Field of the invention The present invention relates to sulphonamide derivatives of for¬ mula (I),

(I)

where Rc is an optionally substituted 4-6-membered heterocyclic ring con¬ taining one or more N atoms, or Rc is -NR1R2, where R1 is hydrogen or alkyl, R2 is alkyl or an optionally substituted 4-6-membered heterocyclic ring containing one or more N atoms, or R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocyclic group, which may contain one or more additional heteroatoms selected from O and N and which may be substituted, or R1 and R2 are absent and the nitrogen atom together with the adja¬ cent carbon atom forms a heterocyclic ring, which may contain one or more additional heteroatoms selected from N and S and which may be substituted, m is 0 or 1 , RA is a group having the formula

-(CH=CH)n- -(CH=CH)n-

(A), R" (B) or (C) -(CH=CH)n-

wherein n is 0 or 1 , and R3 and R4 represent each independently hydrogen, halogen, aryl, alkoxy, carboxy, hydroxy, alkoxyalkyl, alkoxycarbonyl, cyano, trifluoromethyl, alkanoylamino, trifluoromethoxy, an optionally substituted aryl or heterocyclic group, and RB is hydrogen or alkyl. The invention also relates to the use of the derivatives of formula (I) as inhibitors of collagen receptor integrins, especially a2βλ integrin inhibitors and more precisely σ2/?1 integrin l-domain inhibitors, e.g. in connection with diseases and medical conditions that involve the action of cells and platelets expressing collagen receptors, their use as a medicament, e.g. for the treat¬ ment of thrombosis and cancer spread, pharmaceutical compositions contain¬ ing them and a process for preparing them.

Background of the invention The integrins are a large family of cell surface receptors, which me¬ diate cell adhesion to extracellular matrix. They are composed of one a and one β subunit that form a noncovalently bound dimer. In man there are eight β and eighteen a subunits that can form 24 different combinations. Integrins can be divided into three subcategories, namely (i) fibronectin and vitronectin re¬ ceptors, which recognize an RGD-motif in their ligands, (ii) laminin receptors, and (iii) integrins that have a special inserted-domain (l-domain) in their a sub¬ unit. The l-domain integrins have been found only in Chordates (includes ver¬ tebrates), but not in Nematodes or Arthropods (Hynes et al., J. Cell Biol., 2000, 750:F89-96). Four out of nine l-domain integrins, namely σ1/?1 , σ2/?1 , α10/?1 and σ11/?1 are collagen receptors (Gullberg et al., Prog Histochem Cytochem., 2002, 37:3-54). Collagens are the most abundant extracellular matrix proteins. Twenty-six collagen subtypes (types I-XXVI) are known at the moment (MyIIy- harju and Kivirikko, 2001 , Ann. Med. 33:7-21 ). In man all four collagen receptor integrins have different expression pattern. Integrin α2β\ is expressed on epithelial cells, platelets, endothelial cells, fibroblasts, chondrocytes (Zutter and Santoro, Am. J. Pathol., 1990, 737:113-120), lymphocytes, mast cells (Kruger- Krasagakes et al., J. Invest. Dermatol., 1996, 706:538-543), and neutrophilic granulocytes (W err et al., Blood, 2000, 95:1804-1809). lntegrin σ2#1 deficient knock-out animals are viable, but their platelets do not react to stimulation with collagen (Chen et al., Am. J. Pathol., 2002, 767:337-344; Holtkotter et al., J. Biol. Chem., 2002, 277:10789-10794). In animal models σ2/?1 also seems to participate in cancer-related angiogenesis (Senger et al., Proc. Natl. Acad. Sci. U.S.A., 1997, 94:13612-13617; Senger et al., Am. J. Pathol., 2002, 760:195- 204) and chronic inflammation (de Fougerolles et al., J. CHn. Invest, 2000, 705:721-729). Epidemiological studies have indicated that in man high level of σ2/?1 integrin on platelet surface is a risk factor for cerebrovascular stroke and myocardial infarction (Moshfegh et al., Lancet, 1999, 353:351-354; Carlsson et al., Blood, 1999, 93:3583-3586). In addition, integrin α2βJ\ is expressed on variable cancer cell types, and is involved with invasion and progression of melanoma (Klein et al., J. Invest. Dermatol., 1991, 96:281-284), ovarian cancer (Fishman et al., Invasion Metastasis, 7998, 78:15-26), prostate cancer (Bonk- hoff et al., Hum. Pathol., 1993, 24:243-248), and gastric cancer (Kawamura et al., Int. J. Oncol., 2001, 78:809-815). The collagen receptor integrins use their σl-domains in ligand rec- ognition and binding. Human recombinant σl-domains have been used to ana¬ lyze to molecular details of the binding mechanism (Emsley et al., Cell, 2000, 707:47-56). In all four collagen binding σl-domains (termed as σ1 l, σ2l, σ10l, σ11 l) the basic structure is very similar. However, σl-domain binding assays have indicated that their ligand binding mechanisms and, for example, their ability to bind to different collagen subtypes is different (Gullberg et al., Prog Histochem Cytochem., 2002, 37:3-54). One known inhibitor of σ2l-domain binding is a cyclic compound dis¬ closed in the international patent publication WO 9902551. It has now surprisingly been found that the compounds of formula (I) according to the present invention are potent inhibitors for collagen receptor in¬ tegrins, especially σ2/?1 integrin, and may be used in the treatment of human diseases, such as thrombosis, cancer, fibrosis and inflammation. The com¬ pounds of formula (I) may also be used in diagnostic methods both in vitro and in vivo. Summary of the invention The present invention relates sulphonamide derivatives of formula (I)-

(I)

where Rc is an optionally substituted 4-6-membered heterocyclic ring con¬ taining one or more N atoms, or Rc is -NR1, NR2, where R1 is hydrogen or alkyl, R2 is alkyl or an optionally substituted 4-6-membered heterocyclic ring containing one or more N atoms, or R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocyclic group, which may contain one or more additional heteroatoms selected from O and N and which may be substituted, or R1 and R2 are absent and the nitrogen atom together with the adja¬ cent carbon atom forms a heterocyclic ring, which may contain one or more additional heteroatoms selected from N atoms or one S atom and which may be substituted, m is 0 or 1 , RA is a group having the formula

-(CH=CH)n- -(CH=CH)n-

(A), R (B) or (C) -(CH=CH)n-

wherein n is 0 or 1 , and R3 and R4 represent each independently hydrogen, halogen, aryl, alkoxy, carboxy, hydroxy, alkoxyalkyl, alkoxycarbonyl, cyano, trifluoromethyl, alkanoylamino, trifluoromethoxy, an optionally substituted aryl or heterocyclic group. Further the invention relates to derivatives of formula (I) for use as inhibitors for collagen receptor integrins specifically a2βλ integrin inhibitors and more precisely σ2/?1 integrin l-domain inhibitors. The invention also relates to derivatives of formula (I) for use as a medicament. Further the invention relates to the use of a derivative of formula (I) for preparing a pharmaceutical composition for treating disorders relating to thrombosis and cancer spread. The present invention also relates to a pharmaceutical composition comprising an effective amount of a derivative of formula (I) in admixture with a pharmaceutically acceptable carrier. Further the invention relates to a process for preparing benzenesul- phonamide derivatives of formula (I) comprising reacting a compound of for- mula (II),

(II)

(CH2)m-NHRB

where RB, RC and m are as defined above, with a compound of for¬ mula (III), RA-SO2hal (III)

where RA is as defined above and hal is halogen. Detailed description of the invention In the definition of the compound group of formula (I), the term "al- kyl" refers to branched or straight chain alkyl groups having suitably 1 to 6 car¬ bon atoms, preferably 1 to 3 carbon atoms, specifically methyl. Examples of the meaning "4-6-membered heterocyclic ring contain¬ ing at least one N atom" for R2 are pyridyl and pyrimidinyl. Typical examples of heterocyclic groups formed by R1 and R2 to¬ gether with the N atom to which they are attached are groups having formulae

