TECHNICAL FIELD

The present invention relates to novel sulfonamide derivatives, to pharmaceutical compositions comprising these derivatives, to processes for their preparation and to sulfonamide de- rivatives for use in therapy, e.g. for the treatment of inflammation and cancer.

BACKGROUND OF THE INVENTION

In the 1920s Otto Warburg first proposed non-oxidative metabolism of glucose as a unique feature of tumors (Warburg, (1930) Ueber den stoffwechsel der tumoren (London: Constable); Warburg, (1956) Science 123, 309-314). This hypothesis has since caused significant interest and although mechanistic links are still, almost 100 years later, under investigation, a high glucose flux of tumor is today exploited clinically, using PET imaging of ¹⁸ F-2- deoxyglucose uptake as a diagnostic tool for solid tumors.

Lately abnormal energy processing of cancer cells has been given new attention (Vander Hei- den, et al. (2009) Science 324, 1029). The hypoxic microenvironment and consequential lactate accumulation resulting from altered tumor metabolism are predictive for both metastatic potential and therapy resistance, and thus survival of cancer patients (Brown, (1999) Cancer Res. 59, 5863-5870; Walenta & Mueller-Klieser, (2004) Semin. Radiat. Oncol. 14, 267-274; Walenta et al, (2004) Curr. Med. Chem. 11, 2195-2204). Targeting of these hypoxic and aci- dotic tumor areas, has therefore drawn attention as a complement to anti-proliferative treatments (see e.g. Pan & Mak, (2007) Sci. STKE 381, pel 4; Bache et al, (2008) Curr. Med.

Chem. 15, 322-338 for reviews).

Known inhibitors of glycolysis are 2-deoxyglucose and 2-Br-puruvate targeting hexokinase (Liu et al, (2001) Biochemistry 40, 5542-5547; Liu et al. (2002) Biochem. Pharmacol. 64, 1745-1751; Xu et al, (2005) Cancer Res. 65, 613-621; Ramanathan et al, (2005) Proc. Natl. Acad. Sci. USA 102, 5992-5997). Fructose-2,6-bisphosphate (F-2,6-P ₂ ) plays a regulatory role in glucose metabolism by relieving ATP inhibition of phosphofructokinase-1. The levels of F-2,6-P ₂ are regulated by the bifunctional enzyme family 6-phosphofructo-2- kinase/fructose-2,6-bisphosphate (PFKFB 1 -4).

Of these four isozymes, mainly PFKFB3 and PFKFB4 are of particular interest for playing a role in cancer. Anti-sense treatment against PFKFB3 was shown to reduce tumor growth rate in vivo (Chesney et al, (1999) Proc. Natl. Acad. Sci. USA 96, 3047-3052) Also, a decreased anchorage independent growth was shown for siRNA treated fibroblasts (Telang et al., (2006) Oncogene 25, 7225-7234). It has recently been demonstrated that the proinflammatory cytokine interleukin (IL)-6 enhances glycolysis in mouse embryonic fibroblasts and human cell lines (Ando et al. J Nippon Med Sch (2010), 77, (2), 97- 105) indicating the potential for PFKFB3 inhibitors as anti-inflammatory agents. Hypoxia is a prominent feature in rheumatoid arthritis (RA) synovium, and induce significant changes in the expression of PFKFB3 and PFKFB 4 (Del Rey et al, (2010) Arthritis & Rheumatism 62, 3584-3594).

Minchenko et al. showed increased expression of PFKFB4 mRNA in breast and colon malig- nant tumors as compared to corresponding non-malignant tissue counterparts as well as in several cancer cell lines. PFKFB4 was reported to be strongly responsive to hypoxia (Minchenko et al, (2004) FEBS Lett. 576, 14-20); Minchenko et al, (2005), Biochemie 87, 1005- 1010; Bobarykina et al, (2006), Acta Biochemica Polonica 3, 789-799). Recently, Telang et al. showed decreased levels of F-2,6-P ₂ and lactate as well as decreased tumor growth folio w- ing siRNA silencing of PFKFB4 (Telang, S. et al, (2010) US2010/0267815 Al).

Only a small number of specific inhibitors of the kinase activities of PFKFB3 and PFKFB4 have been identified. In one study, an alkylating inhibitor, N-bromoacetylethanolamine phosphate was used as a tool to investigate the binding sites of the kinase and phosphatase domains of PFKFB3 and was demonstrated to irreversibly inactivate PFK-2 (Sakakibara et al. (1984), J. Bio Chem 259, 14023-14028). The compound is a competitive inhibitor of PFK-2 with respect to F6P but a noncompetitive inhibitor with respect to ATP. Analogues of this compound, N-(2-methoxyethyl)-bromoacetamide, N-(2-ethoxyethyl)-bromoacetamide and N- (3-methoxypropyl)-bromoacetamide, have demonstrated in vivo activity with increased survival rate of P388 transplant BDFi mice (Hirata et al. (2000) Biosci. Biotechnol. Biochem. 64, 2047-2052).

A crystal structure of the PFKTB3*ADP*phosphoenolpyruvate complex was described by Kim et al. (Kim et al. (2007), J. Mol. Biol. 370, 14-26). This paper also described the crystal structures of PFKTB3*AMPPCP*fructose-6 phosphate complex where β,γ-methylene- adenosine 5 '-triphosphate (AMPPCP) constituted a non-hydro lysable ATP-analogue.

A drug-like compound was recently described (Clem et al (2008) Mol. Cancer Ther. 7, 110- 120, WO 2008/156783) where 3-(3-pyridinyl)-l-(4-pyridinyl)-2-propen-l-one (3PO), by computational methods, was identified as a PFKFB3 inhibitor. Administration of 3PO reduced the intracellular concentration of F-2,6-P ₂ , glucose uptake, and growth of established tumors in vivo.

SUMMARY OF THE INVENTION

One object of the present invention is to provide small molecule inhibitors of the kinase activities of PFKFB3 and/or PFKFB4.

Another object of the present invention is to provide compounds for use in the treatment of inflammation or cancer.

Thus, according to a first aspect, there is provided a compound according to formula (I)

wherein: n is 0 or 1 ;

A is O, S, -CR ⁴ =CPv ⁴ - or -CR ⁴ =N-;

R ¹ is selected from H; halogen; C1-C6 alkyl, optionally substituted with at least one halogen, and C1-C6 alkoxy substituted with at least one halogen;

R ² and R ³ are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; secondary or tertiary CI -C6 alkylamido; carbocyclylcarbonylamino-C0-C2 alkyl; 5- or 6- membered cyclic aminocarbonyl; C1-C6 alkylcarbonylamino; C1-C6 alkylsulfonyl; hydro xy- C0-C6 alkyl, C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; nitro; carbocy- clyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl- C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ ; or R ² and R ³ form, together with the carbon atoms to which they are attached, a 5- or 6- membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R ⁵ ; each R ⁴ is independently selected from H, halogen, monocyclic C3-C6 carbocyclyl and Cl- C6 alkyl, wherein any alkyl is optionally substituted with at least one halogen; each R ⁵ is independently selected from halogen; C1-C6 alkyl; C1-C6 alkoxy; phenoxy; amino; cyano; nitro; secondary or tertiary C1-C6 alkylamino; 5- or 6-membered cyclic amino; C1-C6 alkylcarbonylamino; carbamoyl; secondary or tertiary C1-C6 alkylamido; 5- or 6- membered cyclic aminocarbonyl; C1-C6 alkoxycarbonylamino; hydroxy-C0-C6 alkyl; Cl- C6-alkylthio; carboxy-C0-C6-alkyl; C1-C6 alkoxycarbonyl; C1-C6 alkylcarbonyl; C1-C6- alkylsulfonyl; and C1-C6 alkylsulfonylamino; wherein any alkyl is optionally substituted with at least one halogen; or a pharmaceutically acceptable salt thereof, for use as a medicament, with the proviso that when A is CR ⁴ =CR ⁴ and n is 0, then neither R ² nor R ³ is selected from 4-hydroxypyrazolo[l,5-a]-l,3,5-triazin-8-yl and 2,4-dihydroxypyrazolo[l,5-a]-l,3,5-triazin-8- yl; and with the further proviso that the compound is not selected from

4-(3 ,4-dichlorophenylsulfonamido)-2-hydroxybenzoic acid,

4-(2,5-dichlorophenylsulfonamido)-2-hydroxybenzoic acid,

4-(2,5-diethylphenylsulfonamido)-2-hydroxybenzoic acid,

4-(4-bromophenylsulfonamido)-2-hydroxybenzoic acid,

4-(3-carboxy-4-hydroxyphenylsulfonamido)-2-hydroxybenzoic acid,

2-hydroxy-4-(4-methylphenylsulfonamido)benzoic acid,

2-hydroxy-4-(phenylsulfonamido)benzoic acid, and

4-(4-ethylphenylsulfonamido)-2-hydroxybenzoic acid.

According to another aspect, novel compounds of formula (I) are provided wherein: n is 0 or 1 ;

A is O, S, -CR ⁴ =CR ⁴ - or -CR ⁴ =N-; R ¹ is selected from H; halogen; C1-C6 alkyl, optionally substituted with at least one halogen; and C1-C6 alkoxy, substituted with at least one halogen;

R ² and R ³ are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; secondary or tertiary CI -C6 alkylamido; carbocyclylcarbonylamino-C0-C2 alkyl; 5- or 6- membered cyclic aminocarbonyl; C1-C6 alkylcarbonylamino; C1-C6 alkylsulfonyl; hydro xy- C0-C6 alkyl, C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; carbocyclyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ ; or R ² and R ³ form, together with the carbon atoms to which they are attached, a 5- or 6- membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R ⁵ ; each R ⁴ is independently selected from H, halogen, monocyclic C3-C6 carbocyclyl and Cl- C6 alkyl, wherein any alkyl is optionally substituted with at least one halogen; each R ⁵ is independently selected from halogen; C1-C6 alkyl; C1-C6 alkoxy; phenoxy; amino; cyano; nitro; secondary or tertiary C1-C6 alkylamino; 5- or 6-membered cyclic amino; C1-C6 alkylcarbonylamino; carbamoyl; secondary or tertiary C1-C6 alkylamido; 5- or 6- membered cyclic aminocarbonyl; C1-C6 alkoxycarbonylamino; hydroxy-C0-C6 alkyl; Cl- C6-alkylthio; carboxy-C0-C6-alkyl; C1-C6 alkoxycarbonyl; C1-C6 alkylcarbonyl; C1-C6- alkylsulfonyl; and C1-C6 alkylsulfonylamino; wherein any alkyl is optionally substituted with at least one halogen; and pharmaceutically acceptable salts thereof, with the proviso that when A is CR ⁴ =CR ⁴ and n is 0, then neither R ² nor R ³ is selected from 4-hydroxypyrazolo[l,5-a]-l,3,5-triazin-8-yl and 2,4-dihydroxypyrazolo[l,5-a]-l,3,5-triazin-8- yi; and when A is -CR ⁴ =CR ⁴ -, n is 0, and R ² and R ³ , together with the carbon atoms to which they are attached, do not form a 5- or 6-membered carbocyclic or heterocyclic ring:

(i) R ² is in meta position relative to the sulfonamide bond;

(ii) when R ¹ , R ² and R ⁴ are all H, R ³ is not selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; C1-C6 alkylcarbonylamino; C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; cyclohexyl; trifluoromethyl and trifluoromethoxy; and

(iii) when R ³ is selected from H, F, CI, Br, methyl and tert-butyl, R ² is not H; and with the further proviso that the compound is not selected from

4-(5-ethylthiophene-2-sulfonamido)-2-hydroxybenzoic acid,

4-(5-bromothiophene-2-sulfonamido)-2-hydroxybenzoic acid,

4-(5-chlorothiophene-2-sulfonamido)-2-hydroxybenzoic acid,

4-(5-methylthiophene-2-sulfonamido)-2-hydroxybenzoic acid,

2-hydroxy-4-(thiophene-2-sulfonamido)benzoic acid,

4-(3-bromothiophene-2-sulfonamido)-2-hydroxybenzoic acid,

4-(2,5-dibromothiophene-3-sulfonamido)-2-hydroxybenzoic acid,

4-(2,5-dichlorothiophene-3-sulfonamido)-2-hydroxybenzoic acid,

4-(2,5-methylthiophene-3-sulfonamido)-2-hydroxybenzoic acid,

4-(4-bromo-3-carboxyphenylsulfonamido)-2-hydroxybenzoic acid,

4-(4-fluoro-3-methylphenylsulfonamido)-2-hydroxybenzoic acid,

4-(3 ,4-diethoxyphenylsulfonamido)-2-hydroxybenzoic acid,

4-(2,3-dihydro-lH-indene-5-sulfonamido)-2-hydroxybenzoic acid,

2-hydroxy-4-(2, 3,4,5, 6-pentamethylphenylsulfonamido)benzoic acid,

4-(3 ,5-dichlorophenylsulfonamido)-2-hydroxybenzoic acid,

4-(2,3-dichlorophenylsulfonamido)-2-hydroxybenzoic acid,

4-(3-chloro-4-fluorophenylsulfonamido)-2-hydroxybenzoic acid, -(2-chloro-5-(trifluoromethyl)phenylsulfonamido)-2-hydroxybe nzoic acid,-hydroxy-4-(3-(trifluoromethyl)phenylsulfonamido)benzoi c acid,

(2-bromo-4,5-dimethoxyphenylsulfonamido)-2-hydroxybenzoic acid, (2,5-difluorophenylsulfonamido)-2-hydroxybenzoic acid,

(3 ,4-dimethoxyphenylsulfonamido)-2-hydroxybenzoic acid,

(3 ,4-dimethylphenylsulfonamido)-2-hydroxybenzoic acid,

(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-2-hydroxyben zoic acid, (3 ,4-difluorophenylsulfonamido)-2-hydroxybenzoic acid,

(2,3-dihydrobenzo[b][l,4]dioxine-6-sulfonamido)-2-hydroxyben zoic acid, (5-bromo-2-methylphenylsulfonamido)-2-hydroxybenzoic acid,

(3-cyanophenylsulfonamido)-2-hydroxybenzoic acid,

(3-acetamido-4-methoxyphenylsulfonamido)-2-hydroxybenzoic acid, (2,5-dichloro-3,6-dimethylphenylsulfonamido)-2-hydroxybenzoi c acid,-hydroxy-4-(5,6,7,8-tetrahydronaphthalene-2-sulfonamido )benzoic acid, 4-bromo-3-methylphenylsulfonamido)-2-hydroxybenzoic acid,

3-acetylphenylsulfonamido)-2-hydroxybenzoic acid,

3-bromophenylsulfonamido)-2-hydroxybenzoic acid,

3 -chlorophenylsulfonamido)-2-hydroxybenzoic acid,

-hydroxy-4-(4-methoxy-3-(lH-tetrazol-l-yl)phenylsulfonami do)benzoic acid,-(3-fluorophenylsulfonamido)-2-hydroxybenzoic acid,

-hydroxy-4-(3-methylphenylsulfonamido)benzoic acid,

-(2,5-dibromophenylsulfonamido)-2-hydroxybenzoic acid,

-(5-(tert-butyl)-2,3-dimethylphenylsulfonamido)-2-hydroxy benzoic acid,-hydroxy-4-(2,3 ,5 ,6-tetramethylphenylsulfonamido)benzoic acid,

3.4- dichlorophenylsulfonamido)-2-hydroxybenzoic acid,

2.5- dimethylphenylsulfonamido)-2-hydroxybenzoic acid,

3-carboxyphenylsulfonamido)-2-hydroxybenzoic acid,

-hydroxy-4-(naphthalene-2-sulfonamido)benzoic acid,

-(2,5-dichlorophenylsulfonamido)-2-hydroxybenzoic acid,

-(2,5-diethylphenylsulfonamido)-2-hydroxybenzoic acid,

-hydroxy-4-(2,4,5-trimethylphenylsulfonamido)benzoic acid,

-(3-carboxy-4-hydroxyphenylsulfonamido)-2-hydroxybenzoic acid,

-hydroxy-4-(benzylsulfonamido)benzoic acid,

-(8-chloronaphthalene- 1 -sulfonamido)-2-hydroxybenzoic acid, 2-hydroxy-4-(4-methoxynaphthalene- 1 -sulfonamido)benzoic acid,

2-hydroxy-4-(4-methylnaphthalene- 1 -sulfonamido)benzoic acid,

4-(4-bromonaphthalene- 1 -sulfonamido)-2-hydroxybenzoic acid,

2-hydroxy-4-(naphthalene- 1 -sulfonamido)benzoic acid,

2-hydroxy-4-(quinoline-8-sulfonamido)benzoic acid,

4-(2-cyanobenzylsulfonamido)-2-hydroxybenzoic acid,

4-(2-benzylsulfonamido)-2-hydroxybenzoic acid,

4-(5-fluoropyridine-3-sulfonamido)-2-hydroxybenzoic acid,

4-(5-bromopyridine-3-sulfonamido)-2-hydroxybenzoic acid,

4-(5-chloropyridine-3-sulfonamido)-2-hydroxybenzoic acid, and

2-hydroxy-4-(pyridine-3-sulfonamido)benzoic acid.

Furthermore, a pharmaceutical composition is provided, comprising a compound as defined herein, and optionally at least one pharmaceutically acceptable excipient.

Another object of the present invention relates to inhibition of the PFKFB3 and/or PFKFB4 protein with the compound as defined herein.

Thus, in one aspect, a compound as defined herein is provided for use in the treatment of a disorder related to or mediated by the PFKFB3 protein.

In another aspect, a compound as defined herein is provided, for use in the treatment of a disorder related to or mediated by the PFKFB4 protein. Thus, the present invention provides a method of treatment of cancer and inflammation, by the inhibition of PFKFB3 and/or PFKFB4, and a compound for use in such a method. This is achieved by either a single molecule inhibiting both PFKFB3 and PFKFB4 or by separate molecules with selective specificities for either PFKFB3 or PFKFB4.

In one aspect, there is provided a compound of formula (I)

wherein: n is 0 or 1 ;

A is O, S, -CR ⁴ =CR ⁴ - or -CR ⁴ =N-;

R ¹ is selected from H; halogen; and C1-C6 alkyl, optionally substituted with at least one halogen; and C1-C6 alkoxy substituted with at least one halogen; R ² and R ³ are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; secondary or tertiary CI -C6 alkylamido; carbocyclylcarbonylamino-C0-C2 alkyl; 5- or 6- membered cyclic aminocarbonyl; C1-C6 alkylcarbonylamino; C1-C6 alkylsulfonyl; hydro xy- C0-C6 alkyl, C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; nitro; carbocy- clyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl- C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ ; or R ² and R ³ form, together with the carbon atoms to which they are attached, a 5- or 6- membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R ⁵ ; each R ⁴ is independently selected from H, halogen, monocyclic C3-C6 carbocyclyl and Cl- C6 alkyl, wherein any alkyl is optionally substituted with at least one halogen; each R ⁵ is independently selected from halogen; C1-C6 alkyl; C1-C6 alkoxy; phenoxy; ami- no; cyano; nitro; secondary or tertiary C1-C6 alkylamino; 5- or 6-membered cyclic amino; C1-C6 alkylcarbonylamino; carbamoyl; secondary or tertiary C1-C6 alkylamido; 5- or 6- membered cyclic aminocarbonyl; C1-C6 alkoxycarbonylamino; hydroxy-C0-C6 alkyl; Cl- C6-alkylthio; carboxy-C0-C6-alkyl; C1-C6 alkoxycarbonyl; C1-C6 alkylcarbonyl; C1-C6- alkylsulfonyl; and C1-C6 alkylsulfonylamino; wherein any alkyl is optionally substituted with at least one halogen; or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, inflammation or an inflammatory disorder, with the proviso that the compound is not selected from 4-(3,4-dichlorophenylsulfonamido)- 2-hydroxybenzoic acid and 4-(4-ethylphenylsulfonamido)-2-hydroxybenzoic acid. The use of a compound as defined herein in the manufacturing of a medicament for the treatment of cancer, inflammation or an inflammatory disorder also is provided.

Finally, one object of the invention is to provide a method for the treatment of cancer, inflammation or an inflammatory disorder in a mammal in need of such treatment by adminis- tering to said mammal a compound as defined herein.

DETAILED DESCRIPTION OF THE INVENTION

As indicated herein above, the present invention provides a compound of formula (I) as defined herein above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, inflammation or an inflammatory disorder, with the proviso that the compound is not selected from 4-(3,4-dichlorophenylsulfonamido)-2-hydroxybenzoic acid and 4-(4- ethylphenylsulfonamido)-2-hydroxybenzoic acid.

The disclaimed compounds, 4-(3,4-dichlorophenylsulfonamido)-2-hydroxybenzoic acid and 4-(4-ethylphenylsulfonamido)-2-hydroxybenzoic acid, are known from the prior art. Thus, the compound 4-(3,4-dichlorophenylsulfonamido)-2-hydroxybenzoic acid is mentioned in an article titled "Small Molecules Can Selectively Inhibit Ephrin Binding to the EphA4 and

EphA2 Receptors" (The Journal of Biological Chemistry, Vol. 283, No. 43, pp. 29461-29472, Oct. 24, 2008) . The article mentions that EphA4 and EphA2 Receptors are involved in pathologies such as nerve injuries and cancer. The compound 4-(4-ethylphenylsulfonamido)-2- hydroxybenzoic acid is mentioned in WO/2007/087266, which is directed to the development of new chemical entities for use in the treatment of disease, and more particularly to methods of identifying lead molecules for use in quasi-rational drug design. In WO/2007/087266 there is described "the provision of a method that can test literally trillions of chemical structures within a living host to find chemical structures that bind to the target (e.g., a protein or other large molecule); uses standard assaying techniques to determine which of the chemical struc- tures that bind to the target will provide the desired activity; and/or uses already known facts about the binding chemical structures to guide the construction of the small molecule lead". 4- (4-ethylphenylsulfonamido)-2-hydroxybenzoic acid is identified as an inhibitor of epidermal growth factor binding to its receptor and it is noted that such compounds have utility as treatments in oncology. In one aspect, the present invention also provides a compound of formula (I) as defined herein above, or a pharmaceutically acceptable salt thereof, for use in therapy, with the proviso that the compound is not selected from

4-(3 ,4-dichlorophenylsulfonamido)-2-hydroxybenzoic acid,

4-(2,5-dichlorophenylsulfonamido)-2-hydroxybenzoic acid,

4-(2,5-diethylphenylsulfonamido)-2-hydroxybenzoic acid,

4-(4-bromophenylsulfonamido)-2-hydroxybenzoic acid,

4-(3-carboxy-4-hydroxyphenylsulfonamido)-2-hydroxybenzoic acid,

2-hydroxy-4-(4-methylphenylsulfonamido)benzoic acid,

2-hydroxy-4-(phenylsulfonamido)benzoic acid, and

4-(4-ethylphenylsulfonamido)-2-hydroxybenzoic acid.

The above disclaimed compounds are known from prior art.

4-(3,4-dichlorophenyl-sulfonamido)-2-hydroxybenzoic acid and 4-(4- ethylphenylsulfonamido)-2-hydroxybenzoic acid have been discussed already herein above. The compounds 4-(2,5-dichloro-phenylsulfonamido)-2-hydroxybenzoic acid, and 4-(2,5- diethylphenylsulfonamido)-2-hydroxybenzoic acid are disclosed in US patent application No. 20090163545, directed to a method for altering the lifespan of a eukaryotic organism.

The compound 4-(4-bromophenylsulfonamido)-2-hydroxybenzoic acid has been disclosed in a scientific article titled "Antimycobacterial activity of 3,4-dichlorophenyl-ureas, N, N- diphenyl-ureas and related derivatives" (Journal of Enzyme Inhibition, 2001, vol. 16, n°5, pp. 425-432).

The compound 2-hydroxy-4-(4-methylphenylsulfonamido)benzoic acid is disclosed in Japanese patent No. JP 36017173 B4, directed to antiviral compounds.

The compound 2-hydroxy-4-(phenylsulfonamido)benzoic acid is disclosed in a scientific article titled "Targeting the fatty acid biosynthesis enzyme, PfKASIII, in the identification of novel antimalarial agents." (J. Med. Chem. 52:952-963. 2009) as well as in a scientific article titled "The role of carbonic anhydrase inhibitors on anion permeability into ox red lood cells" (J. Physiol. (1976), 256, pp. 61-80).

The compound 8- [4-(4-Carboxy-3 -hydroxyphenylaminosulfonyl)phenyl] -4- hydroxypyrazolo[l,5-a]-l,3,5-triazine is described in European patent application No. 0269859, the disclosure of which is directed to compounds useful as a medicine for the prophylaxis and treatment of gout.

