-trifluoromethoxybiphenyl-4-sulfonamide (72).

1H NMR (300 MHz, d-CDCl3) δ8.06 (d, 2H, J = 7.8 Hz), 7.96 (d, 2H, J = 8.4 Hz), 7.85 (d, 1H, J = 7.8 Hz), 7.60 – 7.38 (m, 6H), 7.26 (d, 2H, J = 7.8 Hz), 7.11 (d, 1H, J = 6.0 Hz), 6.88 (d, 1H, J = 6.0 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-4′-methoxybiphenyl-3-sulfonamide (73).

1H NMR (300 MHz, d-CDCl3) δ8.04 (br s, 2H), 7.85 (d, 2H, J = 8.1 Hz ), 7.80 (d, 1H, J = 8.1 Hz), 7.62 (d, 1H, J = 7.2 Hz), 7.52 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.43 – 7.35 (m, 3H), 7.09 (d, 1H, J = 6.0 Hz), 6.85 (d, 1H, J = 6.0 Hz), 6.80 (d, 1H, J = 8.7 Hz), 3.82 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-4′-chlorobiphenyl-3-sulfonamide (74).

1H NMR (300 MHz, d-CDCl3) δ8.04 (br s, 2H), 7.84 (d, 3H, J = 8.1 Hz ), 7.60 – 7.40 (m, 4H), 7.27 – 7.21 (m, 3H), 7.09 (d, 1H, J = 5.7 Hz), 6.86 (d, 1H, J = 5.7 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-3′,4′-dichlorobiphenyl-4-sulfonamide (75).

1H NMR (300 MHz, d-CDCl3) δ8.07 (d, 1H, J = 7.8 Hz), 7.96 (d, 2H, J = 8.4 Hz ), 7.86 (d, 1H, J = 9.0 Hz), 7.60-7.40 (m, 6H), 7.32-7.31 (m, 1H), 7.13 (d, 1H, J = 5.7 Hz), 6.89 (d, 1H, J = 5.7 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)biphenyl-3-sulfonamide (76).

1H NMR (300 MHz, d-CDCl3) δ8.09 (br s, 1H), 8.05 (d, 1H, J = 7.8 Hz), 7.84 (d, 2H, J = 7.8 Hz ), 7.65 (d, 1H, J = 7.8 Hz), 7.52 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.44 – 7.38 (m, 3H), 7.30 (br s, 4H), 7.09 (d, 1H, J = 6.0 Hz), 6.85 (d, 1H, J = 6.0 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-4′-(trifluoromethyl)biphenyl-4-sulfonamide (77).

1H NMR (300 MHz, d-CDCl3) δ8.04 (d, 1H, J = 8.1 Hz), 7.98 (d, 2H, J = 8.1 Hz ), 7.83 (d, 1H, J = 8.1 Hz), 7.66 (d, 2H, J = 8.4 Hz), 7.57 – 7.52 (m, 5H), 7.40 (dist. t, 3H, J = 7.8 Hz), 7.10 (d, 1H, J = 5.7 Hz), 6.86 (d, 1H, J = 5.7 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-3′,4′-dimethoxybiphenyl-4-sulfonamide (78).

1H NMR (300 MHz, d-CDCl3) δ8.06 (d, 1H, J = 8.4 Hz), 7.94 (d, 2H, J = 8.4 Hz), 7.84 (d, 1H, J = 8.1 Hz), 7.04 (d, 1H, J = 8.1 Hz), 6.98 (s, 1H), 6.90 (d, 1H, J = 8.4 Hz), 6.84 (d, 1H, J = 6.0 Hz), 3.92 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-4-(2-chlorophenoxy)benzenesulfonamide (79).

1H NMR (300 MHz, d-CDCl3) δ8.00 (d, 1H, J = 8.1 Hz), 7.88 (d, 3H, J = 8.7 Hz), 7.67 (d, 1H, J = 5.7 Hz), 7.55-7.39 (m, 2H), 7.24 (d, 2H, J = 7.5 Hz), 7.05 – 6.95 (m, 3H), 6.90 (d, 1H, J = 7.8 Hz), 6.79 (d, 1H, J = 8.7 Hz), 3.77 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-4-(2-methoxyphenoxy)benzenesulfonamide (80).