N —

and

When R1 and R2 are absent the N atom may form together with the adjacent carbon atom in the phenyl ring a fused ring e.g. of formula

and

Il

In formulae (A), (B) and (C) the meaning of "n" is preferably 0. Typi¬ cal examples of R3 and R4 having the meaning alkoxyalkyl, alkoxycarbonyl and alkanoyl are those containing 1 to 6 carbon atoms in the alkoxy moiety and 1 to 6 carbon atoms in the alkyl moiety. Examples of optionally substituted aryl and heterocyclic groups are and

Specific examples of preferred compounds are 3',4'dimetoxy-biphenyl-3-sulphonic acid (4-dimethylamino-phenyl)- amide), N-[4-(dimethylamino)phenyl]-4'-fluoro-1 ',1 '-biphenyl-3-sulphon- amide, 2,4-dichloro-N-{4-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino ]phen- yl}benzenesulphonamide, N-[4-(dimethylamino)phenyl]-3-(5-methyl-1 ,3,4-oxadiazol-2-yl)ben- zenesulphonamide, 2,4-dichloro-N-[4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro- 1 H-indol- 1-yl)phenyl]benzenesulphonamide, 2,4-dichloro-N-(2-methyl-1 ,3-benzothiazoll-5-yl)]benzenesulphon- amide, N-[4-(dimethylamino)phenyl]-4-(1-naphtyl)benzenesulphonamide . The compounds of formula (I) may be prepared by reacting a com¬ pound of formula (II) R2 R1 \ / N

(II)

where RB, RC and m are as defined above, with a compound of for- mula (III) RA-SO2hal (III)

where RA is as defined above and hal is halogen. The reaction may be carried out in conventional manner using methods well-known to the person skilled in the art. The pharmaceutical compositions can contain one or more of the sulphonamides of the invention. The administration can be parenteral, subcu- taneous, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal or intradermal injections, or by transdermal, buccal, oromucosal, ocular routes or via inhalation. Alternatively or concurrently, administration can be by the oral route. The required dosage will depend upon the severity of the condition of the patient, for example, and such criteria as the patient's weight, sex, age, and medical history. The dose can also vary depending upon whether it is to be administered in a veterinary setting to an animal or to a human patient. For the purposes of parenteral administration, compositions contain¬ ing the sulphonamides of the invention are preferably dissolved in distilled wa¬ ter for injection and the pH preferably adjusted to about 6 to 8 and the solution is preferably adjusted to be isotonic. If the sulphonamide is to be provided in a lyophilized form, lactose or mannitol can be added to the solution as a bulking agent and, if necessary, buffers, salts, cryoprotectants and stabilizers can also be added to the composition to facilitate the lyophilization process, the solution is then filtered, introduced into vials and lyophilized. Useful excipients for the compositions of the invention for parenteral administration also include sterile aqueous and non-aqueous solvents. The compounds of the invention may also be administered parenterally by using suspensions and emulsions as pharmaceutical forms. Examples of useful non¬ aqueous solvents include propylene glycol, polyethylene glycol, vegetable oil, fish oil, and injectable organic esters. Examples of aqueous carriers include water, water-alcohol solutions, emulsions or suspensions, including saline and buffered medical parenteral vehicles including sodium chloride solution, Ringer's dextrose solution, dextrose plus sodium chloride solution, Ringer's so¬ lution containing lactose, or fixed oils. Examples of intravenous infusion vehi- cles include fluid and nutrient replenishers, electrolyte replenishers, such as those based upon Ringer's dextrose and the like. Injectable preparations, such as solutions, suspensions or emul¬ sions, may be formulated according to known art, using suitable dispersing or wetting agents and suspending agents, as needed. When the active com- pounds are in water-soluble form, for example, in the form of water soluble salts, the sterile injectable preparation may employ a non-toxic parenterally ac- ceptable diluent or solvent as, for example, water for injection (USP). Among the other acceptable vehicles and solvents that may be employed are 5% dex¬ trose solution, Ringer's solution and isotonic sodium chloride solution (as de¬ scribed in the Ph. Eur. / USP). When the active compounds are in a non-water soluble form, sterile, appropriate lipophilic solvents or vehicles, such as fatty oil, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides, are used. Alternatively, aqueous injection suspensions which contain substances which increase the viscosity, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran, and optionally also contain stabilizers may be used. Pharmaceutical preparations for oral (but systemic) administration can be obtained by combining the active compounds with solid excipients, op¬ tionally granulating a resulting mixture and processing the mixture or granules or solid mixture without granulating, after adding suitable auxiliaries, if desired or necessary, to give tablets or capsules after filling into hard capsules. Suitable excipients are, in particular, fillers such as sugars, for ex¬ ample lactose or sucrose, mannitol or sorbitol, cellulose and/or starch prepara¬ tions and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as starches and their deriva- tives, pastes, using, for example, maize starch, wheat starch, rice starch, or potato starch, gelatine, tragacanth, methyl cellulose, hydroxypropylmethyl cel¬ lulose, sodium carboxymethyl cellulose, and/or polyvinyl pyrrolidone, deriva¬ tives, and/or, if desired, disintegrating agents, such as the above-mentioned starches, and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, with suitable coating, which if desired, are resistant to gastric juices and for this purpose, inter alia concentrated sugar solutions, which optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures, but also film coating using cellulose derivatives, polyethylene glycols and/or PVP de¬ rivatives may be used. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate, are used for coating. Dyestuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize different combinations of active com¬ pound doses. Solid dosage forms for oral administration include capsules, tablets, pills, troches, lozenges, powders and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as su¬ crose, lactose or starch. Such dosage forms may also comprise, as is normal practice, pharmaceutical adjuvant substances, e.g., stearate lubricating agents or flavouring agents. Solid oral preparations can also be prepared with enteric or other coatings which modulate release of the active ingredients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing in¬ ert non-toxic diluents commonly used in the art, such as water and alcohol. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying, suspending, sweetening and flavouring agents. The compositions of the invention may also be administered by means of pumps, or in sustained-release form. The compounds of the inven¬ tion may also be delivered to specific organs in high concentration by means of suitably inserted catheters, or by providing such molecules as a part of a chi¬ meric molecule (or complex) which is designed to target specific organs. Administration in a sustained-release form is more convenient for the patient when repeated injections for prolonged periods of time are indi¬ cated so as to maximize the comfort of the patient. Controlled release prepara¬ tion can be achieved by the use of polymers to complex or adsorb the peptides of the invention. Controlled delivery can be achieved by selecting appropriate macromolecules (for example, polyesters, polyamino acids, polyvinyl pyrroli- done, ethylenevinylacetate, methylcellulose, carboxymethylcelluloase pro¬ tamine zinc and protamine sulfate) as well as the method of incorporation in order to control release. Another possible method to control the duration of ac¬ tion by controlled release preparations is to incorporate the desired peptide into particles of a polymeric material such as polyesters, polyamino acids, hy- drogels, poly (lactic acid) or ethylene vinylacetate copolymers. Alternatively, instead of incorporating the sulphonamide into these polymeric particles, the sulphonamide can be entrapped into microparticles, prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hy- droxymethylcellulose or gelatin-microcapsules and poly (methylmethacrylate) microcapsules, respectively, or in colloidal drug delivery systems, for example liposomes, albumin microspheres, microemulsions, nanoparticles, and nano- capsules or in macroemulsions. The above-mentioned technics may be ap¬ plied to both parenteral and oral administration of the pharmaceutical formula¬ tion. The sulphonamides that are used in the compositions and methods of the invention can be employed in dosage forms such as tablets, coated tab¬ lets, capsules, powder sachets, or liquid solutions for oral administration if the biological activity of the material is not destroyed by the digestive process and if the characteristics of the compound allow it to be absorbed across the intes- tinal tissue. The pharmaceutical compositions of the present invention can be manufactured in a manner which is in itself know, for example, by means of conventional mixing, granulating, dragee-making, dissolving, lyophilizing or similar processes. The compounds of the invention are potent collagen receptor inhibi¬ tors and useful for inhibiting or preventing the adhesion of cells on collagen or the migration and invasion of cells through collagen, in vivo or in vitro. The now described compounds inhibit the migration of malignant cells and are thus for treating diseases such as cancers, including prostate, and melanoma, espe- daily where a2βλ integrin dependent cell adhesion/invasion/migration may contribute to the malignant mechanism. The compounds of the invention also inhibit adhesion of platelets to collagen and collagen-induced platelet aggregation. Thus, the compounds of the invention are useful for treating patients in need of preventative or amelio- rative treatment for conditions or diseases such as cardio-vascular diseases that are characterized by a need to prevent adhesion of platelets to collagen and collagen-induced platelet aggregation, for example, in stroke victims or pa¬ tients at risk of having a stroke.