In one further aspect, the present invention provides a novel compound of formula (I) as defined herein above, or a pharmaceutically acceptable salt thereof, with the proviso that the compound is not selected from:

4-(5-ethylthiophene-2-sulfonamido)-2-hydroxybenzoic acid,

4-(5-bromothiophene-2-sulfonamido)-2-hydroxybenzoic acid,

4-(5-chlorothiophene-2-sulfonamido)-2-hydroxybenzoic acid,

4-(5-methylthiophene-2-sulfonamido)-2-hydroxybenzoic acid,

2-hydroxy-4-(thiophene-2-sulfonamido)benzoic acid,

4-(3-bromothiophene-2-sulfonamido)-2-hydroxybenzoic acid,

4-(2,5-dibromothiophene-3-sulfonamido)-2-hydroxybenzoic acid,

4-(2,5-dichlorothiophene-3-sulfonamido)-2-hydroxybenzoic acid,

4-(2,5-methylthiophene-3-sulfonamido)-2-hydroxybenzoic acid,

4-(4-bromo-3-carboxyphenylsulfonamido)-2-hydroxybenzoic acid,

4-(4-fluoro-3-methylphenylsulfonamido)-2-hydroxybenzoic acid,

4-(3 ,4-diethoxyphenylsulfonamido)-2-hydroxybenzoic acid,

4-(2,3-dihydro-lH-indene-5-sulfonamido)-2-hydroxybenzoic acid,

2-hydroxy-4-(2, 3,4,5, 6-pentamethylphenylsulfonamido)benzoic acid,

4-(3 ,5-dichlorophenylsulfonamido)-2-hydroxybenzoic acid,

4-(2,3-dichlorophenylsulfonamido)-2-hydroxybenzoic acid,

4-(3-chloro-4-fluorophenylsulfonamido)-2-hydroxybenzoic acid,

4-(2-chloro-5-(trifluoromethyl)phenylsulfonamido)-2-hydro xybenzoic acid,

2-hydroxy-4-(3-(trifluoromethyl)phenylsulfonamido)benzoic acid,

4-(2-bromo-4,5-dimethoxyphenylsulfonamido)-2-hydroxybenzo ic acid,

4-(2,5-difluorophenylsulfonamido)-2-hydroxybenzoic acid,

4-(3 ,4-dimethoxyphenylsulfonamido)-2-hydroxybenzoic acid,

4-(3 ,4-dimethylphenylsulfonamido)-2-hydroxybenzoic acid,

4-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-2-hydro xybenzoic acid,

4-(3 ,4-difluorophenylsulfonamido)-2-hydroxybenzoic acid,

4-(2,3-dihydrobenzo[b] [ 1 ,4]dioxine-6-sulfonamido)-2-hydroxybenzoic acid,

4-(5-bromo-2-methylphenylsulfonamido)-2-hydroxybenzoic acid,

4-(3-cyanophenylsulfonamido)-2-hydroxybenzoic acid, 4-(3-acetamido-4-methoxyphenylsulfonamido)-2-hydroxybenzoic acid, 4-(2,5-dichloro-3,6-dimethylphenylsulfonamido)-2-hydroxybenz oic acid, 2-hydroxy-4-(5,6,7,8-tetrahydronaphthalene-2-sulfonamido)ben zoic acid, 4-(4-bromo-3-methylphenylsulfonamido)-2-hydroxybenzoic acid,

4-(3-acetylphenylsulfonamido)-2-hydroxybenzoic acid,

4-(3-bromophenylsulfonamido)-2-hydroxybenzoic acid,

4-(3-chlorophenylsulfonamido)-2-hydroxybenzoic acid,

2-hydroxy-4-(4-methoxy-3-(lH-tetrazol-l-yl)phenylsulfonamido )benzoic acid,

4-(3-fluorophenylsulfonamido)-2-hydroxybenzoic acid,

2-hydroxy-4-(3-methylphenylsulfonamido)benzoic acid,

4-(2,5-dibromophenylsulfonamido)-2-hydroxybenzoic acid,

4-(5-(tert-butyl)-2,3-dimethylphenylsulfonamido)-2-hydroxybe nzoic acid,

2-hydroxy-4-(2,3 ,5 ,6-tetramethylphenylsulfonamido)benzoic acid,

4-(3 ,4-dichlorophenylsulfonamido)-2-hydroxybenzoic acid,

4-(2,5-dimethylphenylsulfonamido)-2-hydroxybenzoic acid,

4-(3-carboxyphenylsulfonamido)-2-hydroxybenzoic acid,

2-hydroxy-4-(naphthalene-2-sulfonamido)benzoic acid,

4-(2,5-dichlorophenylsulfonamido)-2-hydroxybenzoic acid,

4-(2,5-diethylphenylsulfonamido)-2-hydroxybenzoic acid,

2-hydroxy-4-(2,4,5-trimethylphenylsulfonamido)benzoic acid,

4-(3-carboxy-4-hydroxyphenylsulfonamido)-2-hydroxybenzoic acid,

2-hydroxy-4-(benzylsulfonamido)benzoic acid,

4-(8-chloronaphthalene- 1 -sulfonamido)-2-hydroxybenzoic acid,

2-hydroxy-4-(4-methoxynaphthalene- 1 -sulfonamido)benzoic acid,

2-hydroxy-4-(4-methylnaphthalene-l-sulfonamido)benzoic acid,

4-(4-bromonaphthalene- 1 -sulfonamido)-2-hydroxybenzoic acid,

2-hydroxy-4-(naphthalene- 1 -sulfonamido)benzoic acid,

2-hydroxy-4-(quinoline-8-sulfonamido)benzoic acid,

4-(2-cyanobenzylsulfonamido)-2-hydroxybenzoic acid,

4-(benzylsulfonamido)-2-hydroxybenzoic acid,

4-(5-fluoropyridine-3-sulfonamido)-2-hydroxybenzoic acid,

4-(5-bromopyridine-3-sulfonamido)-2-hydroxybenzoic acid,

4-(5-chloropyridine-3-sulfonamido)-2-hydroxybenzoic acid, and

2-hydroxy-4-(pyridine-3-sulfonamido)benzoic acid. The above disclaimed compounds were found in a search using the Internet search tool SciFinder. Only a few of the disclaimed compounds have been disclosed for use within the therapeutic field and literature references of these few compounds are provided herein above.

As used herein, the term "carbocyclyl" refers to a cyclic moiety containing only carbon at- oms, while the term "heterocyclyl" refers to a cyclic moiety containing not only carbon atoms, but also at least one other atom in the ring structure, e.g. a nitrogen, sulphur or oxygen atom. For the purpose of the present invention and unless otherwise indicated or apparent from the context, the terms "carbocyclyl" and "heterocyclyl" should not be construed as encompassing cyclic moieties containing an oxo group in the ring, such as in e.g. cyclohexa-2,5- dienone, cyclohexanone or 3H-pyrrol-3-one.

As used herein with respect to any carbocyclyl or heterocyclyl, the term monocyclic refers to a cyclic moiety containing only one ring. The term bicyclic refers to a cyclic moiety containing two rings, fused to each other.

Unless otherwise indicated or apparent from the context, any cyclyl, as referred to herein, may be carbocyclyl or heterocyclyl, saturated or unsaturated, and aromatic or non-aromatic. Thus, cyclohexyl, cyclohexenyl and phenyl are all examples of monocyclic C6 carbocyclyl.

The term "aromatic", as used herein, refers to an unsaturated cyclic (carbocyclic or heterocyclic) moiety that has an aromatic character, while the term "non-aromatic", as used herein, refers to a cyclic moiety, that may be unsaturated, but that does not have an aromatic charac- ter.

In a bicyclic ring system, as referred to herein, the two rings, fused to each other, may be both saturated or both unsaturated, e.g. both aromatic. The rings may also be of different degrees of saturation, and one ring may be aromatic whereas the other is non-aromatic. The rings also may comprise different numbers of atoms, e.g. one ring being 5-membered and the other one being 6-membered, forming together a 9-membered bicyclic ring.

In a bicyclic heterocyclyl (or heterocycle or heterocyclic moiety, etc.), as referred to herein, one or both of the rings may contain one or several, e.g. 1, 2, 3 or 4 heteroatoms. By heteroa- tom according to the invention is meant N, O and S.

An n-membered cyclic moiety as referred to herein contains n ring (or cyclic) atoms. Examples of aromatic heterocyclic moieties according to the invention are pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzothiazol- yl, benzoxadiazolyl, benzimidazolyl, indazolyl, benzothiazolyl, benzo furyl, benzoxazolyl, benzothienyl, isoquinolinyl, naphthyridinyl, quinolinyl, phthalazinyl, quinazolinyl, quinolinyl, quinoxalinyl, cinnolinyl, pteridinyl etc.

As used herein, and unless otherwise specified, the term "non-aromatic heterocycle" or "non- aromatic heterocyclyl" refers to a non-aromatic cyclic group or radical containing one or more heteroatom(s) preferably selected fromN, O and S, such as a dihydropyrrolyl, dioxolanyl, dithiolanyl, imidazolidinyl, imidazolinyl, pyrrolidinyl, pyrazolidinyl, tetrahydro furyl, thiola- nyl, dihydropyranyl, dihydropyridyl, dioxanyl, dithianyl, morpholinyl, piperidyl, piperazinyl, pyranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydro -2H-thiopyranyl, and trithianyl etc.

Other examples of non-aromatic heterocycles are bicyclyl radicals, also including those containing one aromatic and one non-aromatic ring, e.g. indolinyl, chromanyl, thiochromanyl, 1,2,3,4-tetrahydroisoquinolyl, etc.

The term Cn refers to a radical or moiety containing n carbon atoms.

The term Cn-Cm, where m>n, refers to a radical or moiety containing n, n+1, n+2,...or m carbon atoms.

Thus, the term C1-C6 alkyl refers to an alkyl radical that may contain 1, 2, 3, 4, 5 or 6 carbon atoms.

The term CO alkyl refers to a covalent bond. Thus, e.g. the term carbocyclyl-CO alkyl refers to carbocyclyl.

An alkyl moiety according to the invention having from 1-6 C (i.e. a Ci-C ₆ alkyl) may be branched or linear, e.g. selected from methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl, sec- butyl, /er/-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3- methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.

An alkenyl moiety according to the invention is a straight or branched hydrocarbyl comprising at least one double bond between any two adjacent carbon atoms, e.g. a straight or branched hydrocarbyl comprising 1 double bond. As used herein, and unless otherwise specified, the term "halogen" (or "halo") means fluorine (F), chlorine (CI), bromine (Br) or iodine (I).

The term carbocyclyloxy refers to a radical of the type RO-, wherein R is a carbocyclyl moiety. Phenoxy is an example of a carbocyclyloxy radical. The term phenoxy refers to the radical

The term heterocyclyloxy refers to a radical of the type RO-, wherein R is a heterocyclyl moi- ety.

The term alkoxy refers to a radical of the type RO-, wherein R is an alkyl moiety. The term alkoxycarbonyl refers to a radical of the type ROC(O)-, wherein R is an alkyl moiety.

The term carboxy refers to the radical HO(0)C-.

The term alkylthio refers to a radical of the type RS-, wherein R is an alkyl moiety.

The term amino refers to the radical H ₂ N-. The term hydroxy refers to the radical HO-.

The term hydroxy-C0-C6 alkyl refers to a radical selected from hydroxy (viz. hydroxy-CO alkyl) and a C1-C6 alkyl radical substituted with a hydroxy. The hydroxy may be attached at any carbon atom of the alkyl radical, and the alkyl radical may be branched or linear. For example, hydroxy-Cl alkyl is hydroxymethyl. The term cyano refers to the radical NC-.

The term benzyl refers to the radical which radical may also be referred to as phenylmethyl. By "alkyl substituted with at least one halogen" is meant an alkyl radical of the formula C _n X _p H(2n+i-p)-, wherein X _p refers to p independently selected halogen atoms, replacing p hydrogen atoms of the alkyl radical C _n H2 _n +i- at the same or different carbon atoms. An example of an alkyl substituted with at least one halogen is trifluoromethyl. The alkyl substituted with at least one halogen may be a moiety forming a part of another radical, such as in trifluoro- methoxy or difluoromethoxy.

The term trifluoromethyl refers to the radical CF ₃ -.

The term trifluoromethoxy refers to the radical CF ₃ 0-.

The term difluoromethoxy refers to the radical CHF ₂ 0-. The term secondary alkylamino refers to a radical of the type RHN-, wherein R is an alkyl moiety.

The term tertiary alkylamino refers to a radical of the type RR ^' N-, wherein R and R ^' are each an independently selected alkyl moiety.

The term carbamoyl refers to the radical NH ₂ C(0)-. The term secondary alkylamido refers to radical of the type RHNC(O)-, wherein R is an alkyl moiety.

The term tertiary alkylamido refers to a radical of the type RR ^' NC(O)-, wherein R and R ^' are each an independently selected alkyl moiety.

The term alkylcarbonylamino refers to a radical of the type RC(0)NH-, wherein R is an alkyl moiety.

The term carbocyclylcarbonylammo refers to a radical of the type RC(0)NH-, wherein R is a carbocyclic moiety, e.g. an aromatic carbocyclic moiety such as phenyl.

The term carbocyclylcarbonylamino-C0-C2 alkyl, refers to a radical selected from carbocyclylcarbonylammo (viz. carbocyclylcarbonylamino-CO alkyl), carbocyclylcarbonylaminome- thyl (viz. carbocyclylcarbonylamino-Cl alkyl) or carbocyclylcarbonylaminoethyl (viz. carbo- cyclylcarbonylamino-C2 alkyl).

The term alkylcarbonyl refers to a radical of the type RC(O)-, wherein R is an alkyl moiety. The term acetyl refers to an alkylcarbonyl radical of formula CH ₃ C(0)-.

The term cyclic amino refers to a radical of the type RR ^' N-, wherein R and R ^' together with the nitrogen atom to which they are attached form a nitrogen-containing cycle.

A preferred 5- or 6-membered cyclic amino radical according to the invention is pyrrolidin-1- yl or piperidin- 1 -yl, respectively.

The term cyclic aminocarbonyl refers to a radical of the type RR ^' N-C(O)-, wherein RR ^' N- is a cyclic amino as defined herein above.

The term alkylsulfonyl refers to a radical of the type RS(0) ₂ -, wherein R is an alkyl moiety.

The term alkylsulfonylamino refers to a radical of the type RS(0) ₂ NH-, wherein R is an alkyl moiety.

The term nitro refers to the radical -N0 ₂ .

According to one aspect, the present invention provides compounds of formula (I)

as defined herein above, for use as a medicament. In some embodiments of the invention, in a compound of formula (I) as defined herein above, A is S, i.e. the compound may be represented by formula (la)

In some embodiments, a compound of formula (la) is a compound according to formula (Iaa)

In some other embodiments, a compound of formula (la) is a compound according to formula (lab)

In some embodiments of the invention, in a compound of formula (I) as defined herein above, A is O, i.e. the compound may be represented by formula (la')

In some embodiments, a compound of formula (la') is a compound according to formula (laa')

In some other embodiments, a compound of formula (la') is a compound according to formula (lab')

In some other embodiments of the invention, in a compound of formula (I) as defined herein above, A is CR ⁴ =CR ⁴ , i.e. the compound may be represented by formula (lb)

In some embodiments, a compound of formula (lb) is a compound according to formula (Iba)

In other embodiments, a compound of formula (lb) is a compound according to formula

In still some other embodiments of the invention, in a compound of formula (I) as defined herein above, A is CR ⁴ =N, i.e. the compound may be represented by formula (Ic) or formula

A compound of formula (Ic) may be a compound of formula (lea) or (Icb)

while a compound of formula (Ic') may be a compound of formula (lea') or (Icb')

In some embodiments, the compound of formula (Ic) or (Ic') is a compound of formula (lea) or (lea').

It should be understood that for the purpose of the present invention, unless otherwise speci- fied or apparent from the context, any reference to a compound of formula (I) is meant to include a compound of any of the above formulas (la), (Iaa), (lab), (la'), (Iaa'), (lab'), (lb), (Iba), (Ibb), (Ic), (lea), (Icb), (Ic'), (lea'), and (Icb'). Similarly, unless otherwise specified or apparent from the context, any reference to a compound of formula (la) is meant to include a compound of any of the above formulas (Iaa) and (lab); any reference to a compound of for- mula (la') is meant to include a compound of any of the above formulas (Iaa') and (lab'); any reference to a compound of formula (lb) is meant to include a compound a compound of any of the above formulas (Iba) and (Ibb), any reference to a compound of formula (Ic), is meant to include a compound of any of the above formulas (lea) and (Icb), and any reference to a compound of formula (Ic'), is meant to include a compound of any of the above formulas (lea') and (Icb').

In the compound of formula (I) according to the invention, the two ring systems, i.e. the 2- hydroxy benzoic acid ring and the ring containing A, are linked to each other via a linking group -NH-S(0)2-(CH) _n -, referred to herein as a sulfonamide bond; wherein n is 0 or 1. Preferably, n is 0. However, in some embodiments, n is 1. For example, in some embodiments of a compound of formula (lb), n is 1.

In a compound of formula (I), R ¹ is selected from H; halogen; C1-C6 alkyl, optionally substituted with at least one halogen; and C1-C6 alkoxy, substituted with at least one halogen. For example, R ¹ may be selected from H, F, CI, Br, CH ₃ and CF ₃ .

In some embodiments, R ¹ is selected from H; halogen, C1-C6 alkyl, e.g. C1-C3 alkyl, such as methyl, optionally substituted with at least one halogen; and C1-C6 alkoxy, substituted with at least one halogen, e.g. at least one F, such as trifluoromethoxy. For example, R ¹ may be selected from H and halogen. In some embodiments, R ¹ is selected from H and C1-C6 alkyl, e.g. C1-C3 alkyl, such as methyl. For example, R ¹ may be H.

In some embodiments, e.g. when A is S or O, R ¹ is a halogen.

In some embodiments, R ¹ is C1-C6 alkyl. For example, in some embodiments, R ¹ is C1-C6 alkyl; and R ² and R ³ form, together with the carbon atoms to which they are attached, a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R ⁵ . In these embodiments, A preferably is S or O, i.e. the compound is represented by formula (la) or (la'), e.g. (Iaa) or (Iaa').

In a compound of formula (I) as defined herein, R ² and R ³ are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; secondary or tertiary CI -C6 alkylamido; car- bocyclylcarbonylamino-C0-C2 alkyl; 5- or 6-membered cyclic amino carbonyl; C1-C6 alkyl- carbonylamino; C1-C6 alkylsulfonyl; hydroxy-C0-C6 alkyl, C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; nitro; carbocyclyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ ; or R ² and R ³ form, together with the carbon atoms to which they are attached, a 5- or 6- membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R ⁵ .

In some embodiments, R ² and R ³ are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; secondary or tertiary C1-C6 alkylamido; 5- or 6-membered cyclic ami- nocarbonyl; C1-C6 alkylcarbonylamino; C1-C6 alkylsulfonyl; hydroxy; C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; nitro; carbocyclyloxy; heterocyclyloxy; carbocyclyl- C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; or heterocyclyl-C2-C3 alkenyl; wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ ; or R ² and R ³ form, together with the carbon atoms to which they are attached, a 5- or 6- membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R ⁵ .

In some embodiments, R ² and R ³ are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; secondary or tertiary C1-C6 alkylamido; 5- or 6-membered cyclic ami- nocarbonyl; C1-C6 alkylcarbonylamino; C1-C6 alkylsulfonyl; hydroxy; C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; nitro; carbocyclyloxy; heterocyclyloxy; carbocyclyl- C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; or heterocyclyl-C2-C3 alkenyl; wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ ; or R ² and R ³ form, together with the carbon atoms to which they are attached, a 5- or 6- membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R ⁵ . The moieties R ² and R ³ preferably should not both be H. For example, in some embodiments, R ² is as defined herein above, but is not H. In other embodiments R ³ is as defined herein above, but is not H.

In some embodiments, R ² and R ³ are each independently selected from H, halogen, e.g. F, CI and Br; C1-C6 alkyl, e.g. C1-C4 alkyl; C1-C6 alkoxy, e.g. C1-C4 alkoxy; hydroxy-C0-C6 alkyl, e.g. hydroxy-C0-C4 alkyl, such as hydroxy and hydroxymethyl; C1-C6 alkylcarbonyl, e.g. C1-C4 alkylcarbonyl, such as acetyl; secondary or tertiary CI -C6 alkylamido, such as secondary or tertiary CI -C4 alkylamido, e.g. methylamido; carbocyclylcarbonylamino-C0-C2 alkyl, such as benzamido-C0-C2-alkyl; e.g. benzamidomethyl; 5- or 6-membered cyclic ami- nocarbonyl; such as piperidin-l-ylcarbonyl; C1-C6 alkylsulfonyl, e.g. C1-C4 alkylsulfonyl, such as methylsulfonyl; carboxy; C1-C6 alkoxycarbonyl, e.g. C1-C4 alkoxycarbonyl; cyano; nitro; carbocyclyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl, e.g. carbocyclyl; carbocy- clyl-C2-C3 alkenyl, e.g. carbocyclyl-ethenyl; heterocyclyl-C0-C3 alkyl, e.g. heterocyclyl; or heterocyclyl-C2-C3 alkenyl, e.g. heterocyclyl-ethenyl; wherein any alkyl is optionally substituted with at least one halogen, any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ . In some embodiments, R ² and R ³ are each independently selected from H, halogen, e.g. F, CI and Br; C1-C6 alkyl, e.g. C1-C4 alkyl; C1-C6 alkoxy, e.g. C1-C4 alkoxy; hydroxy, C1-C6 alkylcarbonyl, e.g. C1-C4 alkylcarbonyl, such as acetyl; secondary or tertiary C1-C6 alkylamido, such as secondary or tertiary CI -C4 alkylamido, e.g. methylamido; 5- or 6-membered cyclic aminocarbonyl; such as piperidin-l-ylcarbonyl; C1-C6 alkylsulfonyl, e.g. C1-C4 alkyl- sulfonyl, such as methylsulfonyl; carboxy; C1-C6 alkoxycarbonyl, e.g. C1-C4 alkoxycarbon- yl; cyano; nitro; carbocyclyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl, e.g. carbocyclyl; carbocyclyl-C2-C3 alkenyl, e.g. carbocyclyl-ethenyl; heterocyclyl-C0-C3 alkyl, e.g. heterocy- clyl; or heterocyclyl-C2-C3 alkenyl, e.g. heterocyclyl-ethenyl; wherein any alkyl is optionally substituted with at least one halogen, any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ .

It should be understood that any alkyl that is optionally substituted with at least one halogen may optionally be part of a radical, i.e. an alkoxy or alkylcarbonyl. Thus, R ² and R ³ may be e.g. a halogenated alkyl, a halogenated alkoxy or a halogenated alkylcarbonyl etc. The number of halogen atoms attached to any one alkyl may be e.g. 1, 2 or 3 and may be independently selected from e.g. F and CI. For example, any alkyl may be substituted by 1, 2 or 3 halogens that are all fluoro, such as in trifluoromethyl, trifluoromethoxy or difluoromethoxy.

It also should be understood that the reference to "any carbocyclyl or heterocyclyl" as being 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl also inludes the carbocyclyl and heterocylyl, respectively, when present as a moiety of a radical such as e.g. carbocyclyloxy or carbocyclyl-C2-C3 alkenyl.

In some embodiments, R ² and R ³ are each independently selected from H, halogen, e.g. F, CI and Br; C1-C6 alkyl, e.g. C1-C4 alkyl; C1-C6 alkoxy, e.g. C1-C4 alkoxy; C1-C6 alkylcar- bonyl, e.g. C1-C4 alkylcarbonyl, such as acetyl; secondary or tertiary CI -C6 alkylamido, such as secondary or tertiary CI -C4 alkylamido, e.g. methylamido; 5- or 6-membered cyclic aminocarbonyl; such as piperidin-l-ylcarbonyl; C1-C6 alkylcarbonylamino; such as C1-C4 al- kylcarbonylamino; C1-C6 alkylsulfonyl, e.g. C1-C4 alkylsulfonyl, such as methylsulfonyl; carbocyclyl-C0-C3 alkyl, e.g. carbocyclyl; carbocyclyl-C2-C3 alkenyl, e.g. carbocyclyl- ethenyl; heterocyclyl-C0-C3 alkyl, e.g. heterocyclyl; or heterocyclyl-C2-C3 alkenyl, e.g. heterocyclyl-ethenyl; wherein any alkyl is optionally substituted with at least one halogen, any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ .

For example, R ² and R ³ may be independently selected from H, halogen, methyl, tert-butyl, trifluoromethyl, methoxy, acetyl, methylamido, piperidinylcarbonyl, such as piperidinyl-1- carbonyl, methylsulfonyl, phenyl, phenylethenyl, benzofuryl, dihydrobenzofuryl, such as 2,3- dihydro-1 -benzofuryl, quinolyl, 1,3-benzodioxyl, thienyl, pyridyl, thiazolyl, and piperidyl, wherein any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ .

In some embodiments, when either R ² or R ³ is a carbocyclyl or heterocyclyl radical, or a radical comprising a carbocyclyl or heterocyclyl moiety, such carbocyclyl or heterocyclyl radical or moiety is selected from phenyl, benzofuryl, dihydrobenzofuryl, such as 2,3-dihydro-l- benzofuryl, quinolyl, 1,3-benzodioxyl, thienyl, pyridyl, thiazolyl, and piperidyl.