1H NMR (300 MHz, d-CDCl3) δ8.00 (d, 1H, J = 8.1 Hz), 7.88 (d, 3H, J = 8.7 Hz), 7.67 (d, 1H, J = 5.7 Hz), 7.55-7.39 (m, 2H), 7.24 (d, 2H, J = 7.5 Hz), 7.05 – 6.95 (m, 3H), 6.90 (d, 1H, J = 7.8 Hz), 6.79 (d, 1H, J = 8.7 Hz), 3.77 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-6-phenoxypyridine-3-sulfonamide (81).

1H NMR (300 MHz, d-CDCl3) δ8.70 (d, 1H, J = 2.7 Hz), 8.24 (dd, 1H, J = 8.7, 2.7 Hz), 7.90 (dist. t, 2H, J = 9.0, 8.1 Hz), 7.60-7.40 (m, 6H), 7.32-7.28 (m, 1H), 7.02 (d, 2H, J = 8.7 Hz), 6.83 (d, 1H, J = 9.0 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-4-(thiazol-5-yl)benzenesulfonamide (82).

1H NMR (300 MHz, d-CDCl3) δ8.04 (d, 1H, J = 8.1 Hz), 7.85 (d, 1H, J = 8.1 Hz), 7.65 (d, 2H, J = 8.4 Hz), 7.57 (dist. t, 1H, J = 7.2, 6.3 Hz), 7.45-7.29 (m, 2H), 7.12 (d, 1H, J = 6.0 Hz), 6.89 (d, 1H, J = 6.0 Hz), 2.64 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-4-(oxazol-5-yl)benzenesulfonamide (83).

1H NMR (300 MHz, d-CDCl3) δ8.07 (d, 1H, J = 8.1 Hz), 7.96 (d, 1H, J = 8.1 Hz ), 7.94 (s, 1H), 7.85 (d, 1H, J = 8.1 Hz), 7.60 (d, 2H, J = 8.4 Hz), 7.56 (dist. t, 1H, J = 8.4, 8.1 Hz), 7.41 (t, 1H, J = 8.1 Hz), 7.40 (s, 1H), 7.26 (d, 1H, J = 2.1 Hz), 7.11 (d, 1H, J = 5.7 Hz), 6.86 (d, 1H, J = 5.7 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)benzenesulfonamide (84).

1H NMR (300 MHz, d-CDCl3) δ8.50 (s, 1H), 8.18 (d, 1H, J = 8.1 Hz), 8.08 (d, 1H, J = 8.1 Hz), 8.01 (d, 1H, J = 7.8 Hz), 7.57 – 7.38 (m, 3H), 7.12 (d, 1H, J = 6.0 Hz), 6.90 (d, 1H, J = 6.0 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-4-(1H-pyrazol-1-yl)benzenesulfonamide (85).

1H NMR (300 MHz, d-CDCl3) δ8.07 (d, 1H, J = 8.1 Hz), 7.99 (d, 2H, J = 9.0 Hz ), 7.89 (d, 1H, J = 2.0 Hz), 7.86 (d, 1H, J = 8.1 Hz), 7.71 (d, 3H, J = 9.0 Hz), 7.53 (t, 1H, J = 7.8 Hz), 7.41 (t, 1H, J = 7.8 Hz), 7.11 (d, 1H, J = 5.4 Hz), 6.87 (d, 1H, J = 5.4 Hz), 6.48 (t, 1H, J = 2.0 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-5-methyl-1-phenyl-1H-pyrazole-4-sulfonamide (86).