Pharmacological tests

A cell invasion assay was used to demonstrate the anti-cancer potential of the inhibitors in vitro The ability to interact with extracellular matrix basement membranes is essential for the malignant cancer cell phenotype and cancer spread. σ2/?1 levels are known to be upregulated in tumorigenic cells. The overexpression regulates cell adhesion and migration to and invasion through the extracellular matrix. By blocking the interaction between extracellular matrix components li¬ ke collagen and σ2/?1 it is possible to block cancer cell migration and invasion in vitro. Prostate cancer cells (PC-3) expressing a2β'\ endogenously were used to test the in vitro anticancer potential of the inhibitors of the present in- vention.

Experimental procedure Invasion of PC-3 cells (CRL-1435, ATCC) through Matrigel was stu¬ died using BD Biocoat invasion inserts (BD Biosciences). Inserts were stored at -2O0C. Before the experiments inserts were allowed to adjust to the room temperature. 500 μl of serum free media (Ham's F12K medium, 2 mM L- glutamine, 1.5 g/l sodium bicarbonate) was added into the inserts and allowed to rehydrate at 370C in cell incubator for two hours. The remaining media was aspirated. PC-3 cells were detached, pelleted and suspended into serum free media (50 000 cells / 500 μl). 300 μl of cell suspension was added into the in- sert in the absence (control) or presence of the inhibitor according to the pre¬ sent invention. Inserts were placed on the 24-well plates; each well containing 700 μl of cell culture media with 3% of fetal bovine serum as chemo-attractant. Cells were allowed to invade for 72 hours at 370C in cell incubator. Inserts were washed with 700 μl PBS, and fixed with 4 % paraformaldehyde for 10 minutes. Paraformaldehyde was aspirated and cells were washed with 700 μl of PBS and inserts were stained by incubation with hematoxylin for 1 minute. The stain was removed by washing the inserts with 700 μl of PBS. Inserts were allowed to dry. Fixed invaded cells were calculated under the micro¬ scope. Invasion % was calculated as a comparison to the control. The results are presented in attached Figure 1.

A platelet function analyzer PFA100 was used to demonstrate the anti¬ thrombotic potential of the 020*1 inhibitors A platelet function analyzer PFA 100 was used to demonstrate the possible antithrombotic effects of dlβλ inhibitors. The PFA 100 is a high shear- inducing device that simulates primary hemostasis after injury of a small ves¬ sel. The system comprises a test-cartridge containing a biologically active membrane coated with collagen plus ADP. An anticoaculated whole blood sample was run through a capillary under a constant vacuum. The platelet agonist (ADP) on the membrane and the high shear rate resulted in activation of platelet aggregation, leading to occlusion of the aperture with a stable plate- let plug. The time required to obtain full occlusion of the aperture was desig¬ nated as the "closure time". Each hit compound was added to the whole blood sample and the closure time was measured with PFA 100. If the closure time was increased when compared to the control sample the hit compound was suggested to have antithrombotic activity.

Experimental procedure Blood was collected from a single donor via venipuncture into evacuated blood collection tubes containing lithium heparin as anticoagulant. Within 30 minutes, blood was aliquoted into 50 ml_ falcon tubes and treated with either inhibitory compounds (e.g. mAbs P1 H5, 5E8, P1 E6) or, as controls, non-specific rat IgG or PBS only at pH 7.4. All experimental and control com¬ pounds were diluted in PBS before addition to 0.5% total volume (i.e. 15.92 ml_ blood and 80 μl compound in PBS). Samples were kept at room temperature with rotation for the duration of the experiments. Duplicate sample volumes (800 μl) were dispensed into PFA Collagen/ADP cartridges, and individual clo¬ sure times were determined. Control and experimental samples were tested in two or three se¬ quences during the interval of 60 to 180 minutes from draw. This practice al¬ lowed the observation of increasing inhibitory effects over time. Acquisitions resulting in a closure time exceeding the range of mea¬ surement of the instrument (>300 seconds) were assigned a value of 300 sec¬ onds. Mean and standard deviations were calculated for each treatment, and data points falling outside ±2 SD of the mean were excluded. Student's t-test was applied to the resultant data. The results are presented in attached Figure 2. Figures 1 and 2 contain results with coded compounds BTT-3001 = 2,4-dichloro-N-{4-[(4,6-dimethylpyrimidin-2-yl)(methyl)amino ]phenyl}benzene- sulphonamide, compound BTT-3002 = 3',4'-dimethoxy-biphenyl-3-sulphonic acid (4-dimethylamino-phenyl)-amide and compound BTT-3003 = N-[4-(di- methylamino)phenyl]-4'-fluoro-1 ',1 '-biphenyl-3-sulphonamide. Further, the compounds listed in Table 1 and Table 1 B below were tested. The results are presented in Table 2. Table 1 Structure NCE number 223 CH3 ?"V/V4 =\ F 256 261 CH3 > — N / v O 265 CH, 266 F. F ∏-a 268 CH3 CH3 269 M\ Cl 270 o CH, CH, 271 ,S Cl W O \\ Il ιr\ CH, CH, 272 ^ ^^O- CH3 O— CH, CH3 H3C N4' 273 NH2 274 H,C 275 276 H3C^N CH, 277 278 279 H3C CH. .CH, °4 280 O H3C CH3 N^CH3 CH3 H3C °<8 ,Br 281 CH. 282 Cl 283 284 285 267 286 287 288 289 290 291 292 293 294 295 296 297 298 299 301 ? N1 N o; α 302 OH Oi NH 303 NIH2 N "^ CH N W H O 04 [ /> α 3 Br o 305 306 307 Cl 308 309 310 311 312 313 314 315 0 XJ .— CI 316 O 317 O ' H >-" / 318 O 319 320 / o / Cl 321 x)—<f VHN—s—4 I 323 324 325 Cl 326 V-,. VJ 327 \- -/ HHN.YJ-N^ 328 \ 300 Os Py= -Br 130 /N"\ f NH Cl

141

O H

Br VS-NH />- Cl O 167 Cl

135

136 N ^ // O —s-o O

o o—

142 Cl \\ 9 6 H Λ / N-H

137 HN. ..O Cl

Br Cl p- o N=< α V % -S-N-Λ\ } — (\ /> 164 ό o-

Cl

Ct HOΛ 165 ^N

Cl O ^ Cl 168 0 V-N

Cl- 163

9 166 O

131

Cl O IfVsx 132 Cl h'

Cl Cl

,s-° 133

N

134 Cl N 138 OH Cl

Br. 9 1 S* 139 O H

N- O 140 Br. O H

156

157

Br O // X S - -N- \\ /j 158 O

159

O 160 O

161

162

^ 143 144 O ■H-t-r%

H,C, CH, 145

N CH> t- U N=N

NH 146

147

l>^^ I I O 148

α

149

H O CH, 150 o o 151 HX C-S=O Λ 152 o-§=o H , N O- CH, g HN-S*° 4? H Ni Y CH1 ^ "β 153 N N 154