In some embodiments, R ² and R ³ are each independently selected from H, halogen, e.g. F, CI, Br and I; C1-C6 alkyl, e.g. C1-C4 alkyl; C1-C6 alkoxy, e.g. C1-C4 alkoxy; hydroxy, C1-C6 alkylcarbonyl, e.g. C1-C4 alkylcarbonyl, such as acetyl; secondary or tertiary C1-C6 alkylamido, such as secondary or tertiary CI -C4 alkylamido, e.g. methylamido; 5- or 6-membered cyclic aminocarbonyl; such as piperidin-l-ylcarbonyl; C1-C6 alkylsulfonyl, e.g. C1-C4 al- kylsulfonyl, such as methylsulfonyl; carboxy; C1-C6 alkoxycarbonyl, e.g. C1-C4 alkoxycar- bonyl; cyano; and nitro; wherein any alkyl is optionally substituted with at least one halogen.

For example, R ² and R ³ may be independently selected from H, halogen, e.g. F, CI, Br and I; C1-C6 alkyl, e.g. C1-C4 alkyl; C1-C6 alkoxy, e.g. C1-C4 alkoxy; C1-C6 alkylcarbonyl, e.g. C1-C4 alkylcarbonyl, such as acetyl; secondary or tertiary C1-C6 alkylamido, such as secondary or tertiary CI -C4 alkylamido, e.g. methylamido; 5- or 6-membered cyclic aminocarbonyl; such as piperidin-l-ylcarbonyl; C1-C6 alkylsulfonyl, e.g. C1-C4 alkylsulfonyl, such as methylsulfonyl; and C1-C6 alkoxycarbonyl, e.g. C1-C4 alkoxycarbonyl; wherein any alkyl is optionally substituted with at least one halogen.

For example, R ² and R ³ may be independently selected from H; C1-C6 alkyl, e.g. C1-C4 alkyl, such as methyl; halogen, e.g. F and CI; and C1-C6 alkoxy, e.g. C1-C4 alkoxy, such as methoxy, wherein any alkyl is optionally substituted with at least one halogen.

In particular, R ² and R ³ may be independently selected from H, F, CI, Br, I, methyl, trifluoromethyl, trifluoromethoxy and difluoromethoxy. For example, R ² and R ³ may be independently selected from H; halogen, e.g. F and CI; and C1-C6 alkoxy, e.g. C1-C4 alkoxy, such as methoxy.

In some embodiments, e.g. in a compound of formula (la) or (la'), R ² and R ³ are independently selected from H; C1-C6 alkyl, e.g. methyl; and halogen, e.g. F, CI, Br and I, in particular CI and Br; and carbocyclyl-C0-C3 alkyl, carbocyclyl-C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl, heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ and any alkyl is optionally substituted with at least one halogen.

In some embodiments, e.g. in a compound of formula (la) or (la'), R ² and R ³ are independent- ly selected from H; optionally halogenated C1-C6 alkyl, e.g. methyl; and halogen, e.g. F, CI, Br and I, in particular CI and Br.

In some embodiments, e.g. in a compound of formula (lb) wherein n is 0; neither R ² nor R ³ is nitro.

In some embodiments, e.g. in a compound of formula (la) or (la'), e.g. in a compound of for- mula (la) or (la'), R ² is selected from H; C1-C6 alkyl, e.g. methyl; and halogen, e.g. F, CI, Br and I, in particular CI and Br; and carbocyclyl-C0-C3 alkyl, carbocyclyl-C2-C3 alkenyl, het- erocyclyl-C0-C3 alkyl, heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ ; and R ³ is selected from H; C1-C6 alkyl, e.g. methyl; and halogen, e.g. F, CI, Br and I, in particular CI and Br; wherein any alkyl is optionally substituted with at least one halogen.

In some embodiments, R ² is selected from a carbocyclyloxy, heterocyclyloxy, carbocyclyl- C0-C3 alkyl, carbocyclyl-C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl, heterocyclyl-C2-C3 alkenyl, carbocyclyl or heterocyclyl radical as defined herein above, wherein any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ ; and R ³ is as defined herein above, and for example, is selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; hydroxy; C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; or nitro. In particular, R ³ may be selected from H, halogen, C1-C6 alkyl, e.g. C1-C4 alkyl; and C1-C6 alkoxy, e.g. C1-C4 alkoxy; or H, halogen, and C1-C6 alkoxy, e.g. C1-C4 alkoxy; such as H, methoxy, F and CI.

In some embodiments, e.g. where the compound of formula (I) is a compound wherein A is O or S, e.g. a compound of formula (la), such as a compound of formula (Iaa), R ³ is selected from halogen, e.g. R ³ is CI, or Br, e.g. R ³ is CI. In some other embodiments, e.g. where the compound of formula (I) is a compound as represented by formula (lb), R ³ is selected from H; halogen; and C1-C6 alkoxy, e.g. C1-C4 alkoxy; e.g. R ³ is H, F or methoxy, in particular H.

In some other embodiments, e.g. where the compound of formula (I) is a compound as repre- sented by formula (lb), R ³ is selected from H; halogen; and C1-C6 alkyl; e.g. C1-C4 alkyl, optionally substituted with at least one halogen; e.g. R ³ is selected from H, F, CI, Br, I, methyl or trifluoromethyl, in particular H.

In some other embodiments, e.g. where the compound of formula (I) is a compound as represented by formula (lb) or (Ic), in particular (lb), R ³ is selected from H; and halogen; e.g. H, CI, Br and I, or H, CI and Br.

In some embodiments of a compound of formula (I), e.g. a compound of formula (lb) wherein n is 0, neither R ² nor R ³ is selected from 4-hydroxypyrazolo[l,5-a]-l,3,5-triazin-8-yl and 2,4- dihydroxypyrazolo[ 1 ,5-a]- 1 ,3,5-triazin-8-yl.

In some embodiments of a compound of formula (lb) wherein n is 0, at least one of R ² and R ³ , e.g. R ² , is not selected from hydrogen, halogen, hydroxy, carboxy, unsubstituted C1-C4 alkyl, unsubstituted C3-C6 cycloalkyl, unsubstituted aryl, unsubstituted heteroaryl containing from 1 to 4 heteroatoms selected from N, O and S, and C1-C6 alkoxy that is optionally substituted with halogen.

In some embodiments of a compound of formula (lb) wherein n is 0, either R ² and R ³ , togeth- er with the carbon atoms to which they are attached, form a 5- or 6-membered carbocyclic or heterocyclic ring; or:

(i) R ² is in meta position relative to the sulfonamide bond;

(ii) when R ¹ , R ² and R ⁴ are all H, R ³ is not selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; C1-C6 alkylcarbonylamino; C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; cyclohexyl; trifluoromethyl and trifluoromethoxy; and

(iii) when R ³ is selected from H, F, CI, Br, methyl and tert-butyl, R ² is not H.

The first of the three provisos (i) to (iii), i.e. proviso (i) implies that when, in a compound of formula (lb), n is 0, and R ² and R ³ do not together form a cycle, the compound is a compound of formula (Iba), as defined herein. The second of the three provisos, which should be read together with proviso (i), implies that the phenyl ring of formula (Iba) is not unsubstituted and is not a monosubstituted phenyl ring carrying one sole substituent in para position selected from C1-C6 alkyl; C1-C6 alkoxy; Cl- C6 alkylcarbonylamino; C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; cy- clohexyl; trifluoromethyl and trifluoromethoxy.

The third of the tree provisos, which also should be read together with proviso (i), implies that when the phenyl ring of formula (Iba) is not substituted in para position, or is substituted in para position with F, CI, Br, methyl and tert-butyl, then R ² is not hydrogen.

In some embodiments of a compound of formula (lb) wherein n is 0, either R ² and R ³ , togeth- er with the carbon atoms to which they are attached, form a 5- or 6-membered carbocyclic or heterocyclic ring; or:

(i) R ² is in meta position relative to the sulfonamide bond;

(ii) when R ¹ , R ² and R ⁴ are all H, R ³ is not selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; C1-C6 alkylcarbonylamino; C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; cyclohexyl; trifluoromethyl and trifluoromethoxy; and

(iii) when R ³ is selected from H, F, CI, Br, methyl and tert-butyl, R ² is not selected from H, and optionally halogenated C1-C6 alkyl.

In some further embodiments of a compound of formula (lb) wherein n is 0, either R ² and R ³ , together with the carbon atoms to which they are attached, form a 5- or 6-membered carbocy- clic or heterocyclic ring; or:

(i) R ² is in meta position relative to the sulfonamide bond;

(ii) when R ¹ , R ² and R ⁴ are all H, R ³ is not selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; C1-C6 alkylcarbonylamino; C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; cyclohexyl; trifluoromethyl and trifluoromethoxy; and

(iii) when R ³ is selected from H, F, CI, Br, methyl and tert-butyl, R ² is not selected from H, optionally halogenated C1-C6 alkyl and halogen.

In some embodiments, R ² is selected from halogen, e.g. F, CI and Br; C1-C6 alkyl, e.g. C1-C4 alkyl, such as methyl and tert-butyl; C1-C6 alkoxy, e.g. C1-C4 alkoxy; hydroxy-Cl-C6 alkyl, e.g. hydroxy and 1-hydroxyethyl; C1-C6 alkylcarbonyl, e.g. C1-C4 alkylcarbonyl, such as acetyl; secondary or tertiary C1-C6 alkylamido, such as secondary or tertiary C1-C4 alkyl- amido, e.g. methylamido; 5- or 6-membered cyclic aminocarbonyl; such as piperidin-1- ylcarbonyl; C1-C6 alkylsulfonyl, e.g. C1-C4 alkylsulfonyl, such as methylsulfonyl; carboxy; cyano; nitro; carbocyclyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl, e.g. carbocyclyl; carbocyclyl-C2-C3 alkenyl, e.g. carbocyclyl-ethenyl; heterocyclyl-C0-C3 alkyl, e.g. heterocyclyl; or heterocyclyl-C2-C3 alkenyl, e.g. heterocyclyl-ethenyl; wherein any alkyl is optionally substituted with at least one halogen, any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ .

In some embodiments, R ² is selected from halogen, e.g. F, CI and Br; C1-C6 alkyl, e.g. C1-C4 alkyl; C1-C6 alkoxy, e.g. C1-C4 alkoxy; hydroxy, C1-C6 alkylcarbonyl, e.g. C1-C4 alkylcar- bonyl, such as acetyl; secondary or tertiary C1-C6 alkylamido, such as secondary or tertiary C1-C4 alkylamido, e.g. methylamido; 5- or 6-membered cyclic amino carbonyl; such as piper- idin-1 -ylcarbonyl; C1-C6 alkylsulfonyl, e.g. C1-C4 alkylsulfonyl, such as methylsulfonyl; carboxy; C1-C6 alkoxycarbonyl, e.g. C1-C4 alkoxycarbonyl; cyano; nitro; carbocyclyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl, e.g. carbocyclyl; carbocyclyl-C2-C3 alkenyl, e.g. carbocyclyl-ethenyl; heterocyclyl-C0-C3 alkyl, e.g. heterocyclyl; or heterocyclyl-C2-C3 alkenyl, e.g. heterocyclyl-ethenyl; wherein any alkyl is optionally substituted with at least one halogen, any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10- membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ . In some embodiments, when R ² is alkylcarbonyl, it is C2-C6 alkylcarbonyl.

In particular, R ² may be selected from C1-C6 alkyl; e.g. C2-C6 alkyl; C1-C6 alkylcarbonyl; secondary or tertiary C1-C6 alkylamido, such as secondary or tertiary CI -C4 alkylamido, e.g. methylamido, 5- or 6-membered cyclic aminocarbonyl, such as piperidin-1 -ylcarbonyl; Cl- C6 alkylsulfonyl, e.g. C1-C4 alkylsulfonyl, such as methylsulfonyl; carbocyclyloxy; hetero- cyclyloxy; carbocyclyl-C0-C3 alkyl, carbocyclyl-C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl or heterocyclyl-C2-C3 alkenyl; wherein any alkyl is optionally substituted with at least one halogen, any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ .

More particularly, R ² may be selected from C1-C6 alkyl e.g. C2-C6 alkyl; C1-C6 alkylcar- bonyl; carbocyclyl-C0-C3 alkyl, carbocyclyl-C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl or heterocyclyl-C2-C3 alkenyl; wherein any alkyl is optionally substituted with at least one hal- ogen, any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ .

For example, R ² may be selected from carbocyclyl-C0-C3 alkyl, e.g. carbocyclyl; carbocy- clyl-C2-C3 alkenyl, e.g. carbocyclyl-ethenyl; heterocyclyl-C0-C3 alkyl, e.g. heterocyclyl; or heterocyclyl-C2-C3 alkenyl, e.g. heterocyclyl-ethenyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ .

In some embodiments, R ² is selected from carbocyclyl-C0-C3 alkyl, e.g. carbocyclyl; carbo- cyclyl-C2-C3 alkenyl, e.g. carbocyclyl-ethenyl; or heterocyclyl-C0-C3 alkyl, e.g. heterocy- clyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10- membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ .

For example, R ² may be selected from bicyclic 9- or 10-membered or monocyclic 5- or 6- membered carbocyclyl; monocyclic 5- or 6-membered carbocyclyl-ethenyl; bicyclic 9- or 10- membered or monocyclic 5- or 6-membered heterocyclyl; wherein any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ .

Even more particularly, R ² may be selected from phenyl, phenylethenyl, benzofuryl, such as 2 -benzofuryl, dihydrobenzofuryl, such as 2,3-dihydro-l -benzofuryl, quinolyl, 1,3- benzodioxyl, thienyl, pyridyl, thiazolyl, lH-pyrazolyl and piperidyl, and optionally be substituted with at least one R ⁵ .

In some embodiments, when R ² is a carbocyclyl or heterocyclyl radical or a radical containing a carbocyclyl or heterocyclyl moiety, wherein the carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ , said carbocyclyl or heterocyclyl is aromatic.

In some other embodiments, wherein R ² is bicyclic 9- or 10-membered carbocyclyl or hetero- cyclyl, optionally substituted with at least one R ⁵ , said carbocyclyl or heterocyclyl comprises at least one aromatic ring, e.g. at least one phenyl ring, fused to another ring which may be aromatic or non-aromatic. For example, this other ring may be a heterocyclic, non-aromatic or aromatic 5- or 6-membered ring, e.g. comprising 1-3 heteroatoms, e.g. 1 or 2 heteroatoms selected from N, O and S, e.g. N and O. In some embodiments, R ² is selected from carbocyclyl-C0-C3 alkyl, e.g. carbocyclyl; carbo- cyclyl-C2-C3 alkenyl, e.g. carbocyclyl-ethenyl; heterocyclyl-C0-C3 alkyl, e.g. heterocyclyl; or heterocyclyl-C2-C3 alkenyl, e.g. heterocyclyl-ethenyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl; and any cyclyl is optionally substituted with at least one R ⁵ .

In some embodiments, R ² is selected from phenyl-C0-C3 alkyl, e.g. phenyl; phenyl-C2-C3 alkenyl, e.g. phenylethenyl; heterocyclyl-C0-C3 alkyl, e.g. thienyl-C0-C3 alkyl, pyridyl-CO- C3 alkyl, thiazolyl-C0-C3 alkyl, lH-pyrazolyl-C0-C3 alkyl, and piperidyl-C0-C3 alkyl, e.g. thienyl, pyridyl, thiazolyl, lH-pyrazol-4-yl and piperidyl; or heterocyclyl-C2-C3 alkenyl, e.g. thienyl-C2-C3 alkenyl, pyridyl-C2-C3 alkenyl, thiazolyl-C2-C3 alkenyl, lH-pyrazol-4-yl-C2- C3 alkenyl and piperidyl-C2-C3 alkenyl, such as thienylethenyl, pyridylethenyl, thiazol- ylethenyl, lH-pyrazol-4-ylethenyl and piperidylethenyl; wherein said cyclic groups are optionally substituted with at least one R ⁵ .

In some other embodiments, R ² is selected from phenyl-C0-C3 alkyl, e.g. phenyl; phenyl-C2- C3 alkenyl, e.g. phenylethenyl; heterocyclyl-C0-C3 alkyl, e.g. thienyl-C0-C3 alkyl, pyridyl- C0-C3 alkyl, thiazolyl-C0-C3 alkyl, and piperidyl-C0-C3 alkyl, e.g. thienyl, pyridyl, thiazolyl and piperidyl; or heterocyclyl-C2-C3 alkenyl, e.g. thienyl-C2-C3 alkenyl, pyridyl-C2-C3 alkenyl, thiazolyl-C2-C3 alkenyl, and piperidyl-C2-C3 alkenyl, such as thienylethenyl, pyridylethenyl, thiazolylethenyl and piperidylethenyl; wherein any heterocyclyl is 5- or 6- membered monocyclyl; and any phenyl or heterocyclyl is optionally substituted with at least one R ⁵ .

For example, R ² may be selected from phenyl-C0-C3 alkyl, e.g. phenyl; phenyl-C2-C3 alkenyl, e.g. phenylethenyl; monocyclic 5- or 6-membered heterocyclyl-C0-C3 alkyl, e.g. thienyl-C0-C3 alkyl, pyridyl-C0-C3 alkyl, thiazolyl-C0-C3 alkyl, lH-pyrazolyl-C0-C3 alkyl; and piperidyl-C0-C3 alkyl, e.g. thienyl, pyridyl, thiazolyl, lH-pyrazolyl, and piperidyl, wherein any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ ; or from from phenyl-C0-C3 alkyl, e.g. phenyl; phenyl-C2-C3 alkenyl, e.g. phenylethenyl; monocyclic 5- or 6-membered heterocyclyl-C0-C3 alkyl, e.g. thienyl-C0-C3 alkyl, pyridyl-C0-C3 alkyl, thiazolyl-C0-C3 alkyl, and piperidyl-C0-C3 alkyl, e.g. thienyl, pyridyl, thiazolyl, and pi- peridyl, wherein any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ . In particular R ² may be phenyl-C0-C3 alkyl, optionally substituted with at least one R ⁵ . For example, R ² may be phenyl or phenyl substituted with at least one R ⁵ , e.g. 1-3 R ⁵ as defined herein, e.g. independently selected from halogen; C1-C6 alkyl; C1-C6 alkoxy; hydroxy-Cl- C6 alkyl; phenoxy; amino; cyano; nitro; secondary or tertiary C1-C6 alkylamino; 5- or 6- membered cyclic amino; C1-C6 alkylcarbonylamino; carbamoyl; secondary or tertiary C1-C6 alkylamido; 5- or 6-membered cyclic aminocarbonyl; C1-C6 alkoxy carbonylamino; hydroxy- C1-C6 alkyl; Cl-C6-alkylthio; trifluoromethyl; trifluoromethoxy; carboxy-Cl-C6-alkyl; Cl- C6 alkoxycarbonyl; C1-C6 alkylcarbonyl; Cl-C6-alkylsulfonyl; and C1-C6 alkyl, or from halogen; C1-C6 alkyl; C1-C6 alkoxy; hydroxy; phenoxy; amino; cyano; nitro; secondary or tertiary C1-C6 alkylamino; 5- or 6-membered cyclic amino; C1-C6 alkylcarbonylamino; carbamoyl; secondary or tertiary CI -C6 alkylamido; 5- or 6-membered cyclic aminocarbonyl; C1-C6 alkoxycarbonylamino; hydroxy-Cl-C6 alkyl; Cl-C6-alkylthio; trifluoromethyl; trifluoromethoxy; carboxy-Cl-C6-alkyl; C1-C6 alkoxycarbonyl; C1-C6 alkylcarbonyl; C1-C6- alkylsulfonyl; and C1-C6 alkyl, such as fluoro, chloro, methyl, ethyl, butyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, isopropoxy, butoxy, phenoxy, acetylamino, methoxycar- bonylamino, carbamoyl, dimethylcarbamoyl, diisopropylcarbamoyl, cyano, nitro, methylthio, methylsulfonyl, acetyl, methoxycarbonyl, isopropoxycarbonyl, hydroxymethyl, hydroxy, amino, dimethylamino, methylsulfonylamino; e.g. fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, phenoxy, acetylamino, methoxy carbonylamino, carbamoyl, cy- ano, nitro, methylthio, methylsulfonyl, acetyl, isopropoxycarbonyl, 2-carboxyethyl, hydroxymethyl, hydroxy, amino, dimethylamino, and methylsulfonylamino.

In some embodiments, R ² is selected from phenyl, fluorophenyl, chlorophenyl, methylphenyl, ethylphenyl, butylphenyl, trifluoromethylphenyl, hydroxyphenyl, (hydroxymethyl)phenyl, methoxyphenyl, ethoxyphenyl, isopropoxyphenyl, butoxyphenyl, aminophenyl,

(dimethylamino)phenyl, nitrophenyl, acetylphenyl, (methoxycarbonyl)phenyl,

(isopropoxycarbonyl)phenyl, (2-carboxyethyl)phenyl, carbamoylphenyl, (dimethylcar- bamoyl)phenyl, (diisopropylcarbamoyl)phenyl, acetamidophenyl,

((methoxycarbonyl)amino)phenyl, (methylthio )phenyl, trifluoromethoxyphenyl,

phenoxyphenyl, cyanophenyl, (methylsulfonyl)phenyl, (ethylsulfonyl)phenyl, (methylsulfon- amido)phenyl, difluorophenyl, dichlorophenyl, (fluoro)(methyl)phenyl, (fluo- ro)(hydroxy)phenyl, (fluoro)(methoxy)phenyl, (chloro)(methoxy)phenyl, (meth- oxy)(methyl)phenyl, (hydroxy)(methoxy)phenyl, dimethoxyphenyl, (amino)(methoxy)phenyl, (hydroxy)(dimethyl)phenyl, (methoxy)(dimethyl)phenyl, trifluorophenyl, quinolinyl, ben- zo[d][l,3]dioxolyl, 2,3-dihydrobenzofuranyl, naphthalenyl, pyridinyl, methoxypyridinyl, eth- oxypyridinyl, propoxypyridinyl, thiophenyl, oxazolyl, methylthiazolyl, acetylthiophenyl, benzofuranyl, piperidinyl, N-morpholinyl, and (E)-fluorostyryl.

For example, R ² may be a radical such as phenyl, fluorophenyl, trifluoromethylphenyl, tri- fluoromethoxyphenyl, methoxyphenyl, ethoxyphenyl, phenoxyphenyl, acetylaminophenyl, methoxycarbonylaminophenyl, carbamoylphenyl, cyanophenyl, nitrophenyl, methylthio- phenyl, methylsulfonylphenylacetylphenyl, isopropoxycarbonylphenyl, hy- droxymethylphenyl, hydroxyphenyl, aminophenyl, dimethylaminophenyl, methylsulfonyla- minophenyl, difluorophenyl, (fluoro)(hydroxy)phenyl, dichlorophenyl, (hy- droxy)(methoxy)phenyl, (amino)(hydroxy)phenyl, or (dimethyl)(hydroxy)phenyl.

In some embodiments, R ² is selected from: phenyl, 3 -fluorophenyl, 4-fluorophenyl, 3- chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4- ethylphenyl, 4-butylphenyl, 3 -trifluoromethylphenyl, 4-trifluoromethylphenyl, 3- hydroxyphenyl, 2-hydroxyphenyl, 4-hydroxyphenyl, 4-(hydroxymethyl)phenyl, 3- (hydroxymethyl)phenyl, 2-(hydroxymethyl)phenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3- ethoxyphenyl, 4-isopropoxyphenyl, 4-butoxyphenyl, 3 -aminophenyl, 4-aminophenyl, 2- aminophenyl, 4-(dimethylamino)phenyl, 2-nitrophenyl, 4-nitrophenyl, 4-acetylphenyl, 3- acetylphenyl, 2-acetylphenyl, 2-(methoxycarbonyl)phenyl, 3-(isopropoxycarbonyl)phenyl, 4- (2-carboxyethyl)phenyl, 3 -carbamoylphenyl, 4-carbamoylphenyl, 4- (dimethylcarbamoyl)phenyl, 4-(diisopropylcarbamoyl)phenyl, 3-acetamidophenyl, 4- ((methoxycarbonyl)amino)phenyl, 4-(methylthio)phenyl, 4-trifluoromethoxyphenyl, 4- phenoxyphenyl, 3 -cyanophenyl, 3-(methylsulfonyl)phenyl, 4-(methylsulfonyl)phenyl, 4- (ethylsulfonyl)phenyl, 4-(methylsulfonamido)phenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3, 5 -dichlorophenyl, 3,4-dichlorophenyl, 4-fluoro-3- methylphenyl, 3-fluoro-4-hydroxyphenyl, 5-fluoro-2-methoxyphenyl, 3-fluoro-4- methoxyphenyl, 2-fluoro-3 -methoxyphenyl, 4-fluoro-2-methoxyphenyl, 5-chloro-2- methoxyphenyl, 4-methoxy-3 -methylphenyl, 4-hydroxy-3 -methoxyphenyl, 2,3- dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-amino-3-methoxyphenyl, 3-amino-4- methoxyphenyl, 4-hydroxy-3,5-dimethylphenyl, 4-methoxy-3,5-dimethylphenyl, 2,3,6- trifluorophenyl, quinolin-6-yl, benzo[d][l,3]dioxol-5-yl, 2,3-dihydrobenzofuran-5-yl, naph- thalen-2-yl, pyridin-3-yl, pyridin-4-yl, 6-methoxypyridin-3-yl, 6-ethoxypyridin-3-yl, 2- propoxypyridin-3-yl, thiophen-2-yl, oxazol-5-yl, 2-methylthiazol-4-yl, 5-acetylthiophen-2-yl, benzofuran-2-yl, piperidin-l-yl, N-morpholinyl, and (E)-4-fluorostyryl. In some embodiments, e.g. when A is a double bond, R ² is selected from any of the above moieties, except for unsubstituted phenyl.