1H NMR (300 MHz, d-CDCl3) δ8.01 (d, 1H, J = 7.8 Hz), 7.92 (s, 1H), 7.90 (d, 1H, J = 8.1 Hz), 7.53 (dist. t, 1H, J = 8.1, 7.5 Hz), 7.43 (d, 1H, J = 3.9 Hz), 7.42 (br s, 4H), 7.22 (d, 1H, J = 3.9 Hz), 7.19 (d, 1H, J = 5.7 Hz), 6.91 (d, 1H, J = 5.7 Hz), 2.48 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-4-(morpholinosulfonyl)benzenesulfonamide (87).

1H NMR (300 MHz, d-CDCl3) δ8.04 (d, 3H, J = 8.7 Hz), 7.89 (d, 1H, J = 8.4 Hz ), 7.70 (d, 1H, J = 8.4 Hz), 7.57 (dist. t, 1H, J = 8.4, 7.2 Hz), 7.44 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.15 (d, 1H, J = 6.0 Hz), 6.94 (d, 1H, J = 6.0 Hz), 3.68 (t, 4H, J = 4.5 Hz), 2.85 (t, 4H, J = 4.5 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-3-(2-methylpyrimidine-4-yl)benzenesulfonamide (88).

1H NMR (300 MHz, d-CDCl3) δ8.54 (s, 2H), 8.22 (d, 1H, J = 7.8 Hz), 8.07 (d, 1H, J = 8.1 Hz ), 7.98 (d, 1H, J = 7.8 Hz), 7.84 (d, 1H, J = 8.1 Hz), 7.55 – 7.48 (m, 2H), 7.42 (dist. t, 1H, J = 7.8, 7.2 Hz), 7.25 (d, 1H, J = 5.4 Hz), 7.09 (d, 1H, J = 5.4 Hz), 6.88 (d, 1H, J = 5.7 Hz), 2.72 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-4-(3,5-dimethyl-1H-pyrazol-1-yl)benzenesulfonamide (89).

1H NMR (300 MHz, d-CDCl3) δ8.04 – 7.96 (m, 3H), 7.83 (d, 1H, J = 8.1 Hz), 7.54 – 7.44 (m, 3H), 7.38 (t, 1H, J = 8.0 Hz), 7.08 (d, 1H, J = 6.0 Hz), 6.82 (d, 1H, J = 6.0 Hz), 5.97 (s, 1H), 2.26 (s, 3H), 2.22 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-3-dihydrobenzofuran-5-sulfonamide (90).

1H NMR (300 MHz, d-CDCl3) δ8.05 (d, 1H, J = 7.8 Hz), 7.87 (d, 1H, J = 8.1 Hz ), 7.71 (s, 1H), 7.68 (d, 1H, J = 8.4 Hz), 7.54 (dist. t, 1H, J = 8.4, 6.9 Hz), 7.41 (dist. t, 1H, J = 7.8, 6.9 Hz), 7.11 (d, 1H, J = 6.0 Hz), 6.85 (d, 1H, J = 6.0 Hz), 6.68 (d, 1H, J = 8.1 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)benzo[c][1,2,5]oxadiazole-5-sulfonamide (91).

1H NMR (300 MHz, d-CDCl3) δ8.24 (d, 1H, J = 7.8 Hz), 8.13 (d, 1H, J = 7.0 Hz), 8.01 (d, 1H, J = 9.0 Hz), 7.83 (d, 2H, J = 8.1 Hz), 7.63 (dist. t, 1H, J = 8.1, 6.9 Hz), 7.52-7.41 (m, 3H), 7.06 (d, 1H, J = 5.7 Hz), 6.81 (d, 1H, J = 5.7 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)benzo[d]thiazole-6-sulfonamide (92).

1H NMR (300 MHz, d-CDCl3) δ9.14 (s, 1H), 8.60 (s, 1H), 8.10-8.00 (m, 3H), 7.85 (d, 1H, J = 8.1 Hz), 7.57 (t, 1H, J = 8.1 Hz), 7.42 (d, 1H, J = 8.1 Hz), 7.10 (d, 1H, J = 6.0 Hz), 6.87 (d, 1H, J = 6.0 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamide (93).