O \

H3C-N 155

O2N H3C H3C

Cl — // \\_S - N _/ \_ N Y-/ O '' H \L_J/ H

°' H ^N'N H Table 1 B Structure NCE number CL .Cl 171 g^N-\ / NH-SO2 \ \ /-Cl 176 σ Cl 182 NH-SO2 Cl X -N 186 NH-SO2 190 N NH — SO2 203 N NH — SO2 204

N NH — SO2 205

HN N SO2 209

Br Cl

213 N NH — SO2 Cl

H -N NH — SO2 201 //

=N 235 NH — SO2 — N

Λ N NH-SO2 239

-CO-

Cl 242

N- -SO- Cl

NH-SO2 250 Table 2

Compound EC50 in cell adhesion Emax in cell adhesion assay assay NCE131 25 μM 58 % NCE132 40 μM 90 % NCE134 10μM 40 % NCE139 46 μM 75 % NCE142 20 μM 77 % NCE161 34 μM 82 % NCE163 32 μM 66 % at 50 μM NCE164 21 μM 85 % at 50 μM NCE170 24 μM 85 % at 40 μM NCE171 20μM 79 % NCE173 35 μM 59 % at 40 μM NCE176 17 μM 59 % at 50 μM NCE182 25 μM 77 % NCE183 28 μM 81 % NCE186 19 μM 91 % NCE187 18 μM 87 % NCE188 36 μM 81 % NCE189 30 μM 76 % NCE190 25 μM 76 % NCE192 39 μM 75 % NCE193 22 μM 72 % NCE195 49 μM 60 % NCE197 30 μM 74 % NCE202 27 μM 91 % NCE203 19 μM 86 % NCE204 ~25 μM (could not be 63 % defined by Prism) NCE205 20 μM 84 % (50 μM) NCE209 35μM 64 % (50 μM) NCE210 dd could not be detected 80 % (50 μM) NCE213 25 μM 71 % (50 μM) NCE201 36 μM 64 % (50 μM) NCE222 15 //M 66 % NCE223 13 μM 82 % NCE230 >30 μM (could not be 76 % (at 50 μM) defined by Prism) NCE234 35μM 85 % NCE235 20 μM 85 % NCE239 24 μM 64 % (at 50 μM) NCE242 6 μM 70 % NCE250 31 μM 89 % NCE255 17 μM 88 % (at 50 μM) NCE258 40 μM 66 % NCE263 26 μM 88 % NCE266 18 //M 70 % NCE269 19μM 64 % NCE275 26 μM 57 % NCE281 47 μM 78 % NCE282 1.6 //M 59% (at 50 μM) NCE283 23 μM 63 % NCE284 -30 μM 69 % NCE285 20 μM 60 % (at 50 μM) NCE286 37 μM 72 % NCE291 32 μM 50 % NCE295 29 μM 56 % NCE297 26 μM 80 % NCE298 33 μM 79 % NCE299 9.6 μM 79 % NCE302 24 μM 57 % NCE306 24 μM 67 % (at 50 μM) NCE307 20 μM 67 % (at 50 μM) NCE300 45 μM 50 % NCE316 10 μM 87 % (at 50 μM) NCE317 44 μM 45 % NCE320 10μM 45 % NCE321 6.3 μM 55 % The test results showed that the compounds of the present inven¬ tion have an anti-cancer and antithrombotic activity in vitro. The following examples illustrate the invention but are not intended to limitate the scope of the invention.

Example 1

3-bromo-N-[4-(dimethylamino)phenyl]benzenesulphonamide To a solution of 4-dimethylamino aniline (2 g, 0.0147 mol) and triet- hylamine (2.25 mL, 0.0162 mol, 1.1 eq.) in acetonitrile (20 ml_) at 00C under ni¬ trogen was added dropwise a solution of 3-bromobenzene sulphonyl chloride (3.94 g, 0.0154 mol, 1.05 eq.) in acetonitrile (5 mL). The mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was re¬ moved in vacuo and the residue redissolved in ethyl acetate (100 mL). The or¬ ganic layer was washed with sat aqueous NaHC-θ3 (2x200 mL), water (2x200 mL), brine (200 mL), dried (Na2SO4), filtered and concentrated. The product was obtained as a brown solid (3.5g, 67.0%) and was not purified further. 1H NMR (300 MHz d6 DMSO) δ 7.78 — 7.76 (s, 2ff), 7.61 — 7.58 (d, 1 H), 7.48 — 7.43 (t, 1 H)1 6.84 — 6.80 (d, 2H), 6.57 — 6.54 (d, 2H), 2.78 (s, 6H); 13C NIMR (300 MHz d6 DMSO) δ 148.84, 142.15, 135.70, 131.65, 129.46, 126.12, 125.66, 124.77, 122.24, 112.95; LCMS Rt 15.44 min.; m/z — 353.3. MP 187-189°C.

Example 2

3',4'-dimethoxy-biphenyl-3-sulphonic acid (4-dimethylamino-phenyl)-ami- de (BTT-3002) To a solution of 3-bromo-N-(4-dimethylamino-phenyl)-benzene- sulphonamide (2.14 g, 6.02 mmol) and 3,4-dimethoxyphenyl-boronic acid (1.09 g, 6.02 mmol) in toluene (200 mL) and aqueous sodium carbonate solution (2 M, 100 mL) under N2 was added tetrakis (triphenylphosphine) palladium (0) (80 mg). The mixture was stirred under reflux for 18 hours. The reaction mix¬ ture was then filtered through celite and washed with ethyl acetate. The or- ganic layer was separated and dried (MgSO4). After evaporation of the solvent the crude material was purified by column chromatography (SiO2, ethylace- tate/cyclohexane = 4/6) to yield 1.8 g (73%) of NCE-102 as light yellow crys¬ tals: mp 43°C. 1H NMR (300 MHz, CDCI3) 8.2.93 (6 H, s), 3.94 (6 H, s), 6.19 (1 H, bs), 6.60 (2 H, d, J = 9 Hz), 6.9 (4 H, m), 7.09 (1 H, d, J = 9 Hz)1 7.46 (1 H, t, J = 8.8 Hz), 7.64 (1 H, d, J 9 Hz), 7.5 (1 H, d, J 8.8 Hz, CH), 7.87 (1 H1 s); 13C NMR (300 MHz, CDCI3) 840.88, 56.42, 56.45, 110.77, 112.01 , 113.04, 120.05, 124.97, 125.76, 125.87, 126.80, 129.59, 131.18, 132.61 , 140.21 , 142.15, 149.76, 149.81 ; MS (ES+) m/z 413.5 (M + H).

Example 3

N-[4-(dimethylamino)phenyl]-4'-fluoro-1 ,1'-biphenyl-3-sulphonamide (BTT-3003) Crude compound of example 1 (3.98 g, 11.2 mmol), 4-fluoro- benzene boronic acid (1.57 g, 11.2 mmol) and tetrakis (triphenylphosphine) palladium (160 mg, 0.14 mmol) were stirred in toluene (150 ml_, degassed) and 2M sodium bicarbonate solution (100 ml_, degassed) at 1060C overnight. After this time the reaction mixture was filtered through celite, the organic solu¬ tion separated from the aqueous, which was washed with ethyl acetate and the organic solvents combined. The crude dark brown/black material was decol¬ ourised with activated charcoal and recrystallised from isopropanol to give the product (1.8324 g, 44%) as an off white/beige material: mp 158-1600C; 1H NMR (CDCI3) δ 3.03 (s, 6H), 6.69 (s, 1 H), 6.72 (s, 2H), 7.05 — 7.08 (d, J= 9 Hz, 2H), 7.19 — 7.24 (t, J= 8.7 Hz, 2H), 7.52 — 7.62 (m, 3H), 7.79 — 7.8 1 (m, 2H), 7.94-7.95 (m, 1 H); 13C NMR (CDCI3) δ 40.93, 113.14, 116.085, 116.372, 125.02, 126.23, 126.71 , 129.28, 129.73, 131.35, 135.81 , 140,25, 141.30, 149.86, 161.64, 164.93, LCMS Rf= 15.0 mins, (ES) = m/z 371.3 (M + 1 ).