In some embodiments, R ² and R ³ form, together with the carbon atoms to which they are attached, form a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R ⁵ . For example, R ² and R ³ together with the carbon atoms to which they are attached may form a 5- or 6-membered carbocyclic or heterocyclic aromatic ring. For example, in some embodiments, the ring formed by R ² and R ³ is a carbocyclic aromatic ring, e.g. a benzene ring. In some other embodiments, the ring formed by R ² and R ³ is a 5- or 6-membered heterocyclic, aromatic or non-aromatic ring containing 1-4, e.g. 1, 2 or 3 heteroatoms selected from N, O and S, such as a thiadiazole, e.g. a 1,2,5-thiadiazole, an oxadiazole, e.g. a 1,2,5-oxadiazole or a tetrahydrofuran ring.

In some embodiments of the invention, e.g. in a compound of formula (lb), R ² and R ³ are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; secondary or tertiary C1-C6 alkylamido; 5- or 6-membered cyclic aminocarbonyl; C1-C6 alkylsulfonyl; hydroxy- C0-C6 alkyl, C1-C6 alkylcarbonyl; carboxy; nitro; carbocyclyl-C0-C3 alkyl; carbocyclyl-C2- C3 alkenyl; and heterocyclyl-C0-C3 alkyl; wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ ; or R ² and R ³ form, together with the carbon atoms to which they are attached, a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R ⁵ .

For example, in some embodiments of a compound of formula (I), in particular of a compound of formula (lb), R ² is selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; secondary or tertiary C1-C6 alkylamido; 5- or 6-membered cyclic aminocarbonyl; C1-C6 alkylsulfonyl; hydroxy-C0-C6 alkyl, C1-C6 alkylcarbonyl; carboxy; nitro; carbocyclyl-C0-C3 alkyl; carbo- cyclyl-C2-C3 alkenyl; and heterocyclyl-C0-C3 alkyl; wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ ; and R ³ is selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; carboxy; carbocyclyl-C0-C3 alkyl; and heterocyclyl-C0-C3 alkyl;; wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6- membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ ; or R ² and R ³ form, together with the carbon atoms to which they are attached, a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R ⁵ .

In some embodiments of a compound of formula (I), in particular of a compound of formula (Iba), n is 0; R ² is selected from halogen; C1-C6 alkyl; C1-C6 alkoxy; secondary or tertiary C1-C6 alkylamido; 5- or 6-membered cyclic aminocarbonyl; C1-C6 alkylsulfonyl; hydroxy- C0-C6 alkyl, C1-C6 alkylcarbonyl; carboxy; carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; and heterocyclyl-C0-C3 alkyl; wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ ; and R ³ is selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; carboxy; car- bocyclyl-C0-C3 alkyl; and heterocyclyl-C0-C3 alkyl; wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substi- tuted with at least one R ⁵ ; or R ² and R ³ form, together with the carbon atoms to which they are attached, a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R ⁵ .

Each R ⁴ which is present in a compound of formula (lb) or (Ic), is independently selected from H, halogen, monocyclic C3-C6 carbocyclyl and C1-C6 alkyl, wherein any alkyl is op- tionally substituted with at least one halogen; or from H, monocyclic C3-C6 carbocyclyl, e.g. phenyl, and C1-C6 alkyl, such as C1-C3 alkyl, e.g. methyl, wherein any alkyl is optionally substituted with at least one halogen. For example, each R ⁴ may be selected from H, F, tri- fluoromethyl and phenyl; or from H, trifluoromethyl and phenyl. Preferably, each R ⁴ is H.

When R ² and/or R ³ is a cyclic moiety or R ² and R ³ , together with the carbon atoms to which they are attached form a cyclic moiety, such cyclic moiety may optionally be substitued with at least one R ⁵ , e.g. 1-3 R ⁵ , independently selected from halogen, e.g. F and CI; C1-C6 alkyl, e.g. C1-C4 alkyl, such as methyl, ethyl, and n-butyl; C1-C6 alkoxy, e.g. C1-C4 alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy; hydroxy-C0-C6 alkyl, e.g. hydro xy-C0-C2 alkyl, such as hydroxy and hydroxymethyl; phenoxy; amino; cyano; nitro; sec- ondary or tertiary CI -C6 alkylamino, e.g. secondary or tertiary CI -C3 alkylamino, such as dimethylamino; carbamoyl; secondary or tertiary C1-C6 alkylamido, such as dimethylcar- bamoyl and diisopropylcarbamoyl; Cl-C6-alkylthio, such as C1-C3 alkylthio, e.g. methylthio; trifluoromethyl; trifluoromethoxy; carboxy-C0-C6-alkyl, e.g. carboxy and 2-carboxyethyl; C1-C6 alkoxycarbonyl, such as C1-C3 alkoxycarbonyl, e.g. methoxycarbonyl and isopropoxycarbonyl; C1-C6 alkylcarbonyl, such as C1-C3 alkylcarbonyl, e.g. acetyl; C1-C6- alkylsulfonyl; and C1-C6 alkylsulfonylamino, such as C1-C3 alkylsulfonylamino, e.g. me- thylsulfonylamino.

In some embodiments, when either of R ² and R ³ is a cyclic moiety or R ² and R ³ , together with the carbon atoms to which they are attached form a cyclic moiety, such cyclic moiety may optionally be substitued with at least one R ⁵ , e.g. 1-3 R ⁵ , independently selected from halogen, e.g. F and CI; C1-C6 alkyl, e.g. C1-C3 alkyl, such as methyl and ethyl; C1-C6 alkoxy, e.g. C1-C3 alkoxy, such as methoxy and ethoxy; hydroxy; phenoxy; amino; cyano; nitro; secondary or tertiary C1-C6 alkylamino, e.g. secondary or tertiary C1-C3 alkylamino, such as dimethylamino; carbamoyl; secondary or tertiary C1-C6 alkylamido; hydroxy-Cl-C6 alkyl, e.g. hydroxymethyl-; Cl-C6-alkylthio, such as C1-C3 alkylthio, e.g. methylthio; trifluoromethyl; trifluoromethoxy; carboxy-Cl-C6-alkyl; C1-C6 alkoxycarbonyl, such as C1-C3 alkoxycarbonyl, e.g. isopropoxycarbonyl; C1-C6 alkylcarbonyl, such as C1-C3 alkylcarbonyl, e.g. acetyl; Cl-C6-alkylsulfonyl; and C1-C6 alkylsulfonylamino, such as C1-C3 alkylsulfonylamino, e.g. methylsulfonylamino.

In some embodiments, each R ⁵ is independently selected from halogen, e.g. F and CI; C1-C6 alkyl, e.g. C1-C4 alkyl, such as methyl, ethyl, and n-butyl; C1-C6 alkoxy, e.g. C1-C4 alkoxy, such as methoxy, ethoxy, isopropoxy and n-butoxy; hydroxy-C0-C6 alkyl, e.g. hydroxy-CO- C2 alkyl, such as hydroxy and hydroxymethyl; amino; secondary or tertiary CI -C6 alkylamino, e.g. secondary or tertiary C1-C3 alkylamino, such as dimethylamino; C1-C6 alkylcar- bonylamino; e.g. C1-C3 alkylcarbonylamino, such as acetylamino, Cl-C6-alkylthio, such as C1-C3 alkylthio, e.g. methylthio; C1-C6 alkoxycarbonyl, such as C1-C3 alkoxycarbonyl, e.g. methoxycarbonyl and isopropoxycarbonyl; C1-C6 alkylcarbonyl, such as C1-C3 alkylcarbonyl, e.g. acetyl; and C1-C6 alkylsulfonylamino, such as C1-C3 alkylsulfonylamino, e.g. methylsulfonylamino and ethylsulfonylamino.

In some embodiments, each R ⁵ is independently selected from halogen, e.g. F and CI; C1-C6 alkyl, e.g. C1-C3 alkyl, such as methyl and ethyl; C1-C6 alkoxy, e.g. C1-C3 alkoxy, such as methoxy and ethoxy; hydroxy; amino; secondary or tertiary C1-C6 alkylamino, e.g. secondary or tertiary C1-C3 alkylamino, such as dimethylamino; C1-C6 alkylcarbonylamino; e.g. C1-C3 alkylcarbonylamino, such as acetylamino, hydroxy-Cl-C6 alkyl, such as. hydroxy-Cl-C3 alkyl, e.g. hydroxymethyl; Cl-C6-alkylthio, such as C1-C3 alkylthio, e.g. methylthio; C1-C6 alkoxycarbonyl, such as C1-C3 alkoxycarbonyl, e.g. isopropoxycarbonyl; C1-C6 alkylcarbonyl, such as C1-C3 alkylcarbonyl, e.g. acetyl; and C1-C6 alkylsulfonylamino, such as Cl- C3 alkylsulfonylamino, e.g. methylsulfonylamino and ethylsulfonylamino. In one embodiment, the present invention provides a compound for use in therapy, selected from:

4- [(biphenyl-3 -ylsulfonyl)amino] -2-hydroxybenzoic acid,

4- { [(3 -bromophenyl)sulfonyl] amino } -2-hydroxybenzoic acid,

4-({[3-(5-acetyl-2-thienyl)phenyl]sulfonyl}amino)-2-hydro xybenzoic acid,

2-hydroxy-4-{[(4'-hydroxybiphenyl-3-yl)sulfonyl]amino}ben zoic acid,

4-[( {3-[(E)-2-(4-fluorophenyl)vinyl]phenyl} sulfonyl)amino]-2-hydroxybenzoic acid, 4- { [(3 '-amino-4'-methoxybiphenyl-3 -yl)sulfonyl] amino } -2-hydroxybenzoic acid,

2-hydroxy-4- { [(3 -pyridin-3 -ylphenyl)sulfonyl]amino } benzoic acid,

4-({[4'-(dimethylamino)biphenyl-3-yl]sulfonyl}amino)-2-hy droxybenzoic acid,

2-hydroxy-4-({[5-(trifluoromethyl)biphenyl-3-yl]sulfonyl} amino)benzoic acid,

4-{[(4,6-difluorobiphenyl-3-yl)sulfonyl]amino}-2-hydroxyb enzoic acid,

2-hydroxy-4-{[(6-methoxybiphenyl-3-yl)sulfonyl]amino}benz oic acid,

4- {[(5-chloro-4-phenyl-2-thienyl)sulfonyl]amino} -2-hydroxybenzoic acid,

2-hydroxy-4-({[2'-(hydroxymethyl)biphenyl-3-yl]sulfonyl}a mino)benzoic acid,

4- { [(3 '-fluorobiphenyl-3 -yl)sulfonyl] amino } -2-hydroxybenzoic acid,

4-{[(2',6'-difluorobiphenyl-3-yl)sulfonyl]amino}-2-hydroxybe nzoic acid,

2-hydroxy-4-({[3'-(isopropoxycarbonyl)biphenyl-3-yl]sulfo nyl}amino)benzoic acid, 4-( {[3-(2,3-dihydro- 1 -benzofuran-5-yl)phenyl]sulfonyl} amino)-2-hydroxybenzoic acid, 4- {[(3 '-fluoro-4'-hydroxybiphenyl-3-yl)sulfonyl]amino} -2-hydroxybenzoic acid,

2-hydroxy-4- {[(3-quinolin-6-ylphenyl)sulfonyl]amino}benzoic acid,

4- {[(3 '-aminobiphenyl-3-yl)sulfonyl]amino} -2-hydroxybenzoic acid,

2-hydroxy-4-({[3-(2 -methyl- l,3-thiazol-4-yl)phenyl]sulfonyl}amino)benzoic acid,

4- {[(5-chloro-2-thienyl)sulfonyl]amino} -2-hydroxybenzoic acid,

4-( {[5-chloro-4-(2,3-dihydro- 1 -benzofuran-5-yl)-2-thienyl]sulfonyl} amino)-2- hydroxybenzoic acid,

4-({[5-chloro-4-(3-fluoro-4-hydroxyphenyl)-2-thienyl]sulfony l}amino)-2-hydroxybenzoic acid,

4- {[(5-chloro-4-quinolin-6-yl-2-thienyl)sulfonyl]amino} -2-hydroxybenzoic acid, 4-({[4-(l,3-benzodioxol-5-yl)-5-chloro-2-thienyl]sulfonyl}am ino)-2-hydroxybenzoic acid, 4-({[5-chloro-4-(4-hydroxy-3,5-dimethylphenyl)-2-thienyl]sul fonyl}amino)-2- hydroxybenzoic acid,

4-({[5-chloro-4-(2,4-difluorophenyl)-2-thienyl]sulfonyl}amin o)-2-hydroxybenzoic acid, 4-({[4-(3-acetylphenyl)-5-chloro-2-thienyl]sulfonyl}amino)-2 -hydroxybenzoic acid,

4-[({5-chloro-4-[2-(hydroxymethyl)phenyl]-2-thienyl}sulfo nyl)amino]-2-hydroxybenzoic acid,

4-({[5-chloro-4-(3-fluorophenyl)-2-thienyl]sulfonyl}amino)-2 -hydroxybenzoic acid, 4-[({5-chloro-4-[3-(isopropoxycarbonyl)phenyl]-2-thienyl}sul fonyl)amino]-2- hydroxybenzoic acid,

4-({[5-chloro-4-(3,5-difluorophenyl)-2-thienyl]sulfonyl}amin o)-2-hydroxybenzoic acid, 4-({[5-chloro-4-(6-ethoxypyridin-3-yl)-2-thienyl]sulfonyl}am ino)-2-hydroxybenzoic acid, 4-({[4-(3-aminophenyl)-5-chloro-2-thienyl]sulfonyl}amino)-2- hydroxybenzoic acid, 4-({[5-chloro-4-(4-methoxyphenyl)-2-thienyl]sulfonyl}amino)- 2-hydroxybenzoic acid, 4-({[4-(4-aminophenyl)-5-chloro-2-thienyl]sulfonyl}amino)-2- hydroxybenzoic acid, tri- fluoroacetate (salt)

4-({[5-chloro-4-(4-hydroxyphenyl)-2-thienyl]sulfonyl}amino)- 2-hydroxybenzoic acid,

4-[({5-chloro-4-[3-(hydroxymethyl)phenyl]-2-thienyl}sulfo nyl)amino]-2-hydroxybenzoic acid,

4-[( {5-chloro-4-[4-(hydroxymethyl)phenyl]-2-thienyl} sulfonyl)amino]-2-hydroxybenzoic acid,

4-({[4-(3-amino-4-methoxyphenyl)-5-chloro-2-thienyl]sulfonyl }amino)-2-hydroxybenzo acid, trifluoroacetate (salt)

4- { [(5 -chloro-4- {4- [(methylsulfonyl)amino]phenyl} -2-thienyl)sulfonyl] amino } -2- hydroxybenzoic acid,

4-{[(7-chloro-3-methyl-l-benzothien-2-yl)sulfonyl]amino}-2-h ydroxybenzoic acid, 4-{[(5-chloro-3-methyl-l-benzothien-2-yl)sulfonyl]amino}-2-h ydroxybenzoic acid, 2-hydroxy-4-{[(3-piperidin-l-ylphenyl)sulfonyl]amino}benzoic acid,

4- { [(3 -acetylphenyl)sulfonyl] amino } -2-hydroxybenzoic acid,

4-{[(3-tert-butylphenyl)sulfonyl]amino}-2-hydroxybenzoic acid,

2-hydroxy-4-{[(4-phenyl-2-thienyl)sulfonyl]amino}benzoic acid,

2-hydroxy-4-[[3-(piperidine- 1 -carbonyl)phenyl]sulfonylamino]benzoic acid,

2-hydroxy-4- [ [3 -(methylcarbamoyl)phenyl] sulfonylamino]benzoic acid,

2-hydroxy-4- [ [3 -(4-methylsulfonylphenyl)phenyl] sulfonylamino]benzoic acid, 4- [ [3 -(3 -ethoxyphenyl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid,

4- [ [3 -(3 -acetamidophenyl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid,

4-[[3-(3,4-dichlorophenyl)phenyl]sulfonylamino]-2-hydroxy -benzoic acid,

4- [ [3 -(3 -carbamoylphenyl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid,

4- [ [3 -(3 -cyanophenyl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid,

2-hydroxy-4- [ [3 -(4-nitrophenyl)phenyl] sulfonylamino]benzoic acid,

2-hydroxy-4- [ [3 - [3 -(trifluoromethyl)phenyl]phenyl] sulfonylamino]benzoic acid, 2-hydroxy-4-[[3-(4-methylsulfanylphenyl)phenyl]sulfonylamino ]benzoic acid,

2-hydroxy-4- [ [3 - [4-(trifluoromethoxy)phenyl]phenyl]sulfonylamino]benzoic acid, 4-[[3-(2-acetylphenyl)phenyl]sulfonylamino]-2-hydroxy-benzoi c acid,

2-hydroxy-4- [ [3 -(4-phenoxyphenyl)phenyl] sulfonylamino]benzoic acid,

2-hydroxy-4- [ [3 -(4-hydroxy-3 -methoxy-phenyl)phenyl]sulfonylamino]benzoic acid, 2-hydroxy-4-[(3-methylsulfonylphenyl)sulfonylamino]benzoic acid,

4- [ [3 -(benzofuran-2-yl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid,

2-hydroxy-4-[[3-[4-(methoxycarbonylamino)phenyl]phenyl]su lfonylamino]benzoic acid, 4-[(5-fluoro-2-methylbenzene)sulfonamido]-2-hydroxybenzoic acid,

4-[(2-bromo-4-iodobenzene)sulfonamido]-2-hydroxybenzoic acid,

2-hydroxy-4-[(2,4,5-trichlorobenzene)sulfonamido]benzoic acid,

2-hydroxy-4- {[4-(l ,3-oxazol-5-yl)benzene]sulfonamido}benzoic acid,

4-(2, 1 ,3-benzothiadiazole-4-sulfonamido)-2-hydroxybenzoic acid,

4-(2, 1 ,3-benzoxadiazole-4-sulfonamido)-2-hydroxybenzoic acid,

4-{[3-(4-chlorophenyl)benzene]sulfonamido}-2-hydroxybenzo ic acid,

2-hydroxy-4-( {3-[4-(trifluoromethyl)phenyl]benzene} sulfonamido)benzoic acid, 4- { [3 -(4-fluorophenyl)benzene] sulfonamido } -2-hydroxybenzoic acid,

4-{[3-(3,5-dichlorophenyl)benzene]sulfonamido}-2-hydroxyb enzoic acid,

2-hydroxy-4-{[3-(4-methoxyphenyl)benzene]sulfonamido}benz oic acid,

2-hydroxy-4-{[3-(4-methylphenyl)benzene]sulfonamido}benzo ic acid,

2-hydroxy-4-{[3-(trifluoromethyl)benzene]sulfonamido}benz oic acid,

4-( 1 -benzothiophene-2-sulfonamido)-2-hydroxybenzoic acid,

2-hydroxy-4-(5 -methyl- 1 -benzothiophene-2-sulfonamido)benzoic acid,

2-hydroxy-4-(7-methoxy-3-methyl- 1 -benzothiophene-2-sulfonamido)benzoic acid, 2-hydroxy-4-(5-methoxy-3 -methyl- 1 -benzothiophene-2-sulfonamido)benzoic acid, 2-hydroxy-4-[3-methyl-5-(propan-2-yl)- 1 -benzofuran-2-sulfonamido]benzoic acid, 4-(5-fluoro-3-methyl- 1 -benzothiophene-2-sulfonamido)-2-hydroxybenzoic acid, 4-{[3-(2H-l,3-benzodioxol-5-yl)benzene]sulfonamido}-2-hydrox ybenzoic acid, 4-{[3-(2,4-difluorophenyl)benzene]sulfonamido}-2-hydroxybenz oic acid,

2-hydroxy-4- { [3 -(2-nitrophenyl)benzene] sulfonamido } benzoic acid,

2-hydroxy-4-{[3-(4-hydroxy-3,5-dimethylphenyl)benzene]sul fonamido}benzoic acid, 4- { [3 -(4-butylphenyl)benzene] sulfonamido } -2-hydroxybenzoic acid,

4-({3-[4-(ethanesulfonyl)phenyl]benzene}sulfonamido)-2-hydro xybenzoic acid,

2-hydroxy-4- { [3 -(4-methoxy-3 -methylphenyl)benzene]sulfonamido } benzoic acid,

2-hydroxy-4- { [3 -(3 -hydroxyphenyl)benzene] sulfonamido } benzoic acid,

2-hydroxy-4- { [3 -(3 -methanesulfonylphenyl)benzene]sulfonamido } benzoic acid,

4-( {3-[4-(dimethylcarbamoyl)phenyl]benzene} sulfonamido)-2-hydroxybenzoic acid, 4- { [3 -(4-ethylphenyl)benzene] sulfonamido } -2-hydroxybenzoic acid,

4-[(3-{4-[bis(propan-2-yl)carbamoyl]phenyl}benzene)sulfonami do]-2-hydroxybenzoic acid,

4- { [3 -(4-acetylphenyl)benzene] sulfonamido} -2-hydroxybenzoic acid,

4- { [3 -(2,3 -dimethoxyphenyl)benzene] sulfonamido } -2-hydroxybenzoic acid,

4- {[3-(4-fluoro-2-methoxyphenyl)benzene]sulfonamido} -2-hydroxybenzoic acid,

2-hydroxy-4-{[3-(2,3,6-trifluorophenyl)benzene]sulfonamid o}benzoic acid,

4-( {3-[4-(2-carboxyethyl)phenyl]benzene} sulfonamido)-2-hydroxybenzoic acid,

2-hydroxy-4- { [3 -(3 -methylphenyl)benzene]sulfonamido } benzoic acid,

4- { [3 -(3 ,5 -difluorophenyl)benzene] sulfonamido } -2-hydroxybenzoic acid,

2-hydroxy-4- {[3-(4-methoxy-3,5-dimethylphenyl)benzene]sulfonamido}benzoi c acid, 2-hydroxy-4-{[3-(2-methylphenyl)benzene]sulfonamido}benzoic acid,

2-hydroxy-4-{[3-(2-propoxypyridin-3-yl)benzene]sulfonamid o}benzoic acid,

4-{[3-(6-ethoxypyridin-3-yl)benzene]sulfonamido}-2-hydrox ybenzoic acid,

2-hydroxy-4-( {3-[4-(propan-2-yloxy)phenyl]benzene} sulfonamido)benzoic acid,

4-{[3-(4-butoxyphenyl)benzene]sulfonamido}-2-hydroxybenzo ic acid,

4- { [3 -(3 ,4-dimethoxyphenyl)benzene] sulfonamido } -2-hydroxybenzoic acid,

2-hydroxy-4- { [3 -(6-methoxypyridin-3 -yl)benzene] sulfonamido } benzoic acid,

2-hydroxy-4-{[3-(morpholin-4-yl)benzene]sulfonamido}benzo ic acid,

2-hydroxy-4-(5-phenyl-2,3-dihydro- 1 -benzofuran-7-sulfonamido)benzoic acid,

4- {[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino} -2-hydroxybenzoic acid,

4-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-2-hydroxy-b enzoic acid, 4-(4,5-dichloro-thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid,

4-(3-bromo-thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid,

4-(5-bromo-thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid,

4-(4-chloro-3-nitro-benzenesulfonylamino)-2-hydroxy-benzo ic acid,

4-(4-bromo-2,5-dichloro-thiophene-3-sulfonylamino)-2-hydr oxy-benzoic acid,

4-(3-difluoromethoxy-benzenesulfonylamino)-2-hydroxy-benz oic acid,

2-hydroxy-4-(3-methoxy-benzenesulfonylamino)-benzoic acid,

4-[5-(benzoylamino-methyl)-thiophene-2-sulfonylamino]-2-h ydroxy-benzoic acid,

4-(3-chloro-4-methyl-benzenesulfonylamino)-2-hydroxy-benz oic acid,

2-hydroxy-4-(4-methyl-3-nitro-benzenesulfonylamino)-benzo ic acid,

4-(3-fluoro-benzenesulfonylamino)-2-hydroxy-benzoic acid,

4-(2,5-dichloro-thiophene-3-sulfonylamino)-2-hydroxy-benz oic acid,

2-hydroxy-4-(2,3 ,4-trichloro-benzenesulfonylamino)-benzoic acid,

2-hydroxy-4-(4-methyl-naphthalene- 1 -sulfonylamino)-benzoic acid,

4-(4-fluoro-naphthalene- 1 -sulfonylamino)-2-hydroxy-benzoic acid,

4-(5-dimethylamino-naphthalene- 1 -sulfonylamino)-2-hydroxy-benzoic acid,

4-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonylamino)-2 -hydroxy-benzoic acid,