1H NMR (300 MHz, d-CDCl3) δ8.04 (d, 1H, J = 8.1 Hz), 7.86 (d, 1H, J = 7.8 Hz), 7.54 (t, 1H, J = 7.2 Hz), 7.46 (d, 1H, J = 2.1 Hz), 7.40 (dist. t, 1H, J = 8.1, 6.0 Hz), 7.11 (d, 1H, J = 6.0 Hz), 6.84 (d, 1H, J = 6.0 Hz), 6.81 (d, 1H, J = 8.1 Hz), 4.40 - 4.00 (m, 4H).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-sulfonamide (94).

1H NMR (300 MHz, d-CDCl3) δ8.30 (d, 1H, J = 2.1 Hz), 8.04 (d, 1H, J = 8.1 Hz ), 7.85 (d, 1H, J = 7.8 Hz), 7.53 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.39 (dist. t, 1H, J = 7.8, 7.2 Hz), 7.26 (d, 1H, J = 2.1 Hz), 7.11 (d, 1H, J = 6.0 Hz), 6.82 (d, 1H, J = 6.0 Hz), 4.11 (t, 2H, J = 4.5 Hz), 3.45 (t, 4H, J = 4.5 Hz), 3.13 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (95).

1H NMR (300 MHz, d-CDCl3) δ8.04 (d, 1H, J = 8.1 Hz), 7.87 (d, 1H, J = 8.1 Hz), 7.52 (t, 1H, J = 8.1 Hz), 7.39 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.19 (dd, 1H, J = 8.4, 2.1 Hz), 7.11 (d, 1H, J = 6.0 Hz), 7.09 (d, 1H, J = 2.1 Hz), 6.84 (d, 1H, J = 6.0 Hz), 6.66 (d, 1H, J = 8.4 Hz), 4.23 (t, 2H, J = 4.0), 3.17 (t, 2H, J = 4.0).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-3-methylbenzo[b]thiophene-2-sulfonamide (96).

1H NMR (300 MHz, d-CDCl3) δ8.04 (d, 1H, J = 8.1 Hz), 7.85 (d, 1H, J = 8.1 Hz ), 7.66-7.54 (m, 4H), 7.45 – 7.35 (m, 2H), 7.13 (d, 1H, J = 6.0 Hz), 6.89 (d, 1H, J = 6.0 Hz), 2.65 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-5-(isoxazol-5-yl)thiophene-2-sulfonamide (97).

1H NMR (300 MHz, d-CDCl3) δ8.25 (s, 1H), 8.05 (d, 1H, J = 7.8 Hz), 7.62 (d, 1H, J = 3.9 Hz), 7.55 (dist. t, 1H, J = 7.8, 7.0 Hz), 7.41 (dist. t, 1H, J = 7.8, 7.0 Hz), 7.30 (d, 1H, J = 3.9 Hz), 7.18 (d, 1H, J = 5.7 Hz), 6.94 (d, 1H, J = 5.7 Hz), 6.40 (s, 1H).

N-((5-(N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)sulfamoyl)thiophen-2-yl)methyl)-4-chlorobenzamide (98).

1H NMR (300 MHz, d-CDCl3) δ8.02 (d, 1H, J = 7.5 Hz), 7.85 (d, 1H, J = 7.8 Hz ), 7.78 (d, 1H, J = 9.0 Hz), 7.65 (d, 2H, J = 9.0 Hz), 7.55 (t, 2H, J = 8.4 Hz), 7.45-29 (m, 3H), 7.16 (d, 1H, J = 6.0 Hz), 6.90 (d, 1H, J = 6.0 Hz), 4.68 (d, 1H, J = 5.7 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-5-(2-(methylthio)pyrimidin-4-yl)thiophene-2-sulfonamide (99).