Example 4

2,4-dichloro-N-{4-[(4,6-dimethylpyrimidin-2-yl)(methyl)am ino]phenyl}ben- zenesulphonamide (BTT-3001) To a solution of N-(4,6-dimethylpyrimidin-2-yl)-N-methylbenzene- 1 ,4-diamine (2 g, 0.0088 mol) and triethylamine (1.35 ml_, 0.0097 mol, 1.1 eq.) in acetonitrile (30 ml_) at 00C under nitrogen was added dropwise a solution of 2,4-dichlorobenzene suiphonyl chloride (2.26 g, 0.0092 mol, 1.05 eq.) in ace- tonitrile (10 ml_). The mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was removed in vacuo and the residue redis- solved in ethyl acetate (100 ml_). The organic layer was washed with sat aque¬ ous NaHCO3 (2x100 ml_), water (2x100 ml_), brine (100 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (1 :4 AcOEt:cyclohexane) to yield 1.26 g of a yellow oil (bis suiphonamide) and 1.77 g (46.2%) of a light green solid (monosulphonamide). Bis suiphonamide: 1H NMR (300 MHz CDCI3) 8 8.13 — 8.10 (d, 2H), 7.52 — 7.51 (d, 2H), 7.43 — 7.38 (dd, 1 H), 7.37 — 7.34 (d, 2H), 7.26 — 7.22 (d, 2H), 6.43 (s, 1 H), 3.56 (s, 3H), 2.29 (s, 6H). Monosulphonamide: 1H NMR (300 MHz CDCI3) 8 7.88 — 7.85 (d, 1 H), 7.46 (d, 111 ), 7.26 — 7.22 (dd, 1 H), 7.18 — 7.14 (d, 2H), 7.01 — 6.98 (d, 2H), 6.87 (s, NH), 6.29 (s, 1 H), 3.40 (s, 3H), 2.18 (s, 6H); 13C NMR (300 MHz CDCI3) δ 167.35, 144.51 , 140.29, 135.53, 133.39, 131.78, 131.59, 127.97, 126.99, 123.02, 110.88, 38.46, 24.39; LCMS Rt 18.71 min.; m/z — 437.4.

Example 5

Hydrolysis of the 2,4-dichloro-N-[(2,4-dichlorophenyl)sulphonyl]-N-{4- [(4,6-dimethylpyrimidin-2-yl)(methyl)amino]phenyl}benzenesul phonamide To a solution of the bis suiphonamide (1.26 g, 0.002 mol) in ethanol (50 imL) was added NaOEt (653 mg, 0.0097 mol, 5 eq.) and the reaction was heated to 65°C for 5 hrs. The solvent was removed in vacuo and residue dis¬ solved in water. The aqueous layer was washed twice with CHCI3 (50 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated. The solid was purified by column chromatography (1 :4 — 2:3 AcOEtxyclohexane) to yield a beige solid (550 mg, 64.7%, 2,4-dichloro-N-{4-[(4,6-dimethyl- pyrimidin-2-yl)(methyl)amino]phenyl}benzenesulphonamide). 1H NMR (300 MHz CDCI3) δ 7.88 —7.87 (d, 1 H), 7.46 (d, 1 H), 7.26 — 7.22 (dd, 1 H), 7.18 — 7.14 (d, 2H), 7.02 — 6.97 (d, 2H), 6.90 (s, NH), 6.28 (s, 1 H), 3.40 (s, 3H), 2.17 (s, 6H); 13C NMR (300 MHz CDCI3) 6 167.36, 144.49, 140.28, 135.54, 133.39, 131.72, 131.61 , 127.97, 127.00, 123.00, 110.88, 38.47, 24.39; LCMS R1 18.71 min.; m/z — 437.4. LCMS conditions: 0-97% acetonitrile in water, C18, electrospray +ve. Example 6

N-[4-(dimethylamino)phenyl]-3-(5-methyl-1 ,3,4-oxadiazol-2-yl)benzene- sulphonamide To a solution of 4-dimethyl amino aniline (0.05 g, 0.367 mmol) and thethylamine (0.056 ml_, 0.404 mmol, 1.1 eq.) in acetonithle (2 ml_) under ni¬ trogen was added 3-(5-methyl-1 ,3,4-oxadiazol-2-yl) benzene sulphonyl chlo¬ ride (0.0997 g, 0.385 mmol, 1.05 eq.) in acetonitrile (2 mL). The mixture was shaken at room temperature for 18 hours. The solvent was removed in vacuo. The residue was re-dissolved in AcOEt and the organic layer washed with sa- turated aqueous NaHCO3, separated, dried (Na2SO4) and concentrated in va¬ cuo. The residue was analysed by LCMS and was shown to be mainly product (Rt 9.97 min; m/z — 359.3). The residue was purified by MS-directed prep HPLC to give the sulphonamide as a black solid (5.6 mg). 1H NMR (300 MHz CDCI3/d4 MeOH (2 drops)) δ 8.29 — 8.27 (m, 1 H), 8.04 — 8.01 (m, 1 H), 7.97 — 7.94 (m, 1 H), 7.81 — 7.75 (m, 1 H), 7.52 — 7.46 (t, 1 H)1 7.02 — 6.97 (m, 4H), 2.96 (s, 6H), 2.67 (s, 3H); Purity - >95%.

Example 7

2,4-dichloro-N-[4-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahyd ro-1 H-indol-1-yl)- phenyl]benzenesulphonamide To bromo wang resin in DMF (4 ml) was added 1 -(4-aminophenyl)- 2, 6, 6-trimethyl-5,6,7-trihydroindol-4-one (0.375 g, 1.40 mmol, 5 eq.), sodium iodide (0.210 g, 1.40 mmol, 5 eq.) and disopropylethylamine (0.500 ml, 2.80 mmol, 10 eq.). The resin was shaken at 9O0C for 24hrs. The resin was filtered and washed with 5ml of DMF, DCM, DMF, DCM, MeOH, DCM, MeOH and fi- nally Et2O. The resin was dried under vacuum. To the resin was added pyridine (3 ml), 2,4-dichlorobenzene sul¬ phonyl chloride (0.430 g, 1.75 mmol, 5 eq.) and DMAP (0.085 g, 0.700 mmol, 2 eq.). The resin was shaken at 6O0C for 18hrs and washed with 5ml of DMF, DCM, DMF, DCM, MeOH, DCM, MeOH and finally Et2O. The resin was shaken in a solution of 95% TFA / 5% H2O (3 ml) for 24hrs, filtered and the resin washed with DCM (1 ml) and MeOH (1 ml). The combined filtrates were concentrated in vacuo. The residue was purified by MS-directed prep HPLC to give the sulphonamide (1 .1 mg). LCMS Rt 1 1 .46 min.; m/z — 478; Purity -85%. Example 8

2,4-dichloro-N-(2-methyl-1 ,3-benzothiazol-5-yl)benzenesulphonamide To a solution of 2-methyl-1 , 3-benzothiazol-5-amine (0.05 g, 0.211 mmol, 1 eq.) in acetonitrile (2 ml) was added triethyl amine (0.059 ml, 0.232 mmol, 1.1 eq.) and 2,4 dichlorobenzene sulphonyl chloride (0.054 g, 0.222 mmol, 1.05 eq.). The mixture was shaken at room temperature for 18 hours. The solvent was removed in vacuo and the residue dissolved in AcOEt. The AcOEt was washed with saturated aqueous NaHCO3, separated, dried (Na2SO4) and concentrated in vacuo. The residue was purified by MS-directed prep HPLC to yield the sulphonamide (3.1 mg). LCMS Rt 11.15 min.; m/z — 374; Purity -95%.