2-hydroxy-4-(3-pyridin-4-yl-benzenesulfonylamino)-benzoic acid,

4-(4'-fluoro-3'-methyl-biphenyl-3-sulfonylamino)-2-hydrox y-benzoic acid,

4-(3'-chloro-biphenyl-3-sulfonylamino)-2-hydroxy-benzoic acid,

4-(4'-carbamoyl-biphenyl-3-sulfonylamino)-2-hydroxy-benzoic acid,

4-(3'-fluoro-4'-methoxy-biphenyl-3-sulfonylamino)-2-hydro xy-benzoic acid,

4-[6-chloro-5-(4-hydroxy-phenyl)-pyridine-3-sulfonylamino ]-2-hydroxy-benzoic acid, 4-[6-chloro-5-(3-hydroxy-phenyl)-pyridine-3-sulfonylamino]-2 -hydroxy-benzoic acid, 4-[5-(3-amino-phenyl)-6-chloro-pyridine-3-sulfonylamino]-2-h ydroxy-benzoic acid,

4-[6-chloro-5-(lH-pyrazol-4-yl)-pyridine-3-sulfonylamino] -2-hydroxy-benzoic acid,

4-[6-chloro-5-(4-fluoro-3-methyl-phenyl)-pyridine-3-sulfo nylamino]-2-hydroxy-benzoic acid, 4-[6-chloro-5-(3-chloro-phenyl)-pyridine-3-sulfonylamino]-2- hydroxy-benzoic acid,

4- [6-chloro-5 -(2-fluoro-3 -methoxy-phenyl)-pyridine-3 -sulfonylamino] -2-hydroxy benzoic acid,

4-[5-(4-carbamoyl-phenyl)-6-chloro-pyridine-3-sulfonylamino] -2-hydroxy-benzoic acid, 4-[6-chloro-5-(3-fluoro-phenyl)-pyridine-3-sulfonylamino]-2- hydroxy-benzoic acid,

4-[6-chloro-5-(3-fluoro-4-methoxy-phenyl)-pyridine-3-sulf onylamino]-2-hydroxy benzoic acid, 4-(6-chloro-5-quinolin-6-yl-pyridine-3-sulfonylamino)-2-hydr oxy-benzoic acid, 4-(5-chloro-4-pyridin-3-yl-thiophene-2-sulfonylamino)-2-hydr oxy-benzoic acid,

4-[5-chloro-4-(3-hydroxy-phenyl)-thiophene-2-sulfonylamin o]-2-hydroxy-benzoic acid, 4- [5 -chloro-4-(4-hydroxy-3 -methoxy-phenyl)-thiophene-2-sulfonylamino] -2-hydroxy benzoic acid,

4-[5-chloro-4-(3-chloro-phenyl)-thiophene-2-sulfonylamino]-2 -hydroxy-benzoic acid, 4-[4-(4-carbamoyl-phenyl)-5-chloro-thiophene-2-sulfonylamino ]-2-hydroxy-benzoic acid, 4-[5-chloro-4-(3-fluoro-4-methoxy-phenyl)-thiophene-2-sulfon ylamino]-2-hydroxy-benzoic acid,

4-[4-(4-amino-3-methoxy-phenyl)-5-chloro-thiophene-2-sulf onylamino]-2-hydroxy benzoic acid,

3'-(4-carboxy-3-hydroxy-phenylsulfamoyl)-biphenyl-2-carboxyl ic acid methyl ester

4-(5'-chloro-2'-methoxy-biphenyl-3-sulfonylamino)-2-hydroxy- benzoic acid,

4-(2',5'-difluoro-biphenyl-3-sulfonylamino)-2-hydroxy-benzoi c acid,

2-hydroxy-4-(2'-methoxy-biphenyl-3-sulfonylamino)-benzoic acid,

4-(2'-fluoro-3'-methoxy-biphenyl-3-sulfonylamino)-2-hydroxy- benzoic acid,

2-hydroxy-4-(2'-hydroxy-biphenyl-3-sulfonylamino)-benzoic acid,

4-(2'-amino-biphenyl-3-sulfonylamino)-2-hydroxy-benzoic acid,

4-(5'-fluoro-2'-methoxy-biphenyl-3-sulfonylamino)-2-hydroxy- benzoic acid,

4-[5-chloro-4-(5-chloro-2-methoxy-phenyl)-thiophene-2-sul fonylamino]-2-hydroxy-benzoic acid,

4-[5-chloro-4-(2,5-difluoro-phenyl)-thiophene-2-sulfonylamin o]-2-hydroxy-benzoic acid, 4-[5-chloro-4-(2-methoxy-phenyl)-thiophene-2-sulfonylamino]- 2-hydroxy-benzoic acid, 4-[5-chloro-4-(2-fluoro-3-methoxy-phenyl)-thiophene-2-sulfon ylamino]-2-hydroxy-benzoic acid,

4-[4-(2-amino-phenyl)-5-chloro-thiophene-2-sulfonylamino]-2- hydroxy-benzoic acid,

4-[5-chloro-4-(5-fluoro-2-methoxy-phenyl)-thiophene-2-sul fonylamino]-2-hydroxy-benzoic acid,

4-[5-chloro-4-(2-hydroxy-phenyl)-thiophene-2-sulfonylamino]- 2-hydroxy-benzoic acid, 4-(2,3-dichloro-benzenesulfonylamino)-2-hydroxy-benzoic acid,

4-[(3-chloro-4-fluorobenzene)sulfonamido]-2-hydroxybenzoic acid, 4-(4-bromo-2,5-difluoro-benzenesulfonylamino)-2-hydroxy-benz oic acid,

2-hydroxy-4-(toluene-3-sulfonylamino)-benzoic acid,

4-(biphenyl-4-sulfonylamino)-2-hydroxy-benzoic acid,

4-(benzo[b]thiophene-3-sulfonylamino)-2-hydroxy-benzoic acid,

4-(2,5-dichloro-4-methyl-thiophene-3-sulfonylamino)-2-hyd roxy-benzoic acid,

2-hydroxy-4-(2,4,5-trichloro-thiophene-3-sulfonylamino)-b enzoic acid,

4-(2-chloro-6-methyl-benzenesulfonylamino)-2-hydroxy-benz oic acid,

2-hydroxy-4-(3-trifiuoromethoxy-benzenesulfonylamino)-ben zoic acid,

4-(benzofuran-2-sulfonylamino)-2-hydroxy-benzoic acid,

2-hydroxy-4-(5-methyl-2-trifluoromethyl-furan-3-sulfonyla mino)-benzoic acid,

4-(3-chloro-2-methyl-benzenesulfonylamino)-2-hydroxy-benz oic acid,

2-hydroxy-4-(5-isopropyl-3-methyl-benzo[b]thiophene-2-sul fonylamino)-benzoic acid, 4- [4-(2,3 -dihydro-benzo furan-5 -yl)-thiophene-2-sulfonylamino] -2-hydroxy-benzoic acid, 2-hydroxy-4- [3 -( 1 -hydroxy-ethyl)-benzenesulfonylamino] -benzoic acid,

2-hydroxy-4-(3-hydroxy-benzenesulfonylamino)-benzoic acid,

2-hydroxy-4-(2-hydroxy-benzenesulfonylamino)-benzoic acid,

4-(4-chloro-phenylmethanesulfonylamino)-2-hydroxy-benzoic acid,

4-(3-bromo-phenylmethanesulfonylamino)-2-hydroxy-benzoic acid,

4-(4-bromo-phenylmethanesulfonylamino)-2-hydroxy-benzoic acid,

2-hydroxy-4-(2'-hydroxy-biphenyl-4-ylmethanesulfonylamino )-benzoic acid,

4- [4-(2,3 -dihydro-benzo furan-5 -yl)-phenylmethanesulfonylamino] -2-hydroxy-benzoic acid, 4-(2',5'-difluoro-biphenyl-4-ylmethanesulfonylamino)-2-hydro xy-benzoic acid,

4-(biphenyl-4-ylmethanesulfonylamino)-2-hydroxy-benzoic acid,

4- [3 -(2,3 -dihydro-benzo furan-5 -yl)-phenylmethanesulfonylamino] -2-hydroxy-benzoic acid,

4-(2',5'-difluoro-biphenyl-3-ylmethanesulfonylamino)-2-hydro xy-benzoic acid,

4-(3,5-dibromo-thiophene-2-sulfonylamino)-2-hydroxy-benzo ic acid,

4-(3,4-dibromo-thiophene-2-sulfonylamino)-2-hydroxy-benzo ic acid,

4-(4,5-dibromo-thiophene-2-sulfonylamino)-2-hydroxy-benzo ic acid,

4-(5-bromo-4-methyl-thiophene-2-sulfonylamino)-2-hydroxy- benzoic acid, 4-(5-chloro-4-methyl-thiophene-2-sulfonylamino)-2-hydroxy-be nzoic acid, 4-(3 ,5-dichloro-benzenesulfonylamino)-2-hydroxy-benzoic acid,

4-(3-bromo-5-trifluoromethyl-benzenesulfonylamino)-2-hydr oxy-benzoic acid,

4-(2',5'-difluoro-5-trifluoromethyl-biphenyl-3-sulfonylam ino)-2-hydroxy-benzoic acid, 4- [3 -(2,3 -dihydro-benzo furan-5 -yl)-5 -trifluoromethyl-benzenesulfonylamino] -2-hydroxy- benzoic acid,

2-hydroxy-4-(2'-hydroxy-5-trifluoromethyl-biphenyl-3-sulfony lamino)-benzoic acid, 4-(3-chloro-2-fluoro-benzenesulfonylamino)-2-hydroxy-benzoic acid,

4-(5-chloro-2-fluoro-benzenesulfonylamino)-2-hydroxy-benz oic acid,

4-(2,5-dimethyl-furan-3-sulfonylamino)-2-hydroxy-benzoic acid,

4-[5-(2,5-difluoro-phenyl)-thiophene-2-sulfonylamino]-2-hydr oxy-benzoic acid,

4- [5 -(2,3 -dihydro-benzo furan-5 -yl)-thiophene-2-sulfonylamino] -2-hydroxy-benzoic acid, 2-hydroxy-4-(5-phenyl-thiophene-2-sulfonylamino)-benzoic acid,

2-hydroxy-4-[5-(2-hydroxy-phenyl)-thiophene-2-sulfonylami no]-benzoic acid,

2-hydroxy-4-[(4-phenoxybenzene)sulfonamido]benzoic acid,

4-(2,5-dimethyl-thiophene-3-sulfonylamino)-2-hydroxy-benzoic acid,

4-(4-chloro-benzenesulfonylamino)-2-hydroxy-benzoic acid,

2-hydroxy-4-(3-nitro-benzenesulfonylamino)-benzoic acid,

2-hydroxy-4-(naphthalene- 1 -sulfonylamino)-benzoic acid,

2-hydroxy-4-(naphthalene-2-sulfonylamino)-benzoic acid,

4-(3-carboxy-benzenesulfonylamino)-2-hydroxy-benzoic acid,

4-(4-carboxy-benzenesulfonylamino)-2-hydroxy-benzoic acid,

4-(3-chloro-benzenesulfonylamino)-2-hydroxy-benzoic acid,

4-(3-bromo-5-chloro-thiophene-2-sulfonylamino)-2-hydroxy- benzoic acid, and

4-(4-bromo-thiophene-3-sulfonylamino)-2-hydroxy-benzoic acid,

or a pharmaceutically acceptable salt thereof.

Preferably, the compound for use in therapy is a compound selected from

4- [(biphenyl-3 -ylsulfonyl)amino] -2-hydroxybenzoic acid,

2-hydroxy-4-({[5-(trifluoromethyl)biphenyl-3-yl]sulfonyl} amino)benzoic acid,

4- {[(5-chloro-4-phenyl-2-thienyl)sulfonyl]amino} -2-hydroxybenzoic acid,

4- { [(3 '-fluorobiphenyl-3 -yl)sulfonyl] amino } -2-hydroxybenzoic acid,

4-{[(2',6'-difluorobiphenyl-3-yl)sulfonyl]amino}-2-hydrox ybenzoic acid,

2-hydroxy-4-({[3'-(isopropoxycarbonyl)biphenyl-3-yl]sulfo nyl}amino)benzoic acid, 4-( {[3-(2,3-dihydro- 1 -benzofuran-5-yl)phenyl]sulfonyl} amino)-2-hydroxybenzoic acid, 4-{[(3'-fluoro-4'-hydroxybiphenyl-3-yl)sulfonyl]amino}-2-hyd roxybenzoic acid,

2-hydroxy-4- { [(3 -quino lin-6-ylphenyl)sulfonyl]amino } benzoic acid,

4-{[(3'-aminobiphenyl-3-yl)sulfonyl]amino}-2-hydroxybenzo ic acid,

2-hydroxy-4-({[3-(2 -methyl- l,3-thiazol-4-yl)phenyl]sulfonyl}amino)benzoic acid, 4-( {[5-chloro-4-(2,3-dihydro- 1 -benzofuran-5-yl)-2-thienyl]sulfonyl} amino)-2- hydroxybenzoic acid,

4-({[5-chloro-4-(3-fluoro-4-hydroxyphenyl)-2-thienyl]sulfony l}amino)-2-hydroxybenzoic acid,

4-{[(5-chloro-4-quinolin-6-yl-2-thienyl)sulfonyl]amino}-2 -hydroxybenzoic acid,

4-({[4-(l,3-benzodioxol-5-yl)-5-chloro-2-thienyl]sulfonyl}am ino)-2-hydroxybenzoic acid, 4-({[5-chloro-4-(4-hydroxy-3,5-dimethylphenyl)-2-thienyl]sul fonyl}amino)-2- hydroxybenzoic acid,

4-({[5-chloro-4-(2,4-difluorophenyl)-2-thienyl]sulfonyl}amin o)-2-hydroxybenzoic acid, 4-({[4-(3-acetylphenyl)-5-chloro-2-thienyl]sulfonyl}amino)-2 -hydroxybenzoic acid,

4-[({5-chloro-4-[2-(hydroxymethyl)phenyl]-2-thienyl}sulfo nyl)amino]-2-hydroxybenzoic acid,

4-({[5-chloro-4-(3-fluorophenyl)-2-thienyl]sulfonyl}amino)-2 -hydroxybenzoic acid, 4-[({5-chloro-4-[3-(isopropoxycarbonyl)phenyl]-2-thienyl}sul fonyl)amino]-2- hydroxybenzoic acid,

4-({[5-chloro-4-(3,5-difluorophenyl)-2-thienyl]sulfonyl}amin o)-2-hydroxybenzoic acid, 4-({[5-chloro-4-(6-ethoxypyridin-3-yl)-2-thienyl]sulfonyl}am ino)-2-hydroxybenzoic acid, 4-({[4-(3-aminophenyl)-5-chloro-2-thienyl]sulfonyl}amino)-2- hydroxybenzoic acid, 4-({[5-chloro-4-(4-methoxyphenyl)-2-thienyl]sulfonyl}amino)- 2-hydroxybenzoic acid, 4-({[4-(4-aminophenyl)-5-chloro-2-thienyl]sulfonyl}amino)-2- hydroxybenzoic acid, tri- fluoroacetate (salt)

4-({[5-chloro-4-(4-hydroxyphenyl)-2-thienyl]sulfonyl}amino)- 2-hydroxybenzoic acid,

4-[({5-chloro-4-[3-(hydroxymethyl)phenyl]-2-thienyl}sulfo nyl)amino]-2-hydroxybenzoic acid,

4-[( {5-chloro-4-[4-(hydroxymethyl)phenyl]-2-thienyl} sulfonyl)amino]-2-hydroxybenzoic acid,

4-({[4-(3-amino-4-methoxyphenyl)-5-chloro-2-thienyl]sulfonyl }amino)-2-hydroxybenzoic acid, trifluoroacetate (salt) 4- { [(5 -chloro-4- {4- [(methylsulfonyl)amino]phenyl} -2-thienyl)sulfonyl] amino } -2- hydroxybenzoic acid,

4- [ [3 -(3 -ethoxyphenyl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid,

4- [ [3 -(3 -acetamidophenyl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid,

4-{[3-(2h-l,3-benzodioxol-5-yl)benzene]sulfonamido}-2-hyd roxybenzoic acid,

4-{[3-(2,4-difluorophenyl)benzene]sulfonamido}-2-hydroxyb enzoic acid,

2-hydroxy-4-{[3-(2-nitrophenyl)benzene]sulfonamido}benzoi c acid,

4- { [3 -(3 ,5 -difluorophenyl)benzene] sulfonamido } -2-hydroxybenzoic acid,

4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-2-hydroxy benzoic acid,

4-(4,5-dichloro-thiophene-2-sulfonylamino)-2-hydroxy-benz oic acid,

4-(3-bromo-thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid,

4-(4-bromo-2,5-dichloro-thiophene-3-sulfonylamino)-2-hydr oxy-benzoic acid,

4-(2,5-dichloro-thiophene-3-sulfonylamino)-2-hydroxy-benz oic acid,

2-hydroxy-4-(4-methyl-naphthalene- 1 -sulfonylamino)-benzoic acid,

4-(4-fluoro-naphthalene- 1 -sulfonylamino)-2-hydroxy-benzoic acid,

4-[5-chloro-4-(3-hydroxy-phenyl)-thiophene-2-sulfonylamino]- 2-hydroxy-benzoic acid,

4- [5 -chloro-4-(4-hydroxy-3 -methoxy-phenyl)-thiophene-2-sulfonylamino] -2-hydroxy benzoic acid,

4-[4-(4-carbamoyl-phenyl)-5-chloro-thiophene-2-sulfonylamino ]-2-hydroxy-benzoic acid, 4-[5-chloro-4-(3-fluoro-4-methoxy-phenyl)-thiophene-2-sulfon ylamino]-2-hydroxy-benzoic acid,

4-(2',5'-difluoro-biphenyl-3-sulfonylamino)-2-hydroxy-benzoi c acid,

4-(2'-fluoro-3'-methoxy-biphenyl-3-sulfonylamino)-2-hydro xy-benzoic acid,

2-hydroxy-4-(2'-hydroxy-biphenyl-3-sulfonylamino)-benzoic acid,

4-[5-chloro-4-(5-chloro-2-methoxy-phenyl)-thiophene-2-sul fonylamino]-2-hydroxy-benzoic acid,

4-[5-chloro-4-(2,5-difluoro-phenyl)-thiophene-2-sulfonylamin o]-2-hydroxy-benzoic acid, 4-[5-chloro-4-(2-methoxy-phenyl)-thiophene-2-sulfonylamino]- 2-hydroxy-benzoic acid, 4-[5-chloro-4-(2-fluoro-3-methoxy-phenyl)-thiophene-2-sulfon ylamino]-2-hydroxy-benzoic acid,

4-[5-chloro-4-(5-fluoro-2-methoxy-phenyl)-thiophene-2-sulfon ylamino]-2-hydroxy-benzoic acid,

4-[5-chloro-4-(2-hydroxy-phenyl)-thiophene-2-sulfonylamino]- 2-hydroxy-benzoic acid, 4-(benzo[b]thiophene-3-sulfonylamino)-2-hydroxy-benzoic acid, 4-(2,5-dichloro-4-methyl-thiophene-3-sulfonylamino)-2-hydrox y-benzoic acid, 2-hydroxy-4-(2,4,5-trichloro-thiophene-3-sulfonylamino)-benz oic acid,

2-hydroxy-4-(5-methyl-2-trifluoromethyl-furan-3-sulfonyla mino)-benzoic acid,

2-hydroxy-4-(2'-hydroxy-biphenyl-4-ylmethanesulfonylamino )-benzoic acid,

4-(3 ,5-dibromo-thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid,

4-(3,4-dibromo-thiophene-2-sulfonylamino)-2-hydroxy-benzo ic acid,

4-(4,5-dibromo-thiophene-2-sulfonylamino)-2-hydroxy-benzo ic acid,

4-(5-bromo-4-methyl-thiophene-2-sulfonylamino)-2-hydroxy- benzoic acid,

4-(5-chloro-4-methyl-thiophene-2-sulfonylamino)-2-hydroxy -benzoic acid,

4-(3,5-dichloro-benzenesulfonylamino)-2-hydroxy-benzoic acid,

4-(3-bromo-5-trifluoromethyl-benzenesulfonylamino)-2-hydroxy -benzoic acid,

2-hydroxy-4-(naphthalene-l-sulfonylamino)-benzoic acid, and

4-(3-bromo-5-chloro-thiophene-2-sulfonylamino)-2-hydroxy- benzoic acid,

or a pharmaceutically acceptable salt thereof. According to one aspect, the present invention provides novel compounds of formula (I), wherein A, R ¹ , R ³ , R ⁴ and R ⁵ are as defined herein above, and R ² is a radical as defined herein above, selected from C1-C6 alkyl; C1-C6 alkylcarbonyl; carbocyclyl-C0-C3 alkyl, carbocy- clyl-C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl or heterocyclyl-C2-C3 alkenyl; or selected from within any of the subgroups within these groups as defmied herein above with respect to R ² , wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10- membered bicyclyl, and any cyclyl is optionally substituted with at least one R ⁵ ; or R ² and R ³ form, together with the carbon atoms to which they are attached, a 5- or 6-membered carbo- cyclic or heterocyclic ring, which ring is optionally substituted with at least one R ⁵ , and pharmaceutically acceptable salts thereof; with the proviso that the compound is not: 4-[[(4-fluoro-3-methylphenyl)sulfonyl]amino]-2-hydroxy-benzo ic acid,

4- [ [(2,3 -dihydro- 1 H-inden-5 -yl)sulfonyl] amino] -2-hydroxy-benzoic acid,

2-hydroxy-4-[[(2, 3,4,5, 6-pentamethylphenyl)sulfonyl]amino]-benzoic acid,

4-[[(3,4-dimethylphenyl)sulfonyl]amino]-2-hydroxy-benzoic acid,

4-[[(2,3-dihydro- 1 ,4-benzodioxin-6-yl)sulfonyl]amino]-2-hydroxy-benzoic acid,

2-hydroxy-4-[[(5 ,6,7,8-tetrahydro-2-naphthalenyl)sulfonyl]amino]-benzoic acid,

4- [ [(4-bromo-3 -methylphenyl)sulfonyl] amino] -2-hydroxy-benzoic acid,

2-hydroxy-4- [ [ [4-methoxy-3 -( 1 H-tetrazol- 1 -yl)phenyl] sulfonyl] amino] -benzoic acid, 2-hydroxy-4- [ [(3 -methylphenyl)sulfonyl] amino] -benzoic acid, 4-[[[5-(l,l-dimethylethyl)-2,3-dimethylphenyl]sulfonyl]amino ]-2-hydroxy-benzoic acid, 2-hydroxy-4-[[(2,3,5,6-tetramethylphenyl)sulfonyl]amino]-ben zoic acid,

4-[[(2,5-dimethylphenyl)sulfonyl]amino]-2-hydroxy-benzoic acid,

2-hydroxy-4- [(2 -naphthalenylsulfonyl)amino] -benzoic acid,

4-[[(2,5-diethylphenyl)sulfonyl]amino]-2-hydroxy-benzoic acid

2-hydroxy-4- [ [(2 ,4,5 -trimethylphenyl)sulfonyl]amino] -benzoic acid,

4-[[[5-(l,l-dimethylethyl)-2,3-dimethylphenyl]sulfonyl]am ino]-2-hydroxy-benzoic acid, 4-[[(8-chloro-l-naphthalenyl)sulfonyl]amino]-2-hydroxy-benzo ic acid,

2-hydroxy-4-[[(4-methoxy- 1 -naphthalenyl)sulfonyl]amino]-benzoic acid,

4-[[[4-(l,l-dimethylethyl)-2,6-dimethylphenyl]sulfonyl]am ino]-2-hydroxy-benzoic acid, 2-hydroxy-4- [ [(2-methylphenyl)sulfonyl] amino] -benzoic acid,

2-hydroxy-4-[[(4-methyl- 1 -naphthalenyl)sulfonyl]amino]-benzoic acid,

4-[[(4-bromo- 1 -naphthalenyl)sulfonyl]amino]-2-hydroxy-benzoic acid,

4-[[(2,4-dimethylphenyl)sulfonyl]amino]-2-hydroxy-benzoic acid,

2-hydroxy-4-[(l-naphthalenylsulfonyl)amino] -benzoic acid,

2-hydroxy-4-[[(2,4,6-trimethylphenyl)sulfonyl]amino]-benzoic acid,

2-hydroxy-4-[(8-quinolinylsulfonyl)amino]-benzoic acid,

4- [ [ [3-(acetylamino)-4-methoxyphenyl] sulfonyl] amino] -2-hydroxy-benzoic acid,

2-hydroxy-4-[[[2-methyl-5-(2-oxo- 1 -pyrrolidinyl)phenyl]sulfonyl]amino]-benzoic acid, or 4- [ [ [4-(acetylamino)phenyl] sulfonyl]amino] -2-hydroxy-benzoic acid.

For example, in some embodiments, in a compound of formula (I) according to the invention, R ² is selected from C1-C6 alkyl; C1-C6 alkylcarbonyl; carbocyclyl-C0-C3 alkyl, carbocyclyl- C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl or heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ .

In some other embodiments, R ² is selected from CI -C6 alkyl; carbocyclyl-C0-C3 alkyl, car- bocyclyl-C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl or heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ .

In some embodiments, when R ² is an alkyl radical, said alkyl radical is selected from C2-C6 alkyl, e.g. C2-C4 alkyl. For example, R ² may be selected from C2-C6 alkyl; carbocyclyl-C0-C3 alkyl, carbocyclyl- C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl or heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ . In some embodiments, R ² is selected from carbocyclyl-C0-C3 alkyl, carbocyclyl-C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl or heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R ⁵ .

In one embodiment, the novel compound of formula (I) is a compound selected from

4- [(biphenyl-3 -ylsulfonyl)amino] -2-hydroxybenzoic acid,

4-({[3-(5-acetyl-2-thienyl)phenyl]sulfonyl}amino)-2-hydroxyb enzoic acid,

2-hydroxy-4-{[(4'-hydroxybiphenyl-3-yl)sulfonyl]amino}ben zoic acid,

4-[( {3-[(E)-2-(4-fluorophenyl)vinyl]phenyl} sulfonyl)amino]-2-hydroxybenzoic acid, 4- { [(3 '-amino-4'-methoxybiphenyl-3 -yl)sulfonyl] amino } -2-hydroxybenzoic acid,

2-hydroxy-4- { [(3 -pyridin-3 -ylphenyl)sulfonyl]amino } benzoic acid,

4-({[4'-(dimethylamino)biphenyl-3-yl]sulfonyl}amino)-2-hydro xybenzoic acid,

2-hydroxy-4-({[5-(trifluoromethyl)biphenyl-3-yl]sulfonyl} amino)benzoic acid,

4-{[(4,6-difiuorobiphenyl-3-yl)sulfonyl]amino}-2-hydroxyb enzoic acid,

2-hydroxy-4-{[(6-methoxybiphenyl-3-yl)sulfonyl]amino}benz oic acid,

4- {[(5-chloro-4-phenyl-2-thienyl)sulfonyl]amino} -2-hydroxybenzoic acid,

2-hydroxy-4-({[2'-(hydroxymethyl)biphenyl-3-yl]sulfonyl}amin o)benzoic acid,

4- { [(3 '-fluorobiphenyl-3 -yl)sulfonyl] amino } -2-hydroxybenzoic acid,

4-{[(2',6'-difluorobiphenyl-3-yl)sulfonyl]amino}-2-hydrox ybenzoic acid,

2-hydroxy-4-({[3'-(isopropoxycarbonyl)biphenyl-3-yl]sulfo nyl}amino)benzoic acid,

4-( {[3-(2,3-dihydro- 1 -benzofuran-5-yl)phenyl]sulfonyl} amino)-2-hydroxybenzoic acid, 4- {[(3 '-fluoro-4'-hydroxybiphenyl-3-yl)sulfonyl]amino} -2-hydroxybenzoic acid,

2-hydroxy-4- { [(3 -quino lin-6-ylphenyl)sulfonyl]amino } benzoic acid,

4- {[(3 '-aminobiphenyl-3-yl)sulfonyl]amino} -2-hydroxybenzoic acid,

2-hydroxy-4-({[3-(2 -methyl- l,3-thiazol-4-yl)phenyl]sulfonyl}amino)benzoic acid,

4-( {[5-chloro-4-(2,3-dihydro- 1 -benzofuran-5-yl)-2-thienyl]sulfonyl} amino)-2- hydroxybenzoic acid,

4-({[5-chloro-4-(3-fiuoro-4-hydroxyphenyl)-2-thienyl]sulfony l}amino)-2-hydroxybenzoic acid, 4-{[(5-chloro-4-quinolin-6-yl-2-thienyl)sulfonyl]amino}-2-hy droxybenzoic acid,

4-({[4-(l,3-benzodioxol-5-yl)-5-chloro-2-thienyl]sulfonyl }amino)-2-hydroxybenzoic acid, 4-({[5-chloro-4-(4-hydroxy-3,5-dimethylphenyl)-2-thienyl]sul fonyl}amino)-2- hydroxybenzoic acid,

4-({[5-chloro-4-(2,4-difluorophenyl)-2-thienyl]sulfonyl}a mino)-2-hydroxybenzoic acid, 4-({[4-(3-acetylphenyl)-5-chloro-2-thienyl]sulfonyl}amino)-2 -hydroxybenzoic acid, 4-[({5-chloro-4-[2-(hydroxymethyl)phenyl]-2-thienyl}sulfonyl )amino]-2-hydroxybenzoic acid,

4-({[5-chloro-4-(3-fluorophenyl)-2-thienyl]sulfonyl}amino)-2 -hydroxybenzoic acid, 4-[({5-chloro-4-[3-(isopropoxycarbonyl)phenyl]-2-thienyl}sul fonyl)amino]-2- hydroxybenzoic acid,

4-({[5-chloro-4-(3,5-difluorophenyl)-2-thienyl]sulfonyl}amin o)-2-hydroxybenzoic acid, 4-({[5-chloro-4-(6-ethoxypyridin-3-yl)-2-thienyl]sulfonyl}am ino)-2-hydroxybenzoic acid, 4-({[4-(3-aminophenyl)-5-chloro-2-thienyl]sulfonyl}amino)-2- hydroxybenzoic acid, 4-({[5-chloro-4-(4-methoxyphenyl)-2-thienyl]sulfonyl}amino)- 2-hydroxybenzoic acid, 4-({[4-(4-aminophenyl)-5-chloro-2-thienyl]sulfonyl}amino)-2- hydroxybenzoic acid, tri- fluoroacetate (salt)

4-({[5-chloro-4-(4-hydroxyphenyl)-2-thienyl]sulfonyl}amino)- 2-hydroxybenzoic acid, 4-[({5-chloro-4-[3-(hydroxymethyl)phenyl]-2-thienyl}sulfonyl )amino]-2-hydroxybenzoic acid,

4-[({5-chloro-4-[4-(hydroxymethyl)phenyl]-2-thienyl}sulfonyl )amino]-2-hydroxybenzoic acid,

4-({[4-(3-amino-4-methoxyphenyl)-5-chloro-2-thienyl]sulfonyl }amino)-2-hydroxybenzo acid, trifluoroacetate (salt)

4-{[(5-chloro-4-{4-[(methylsulfonyl)amino]phenyl}-2-thien yl)sulfonyl]amino}-2- hydroxybenzoic acid,

4-{[(7-chloro-3-methyl-l-benzothien-2-yl)sulfonyl]amino}-2-h ydroxybenzoic acid, 4-{[(5-chloro-3-methyl-l-benzothien-2-yl)sulfonyl]amino}-2-h ydroxybenzoic acid, 2-hydroxy-4-{[(3-piperidin-l-ylphenyl)sulfonyl]amino}benzoic acid,

4-{[(3-tert-butylphenyl)sulfonyl]amino}-2-hydroxybenzoic acid,

2-hydroxy-4-{[(4-phenyl-2-thienyl)sulfonyl]amino}benzoic acid,

2-hydroxy-4-[[3-(piperidine- 1 -carbonyl)phenyl]sulfonylamino]benzoic acid,

2-hydroxy-4- [ [3 -(methylcarbamoyl)phenyl] sulfonylamino]benzoic acid,

2-hydroxy-4- [ [3 -(4-methylsulfonylphenyl)phenyl] sulfonylamino]benzoic acid, 4- [ [3 -(3 -ethoxyphenyl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid,

4- [ [3 -(3 -acetamidophenyl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid,

4-[[3-(3,4-dichlorophenyl)phenyl]sulfonylamino]-2-hydroxy -benzoic acid,

4- [ [3 -(3 -carbamoylphenyl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid,

4- [ [3 -(3 -cyanophenyl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid,

2-hydroxy-4- [ [3 -(4-nitrophenyl)phenyl] sulfonylamino]benzoic acid,

2-hydroxy-4- [ [3 - [3 -(trifluoromethyl)phenyl]phenyl] sulfonylamino]benzoic acid, 2-hydroxy-4-[[3-(4-methylsulfanylphenyl)phenyl]sulfonylamino ]benzoic acid,

2-hydroxy-4- [ [3 - [4-(trifluoromethoxy)phenyl]phenyl]sulfonylamino]benzoic acid, 4-[[3-(2-acetylphenyl)phenyl]sulfonylamino]-2-hydroxy-benzoi c acid,

2-hydroxy-4- [ [3 -(4-phenoxyphenyl)phenyl] sulfonylamino]benzoic acid,

2-hydroxy-4- [ [3 -(4-hydroxy-3 -methoxy-phenyl)phenyl]sulfonylamino]benzoic acid, 2-hydroxy-4-[(3-methylsulfonylphenyl)sulfonylamino]benzoic acid,

4- [ [3 -(benzofuran-2-yl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid,

2-hydroxy-4-[[3-[4-(methoxycarbonylamino)phenyl]phenyl]su lfonylamino]benzoic acid, 4-[(5-fluoro-2-methylbenzene)sulfonamido]-2-hydroxybenzoic acid,

4-[(2-bromo-4-iodobenzene)sulfonamido]-2-hydroxybenzoic acid,

2-hydroxy-4-[(2,4,5-trichlorobenzene)sulfonamido]benzoic acid,

2-hydroxy-4- {[4-(l ,3-oxazol-5-yl)benzene]sulfonamido}benzoic acid,

4-(2, 1 ,3-benzothiadiazole-4-sulfonamido)-2-hydroxybenzoic acid,

4-(2, 1 ,3-benzoxadiazole-4-sulfonamido)-2-hydroxybenzoic acid,

4-{[3-(4-chlorophenyl)benzene]sulfonamido}-2-hydroxybenzo ic acid,

2-hydroxy-4-( {3-[4-(trifluoromethyl)phenyl]benzene} sulfonamido)benzoic acid, 4- { [3 -(4-fluorophenyl)benzene] sulfonamido } -2-hydroxybenzoic acid,

4-{[3-(3,5-dichlorophenyl)benzene]sulfonamido}-2-hydroxyb enzoic acid,

2-hydroxy-4-{[3-(4-methoxyphenyl)benzene]sulfonamido}benz oic acid,

2-hydroxy-4-{[3-(4-methylphenyl)benzene]sulfonamido}benzo ic acid,

4-( 1 -benzothiophene-2-sulfonamido)-2-hydroxybenzoic acid,

2-hydroxy-4-(5 -methyl- 1 -benzothiophene-2-sulfonamido)benzoic acid,

2-hydroxy-4-(7-methoxy-3-methyl- 1 -benzothiophene-2-sulfonamido)benzoic acid, 2-hydroxy-4-(5-methoxy-3 -methyl- 1 -benzothiophene-2-sulfonamido)benzoic acid, 2-hydroxy-4-[3-methyl-5-(propan-2-yl)- 1 -benzofuran-2-sulfonamido]benzoic acid, 4-(5-fluoro-3-methyl- 1 -benzothiophene-2-sulfonamido)-2-hydroxybenzoic acid, 4-{[3-(2H-l,3-benzodioxol-5-yl)benzene]sulfonamido}-2-hydrox ybenzoic acid, 4-{[3-(2,4-difluorophenyl)benzene]sulfonamido}-2-hydroxybenz oic acid,

2-hydroxy-4-{[3-(2-nitrophenyl)benzene]sulfonamido}benzoi c acid,

2-hydroxy-4-{[3-(4-hydroxy-3,5-dimethylphenyl)benzene]sul fonamido}benzoic acid, 4- { [3 -(4-butylphenyl)benzene] sulfonamido } -2-hydroxybenzoic acid,

4-({3-[4-(ethanesulfonyl)phenyl]benzene}sulfonamido)-2-hy droxybenzoic acid,

2-hydroxy-4- { [3 -(4-methoxy-3 -methylphenyl)benzene]sulfonamido } benzoic acid,

2-hydroxy-4- { [3 -(3 -hydroxyphenyl)benzene] sulfonamido } benzoic acid,

2-hydroxy-4- { [3 -(3 -methanesulfonylphenyl)benzene]sulfonamido } benzoic acid,

4-( {3-[4-(dimethylcarbamoyl)phenyl]benzene} sulfonamido)-2-hydroxybenzoic acid, 4- { [3 -(4-ethylphenyl)benzene] sulfonamido } -2-hydroxybenzoic acid,

4-[(3-{4-[bis(propan-2-yl)carbamoyl]phenyl}benzene)sulfonami do]-2-hydroxybenzoic acid,

4- { [3 -(4-acetylphenyl)benzene] sulfonamido} -2-hydroxybenzoic acid,

4- { [3 -(2,3 -dimethoxyphenyl)benzene] sulfonamido } -2-hydroxybenzoic acid,

4- {[3-(4-fluoro-2-methoxyphenyl)benzene]sulfonamido} -2-hydroxybenzoic acid,

2-hydroxy-4-{[3-(2,3,6-trifluorophenyl)benzene]sulfonamid o}benzoic acid,

4-( {3-[4-(2-carboxyethyl)phenyl]benzene} sulfonamido)-2-hydroxybenzoic acid,

2-hydroxy-4- { [3 -(3 -methylphenyl)benzene]sulfonamido } benzoic acid,

4- { [3 -(3 ,5 -difluorophenyl)benzene] sulfonamido } -2-hydroxybenzoic acid,

2-hydroxy-4- { [3 -(4-methoxy-3 ,5 -dimethylphenyl)benzene] sulfonamido } benzoic acid, 2-hydroxy-4- {[3-(2-methylphenyl)benzene]sulfonamido}benzoic acid,

2-hydroxy-4-{[3-(2-propoxypyridin-3-yl)benzene]sulfonamido}b enzoic acid,

4-{[3-(6-ethoxypyridin-3-yl)benzene]sulfonamido}-2-hydrox ybenzoic acid,

2-hydroxy-4-( {3-[4-(propan-2-yloxy)phenyl]benzene} sulfonamido)benzoic acid,

4-{[3-(4-butoxyphenyl)benzene]sulfonamido}-2-hydroxybenzo ic acid,

4-{[3-(3,4-dimethoxyphenyl)benzene]sulfonamido}-2-hydroxy benzoic acid,

2-hydroxy-4- { [3 -(6-methoxypyridin-3 -yl)benzene] sulfonamido } benzoic acid,

2-hydroxy-4-{[3-(morpholin-4-yl)benzene]sulfonamido}benzo ic acid,

2-hydroxy-4-(5-phenyl-2,3-dihydro- 1 -benzofuran-7-sulfonamido)benzoic acid,

4- {[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino} -2-hydroxybenzoic acid,

4-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-2-hydroxy-b enzoic acid,

4-(4,5-dichloro-thiophene-2-sulfonylamino)-2-hydroxy-benz oic acid,

4-(4-bromo-2,5-dichloro-thiophene-3-sulfonylamino)-2-hydr oxy-benzoic acid,

4-(3-difluoromethoxy-benzenesulfonylamino)-2-hydroxy-benz oic acid,

2-hydroxy-4-(3-methoxy-benzenesulfonylamino)-benzoic acid, 4-[5-(benzoylamino-methyl)-thiophene-2-sulfonylamino]-2-hydr oxy-benzoic acid,

4-(3-chloro-4-methyl-benzenesulfonylamino)-2-hydroxy-benz oic acid,

2-hydroxy-4-(4-methyl-3-nitro-benzenesulfonylamino)-benzo ic acid,

2-hydroxy-4-(2,3 ,4-trichloro-benzenesulfonylamino)-benzoic acid,

4-(4-fluoro-naphthalene- 1 -sulfonylamino)-2-hydroxy-benzoic acid,

4-(5-dimethylamino-naphthalene- 1 -sulfonylamino)-2-hydroxy-benzoic acid,

4-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonylamino)-2 -hydroxy-benzoic acid,

2-hydroxy-4-(3-pyridin-4-yl-benzenesulfonylamino)-benzoic acid,

4-(4'-fluoro-3'-methyl-biphenyl-3-sulfonylamino)-2-hydrox y-benzoic acid,

4-(3'-chloro-biphenyl-3-sulfonylamino)-2-hydroxy-benzoic acid,

4-(4'-carbamoyl-biphenyl-3-sulfonylamino)-2-hydroxy-benzoic acid,

4-(3'-fluoro-4'-methoxy-biphenyl-3-sulfonylamino)-2-hydro xy-benzoic acid,

4-[6-chloro-5-(4-hydroxy-phenyl)-pyridine-3-sulfonylamino ]-2-hydroxy-benzoic acid, 4-[6-chloro-5-(3-hydroxy-phenyl)-pyridine-3-sulfonylamino]-2 -hydroxy-benzoic acid, 4-[5-(3-amino-phenyl)-6-chloro-pyridine-3-sulfonylamino]-2-h ydroxy-benzoic acid,

4-[6-chloro-5-(lH-pyrazol-4-yl)-pyridine-3-sulfonylamino] -2-hydroxy-benzoic acid,

4-[6-chloro-5-(4-fluoro-3-methyl-phenyl)-pyridine-3-sulfo nylamino]-2-hydroxy-benzoic acid, 4-[6-chloro-5-(3-chloro-phenyl)-pyridine-3-sulfonylamino]-2- hydroxy-benzoic acid,

4- [6-chloro-5 -(2-fluoro-3 -methoxy-phenyl)-pyridine-3 -sulfonylamino] -2-hydroxy benzoic acid,

4-[5-(4-carbamoyl-phenyl)-6-chloro-pyridine-3-sulfonylamino] -2-hydroxy-benzoic acid, 4-[6-chloro-5-(3-fluoro-phenyl)-pyridine-3-sulfonylamino]-2- hydroxy-benzoic acid,

4-[6-chloro-5-(3-fluoro-4-methoxy-phenyl)-pyridine-3-sulf onylamino]-2-hydroxy benzoic acid,

4-(6-chloro-5-quinolin-6-yl-pyridine-3-sulfonylamino)-2-h ydroxy-benzoic acid,

4-(5-chloro-4-pyridin-3-yl-thiophene-2-sulfonylamino)-2-h ydroxy-benzoic acid,

4-[5-chloro-4-(3-hydroxy-phenyl)-thiophene-2-sulfonylamin o]-2-hydroxy-benzoic acid, 4- [5 -chloro-4-(4-hydroxy-3 -methoxy-phenyl)-thiophene-2-sulfonylamino] -2-hydroxy benzoic acid,

4-[5-chloro-4-(3-chloro-phenyl)-thiophene-2-sulfonylamino ]-2-hydroxy-benzoic acid,

4-[4-(4-carbamoyl-phenyl)-5-chloro-thiophene-2-sulfonylam ino]-2-hydroxy-benzoic acid,

4-[5-chloro-4-(3-fluoro-4-methoxy-phenyl)-thiophene-2-sul fonylamino]-2-hydroxy-benzoic acid, 4-[4-(4-amino-3-methoxy-phenyl)-5-chloro-thiophene-2-sulfony lamino]-2-hydroxy benzoic acid,

3'-(4-carboxy-3-hydroxy-phenylsulfamoyl)-biphenyl-2-carboxyl ic acid methyl ester 4-(5'-chloro-2'-methoxy-biphenyl-3-sulfonylamino)-2-hydroxy- benzoic acid,

4-(2',5'-difluoro-biphenyl-3-sulfonylamino)-2-hydroxy-ben zoic acid,

2-hydroxy-4-(2'-methoxy-biphenyl-3-sulfonylamino)-benzoic acid,

4-(2'-fluoro-3'-methoxy-biphenyl-3-sulfonylamino)-2-hydro xy-benzoic acid,

2-hydroxy-4-(2'-hydroxy-biphenyl-3-sulfonylamino)-benzoic acid,

4-(2'-amino-biphenyl-3-sulfonylamino)-2-hydroxy-benzoic acid,

4-(5'-fluoro-2'-methoxy-biphenyl-3-sulfonylamino)-2-hydro xy-benzoic acid,

4-[5-chloro-4-(5-chloro-2-methoxy-phenyl)-thiophene-2-sulfon ylamino]-2-hydroxy-benzoic acid,

4-[5-chloro-4-(2,5-difluoro-phenyl)-thiophene-2-sulfonylamin o]-2-hydroxy-benzoic acid, 4-[5-chloro-4-(2-methoxy-phenyl)-thiophene-2-sulfonylamino]- 2-hydroxy-benzoic acid, 4-[5-chloro-4-(2-fluoro-3-methoxy-phenyl)-thiophene-2-sulfon ylamino]-2-hydroxy-benzoic acid,

4-[4-(2-amino-phenyl)-5-chloro-thiophene-2-sulfonylamino]-2- hydroxy-benzoic acid,

4-[5-chloro-4-(5-fluoro-2-methoxy-phenyl)-thiophene-2-sul fonylamino]-2-hydroxy-benzoic acid,

4-[5-chloro-4-(2-hydroxy-phenyl)-thiophene-2-sulfonylamin o]-2-hydroxy-benzoic acid, 4-(4-bromo-2,5-difluoro-benzenesulfonylamino)-2-hydroxy-benz oic acid,

4-(biphenyl-4-sulfonylamino)-2-hydroxy-benzoic acid,

4-(benzo[b]thiophene-3-sulfonylamino)-2-hydroxy-benzoic acid,

4-(2,5-dichloro-4-methyl-thiophene-3-sulfonylamino)-2-hyd roxy-benzoic acid,

2-hydroxy-4-(2,4,5-trichloro-thiophene-3-sulfonylamino)-b enzoic acid,

4-(2-chloro-6-methyl-benzenesulfonylamino)-2-hydroxy-benz oic acid,

2-hydroxy-4-(3-trifluoromethoxy-benzenesulfonylamino)-ben zoic acid,

4-(benzofuran-2-sulfonylamino)-2-hydroxy-benzoic acid,

2-hydroxy-4-(5-methyl-2-trifluoromethyl-furan-3-sulfonyla mino)-benzoic acid,

4-(3-chloro-2-methyl-benzenesulfonylamino)-2-hydroxy-benz oic acid,

2-hydroxy-4-(5-isopropyl-3-methyl-benzo[b]thiophene-2-sulfon ylamino)-benzoic acid, 4- [4-(2,3 -dihydro-benzo furan-5 -yl)-thiophene-2-sulfonylamino] -2-hydroxy-benzoic acid, 2-hydroxy-4- [3 -( 1 -hydroxy-ethyl)-benzenesulfonylamino] -benzoic acid,

2-hydroxy-4-(3-hydroxy-benzenesulfonylamino)-benzoic acid, 2-hydroxy-4-(2-hydroxy-benzenesulfonylamino)-benzoic acid,

4-(4-chloro-phenylmethanesulfonylamino)-2-hydroxy-benzoic acid,

4-(3-bromo-phenylmethanesulfonylamino)-2-hydroxy-benzoic acid,

4-(4-bromo-phenylmethanesulfonylamino)-2-hydroxy-benzoic acid,

2-hydroxy-4-(2'-hydroxy-biphenyl-4-ylmethanesulfonylamino )-benzoic acid,

4- [4-(2,3 -dihydro-benzo furan-5 -yl)-phenylmethanesulfonylamino] -2-hydroxy-benzoic acid, 4-(2',5'-difluoro-biphenyl-4-ylmethanesulfonylamino)-2-hydro xy-benzoic acid,

4-(biphenyl-4-ylmethanesulfonylamino)-2-hydroxy-benzoic acid,

4- [3 -(2,3 -dihydro-benzo furan-5 -yl)-phenylmethanesulfonylamino] -2-hydroxy-benzoic Acid

4-(2',5'-difluoro-biphenyl-3-ylmethanesulfonylamino)-2-hydro xy-benzoic acid,

4-(3,5-dibromo-thiophene-2-sulfonylamino)-2-hydroxy-benzo ic acid,

4-(3,4-dibromo-thiophene-2-sulfonylamino)-2-hydroxy-benzo ic acid,

4-(4,5-dibromo-thiophene-2-sulfonylamino)-2-hydroxy-benzo ic acid,

4-(5-bromo-4-methyl-thiophene-2-sulfonylamino)-2-hydroxy- benzoic acid,

4-(5-chloro-4-methyl-thiophene-2-sulfonylamino)-2-hydroxy -benzoic acid,

4-(3-bromo-5-trifluoromethyl-benzenesulfonylamino)-2-hydr oxy-benzoic acid,

4-(2',5'-difluoro-5-trifluoromethyl-biphenyl-3-sulfonylam ino)-2-hydroxy-benzoic acid, 4- [3 -(2,3 -dihydro-benzo furan-5 -yl)-5 -trifluoromethyl-benzenesulfonylamino] -2-hydroxy- benzoic acid,

2-hydroxy-4-(2'-hydroxy-5-trifluoromethyl-biphenyl-3-sulfony lamino)-benzoic acid, 4-(3-chloro-2-fluoro-benzenesulfonylamino)-2-hydroxy-benzoic acid,

4-(5-chloro-2-fluoro-benzenesulfonylamino)-2-hydroxy-benz oic acid,

4-(2,5-dimethyl-furan-3-sulfonylamino)-2-hydroxy-benzoic acid,

4-[5-(2,5-difluoro-phenyl)-thiophene-2-sulfonylamino]-2-h ydroxy-benzoic acid,

4- [5 -(2,3 -dihydro-benzo furan-5 -yl)-thiophene-2-sulfonylamino] -2-hydroxy-benzoic acid, 2-hydroxy-4-(5-phenyl-thiophene-2-sulfonylamino)-benzoic acid,

2-hydroxy-4-[5-(2-hydroxy-phenyl)-thiophene-2-sulfonylami no]-benzoic acid,

2-hydroxy-4-[(4-phenoxybenzene)sulfonamido]benzoic acid,

2-hydroxy-4-(3-nitro-benzenesulfonylamino)-benzoic acid,

4-(4-carboxy-benzenesulfonylamino)-2-hydroxy-benzoic acid,

4-(3-bromo-5-chloro-thiophene-2-sulfonylamino)-2-hydroxy- benzoic acid,

4-(4-bromo-thiophene-3-sulfonylamino)-2-hydroxy-benzoic acid, or a pharmaceutically acceptable salt thereof.