1H NMR (300 MHz, d-CDCl3) δ8.50 (d, 1H, J = 5.1 Hz), 8.07 (d, 1H, J = 7.8 Hz ), 7.86 (d, 1H, J = 8.1 Hz), 7.64 (d, 2H, J = 3.9 Hz), 7.55 (t, 1H, J = 8.4 Hz), 7.52 (d, 1H, J = 3.9 Hz), 7.41 (dist. t, 1H, J = 7.8, 7.2 Hz), 7.18 (d, 1H, J = 5.7 Hz), 7.12 (d, 1H, J = 5.1 Hz), 6.95 (d, 1H, J = 5.7 Hz), 2.53 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)furan-2-sulfonamide (100).

1H NMR (300 MHz, d-DMSO) δ8.13 (br s, 1H), 7.89 (br s, 1H), 7.73 (br s, 1H), 7.30 (br s, 1H), 7.17 (d, 1H, J = 8.4Hz), 7.13 (s, 1H), 6.96 (br s, 1H, J = 6.0 Hz), 6.76 (dist. t, 2H, J = 8.4, 8.1 Hz), 6.63 (br s, 1H).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-1-(methylsulfonyl)methanesulfonamide (101).

1H NMR (300 MHz, d-CDCl3) δ8.02 (d, 1H, J = 8.1 Hz), 7.84 (d, 1H, J = 7.8 Hz), 7.58 (dist. t, 1H, J = 8.1, 7.5 Hz), 7.46 (dist. t, 1H, J = 8.1, 7.5 Hz), 7.04 (d, 1H, J = 6.3 Hz), 6.73 (d, 1H, J = 6.3 Hz), 4.63 (s, 2H), 3.41 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)thiopen-2-yl)-4-bromo-3-chlorobenzenesulfonamide (123).

1H NMR (300 MHz, d-CDCl3) δ8.05 (d, 1H, J = 8.1 Hz), 7.98 (t, 1H, J = 1.2 Hz), 7.89 (d, 1H, J = 8.1 Hz), 7.60 (br s, 2H), 7.56 (dist. t, 1H, J = 8.7, 8.1 Hz), 7.44 (t, 1H, J = 8.1 Hz), 7.15 (d, 1H, J = 5.7 Hz), 6.10 (d, 1H, J = 5.7 Hz).

N-(benzo[d]thiazol-2-yl)-3-chloro-4-methylbenzenesulfonamide (102).

1H NMR (300 MHz, d-CDCl3) δ7.96 (s, 1H), 7.77 (dist. t, 2H, J = 7.8 Hz), 7.59 (d, 1H, J = 7.8 Hz ), 7.44 (dist. t, 1H, J = 7.5 Hz), 7.35-7.30 (m, 2H), 2.43 (s, 3H).

N-(benzo[d]thiazol-2-yl)-4′-methoxybiphenyl-4-sulfonamide (103).

1H NMR (300 MHz, d-DMSO) δ7.90 (d, 2H, J = 8.4 Hz), 7.83-7.79 (m, 3H), 7.67 (d, 2H, J = 8.7 Hz), 7.46 – 7.20 (m, 5H), 7.05 (d, 1H, J = 8.7 Hz ), 3.81 (s, 3H).

N-(benzo[d]thiazol-2-yl)-4′-chlorobiphenyl-4-sulfonamide (104).

1H NMR (300 MHz, d-DMSO) δ7.95-7.73 (m, 8H), 7.56 (d, 1H, J = 8.4 Hz), 7.40-7.30 (m, 2H), 7.23 (t, 1H, J = 6.6Hz).

N-(3-benzo[d]thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-4′-methoxybiphenyl-4-sulfonamide (105).

1H NMR (300 MHz, d-CDCl3) δ8.08 (d, 1H, J = 8.1 Hz), 7.90-7.83 (m, 3H), 7.57 (t, 2H, J = 8.0 Hz), 7.47 – 7.38 (m, 5H), 6.96 (d, 2H, J = 6.0 Hz), 3.85 (s, 3H), 2.81 (br s, 1H), 2.72 (br s, 1H), 1.88 (br s, 4H).

N-(3-benzo[d]thiazol-2-yl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-4′-chlorobiphenyl-4-sulfonamide (106).