Example 9

4-bromo-N-[4-(dimethylamino)phenyl]benzenesulphonamide To a solution of 4-dimethyl amino aniline (2 g, 0.0147 mol) and triet- hylamine (2.25 mL, 0.0162 mol, 1.1 eq.) in acetonitrile (20 mL) at O0C under ni¬ trogen was added 4-bromo-benzene sulphonyl chloride (3.94 g, 0.0154 mol, 1.05 eq.). The mixture was cooled to O0C for 30 mins, and then allowed to warm to room temperature. The reaction was stirred for 18 hours. The solvent was removed in vacuo and the residue redissolved in ethyl acetate (100 mL). The organic layer was washed with sat aqueous NaHCO3 (2x200 mL), water (2x200 mL), brine (200 mL), separated, dried (Na2SO4), filtered and concen¬ trated in vacuo. The residue was dissolved in DCM, filtered through a pad of silica and the pad washed twice with DCM (100 ml). The filtrates were com¬ bined and concentrated in vacuo. The sulphonamide was obtained as a or- ange coloured solid (4.0 g, 76.6 %). 1H NMR (300 MHz CDCI3) δ IAl (s, 4H), 6.83 — 6.71 (d, 2H), 6.50 — 6.46 (d, 2H), 6.31 (b s, 1 H), 2.83 (s, 6H); 13C NMR (300 MHz CDCI3) δ 149.92, 138.83, 132.47, 129.32, 128.00, 126.77, 124.40, 113.07, 40.86; LCMS Rt 11.57 min.; m/z — 356:358 (1 :1 ratio). Example 10

N-[4-(dimethylamino)phenyl]-4-(1 -naphthyl)benzenesulfonamide 4-bromo-N-[4-(dimethylamino)phenyl]benzenesulphonamide (25 mg, 0.07 mmol) and 1-naphthyl boronic acid (17.2 mg, 0.07 mmol, 1 eq.) was dissolved in toluene (2 ml) under N2. Saturated aqueous Na2CO3 (1 ml) was added followed by palladium tetrakis(triphenylphosphine) (1 mg, cat.). The re¬ action was refluxed for 4 hrs and then left to stirring at room temperature for 18 hrs. The reaction was diluted with AcOEt (4 ml) and the organic layer decanted off. The organic layer was filtered through a pad of celite and the solvent re- moved in vacuo. The residue was analysed by LCMS and confirmed to be the sulphonamide product (17.2 mg, 60.4%). LCMS Rt 12.91 min.; m/z — 404; Purity -95%. The compounds of example 1 1 to 37 were prepared according to the following general coupling procedure.

General Coupling Procedure 1 : Coupling of sulfonyl chloride to amine in acetonitrile To a stirred solution of the amine (0.75 mmol) and triethylamine (0.75 mmol) in anhydrous acetonitrile (1 ml) at 0 0C was added 2, 4- dichlorobenzenesulphonyl chloride (0.50 mmol) in acetonitrile (1 ml). The mix- ture was stirred at this temperature for 2-3 hours and/or warmed up to ambient temperature and stirred until reaction had completed by TLC. The solvent was removed in vacuo and the residue partitioned bet¬ ween ethyl acetate (25 ml) and saturated aqueous sodium bicarbonate solution (25 ml). The organic layer was separated and further washed with sodium bi- carbonate (2x25ml), brine (2x25ml), dried over sodium sulphate and concent¬ rated down. The product was purified either by flash chromatography or prepa¬ rative HPLC.

Example 11

NCE131 2,4-Dichloro-N-(2-methyl-1 H-indol-5-yl)-benzenesulfonamide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR (300 MHz; CDCI3) 2.38 (3H, s, 2'-CH3), 6.1 1 (1 H, m, 3'-H), 6.84 (1 H, dd, J 2.1 and 8.5 Hz), 6.96 (1 H, s), 7.09 (1 H, d, J 8.5 Hz), 7.16 (1 H, dd, J 2.0 and 8.5 Hz), 7.23 (1 H, d, J 2.0 Hz), 7.50 (1 H, d, J 2.0 Hz)1 7.77 (1 H, d, J 8.5 Hz), 7.93 (1 H, br, N-H) 13C NMR (300 MHz, CDCI3) 13.69 (CH3), 100.66 (3'-CH), 110.75 (CH), 115.44 (CH), 117.83 (CH), 127.14, 127.45 (CH), 129.35, 131.17 (CH), 132.24, 132.99 (CH), 134.74, 135.07, 136.80, 139.51 Actual Mass: 354.95 LCMS: Mass detected [M-H]" 353.00; Retention time 17.2 mins; Pu¬ rity 87%

Example 12

NCE132 2,4-Dichloro-N-(2-methyl-benzothiazol-5-yl)-benzenesulfon- amide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR (300 MHz; CDCI3) 2.79 (3H, s, 2'-CH3), 7.18-7.28 (3H, m, 3xAr-H), 7.49 (1 H, d, J 2.0 Hz), 7.67 (1 H, d, J 8.6 Hz), 7,94 (1 H, d, J 11.5 Hz) 13C NMR (300 MHz, CDCI3) 20.19 (CH3), 115.59 (CH), 119.82 (CH), 122.13 (CH), 127.65 (CH), 131.46 (CH), 132.26, 133.04 (CH), 133.44, 134.61 , 140.08, 153.89, 169.12 Actual Mass: 404.85 LCMS: Mass detected [M-H]" 402.85; Retention time 16.6 mins; Pu¬ rity 96%

Example 13

NCE133 2,4-Dichloro-N-(2-methyl-benzothiazol-6-yl)-benzenesulfon- amide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR (300 MHz; CDCI3) 2.78 (3H, s, 2'-CH3), 7.12 (1 H, dd, J 2.2 and 8.7 Hz), 7.15 (1 H, br, N-H), 7.27 (1 H, dd, J 2.0 and 8.5 Hz), 7.52 (1 H, d, J 2.0 Hz), 7.67 (1 H, d, J 2.2 Hz), 7.76 (1 H, d, J 8.7 Hz), 7.88 (1 H, d, J 8.5 Hz) Actual Mass: 373.00 LCMS: Mass detected [M-H]" 370.95; Retention time 13.2 mins; Pu¬ rity 97% Example 14

NCE134 2,4-Dichloro-N-(1 H-indol-5-yl)-benzenesulfonamide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR (300 MHz; CDCI3) 2.04 (3H, s, 2'-CH3), 6.45-6.46 (1 H, m), 6.94 (1 H, dd, J 2.0 and 8.6 Hz), 7.00 (1 H, s), 7.17-7.25 (3H, m), 7.38 (1 H, d, J 1.6 Hz)1 7.52 (1 H, d, J 2.0 Hz), 7.80 (1 H, d, J 8.5 Hz), 8.25 (1 H, br, N-H) Actual Mass: 341 .00 LCMS: Mass detected [M-H]" 339.05; Retention time 13.2 mins; Pu- rity 96%

Example 15

NCE138 2,4-Dichloro-N-(benzothiazol-6-yl)-benzenesulfonamide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR (300 MHz; CDCI3) 7.22 (1 H, dd, J 2.2 and 8.7 Hz), 7.28 (1 H, dd, J 2.0 and 8.5 Hz), 7.51 (1 H, d, J 2.0 Hz)1 7.56 (1 H, br, N-H), 7.82 (1 H, d, J 2.1 Hz), 7.94 (2H, dd, J 8.7 and 13.3 Hz), 8.94 (1 H, s, 2'-H) Actual Mass: 358.90 LCMS: Mass detected [M-H]" 356.90; Retention time 12.2 mins; Pu- rity 88%

Example 16

NCE139 N-Benzolthiazol-6-yl-3-bromo-benzenesulfonamide Synthesised according to general coupling procedure 1 and purified by flash chromatography. NMR-To be purified and determined. Actual Mass: 369 LCMS: No ionization; Retention time 10.3 mins; Purity 93% Example 17