Preferably, the novel compound of the invention is a compound selected from

4- [(biphenyl-3 -ylsulfonyl)amino] -2-hydroxybenzoic acid,

2-hydroxy-4-({[5-(trifluoromethyl)biphenyl-3-yl]sulfonyl} amino)benzoic acid,

4- {[(5-chloro-4-phenyl-2-thienyl)sulfonyl]amino} -2-hydroxybenzoic acid,

4- { [(3 '-fluorobiphenyl-3 -yl)sulfonyl] amino } -2-hydroxybenzoic acid,

4-{[(2',6'-difluorobiphenyl-3-yl)sulfonyl]amino}-2-hydrox ybenzoic acid,

2-hydroxy-4-({[3'-(isopropoxycarbonyl)biphenyl-3-yl]sulfo nyl}amino)benzoic acid, 4-( {[3-(2,3-dihydro- 1 -benzofuran-5-yl)phenyl]sulfonyl} amino)-2-hydroxybenzoic acid, 4- {[(3 '-fluoro-4'-hydroxybiphenyl-3-yl)sulfonyl]amino} -2-hydroxybenzoic acid,

2-hydroxy-4- { [(3 -quino lin-6-ylphenyl)sulfonyl]amino } benzoic acid,

4- {[(3 '-aminobiphenyl-3-yl)sulfonyl]amino} -2-hydroxybenzoic acid,

2-hydroxy-4-({[3-(2 -methyl- l,3-thiazol-4-yl)phenyl]sulfonyl}amino)benzoic acid, 4-( {[5-chloro-4-(2,3-dihydro- 1 -benzofuran-5-yl)-2-thienyl]sulfonyl} amino)-2- hydroxybenzoic acid,

4-({[5-chloro-4-(3-fluoro-4-hydroxyphenyl)-2-thienyl]sulfony l}amino)-2-hydroxybenzoic acid,

4- {[(5-chloro-4-quinolin-6-yl-2-thienyl)sulfonyl]amino} -2-hydroxybenzoic acid,

4-({[4-(l,3-benzodioxol-5-yl)-5-chloro-2-thienyl]sulfonyl }amino)-2-hydroxybenzoic acid, 4-({[5-chloro-4-(4-hydroxy-3,5-dimethylphenyl)-2-thienyl]sul fonyl}amino)-2- hydroxybenzoic acid,

4-({[5-chloro-4-(2,4-difluorophenyl)-2-thienyl]sulfonyl}amin o)-2-hydroxybenzoic acid, 4-({[4-(3-acetylphenyl)-5-chloro-2-thienyl]sulfonyl}amino)-2 -hydroxybenzoic acid, 4-[({5-chloro-4-[2-(hydroxymethyl)phenyl]-2-thienyl}sulfonyl )amino]-2-hydroxybenzoic acid,

4-({[5-chloro-4-(3-fluorophenyl)-2-thienyl]sulfonyl}amino)-2 -hydroxybenzoic acid, 4-[({5-chloro-4-[3-(isopropoxycarbonyl)phenyl]-2-thienyl}sul fonyl)amino]-2- hydroxybenzoic acid,

4-({[5-chloro-4-(3,5-difluorophenyl)-2-thienyl]sulfonyl}amin o)-2-hydroxybenzoic acid, 4-({[5-chloro-4-(6-ethoxypyridin-3-yl)-2-thienyl]sulfonyl}am ino)-2-hydroxybenzoic acid, 4-({[4-(3-aminophenyl)-5-chloro-2-thienyl]sulfonyl}amino)-2- hydroxybenzoic acid, 4-({[5-chloro-4-(4-methoxyphenyl)-2-thienyl]sulfonyl}amino)- 2-hydroxybenzoic acid, 4-({[4-(4-aminophenyl)-5-chloro-2-thienyl]sulfonyl}amino)-2- hydroxybenzoic acid, tri- fluoroacetate (salt)

4-({[5-chloro-4-(4-hydroxyphenyl)-2-thienyl]sulfonyl}amino)- 2-hydroxybenzoic acid, 4-[({5-chloro-4-[3-(hydroxymethyl)phenyl]-2-thienyl}sulfonyl )amino]-2-hydroxybenzoic acid,

4-[({5-chloro-4-[4-(hydroxymethyl)phenyl]-2-thienyl}sulfonyl )amino]-2-hydroxybenzoic acid,

4-({[4-(3-amino-4-methoxyphenyl)-5-chloro-2-thienyl]sulfonyl }amino)-2-hydroxybenzoic acid, trifluoroacetate (salt)

4- {[(5-chloro-4- {4-[(methylsulfonyl)amino]phenyl} -2-thienyl)sulfonyl] amino} -2- hydroxybenzoic acid,

4- [ [3 -(3 -ethoxyphenyl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid,

4- [ [3 -(3 -acetamidophenyl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid,

4-{[3-(2h-l,3-benzodioxol-5-yl)benzene]sulfonamido}-2-hyd roxybenzoic acid,

4-{[3-(2,4-difluorophenyl)benzene]sulfonamido}-2-hydroxyb enzoic acid,

2-hydroxy-4-{[3-(2-nitrophenyl)benzene]sulfonamido}benzoi c acid,

4- { [3 -(3 ,5 -difluorophenyl)benzene] sulfonamido } -2-hydroxybenzoic acid,

4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-2-hydroxy benzoic acid,

4-(4,5-dichloro-thiophene-2-sulfonylamino)-2-hydroxy-benz oic acid,

4-(3-bromo-thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid,

4-(4-bromo-2,5-dichloro-thiophene-3-sulfonylamino)-2-hydroxy -benzoic acid,

4-(4-fluoro-naphthalene- 1 -sulfonylamino)-2-hydroxy-benzoic acid,

4-[5-chloro-4-(3-hydroxy-phenyl)-thiophene-2-sulfonylamin o]-2-hydroxy-benzoic acid, 4- [5 -chloro-4-(4-hydroxy-3 -methoxy-phenyl)-thiophene-2-sulfonylamino] -2-hydroxy benzoic acid,

4-[4-(4-carbamoyl-phenyl)-5-chloro-thiophene-2-sulfonylamino ]-2-hydroxy-benzoic acid,

4-[5-chloro-4-(3-fluoro-4-methoxy-phenyl)-thiophene-2-sul fonylamino]-2-hydroxy-benzoic acid,

4-(2',5'-difluoro-biphenyl-3-sulfonylamino)-2-hydroxy-benzoi c acid,

4-(2'-fluoro-3'-methoxy-biphenyl-3-sulfonylamino)-2-hydro xy-benzoic acid,

2-hydroxy-4-(2'-hydroxy-biphenyl-3-sulfonylamino)-benzoic acid,

4-[5-chloro-4-(5-chloro-2-methoxy-phenyl)-thiophene-2-sulfon ylamino]-2-hydroxy-benzoic acid,

4-[5-chloro-4-(2,5-difluoro-phenyl)-thiophene-2-sulfonylamin o]-2-hydroxy-benzoic acid, 4-[5-chloro-4-(2-methoxy-phenyl)-thiophene-2-sulfonylamino]- 2-hydroxy-benzoic acid,

4-[5-chloro-4-(2-fluoro-3-methoxy-phenyl)-thiophene-2-sul fonylamino]-2-hydroxy-benzoic acid,

4-[5-chloro-4-(5-fluoro-2-methoxy-phenyl)-thiophene-2-sulfon ylamino]-2-hydroxy-benzoic acid,

4-[5-chloro-4-(2-hydroxy-phenyl)-thiophene-2-sulfonylamino]- 2-hydroxy-benzoic acid, 4-(benzo[b]thiophene-3-sulfonylamino)-2-hydroxy-benzoic acid,

4-(2,5-dichloro-4-methyl-thiophene-3-sulfonylamino)-2-hyd roxy-benzoic acid,

2-hydroxy-4-(2,4,5-trichloro-thiophene-3-sulfonylamino)-b enzoic acid,

2-hydroxy-4-(5-methyl-2-trifluoromethyl-furan-3-sulfonyla mino)-benzoic acid,

2-hydroxy-4-(2'-hydroxy-biphenyl-4-ylmethanesulfonylamino )-benzoic acid,

4-(3,5-dibromo-thiophene-2-sulfonylamino)-2-hydroxy-benzo ic acid,

4-(3,4-dibromo-thiophene-2-sulfonylamino)-2-hydroxy-benzo ic acid,

4-(4,5-dibromo-thiophene-2-sulfonylamino)-2-hydroxy-benzo ic acid,

4-(5-bromo-4-methyl-thiophene-2-sulfonylamino)-2-hydroxy- benzoic acid,

4-(5-chloro-4-methyl-thiophene-2-sulfonylamino)-2-hydroxy -benzoic acid,

4-(3 ,5-dichloro-benzenesulfonylamino)-2-hydroxy-benzoic acid,

4-(3-bromo-5-trifluoromethyl-benzenesulfonylamino)-2-hydr oxy-benzoic acid,

4-(3-bromo-5-chloro-thiophene-2-sulfonylamino)-2-hydroxy- benzoic acid,

or a pharmaceutically acceptable salt thereof.

As indicated herein above, the present invention also provides novel compounds. Thus, according to this aspect, the present invention provides a compound.

Examples of pharmaceutically acceptable salts of the compounds of the invention include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphos- phoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulphonic acids.

It should be understood that any optical isomer or diastereomer of the inventive compounds are comprised within the scope of the invention, as well as any mixture, racemic or not, of any such isomers. The compounds of the present invention may act as inhibitors of the PFKFB3 and/or PFKFB4 protein. In some embodiments, the compounds of the above formula can exhibit a PFKFB3 and/or PFKFB4 inhibiting activity corresponding to an IC ₅₀ of from about 50 nM to about 15 μΜ (e.g., from about 50 nM to about 13 μΜ, from about 50 nM to about 10 μΜ, from about 50 nM to about 500 nM, from about 50 nM to about 100 nM) or a lower concentration as tested in an conventional assay as will be described below. While not wishing to be bound by theory, it is believed that the compounds described herein, by virtue of their PFKFB3 and/or PFKFB4 inhibitory activity, can be used, e.g., for the treatment or prevention of cancer and inflammation, and/or in treatment of disorders related to cancer and inflammation.

Of particular interest are tumors with elevated glucose uptake compared to normal nontumor tissues, identified by for example PET studies. These tumors include, but are not limited to breast cancer, lung cancer, prostate cancer, colorectal cancers, haematological cancers and malignant melanoma.

In a further aspect the present invention relates to a method for the treatment or prophylaxis of a disease, disorder, or condition related to undesired activity of PFKFB3 and/or PFKFB4. The method includes administering to a subject (e.g., a subject in need thereof, e.g., a mammal; e.g., a human; e.g., a human having, identified as having, at risk of having, or identified as being at risk of having one or more of the diseases or disorders described herein) an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

In one aspect, this invention relates to a method for the treatment or prophylaxis of cancer, which includes administering to a subject (e.g., a subject in need of such treatment as described herein) an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a method for the treatment or prophylaxis (e.g., treatment) of inflammation, which includes administering to a subject (e.g., a subject in need of such treatment as described herein) an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject can be a subject in need of treatment of inflammation (e.g., a subject identified as being in need of such treatment as described herein). Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method). In some embodiments, the subject can be a mammal. In certain embodiments, the subject is a human.

In a further aspect, this invention relates to the use of a compound of formula I (e.g., as a medicament) or in the manufacture of a medicament containing a compound of formula I for the treatment or prophylaxis (e.g., treatment) of a disease, disorder, or condition related to unde- sired activity of PFKFB3 and/or PFKFB4 as described herein.

In one aspect, the invention relates to a compound (including a pharmaceutically acceptable salt thereof) of any of the formulae delineated herein (e.g., a compound having formula I, (or subgenera thereof), including the specific compounds described herein); or a composition or formulation (e.g., a pharmaceutical composition or formulation) comprising a compound (including a pharmaceutically acceptable salt thereof) of any of the formulae delineated herein (e.g., a compound having formula I (or subgenera thereof), including the specific compounds described herein). In some embodiments, the composition or formulation can further include a pharmaceutically acceptable adjuvant, carrier or diluent. Any such compound can be used in the methods described herein.

In some embodiments, the compound of the present invention may be administered in combination with at least one other therapeutically active compound. Thus, compounds of the present invention may be used or administered in combination with one or more additional drugs useful in the treatment of inflammation or cancer. The components may be in the same formu- lation or in separate formulations for administration simultaneously or at different times. The compounds of the present invention may also be used or administered in combination with other treatment such as irradiation for the treatment of cancer.

The dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the mammal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the purpose of the treatment, the potency of the specific compound, the age, condition and body weight of the patient, as well as the stage/severity of the disease. The dose will also be determined by the route (administration form) timing and frequency of administration. One object of the present invention is to provide a pharmaceutical composition comprising a compound according to formula (I), and optionally at least one pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be e.g. a carrier, a solvent, or a diluent, such as is well-known to those who are skilled in the art and readily available to the public. The pharmaceutically acceptable carrier may be one that is chemically inert to the active compounds and that has no detrimental side effects or toxicity under the conditions of use. Pharmaceutical formulations are found e.g. in Remington: The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995).

Pharmaceutical formulations are usually prepared by mixing the active substance, i.e. a compound of the invention, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutical excipients. The formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc. The formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections. Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated in a conventional manner.

For clinical use, the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. These pharmaceutical preparations are a further object of the invention. Usually the amount of active compounds is between 0.1-95% by weight of the preparation, preferably between 0.2-20% by weight in preparations for parenteral use and preferably between 1 and 50% by weight in preparations for oral administration.

The dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated, and the patient undergoing therapy. The daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen. In the preparation of pharmaceutical formulations containing a compound of the present invention in the form of dosage units for oral administration the compound selected may be mixed with solid, powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into granules or pressed into tablets.

Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Hard gelatine capsules may contain granules of the active compound. Hard gelatine capsules may also contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatine.

Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.

Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.2% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.

Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent, preferably in a concentration from 0.1% to 10% by weight. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.

A brief review of methods of drug delivery is also found in e.g. Langer, Science 249: 1527- 1533 (1990). The invention will now be further illustrated by the following non-limiting Examples. The specific examples below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. The necessary starting materials for preparing the compounds of formula I are either known or may be prepared, by a person skilled in the art, in analogy with the preparation of known compounds. All references and publications cited herein are hereby incorporated by reference in their entirety.

The compounds of the invention may be prepared according to known methods for those skilled in the art. For example, the sulfone amides were prepared from aryl sulfonyl chlorides and anilines following any of the three methods illustrated in Scheme 1. The sulfonyl chlorides of substituted aryls and anilines were allowed to react at room temperature or 50-60 °C until the sulfone amide coupling reactions were completed. When methyl 4-aminosalicylate was used as starting material, the sulfone amide coupling was followed by alkaline hydrolysis at 50 °C.

Scheme 1

a) Pyridine (dry), CH ₂ CI ₂ (dry), room temp b) aq. dioxane, room temperature, c) pyridine, MeCN, 50-60 °C d) aq. NaOH, 50 °C. A=S, O or CR=CR

The biaryl compounds (wherein A is S or CR ⁴ =CR ⁴ ) were prepared by Suzuki couplings (steps c or d, Scheme 2) either in a micro wave reactor according to modifications of the procedures described by Zhang et al. and Jiang et al. (Zhang et al., (2004) Org. Lett. 6, 1473- 1476; Jiang et al., (2006) Tetrahedron Lett. 47, 197-200) or at 80 °C using conventional heating over night. The same synthetic procedures should be applicable for biaryl compounds with A=0.

Scheme 2

a) Pyridine (dry), CH ₂ CI ₂ (dry), room temp b) aq. dioxane, room temp, c) Aryl boronic acid, K ₂ CO ₃ (aq), Pd(dppf)Cl ₂ :CH ₂ Cl ₂ , dioxane 145 °C for 900 s in a microwave reactor, d) Aryl boronic acid, K ₂ C0 ₃ or DIPEA, Pd(dppf)C12:CH2C12, aq. dioxane 80 °C over night e) Pyridine (dry), CH ₂ CI ₂ (dry), 60 °C (sealed tube) f) pyridine, MeCN, 50-60 °C g) aq. NaOH, 50 °C. A=S or CR=CR.

The benzothiophene sulfonyl chlorides were synthesized according to Scheme 3 as described in by Pie et al. (Pie et al, (1988) J. Heterocyclic Chem. 25, 1271-1272). Alkylation of substituted thiophenols with chloroacetone, followed by a two-phase cyclization of the ketones gave 5- and 7-substituted 3-methylbenzothiophenes. The preparation of the sulfonyl chlorides were performed either by a two step procedure (S0 ₃ /dioxane complex or H ₂ SO ₄ /AC ₂ O followed by POCl ₃ or SOCI ₂ ) or with chlorosulfonic acid. Regarding the handling and use of S0 ₃ /dioxane- complex see Paquette, Encyclopedia of Reagents for Organic Synthesis and references therein.

Scheme 3

a) chloroacetone, K ₂ CO ₃ or NaHC0 ₃ , acetone, reflux b) polyphosphoric acid, chlorobenzene, reflux c) S0 ₃ /dioxane-complex, 1 ,2-dichloroethylene or H ₂ SO ₄ /AC ₂ O, EtOAc d)

P0C1 ₃ /CH ₂ C1 ₂ , 60° or SOCl ₂ , DMF, e) Chlorosulfonic acid, chloroform, 0°C.

A substituted benzofurane was synthesized from 4-isopropylphenol in three steps according to Scheme 4 (Xie et al, (2004) Tetrahedron Lett. 45, 6235-6237). Iodination of 4-z ^' Pr-phenol with N-iodo-succinimide and allylation with allylbromide followed by a palladium mediated Heck coupling gave 3-methyl-5-z ^' Pr-benzofuran. The corresponding sulfonyl chloride was thereafter prepared with H ₂ SO ₄ /AC ₂ O in EtOAc according to the sulfonylation reactions described in Scheme 3 (Graham et al, (1990) J. Med. Chem. 33, 749-754).

Scheme 4 a) N-iodosuccinimide, p-TsOH, CH ₂ CI ₂ , room temp over night, b) allylbromide, K ₂ C0 ₃ ,THF, reflux, 24 h. c) NBu ₃ , ammoniumformate, PdCl ₂ , l-butyl-3-metylimidazolium- tetrafluoroborate, 60 °C over night. The introduction of amine moieties were performed via palladium catalysed coupling described by Harris et al. (Harris et al., (2002) Org. Lett. 4, 2885-2888) as outlined in Scheme 5.

Scheme 5

a) Amine, tris(dibenzylideneacetone)dipalladium(0), 2-dicyclohexylphosphino-2 ^' -(N,N- dimethylamino)biphenyl, LiHMDS, 130°C 1000s in a micro wave reactor.

EXAMPLES

Preparative HPLC/MS was performed on a Waters/Micromass Platform ZQ system and preparative HPLC/UV was performed on a Gilson system in accordance to the experimental de- tails specified in the examples. Analytical HPLC/MS was performed using an Agilent

1100/1200 Series Liquid Chromatograph/Mass Selective Detector (MSD) (Single Quadru- pole) (1946A/1946C/1956C/6110) equipped with an electrospray interface. GC-MS was performed on a Hewlett-Packard 5890/6890 gas chromatograph equipped with a HP-5MS cross- linked 5% PhMe Siloxane column (30 m x 0.25 mm x 0.25 μιη film thickness) with a

Hewlett-Packard 5971A/5972A mass selective detector using EI. Preparative flash chromatography was performed on Merck silica gel 60 (230-400 mesh). The compounds were named using ACD Name 6.0 or ISIS Draw 2.4. Microwave reactions were performed with a Personal Chemistry Smith Creator or Optimizer using 0.5-2 mL or 2-5 mL Smith Process Vials fitted with aluminum caps and septa. Accurate masses were measured using an Agilent MSD-TOF connected to an Agilent 1100 HPLC system. During the analyses the calibration was checked by two masses and automatically corrected when needed. Spectra were acquired in positive electrospray mode. The acquired mass range was m/z 100-1100. Profile detection of the mass peaks was used. Intermediate 1

-{[(3-bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid

The product was prepared according to the procedure described for Intermediate 2. 4- aminosalicylic acid (0.57 g, 3.7 mmol) and 3-bromobenzenesulfonyl chloride (0.87 g, 3.4 mmol) were stirred at room temperature over night giving 0.41 g of the title compound as light brown solid (32%). 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 6.64 (d, J=2.20 Hz, 1 H) 6.69 (dd, J=8.67, 2.08 Hz, 1 H) 7.56 (t, J=8.06 Hz, 1 H) 7.66 (d, J=8.55 Hz, 1 H) 7.81 - 7.84 (m, 1 H) 7.86 - 7.91 (m, 1 H) 7.96 (t, J=1.71 Hz, 1 H) 10.94 (s, 1 H) 11.36 (br. s., 1 H); MS (ESI+) 372 [M+H].

Intermediate 2

-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-2-hydroxybenz oic acid

A mixture of 4-amino salicylic acid (0.57 g, 3.7 mmol) and 3-bromo-2-chlorothiophene-5- sulfonyl chloride (1.0 g, 3.4 mmol) in aqueous dioxane (50 mL dioxane, 50 mL H ₂ 0) was stirred at room temperature for 3 days. 100 mL EtOAc was added. The organic phase was washed with 1 M HCl (3x 50 mL), H ₂ 0 and Brine and then dried over MgS0 ₄ , filtered and concentrated. The brown residue was crystallized from H ₂ 0/MeOH at 50 °C. The precipitate was collected by filtration and dried in vacuum giving the title compound as a light brown solid (0.64 g, 43%). 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 6.71 (d, J=2.20 Hz, 1 H) 6.75 (dd, J=8.55, 2.20 Hz, 1 H) 7.72 (d, J=8.55 Hz, 1 H) 7.80 (s, 1 H) 11.26 (br. s., 1 H) 11.39 (br. s., 1 H); MS (ESI+) 412 [M+H]. Intermediate 3

7-chloro-3-methyl-l-benzothiophene

A mixture of o-chloro-thiophenol (956 mg, 6.6 mmol), chloroacetone (1.1 mL, 13.8 mmol) and K ₂ CO ₃ (1.8 g, 13 mmol) in acetone (15 mL) was re fluxed for 2 h. The mixture was filtered and the solvent evaporated. The crude product was dissolved in chlorobenzene (30 mL), polyphosphoric acid (0.5 g) was added and the resulting mixture was refluxed over night (Pie et al, (1988) J. Heterocyclic Chem. 25, 1271-1272). Additional PPA (0.5 g) was added and the reaction mixture was refluxed for 7 h. The solvent was decanted from the PPA-residue, the residue was treated with CH ₂ CI ₂ and the combined organic extracts were washed with

H ₂ 0, dried and evaporated. The crude product was purified on silica, eluting with heptane, to give 770 mg of the title compound (64% over two steps). 1H NMR (400 MHz, chloroform-<i) δ ppm 2.45 (d, J=l .00 Hz, 3 H) 7.15 (d, J=0.75 Hz, 1 H) 7.36 (d, J=2.26 Hz, 1 H) 7.37 (s, 1 H) 7.64 (dd, J=5.52, 3.51 Hz, 1 H).

Intermediate 4

7-Chloro-3-methyl-l-benzothiophene-2-sulfonyl chloride

A solution of 7-chloro-3-methyl-l-benzothiophene (Intermediate 3) (360 mg, 2.0 mmol), AC ₂ O (600 μί, 6.3 mmol) and cone. H ₂ SO ₄ (115 μί) in EtOAc (5 mL) was shaken for 4 h at room temperature, then diluted with more EtOAc and washed with a small amount of H ₂ O. The aqueous phase was extracted several times with EtOAc and the combined organic phases were dried and evaporated. The crude product was dissolved in EtOAc (50 mL) and the product was precipitated with KOAc (200 mg in EtOH, 3 mL). Since little precipitate was formed more KOAc (200 mg in EtOH, 3 mL) was added, followed by Et ₂ 0 (100 mL). The potassium 7-chloro-3-methyl-l-benzothiophene-2-sulfonate was collected and dried in vacuum. Gave 0.76 g. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.50 (s, 3 H) 7.40 - 7.46 (m, 1 H) 7.46 - 7.50 (m, 1 H) 7.73 (dd, J=7.65, 0.88 Hz, 1 H).

A mixture of potassium 7-chloro-3-methyl-l-benzothiophene-2-sulfonate (100 mg, 0.34 mmol) in POCI ₃ (5 mL) was heated at 60 °C over night. The POCI ₃ was evaporated and the crude product was purified on a small amount of silica eluting with CH ₂ CI ₂ to give 58 mg of the title compound.