1H NMR (300 MHz, d-CDCl3) δ8.08 (d, 1H, J = 8.4 Hz), 7.93-7.84 (m, 3H), 7.57 (t, 1H, J = 8.1 Hz), 7.50 – 7.44 (m, 3H), 7.40 (s, 4H), 2.83 (br s, 1H), 2.73 (br s, 1H), 1.88 (br s, 4H).

N-(3-(benzo[d]thiazol-2-yl)isoxazol-5-yl)-4′-methoxybiphenyl-4-sulfonamide (107).

1H NMR (300 MHz, d-CDCl3) δ8.27 (s, 1H), 8.00 (d, 2H, J = 8.4 Hz), 7.97 – 7.89 (m, 2H), 7.72 (d, 2H, J = 7.0 Hz), 7.58 (d, 2H, J = 7.0 Hz), 7.49 (t, 1H, J = 7.0 Hz), 7.40 (d, 1H, J = 8.4 Hz), 7.04 (d, 1H, J = 7.5 Hz), 3.90 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)isoxazol-5-yl)-4′-chlorobiphenyl-4-sulfonamide (108).

1H NMR (300 MHz, d-CDCl3) δ8.22 (s, 1H), 8.02 (d, 1H, J = 8.1 Hz), 7.94 – 7.86 (m, 2H), 7.71 (d, 1H, J = 8.4 Hz), 7.57 – 7.40 (m, 5H), 7.37 (d, 2H, J = 7.8 Hz).

N-(2-(benzo[d]thiazol-2-yl)ethyll)-4′-methoxybiphenyl-4-sulfonamide (109).

1H NMR (300 MHz, d-CDCl3) δ7.92 - 7.86 (m, 3H), 7.72 (d, 1H, J = 8.1 Hz), 7.64 (d, 2H, J = 8.7 Hz), 7.53 (d, 2H, J= 8.7 Hz), 7.50 (d, 1H, J = 7.8 Hz), 7.38 (t, 1H, J = 7.8 Hz), 7.10 (dist. t, 2H, J = 9.0, 7.8 Hz), 6.99 (d, 1H, J = 9.0 Hz), 3.86 (s, 3H), 2.79 (t, 2H, J = 7.0 Hz), 2.40 (t, 2H, J = 7.0 Hz).

N-(2-(benzo[d]thiazol-2-yl)ethyll)-4′-chlorobiphenyl-4-sulfonamide (110).

1H NMR (300 MHz, d-CDCl3) δ7.93 (d, 2H, J = 8.1 Hz), 7.87 (br s, 1H), 7.71 (d, 1H, J = 8.4 Hz), 7.65 (d, 2H, J = 8.1 Hz), 7.53 – 7.35 (m, 6H), 7.10 (t, 1H, J = 7.8 Hz), 2.82 (t, 2H, J = 7.0 Hz), 2.42 (t, 2H, J = 7.0 Hz).

N-(2-(benzo[d]thiazol-2-yl)phenyl)-4′-methoxybiphenyl-4-sulfonamide (111).

1H NMR (300 MHz, d-CDCl3) δ8.15 (d, 1H, J = 8.1 Hz), 7.86 (dist. t, 2H, J = 7.2, 6.9 Hz), 7.78 (d, 2H, J= 8.4 Hz), 7.72 (d, 1H, J = 7.8 Hz), 7.58 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.46 (dist. t, 2H, J = 8.4, 8.1 Hz), 7.43 - 7.37 (m, 4H), 7.15 (t, 1H, J = 7.8 Hz), 6.95 (d, 2H, J = 6.9 Hz), 3.84 (s, 3H).

N-(2-(benzo[d]thiazol-2-yl)phenyl)-4′-chlorobiphenyl-4-sulfonamide (112).