NCE140 3-Bromo-N-(2-methyl-benzothiazol-5-yl)-benzenesulfonamide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR (300 MHz; CDCI3) 2.80 (3H, s, 2'-CH3), 7.18 (1 H, dd, J 2.1 and 8.6Hz), 7.26 (1 H, dd, J 2.7 and 10.6Hz), 7.33 (1 H, br, N-H), 7.60-7.72 (4H, m, 4xAr-H), 7.94 (1 H, m, Ar-H) Actual Mass: 383 LCMS: No ionization; Retention time 17.1 mins; Purity 93%

Example 18

NCE156 2,4-Dichloro-N-(2-methyl-benzooxazol-5-yl)-benzenesulfon- amide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR (300 MHz; CDCI3) 2.59 (3H, s, 2'-CH3), 7.07 (1 H, br, N-H), 7.11 (1 H, dd, J 2.2 and 8.6 Hz), 7.24 (1 H, dd, J 2.0 and 8.6 Hz), 7.34 (1 H, d, J 8.6 Hz), 7.38 (1 H, d, J 2.0 Hz), 7.52 (1 H, d, J 2.0 Hz), 7.84 (1 H, d, J 8.6 Hz) Actual Mass: 356.80 LCMS: Mass detected [M-H]' 355.00; Retention time 17.6 mins; Pu- rity 80%

Example 19

NCE157 N-Benzo[1 ,3]dioxol-5-yl-2,4-dichloro-benzenesulfonamide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR (300 MHz; CDCI3) 5.92 (2H, s, 2'-CH2), 6.50 ( 1 H, dd, J 2.1 and 8.3 Hz), 6.61 (1 H, d, J 8.3 Hz), 6.70 (1 H, d, J 2.1 Hz), 6.93 (1 H, br, N-H), 7.30 (1 H, dd, J 2.2 and 8.5 Hz), 7.53 (1 H, d, J 2.0 Hz), 7.86 (1 H, d, 8.5 Hz) Actual Mass: 345.95 LCMS: Mass detected [M-H]" 343.80; Retention time 14.3 mins; Pu- rity 97% Example 20

NCE158 3-Bromo-N-(2-methyl-benzooxazol-5yl)-benzenesulfonamide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR (300 MHz; CDCI3) 2.62 (3H, s, 2'-CH3), 6.70 (1 H, br, N-H), 7.06 (1 H, dd, J 2.2 and 8.6 Hz), 7.25-7.31 (2H, m 2xAr-H), 7.37 (1 H1 d, J 8.6 Hz), 7.59- 7.64 (2H, m, 2xAr-H), 7.90 (1 H, t, J 1.8 Hz) Actual Mass: 367.00 LCMS: Mass detected [M-H]" 365.00; Retention time 11.1 mins; Pu- rity 86%

Example 21

NCE159 N-Benzo[1 ,3]dioxol-5-yl-3-bromo-benzenesulfonamide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR (300 MHz; CDCI3) 5.95 (2H, s, 2'-CH2), 6.44 (1 H, dd, J 2.2 and 8.3 Hz), 6.65 (1 H, d, J 8.3 Hz), 6.67 (1 H, d, J 2.2 Hz), 6.80 (1 H, br, N-H), 7.32 (1 H, t, J 7.9 Hz), 7.65 (2H, dt, J 0.9 and 7.9 Hz), 7.90 (1H, t, J 1.8 Hz) Actual Mass: 356.00 LCMS: Mass detected [M-H]" 353.95; Retention time 13.4 mins; Pu- rity 98%

Example 22

NCE-160 2,4-Dichloro-N-(2-methyl-benzooxazol-6-yl)-benzenesulfon- amide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR (300 MHz; CDCI3) 2.59 (3H, s, 2'-CH3), 7.00 (1 H, dd, J 3.1 and 6.4 Hz)1 7.26 (1 H, dd, J 2.0 and 8.5 Hz), 7.39 (1 H, d, J 2.0 Hz), 7.43 (1 H, d, J 4.7 Hz), 7.49 (1 H, d, J 2.0 Hz), 7.67 (1 H, br, N-H), 8.17 (1 H, d, J 8.5 Hz) Actual Mass: 357.00 LCMS: Mass detected [M-H]" 355.00; Retention time 11.7 mins; Purity 99% Example 23

NCE 169 3-Bromo-N-(2-methyl-benzooxazol-6-yl)-benzenesulfonamide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR (300 MHz; CDCI3) 2.62 (3H, s, 2'-CH3), 6.91 (1 H, dd, J 2.0 and 8.4 Hz), 7.28 (1 H, t, J 7.9 Hz), 7.38-7.40 (2H, m), 7.47 (1 H, d, J 8.5 Hz), 7.61-7.66 (2H, m), 7.9 (1 H, t, J 1.8 Hz) Actual Mass: 366.95 LCMS: Mass detected [M-H]" 364.90; Retention time 10.6 mins; Pu- rity 89%

Example 24

NCE161 2,4-Dichloro-N-(1 H-indol-6-yl)-benzenesulfonamide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR (300 MHz; CDCI3) 6.47 (1 H, m), 6.76 (1 H, dd, J 1.9 and 8.4 Hz), 7.50 (1 H, s), 7.18-7.26 (3H, m ), 7.32 (1 H, s), 7.44 (1 H, d, J 8.4 Hz), 7.51 (1 H, d, J 2.0 Hz), 7.82 (1H, d, J 8.5 Hz), 8.21 (1 H, br, N-H) Actual Mass: 341.05 LCMS: Mass detected [M-H]" 339.05; Retention time 14.1 mins; Pu- rity 99%

Example 25

NCE162 3-Bromo-N-(1 H-indol-6-yl)-benzenesulfonamide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR (300 MHz; CDCI3) 6.51 (1 H, m ), 6.57 (1 H, s), 6.64 (1 H, dd, J 1.9 and 8.4 Hz), 7.22 (1 H, dd, J 2.4 and 5.6 Hz), 7.33 (1 H, s), 7.47 (1 H, d, J 8.4 Hz), 7.55-7.62 (2H, m), 7.91 (1 H, t, 1.8 Hz), 8.22 (1 H, br, N-H) Actual Mass: 350.90 LCMS: Mass detected [M-H]" 348.90; Retention time 12.9 mins; Pu- rity 98% Example 26

NCE 130 4-Bromo-2-chloro-N-(4-dimethylamino-phenyl)-benzenesulfon- amide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR 300 MHz; δH (CDCI3) 7.73 (1 H, d, J 8.4Hz, ArH), 7.69 (1 H, d, J 2.0Hz, ArH), 7.41 (1 H, dd, J 2.0, 8.4Hz, ArH), 6.97 (2H, d, J 8.8Hz, ArH), 6.54 (2H, d, J 8.8Hz, ArH), 2.90 (6H, s, N(CH3)2). ESMS +ve calculated 389.7, [M+H]+ 389.17. Purity Estimated >90%

Example 27

NCE 141 4-Bromo-N-(2,4-dichloro-phenyl)-benzenesulfonamide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR 400 MHz δH (DMSO) 7.93 (4H, m, ArH), 7.75 (2H1 dd, J 2.0, 7.2 Hz), 7.32 (1H, J 7.2Hz, ArH). Actual Mass: 381.08 LCMS: Mass detected [M-H]" no ionisation; Retention time 16.25 mins; Purity 95.2%

Example 28

NCE 167 4-Bromo-N-(3,4-dichloro-phenyl)-benzenesulfonamide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR 400 MHz δH (DMSO) 7.92 (2H, d, J 8.8Hz, ArH), 7.67 (2H, d, J 8.8Hz, ArH). 7.66 (1 H, d, ArH), 7.50 (1 H, d, J 2.0Hz, ArH), 7.04 (1 H, dd, J 2.0, 7.6Hz, ArH). Actual Mass: 381.08 LCMS: Mass detected [M-H]" 380.10; Retention time 21.57 mins; Purity 92.1 % Example 29