1H NMR (300 MHz, d-CDCl3) δ8.15 (d, 1H, J = 8.1 Hz), 7.87 (t, 2H, J = 9.0 Hz), 7.80 (d, 2H, J= 8.1 Hz), 7.74 (d, 1H, J = 8.1 Hz), 7.60 (dist. t, 1H, J = 7.8, 7.5 Hz), 7.47 (dist. t, 2H, J = 8.4, 8.1 Hz), 7.42 - 7.38 (m, 6H), 7.12 (dist. t, 1H, J = 7.8, 7.5 Hz).

3-chloro-4-methyl-N-(thiophen-2-yl)benzenesulfonamide (113).

1H NMR (300 MHz, d-CDCl3) δ7.79 (d, 1H, J = 2.0 Hz ), 7.57 (dd, 1H, J = 8.1, 2.0 Hz), 7.34 (d, 1H, J = 8.1 Hz), 7.05 (dd, 1H, J = 5.1, 1.2 Hz), 6.86-6.82 (m, 1H), 6.74 (dd, 1H, J = 5.1, 2.0 Hz), 2.45(s, 3H).

4′-methoxy-N-(thiophen-2-yl)biphenyl-4-sulfonamide (114).

1H NMR (300 MHz, d-CDCl3) δ7.82 (d, 2H, J = 9.0 Hz), 7.67 (d, 2H, J = 8.7 Hz), 7.58 (d, 2H, J = 9.0 Hz), 7.04 (dist. t, 3H, J = 9.0, 8.7 Hz), 6.86 (dist. t, 1H, J = 5.7, 3.6 Hz), 6.77 (d, 1H, J = 3.6 Hz), 6.56 (br s, 1H), 3.89 (s, 3H).

4′-chloro-N-(thiophen-2-yl)biphenyl-4-sulfonamide (115).

1H NMR (300 MHz, d-CDCl3) δ7.93 (d, 2H, J = 8.4 Hz), 7.84 (d, 2H, J = 8.1 Hz), 7.79 (d, 2H, J = 8.1 Hz), 7.74 (d, 1H, J = 8.7 Hz), 7.56 (d, 2H, J = 8.4 Hz), 7.40 – 7.30 (m, 2H), 7.23 (t, 1H, J = 6.6 Hz).

N-(3-chloro-4-methylphenyl)thiophene-2-sulfonamide (116).

1H NMR (300 MHz, d-CDCl3) δ7.61 (d, 1H, J = 4.2 Hz), 7.54 (d, 1H, J = 3.6 Hz), 7.35 (s, 1H), 7.26 (d, 2H, J = 3.6 Hz), 7.07 (t, 1H, J = 4.2 Hz), 6.91 (br s, 1H), 2.46 (s, 3H).

N-(4-methyl-3-(trifluoromethyl)phenyl)thiophene-2-sulfonamide (117).

1H NMR (300 MHz, d-CDCl3) δ7.61 (d, 1H, J = 4.2 Hz), 7.54 (d, 1H, J = 3.6 Hz), 7.35 (s, 1H), 7.26 (d, 2H, J = 3.6 Hz), 7.07 (t, 1H, J = 4.2 Hz), 6.91 (br s, 1H), 2.46 (s, 3H).

N-(3-trifluoromethyl)phenyl)thiophene-2-sulfonamide (118).

1H NMR (300 MHz, d-CDCl3) δ7.62-7.57 (m, 2H), 7.45-7.38 (m, 4H), 7.16 (br s, 1H), 7.06 (t, 1H, J = 3.9 Hz).

N-phenylthiophene-2-sulfonamide (119).

1H NMR (300 MHz, d-CDCl3) δ7.55 (t, 2H, J = 5.7 Hz), 7.31 (dist. t, 2H, J = 8.1 Hz), 7.19 (dist. t, 3H, J = 8.1 Hz), 7.08 (br s, 1H), 7.03 (q, 1H, J = 3.9, 1.2 Hz).

General procedure for the synthesis of disubstituted benzothiazole sufonylamides

To a solution of the amine (0.812 mmol) and the sulfonyl chloride (1.60 mmol) in dichloromethane (10 mL) was added triethylamine (29.23 mmol) dropwise and the mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 (20 mL) and extracted with 3N HCl (3X) and the aqueous portion was extracted with CH2Cl2 once. The organic layer was dried with Na2SO4 and concentrated. Purification was done via flash column chromatography using ethyl acetate and hexane to give the desired compound.