NCE 135 [4-(2,4-Dichloro-benzenesulfonylamino)-phenyl]-(4,6-dimethyl - pyrimidin-2-yl)-methyl-ammonium; chloride NCE 50 2)4-dichloro-N-{4-[(4,6-dimethyl-pyrimidin-2-yl)-methyl-amin o]-phenyl}- benzenesulfonamide (75mg, UmM) was dissolved in ethyl acetate (10ml) with stirring. To this solution was carefully added a solution of 2M hydrochloric acid in diethyl ether (1 ml). A white precipitate is then observed. This solid was fil¬ tered off, washed with diethyl ether and dried under high vacuum. The salt produced was redissolved in distilled water with a minimum of acetonitrile to ensure complete solubility and freeze dried to yield an off white solid. 1H NMR 300 MHz δH (CD3OD) 9.37 (1 H, d, J 8.4Hz, ArH), 8.98 (1 H, d, J 2.0Hz, ArH), 8.83 (1 H, dd, J 2.0, 8.4Hz, ArH)1 8.57 (4H, m, ArH), 7.94 (1 H, s, Pyrimidyl), 3.50 (6H, ArCH3). Purity Estimated >90%

Example 30

NCE 136 Methanesulfonate[4-(2,4-dichloro-benzenesulfonylamino)-phen- yl]-(4,6-dimethyl-pyrimidin-2-yl)-methyl-ammonium NCE 50 2,4-dichloro-N-{4-[(4,6-dimethyl-pyrimidin-2-yl)-methyl-amin o]-phenyl}- benzenesulfonamide (75mh, 1 JmM) was dissolved in ethyl acetate (10ml) with stirring. To this solution is added a solution of methane sulfonic acid in ethyl acetate (1 M, 2ml), this solution was then evacuated to dryness to yield a light brown oil. The oil was repeatedly suspended in dry diethyl ether and the sol¬ vent decanted off to remove excess acid. The salt produced was the redis¬ solved in distilled water with a minimum of acetonitrile to ensure complete solubility and freeze dried to yield a brown oil. 1H NMR 300 MHz δH (CD3OD) 9.46 (1 H, d, J 8.4Hz, ArH), 9.01 (1 H, d, J 2.0Hz, ArH), 8.88 (1 H, dd, J 2.0, 8.4Hz, ArH), 8.74 (2H, d, ArH), 8.66 (2H, d, ArH), 8.24 (1 H, s, Pyrimidyl), 4.83 (3H, s), 3.75 (6H, ArCH3). Purity Estimated >90% Example 31

NCE 142 [4-(3',4'-Dimethoxy-biphenyl-3-sulfonylamino)-phenyl]-dimeth yl- ammonium; chloride Procedure used identical to that for NCE 135 using NCE 102 as the starting material. 1H NMR 400 MHz δH (CDCI3) 7.94 (1 H, s, ArH), 7.89 (1 H, d, J 7.6Hz, ArH), 7.65 (1 H, d, J 7.6Hz, ArH), 7.58 (1 H1 1, J 7.6Hz, ArH), 7.05-7.16 (7H, m, ArH), 3.83 (3H, s, OCH3), 3.79 (3H, s, OCH3), 2.92 (6H, s, N(CH3J2) Purity Estimated >90%

Example 32

NCE 137 4-Bromo-2-chloro-N-{4-[(4,6-dimethyl-pyrimidin-2-yl)-methyl- amino]-phenyl}-benzenesulfonamide Synthesised according to general coupling procedure 1 and purified by flash chromatography 1H NMR 400 MHz δH (CDCI3) 7.78 (1 H, d, J 8.8 Hz, ArH), 7.69 (1 H, s), 7.48 (1 H, d, J 8.8Hz, ArH), 7.25 (2H, d, J 8.7Hz, ArH), 7.06 (2H, d, J 8.7Hz, ArH), 6.37 (1 H, s, Pyrimidyl), 3.48 (3H, s), 2.25 (6H, s). Actual Mass: 481 .80 LCMS: Mass detected [M-H]" 481.30; Retention time 16.58 mins; Purity 96.6%

Example 33

NCE 164 2,4-Dichloro-N-[4-(4,6-dimethoxy-pyrimidin-2-yl)-phenyl]-ben z- enesulfonamide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR 300 MHz <5H (CDCI3) 8.6 (2H, d, J 7.6Hz, ArH), 7.98 (1 H, d, J 8.5Hz, ArH), 7.49 (1 H, d, J 2.0Hz, ArH), 7.30 (1 H, dd, J 2.0, 8.5Hz, ArH), 7.18 (2H, d, J 7.5Hz, ArH), 7.14 (1 H, br s, NH), 5.93 (1 H, s, Pyrimidyl), 4.00 (6H, s, OCH3). Actual Mass: 440.30 LCMS: Mass detected [M-H]" No lonisation; Retention time 16.04 mins; Purity 96.9% Example 34

NCE 165 2,4-Dichloro-N-[4-(4,6-dimethyl-pyrimidin-2-yloxy)-phenyl]-b enz- enesulfonamide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR 300 MHz δH (CDCI3) 7.91 (1 H, d, J 8.5Hz, ArH), 7.54 (1 H1 d, J 2.0Hz, ArH), 7.31 (1 H, dd, J 2.0, 8.5Hz, ArH), 7.12 (4H, m, AB d), 6.96 (1 H, br s, NH), 6.76 (1 H, s, pyrimidyl), 2.37 (6H1 s). Actual Mass: 424.31 LCMS: Mass detected [M-H]" 422.40; Retention time 13.59 mins; Purity 97.0%

Example 35

NCE 168 2,4-Dichloro-N-[4-(4,6-dimethyl-pyrimidin-2-ylsulfonyl)-phen yl]- benzenesulfonamide Synthesised according to general coupling procedure 1 and purified by flash chromatography. 1H NMR 400 MHz δH (CDCI3) 7.95 (1 H, d, J 8.5Hz, ArH), 7.49 (1 H, d, J 2.0Hz, ArH), 7.45 (1 H, d, J 8.4Hz, ArH), 7.30 (1 H, dd, J 2.0, 8.4Hz, ArH), 7.11 (2H1 d, J 8.4Hz, ArH), 6.67 (1 H, br s, NH), 2.27 (6H, s, CH3) Actual Mass: 440.37 LCMS: Mass detected [M-H]' 438.40; Retention time 16.25 mins; Purity >95%

Example 36

NCE 163 2,4-Dichloro-N-(4-pyrrol-1 -yl-phenyl)-benzenesulfonamide Synthesised according to general coupling procedure 1 and purified by prep HPLC. 1H NMR 300 MHz δH (CDCI3) 7.90 (1 H, d, J 8.4Hz, ArH), 7.54 (1 H, d, J 2.0Hz, ArH), 7.30 (1 H, dd, J 2.0, 8.4Hz, ArH), 7.25 (2H, d, ArH), 7.17 (2H, d, ArH), 6.98 (2H1 1, J 2.0Hz, Pyrrole), 6.31 ((2H, t, J 2.0Hz, Pyrrole). Actual Mass: 367.27 LCMS: Mass detected [M-H]" 365.20; Retention time 16.55 mins; Purity 96.8% Example 37

NCE 166 Biphenyl-3-sulfonic acid (4-dimethylamino-phenyl)-amide Synthesised according to general coupling procedure 1 and purified by Prep HPLC. 1H NMR 400 MHz δ∏ (CDCI3) 7.82 (1 H, t, ArH), 7.73 (1 H, td, J 7.8Hz, ArH), 7.64 (1 H, td, J 7.8Hz, ArH), 7.33-7.49 (6H, m, ArH), 6.90 (2H, d, J 8.8Hz, ArH), 6.56 (2H, d, ArH), 6.12 (1 H, br s, ArH), 2.90 (6H, s, N(CH3)2. Actual Mass: 352.46 LCMS: Mass detected [M-H]" 351.4.; Retention time mins; Purity 98.5 %