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-3-(trifluoromethyl)-N-(3-(trifluoromethyl)phenylsulfonyl)benzenesulfonamide (120).

1H NMR (300 MHz, d-CDCl3) δ 8.31 (s, 2H), 8.11 (d, 2H, J = 7.8 Hz), 7.92 (d, 1H, J = 8.1 Hz), 7.75 (d, 1H, J = 8.1 Hz), 7.59 (d, 2H, J = 7.8 Hz), 7.49 (dist. t, 1H, J = 8.1, 7.2), 7.41 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.34 (t, 2H, J = 7.8 Hz), 7.25 (s, 1H), 2.46 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-4-(trifluoromethoxy)-N-(4-(trifluoromethoxy)phenylsulfonyl)benzenesulfonamide (121).

1H NMR (300 MHz, d-CDCl3) δ 8.01 (m, 5H), 7.77 (d, 1H, J = 7.8 Hz), 7.54 (dist. t, 1H, J = 8.1, 7.2 Hz), 7.42 (t, 1H, J = 8.1 Hz), 7.19 (s, 1H), 7.05 (d, 4H, J = 8.1Hz), 2.46 (s, 3H).

N-(3-(benzo[d]thiazol-2-yl)-4-methylthiophen-2-yl)-4-fluoro-N-(4-fluorophenylsulfonyl)benzenesulfonamide (122).

1H NMR (300 MHz, d-CDCl3) δ 8.03 (d, 1H, J = 8.1 Hz), 7.97 (dd, 4H, J = 9.3, 5.1 Hz), 7.80 (d, 1H, J = 8.1 Hz), 7.55 (t, 1H, J = 8.1 Hz), 7.44 (t, 1H, J = 8.1Hz), 7.18 (s, 1H), 6.91 (t, 4H, J = 9.3 Hz), 2.41 (s, 3H).

General Procedure for Suzuki Coupling Conditions31

A solution of bromobenzothiazole derivative (0.206 mmol), Pd(PPh3)4 (0.0206 mmol), boric acid derivative (0.247 mmol), EtOH (0.5 mL) and Na2CO3 (2 M, 2 mL) in toluene (10mL) was refluxed for 18 hrs. The reaction mixture was filtered and concentrated. The residue was dissolved in dichloromethane and extracted with water, brine and dried with Na2SO4. Purification was done via flash column chromatography using ethyl acetate and hexane (1:2) to give the desired compound.

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-4′-(trifluoromethoxy)biphenyl-4-sulfonamide (72).

1H NMR (300 MHz, d-CDCl3) δ 8.05 (d, 1H, J = 7.8 Hz), 7.96 (d, 2H, J = 8.4 Hz ), 7.85 (d, 1H, J = 7.8 Hz), 7.60 – 7.38 (m, 6H), 7.40 (d, 2H, J = 7.8 Hz), 7.11 (d, 1H, J = 6.0 Hz), 6.87 (d, 1H, J = 6.0 Hz).

N-(3-(benzo[d]thiazol-2-yl)thiophen-2-yl)-2-chloro-4′-methoxybiphenyl-4-sulfonamide (124).

1H NMR (300 MHz, d-CDCl3) δ 8.07 (d, 1H, J = 8.1 Hz), 8.00 (s, 1H), 7.87 (d, 2H, J = 8.1 Hz), 7.77 (d, 1H, J = 8.1 Hz), 7.55 (t, 1H, J = 8.1 Hz), 7.42 (t, 1H, J = 8.1 Hz), 7.31 – 7.23 (m, 3H), 7.15 (d, 1H, J = 6.0 Hz), 6.96 – 6.90 (m, 3H), 6.81 (s, 1H), 3.86 (s, 3H).

Acknowledgments

This work was supported in part by NIH grant 1UO1 AI056385.

Footnotes

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