Intermediate 5

(4-(3-carboxy-benzenesulfonylamino)-2-hydroxy-benzoic acid methyl ester

A solution of methyl 4-amino-2-hydroxy-benzoate (200 mg, 1.33 mmol), 3-(chlorosulfonyl) benzoic acid (220 mg, 1 mmol) and pyridine (0.65 mL) in dry CH ₂ CI ₂ (10 mL) was stirred at room temperature over night. The reaction mixture was diluted with CH ₂ CI ₂ and washed with HCl. The crude material was purified on silica gel (CHCI ₃ with MeOH (1%) and formic acid (0.5%) as eluent) giving 100 mg (yield 21%) of (4-(3-carboxy-benzenesulfonylamino)-2- hydroxy-benzoic acid methyl ester. H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.81 (s, 3 H) 6.69 (dd, J=8.16, 2.26 Hz, 1 H) 6.68 - 6.69 (m, 1 H) 7.63 - 7.67 (m, 1 H) 7.73 (td, J=7.88, 0.38 Hz, 1 H) 8.05 (ddd, J=7.88, 1.98, 1.13 Hz, 1 H) 8.16 (ddd, J=7.88, 1.51, 1.13 Hz, 1 H) 8.35 (ddd, J=1.98, 1.51, 0.38 Hz, 1 H) 10.57 (s, 1 H) 11.00 (br. s., 1 H); MS (ESI+) 352 [M+H].

Intermediate 6

-(5-Bromo-6-chloro-pyridine-3-sulfonylamino)-2-hydroxy-benzo ic acid

A mixture of 4-amino salicylic acid (0.57 g, 3.7 mmol) and 3-bromo-2-chloropyridine-5- sulfonyl chloride (1.0 g, 3.4 mmol) in aqueous dioxane (50 mL dioxane, 50 mL H ₂ 0) was stirred at room temperature over night. The precipitate was collected by filtration, washed with H ₂ 0 and dried in vacuum giving the title compound as a white solid (0.59 g, 38%). 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 6.68 (d, J=2.20 Hz, 1 H) 6.73 (dd, J=8.67, 2.08 Hz, 1 H) 7.69 (d, J=8.55 Hz, 1 H) 8.55 (d, J=2.20 Hz, 1 H) 8.80 (d, J=2.20 Hz, 1 H) 11.12 (br. s., 1 H) 11.37 (br. s., 1 H); MS (ESI+) 407 [M+H].

Intermediate 7

7-Methox -3-methyl-benzo[b]thiophene-2-sulfonyl chloride

A mixture of 2-methoxythiophenol (915 mg, 6.5 mmol), chloroacetone (1.1 mL, 13.8 mmol) and K ₂ CO ₃ (1.8 g, 13 mmol) in acetone (15 mL) was refluxed for 2 h. The mixture was filtered and the solvent evaporated. The crude product was dissolved in chlorobenzene (30 mL) and polyphosphoric acid (PPA, 0.5 g) was added (Pie et al., (1988) J. Heterocyclic Chem. 25, 1271-1272). The resulting mixture was heated at 100°C over night, and then refluxed for 5 h. The solvent was decanted from the PPA-residue. The residue was then treated with CH ₂ CI ₂ and the combined organic extracts were washed with ¾0 and dried before the solvents were evaporated. The crude product was purified on silica using heptane as eluent, to give 7- methoxy-3-methylbenzothiophene (620 mg, 53% over two steps). 1H NMR (400 MHz, chlo- rofornw ) δ ppm 2.44 (d, 3 H) 4.02 (s, 3 H) 6.81 (dd, 1 H) 7.07 (d, 1 H) 7.35 (s, 1 H) and 7.36 (d, 1 H).

A solution of 7-methoxy-3-methylbenzothiophene (365 mg, 2.0 mmol), AC ₂ O (900 μί, 9.45 mmol) and cone. H ₂ SO ₄ (170 μί) in EtOAc (5 mL) was shaken for 9 h at room temperature, then diluted with more EtOAc. The product was precipitated with KOAc (300 mg in EtOH, 5 mL). The solid was collected and dried and gave 0.62 g (100%) of potassium 7-methoxy-3- methyl-l-benzothiophene-2-sulfonate. 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.46 (s, 3 H) 3.93 (s, 3 H) 6.93 (dd, 1 H) and 7.28 - 7.37 (m, 2 H). A mixture of potassium 7-methoxy-3 -methyl- l-benzothiophene-2-sulfonate (100 mg, 0.34 mmol) in POCI ₃ (5 mL) was heated at 60 °C over night. The POCI ₃ was evaporated and the crude product was purified on a small amount of silica eluting with CH ₂ CI ₂ to give the title compound in 46% yield (43 mg). Intermediate 8

5-Methoxy-3-methyl-benzo [b] thiophene-2-sulfonyl chloride

A mixture of 4-methoxythiophenol (2.8 g, 20 mmol), K ₂ CO ₃ (5.5 g, 40 mmol) and chloroace- tone (6.6 mL, 82 mmol) in acetone (50 mL) was heated at reflux over night. The reaction mix- ture was filtered and the solvent was evaporated giving 5.0 g crude product. The intermediate thioether was dissolved in chlorobenzene (50 mL) and polyphosphoric acid (PPA, 0.5 g) was added (Pie et ah, (1988) J. Heterocyclic Chem. 25, 1271-1272). The reaction mixture was refluxed over night. The solvent was decanted and the PPA residue was treated with CH ₂ CI ₂ and the combined organic extracts were washed with ¾0 and dried before the solvents were evaporated. The crude product was purified on silica using heptane as eluent to give 5- methoxy-3-methyl-l-benzothiophene (0.96 g, 27% over two steps). 1H NMR (400 MHz, chlo- rofornw ) δ ppm 2.42 (d, 3 H) 3.91 (s, 3 H) 7.02 (dd, 1 H) 7.09 (s, 1 H) 7.15 (d, 1 H) 7.72 (d, 1 H).

A solution of 5 -methoxy-3 -methyl- 1-benzothiophene (360 mg, 2.0 mmol), AC ₂ O (600 μί, 6.3 mmol) and cone. H ₂ SO ₄ (115 μί) in EtOAc (5 mL) was shaken for 4 h at room temperature and then diluted with EtOAc. The potassium salt of the product was precipitated by addition of KOAc (196 mg) in EtOH (3 mL). The crystals were collected and dried giving 0.47 g of potassium 5-methoxy-3-methyl-l-benzothiophene-2-sulfonate (yield 80%). 1H NMR (400 MHz, DMSO-dg) δ ppm 2.46 (s, 3 H) 3.83 (s, 3 H) 6.99 (dd,l H) 7.17 (d, 1 H) 7.72 (d, 1 H). A mixture of potassium 5-methoxy-3-methyl-l-benzothiophene-2-sulfonate (100 mg, 0.34 mmol) in POCI ₃ (5 mL) was heated at 60 °C over night. The POCI ₃ was evaporated and the remaining crude product was purified on a small amount of silica using CH ₂ CI ₂ as eluent to give 80 mg (90%) of the title compound. Intermediate 9

5-Iso ropyl-3-methyl-benzofuran-2-sulfonyl chloride

A solution of 4-isopropylphenol (5.09 g, 37.4 mmol), N-iodosuccinimide (8.4 g, 37.4 mmol) and p-TsOH (700 mg, 3.7 mmol) in CH ₂ CI ₂ (200 mL) was stirred at room temperature over night. The reaction mixture was diluted with CH ₂ CI ₂ and washed with H ₂ O. The organic phase was dried and evaporated and gave 9.52 g of 2-iodo-4-isopropylphenol (98%> yield). 1H NMR (400 MHz, chloroform-;/) δ ppm 1.22 (d, 6 H) 2.82 (spt, 1 H) 6.92 (d, 1 H) 7.11 (dd, 1 H) 7.50 (d, 1 H). MS (ESI+) 261 [M+H].

A mixture of 2-iodo-4-isopropylphenol (9.52 g, 37.4 mmol), allylbromide (12 mL) and K ₂ CO ₃ (10 g, 72.3 mmol) in THF (200 mL) was refluxed for 24 h and then stirred at room temperature for 48 h. The reaction mixture was filtered and the solvent evaporated. The resulting crude material was purified on silica gel (heptane: CH ₂ CI ₂ 3:2 as eluent), giving 10.33 g of allyl-2-iodo-4-isopropylphenyl ether (yield 94%>).

According to the method described by Xie et al. (Xie et al, (2004) Tetrahedron Lett. 45, 6235-6237) a mixture of allyl 2-iodo-4-isopropylphenyl ether (10.33 g, 34.2 mmol), NBu ₃ (12 mL, 51 mmol), ammoniumformate (2.25 g, 35.7 mmol) and PdCi ₂ (500 mg, 2.82 mmol) in 1- butyl-3-metylimidazolium-tetrafluoroborate (50 mL) was heated at 60 °C over night. A second portion of PdCi ₂ (560 mg, 3.16 mmol) was added and the mixture was heated at 60 °C over night. A third portion of PdCi ₂ (280 mg, 1.58 mmol) was added and the reaction mixture was heated at 70 °C for 4 h. The organic liquid was extracted with heptane. Evaporation of the solvent afforded 9.97 g crude product, which still contained some amine. An analytical sample was purified on silica eluting with heptane to give the 5 -isopropyl-3 -methyl- 1- benzofuran. 1H NMR (400 MHz, chloroform-^/) δ ppm 1.32 (d, 6 H) 2.25 (d, 3 H) 3.04 (spt, 1 H) 7.18 (dd, l H) 7.38 (m, 3 H).

Crude 5-isopropyl-3-methyl-l-benzofuran (8.7 g, 50 mmol) was dissolved in EtOAc (100 mL) and Ac ₂ 0 (14 mL, 148 mmol) was added. Cone H ₂ SO ₄ (3 mL, 53 mmol) was added drop wise. The mixture was stirred at room temperature for 1 h. The product was precipitated by the dropwise addition of KOAc (5.0 g) in EtOH (50 mL) and separated by centrifugation. The solvent was decanted giving 5.02 g of potassium 5 -isopropyl-3 -methyl- l-benzofuran-2- sulfonate (39%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.25 (d, J=7.03 Hz, 6 H) 2.33 (s, 3 H) 3.00 (spt, 1 H) 7.21 (dd, J=8.66, 1.38 Hz, 1 H) 7.36 - 7.41 (m, 2 H). The NMR spectra showed 2.7 equiv of EtOH in the crystals. The potassium salt of 5-isopropyl-3-methyl-l-benzofuran-2-sulfonic acid (100 mg, 0.34 mmol) was mixed with POCI ₃ (5 mL) and the reaction mixture was heated at 60 °C over night. The POCI ₃ was evaporated and the crude product was dissolved in CH ₂ C1 ₂ and passed through a small amount of silica to give the title compound (30 mg, yield 33%).

Intermediate 10

-Fluoro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride

A solution of commercially available 5-fluoro-3-methyl-l-benzothiophene (215 mg, 1.29 mmol), Ac ₂ 0 (365 μί, 3.86 mmol) and cone. H ₂ SO ₄ (83 μί) in EtOAc (4 mL) was shaken over night at room temp. The reaction mixture was diluted with EtOAc, washed with H ₂ 0 and Brine and then dried. Evaporation of the solvent afforded 234 mg of 5-fluoro-3-methyl- benzo[b]thiophene-2-sulfonic acid (yield 74%). 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.45 (s, 3 H) 7.22 (td, 1 H) 7.52 (dd, 1 H) 7.89 (dd, 1 H).

A mixture of 5-fluoro-3-methylbenzothiophene-2-sulfonic acid (230 mg, 0.93 mmol) in POCI ₃ (5 mL) was heated at 60 °C over night. The POCI ₃ was evaporated and the crude prod- uct was dissolved in CH ₂ C1 ₂ and washed with water. The organic phase was dried and evaporated and gave 0.23 g (93%) of the title compound. Intermediate 11

5-isopropyl-3-methylbenzothiophene-2-sulfonyl chloride

A mixture of 4-isopropyl-thiophenol (5.0 g, 32.8 mmol), chloroacetone (7.0 mL, 88 mmol) and K ₂ CO ₃ (6.4 g, 46.3 mmol) in acetone (100 mL) was refluxed over night. More K ₂ CO ₃ (2 g, 14.5 mmol) and chloroacetone (3.5 mL, 43 mmol) were added and the reaction mixture was heated for another 5 h. The reaction mixture was filtered and the solvent was evaporated. The crude product was mixed with polyphosphoric acid (15 g) and chlorobenzene (100 mL) and the reaction mixture was heated at reflux for 5 h (Pie et al., (1988) J. Heterocyclic Chem. 25, 1271-1272). The reaction mixture was diluted with CH ₂ CI ₂ and washed with H ₂ O. The organic phases were dried and the solvent was evaporated. The crude product was purified on silica using heptane as eluent. 5-Isopropyl-3-methylbenzothiophene was obtained as a colourless oil. (4.2 g, 67% over two steps). 1H NMR (400 MHz, chloroform-;/) δ ppm 1.37 (d, 6 H) 2.47 (d, 3 H) 3.02 - 3.16 (m, 1 H) 7.08 (s, 1 H) 7.27 - 7.30 (m, 1 H) 7.58 (d, 1 H) 7.80 (d, 1 H).

A solution of sulfur trioxide (580 mg, 7.24 mmol) in 1 ,2-dichloroethylene (10 mL) was cooled on ice and dioxane (610 μί, 7.15 mmol) in 1 ,2-dichloroethylene (1 mL) was added dropwise. The resulting white mixture was stirred 30 min at 0 °C. A solution of 5-isopropyl-3- methyl-l-benzothiophene (420 mg, 2.2 mmol) in 1 ,2-dichloroethylene (4 mL) was added and the resulting dark purple mixture was stirred at room temperature for 1 h. The mixture was poured on ice and extracted with EtOAc. The acid crystallized spontaneously in the organic phase and 265 mg (44%) of 5-isopropyl-3-methyl-l-benzothiophene-2-sulfonic acid were collected. 1H NMR (400 MHz, METHANOL-^) δ ppm 1.31 (d, 6 H) 2.63 (s, 3 H) 2.98 - 3.10 (m, 1 H) 7.31 (dd, 1 H) 7.60 (d, 1 H) 7.71 (d, 1 H).

A mixture of 5-isopropyl-3-methyl-l-benzothiophene-2-sulfonic acid (2.54 g, 9.4 mmol), POCI ₃ (10 mL) and PC1 ₅ (4.0 g, 19.2 mmol) in CH ₂ C1 ₂ (100 mL) was stirred at room tempera- ture for 2 h. The reaction was quenched by addition of ice and H ₂ 0 and stirred for 1 h. The organic phase was separated and dried. 1.74 g sulfonyl chloride was obtained as an oil after evaporation of the solvents. The crude product was purified on silica using CH ₂ C1 ₂ as eluent, 1.46 g (54%) of the title compound was obtained. Intermediate 12

2,5-Dichloro-4-methyl-thiophene-3-sulfonyl chloride

Chlorosulfonic acid (52 μΐ,, 0.77 mmol) was added to a solution of 2,5-dichloro-3-methyl- thiophene (125 mg, 0.75 mmol) in CH ₂ C1 ₂ . After 1 h of stirring at room temperature another portion of chlorosulfonic acid (52 μΐ,, 0.77 mmol) was added. Complete conversion to the intermediate sulfonic acid was observed after stirring at room temperature over night.

Chlorosulfonic acid (100 μΐ,, 1.55 mmol) was added to the reaction mixture, which was then heated at 50 °C for 3 h and then at room temperature for 3 days. The reaction was quenched by slow addition of H ₂ 0. The product was extracted with CH ₂ C1 ₂ . The organic phase was dried. Removal of the solvents gave the title compound as a dark oil (119 mg). The crude product was used without further purification.

Intermediate 13

-Trichloro-thiophene-3-sulfonyl chloride

The title compound was prepared from 2,3,5-trichloro-thiophene (138 mg, 0.74 mmol) and chlorosulfonic acid (2x 52 μΐ,, 2x0.77 mmol) followed by addition of more chlorosulfonic acid (100 μΐ,, 1.55 mmol) in the second step according the procedure described for synthesis of 2,5-dichloro-4-methyl-thiophene-3-sulfonyl chloride (Intermediate 12). 165 mg 2,4,5- trichloro-thiophene-3-sulfonyl chloride was obtained as a dark oil. Intermediate 14

4- 3-Bromo-phenylmethanesulfonylamino)-2-hydroxy-benzoic acid

The intermediate was prepared from methyl 4-aminosalicylate (67 mg, 0.400 mmol) and 3- bromobenzylsulfonyl chloride (108 mg, 0.400 mmol) as described in Example 192. The title compound was obtained as white solid (24 mg, 17%). 1H NMR (500 MHz, METHANOL-^) δ ppm 4.50 (s, 2 H) 6.65 (dd, J=8.55, 2.20 Hz, 1 H) 6.73 (d, J=2.20 Hz, 1 H) 7.22 - 7.26 (m, 2 H) 7.44 (br. s., 1 H) 7.47 - 7.52 (m, 1 H) 7.77 (d, J=8.55 Hz, 1 H). MS (ESI+) 386 [M+H].

Intermediate 15

-(4-Bromo-phenylmethanesulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from methyl 4-aminosalicylate (67 mg, 0.400 mmol) and 4- bromobenzylsulfonyl chloride (108 mg, 0.400 mmol) as described in Example 193. The title compound was obtained as a white solid (69 mg, 51%). 1H NMR (500 MHz, METHANOL- d ₄ ) δ ppm 4.47 (s, 2 H) 6.64 (dd, J=8.79, 2.20 Hz, 1 H) 6.72 (d, J=2.20 Hz, 1 H) 7.15 - 7.22 (m, 2 H) 7.45 - 7.53 (m, 2 H) 7.77 (d, J=8.55 Hz, 1 H). MS (ESI+) 386 [M+H].

Intermediate 16

4-(3-Bromo-5-trifluoromethyl-benzenesulfonylamino)-2-hydroxy -benzoic acid methyl ter

A reaction mixture with methyl 4-amino-salicylate (170 mg, 1.0 mmol), 3-bromo-5- trifluoromethylbenzenesulphonyl chloride (320 mg, 1.0 mmol) and pyridine (156 mg, 2.0 mmol) in MeCN (50 mL) was heated at 70 °C over night. After removal of the solvent under reduced pressure, EtOAc (100 mL) followed by 1 M K ₂ CO ₃ (50 mL) were added. The organic phase was washed with 1 M K ₂ CO ₃ , 1 M HC1, H ₂ 0 and Brine, dried over MgS0 ₄ , filtered and concentrated. The residue was recrystallized from refluxing MeOH/H ₂ 0. The title compound was obtained as a white solid (280 mg, 61%). 1H NMR (500 MHz, CHLOROFORM-;/) δ ppm 3.93 (s, 3 H) 6.63 - 6.69 (m, 2 H) 6.92 (s, 1 H) 7.74 - 7.82 (m, 1 H) 7.96 (s, 1 H) 8.04 (s, 1 H) 8.18 (s, 1 H) 10.90 (s, 1 H). MS (ESI+) 454 [M+H].

Intermediate 17

-(5-Bromo-thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from 4-amino salicylic acid (1.16 g, 7.6 mmol) and 5- bromothiophene-2-sulfonyl chloride (1.0 g, 3.8 mmol) as described in Example 1 19. 0.64 g of the title compound was obtained as light brown solid (45%). 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 6.70 (d, J=1.95 Hz, 1 H) 6.72 (dd, J=8.55, 2.20 Hz, 1 H) 7.33 (d, J=4.15 Hz, 1 H) 7.52 (d, J=4.15 Hz, 1 H) 7.70 (d, J=8.79 Hz, 1 H) 1 1.1 1 (s, 1 H); MS (ESI+) 378 [M+H].

Example 1, General procedure 1

4- [(biphenyl-3-ylsulfonyl)amino] -2-hydroxybenzoic acid

A mixture of 3-phenylbenzenesulfonyl chloride (15 mg, 0.060 mmol) and 4-amino-salicylic acid (8.3 mg, 0.054 mmol) in CH ₂ C1 ₂ (200 μί) and pyridine (13 μί, 3 equivs) was stirred at 60 °C for 4 h. The reaction mixture was concentrated and the crude product was purified by preparative HPLC (ACE C8, 5u 21x50mm, flow 25ml/min, 50 mM NH ₄ Ac in H ₂ 0/ MeCN) to give 14.8 mg (74%) of the title compound. MS (ESI+) calcd for Ci ₉ Hi ₅ N0 ₅ S 369.0671 , found 369.0668 . Example 2

4-{[(3-bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid

The product was prepared according to General procedure 1 , described in Example 1 , with 3- bromobenzene sulfonyl chloride (25 mg, 0.10 mmol) and 4-amino salicylic acid (15 mg, 0.10 mmol) and gave 6.29 mg (16%) of the title compound. MS (ESI+) calcd for Ci ₃ Hi ₀ BrNO ₅ S 370.946306, found 370.946216 .

Example 3, General procedure 2

4-({[3-(5-acetyl-2-thienyl)phenyl]sulfonyl}amino)-2-hydroxyb enzoic acid

A mixture of (5-acetyl-2-thienyl)boronic acid (8.91 mg, 0.052 mmol), aqueous K ₂ C0 ₃ (0.15 M, 0.8 mL), 4- {[(3-bromophenyl)sulfonyl]amino} -2-hydroxybenzoic acid (Intermediate 1) (15 mg, 0.04 mmol) and Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (3 mg, 0.004 mmol) in dioxane (3.2 mL) was heated at 145°C for 900 s in a microwave reactor. The reaction mixture was concentrated and the crude product was purified by preparative HPLC (ACE C8, 5μιη 21x50mm, flow

25ml/min, 0.1% TFA in H ₂ 0/ MeCN) to give 3.4 mg (20%) of the title compound. MS (ESI+) calcd for Ci ₉ Hi ₅ N0 ₆ S ₂ 417.034079, found 417.034929 .

Example 4, General procedure 3

2-hydroxy-4-{[(4'-hydroxybiphenyl-3-yl)sulfonyl]amino}benzoi c acid

A mixture of 4-hydroxyphenyl boronic acid (9.0 mg, 0.065 mmol), 4- {[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (19 mg, 0.05 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol) and Pd(dppf)Cl ₂ :CH ₂ Ci ₂ (4 mg, 0.005 mmol) in aqueous dioxane (3.2 mL diox- ane, 0.8 mL ¾0) was heated at 145°C for 900 s in a microwave reactor. The reaction mixture was concentrated and the crude product was purified by preparative HPLC (ACE C8, 5μιη 21x50mm, flow 25ml/min, 50 mM N¾Ac in H ₂ O/ MeCN). The title compound was obtained in 79% yield (15.3 mg). MS (ESI+) calcd for Ci ₉ Hi ₅ N0 ₆ S 385.062008, found 385.062428 .

Example 5

- [({3- [(E)-2-(4-fluorophenyl)vinyl] phenyl} sulfony l)amino ] -2-hydroxybenzoic acid

The product was prepared according to the General procedure 2, described in Example 3, with [(E)-2-(4-f uorophenyl)vinyl]boronic acid (8.7 mg, 0.052 mmol) and 4- {[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (19 mg, 0.05 mmol). The title compound was obtained in 21% yield (3.5 mg). MS (ESI+) calcd for C ₂ iHi ₆ FN0 ₅ S 413.073322, found 413.073482 .

Example 6

-{[(3'-amino-4'-methoxybiphenyl-3-yl)sulfonyl]amino}-2-hydro xybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with (3-amino-4-methoxyphenyl)boronic acid (12 mg, 0.07 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol), Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4- {[(3-bromophenyl)sulfonyl]-amino}-2- hydroxybenzoic acid (Intermediate 1) (19 mg, 0.05 mmol) and gave 4.0 mg (19%) of the title compound. MS (ESI+) calcd for C ₂ oHi ₈ N ₂ 0 ₆ S 414.088557, found 414.088717 . Example 7

-hydroxy-4-{[(3-pyridin-3-ylphenyl)sulfonyl]amino}benzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with pyridine-3-boronic acid (8 mg, 0.065 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol),

Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4-{[(3-bromophenyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 1) (19 mg, 0.05 mmol) and gave 5.7 mg (31%) of the title compound. MS (ESI+) calcd for Ci ₈ Hi ₄ N ₂ 0 ₅ S 370.062342, found 370.063772 .

Example 8

4- 4'-(dimethylamino)biphenyl-3-yl]sulfonyl}amino)-2-hydroxyben zoic acid

The product was prepared according to the General procedure 3, described in Example 4, with [4-(dimethylamino)phenyl]boronic acid (1 mg, 0.065 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol), Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4-{[(3-bromophenyl)sulfonyl]-amino}-2- hydroxybenzoic acid (Intermediate 1) (19 mg, 0.05 mmol) and gave 1.6 mg (7.8%) of the title compound. MS (ESI+) calcd for C ₂ iH ₂ oN ₂ 0 ₅ S 412.109292, found 412.110152 .

Example 9, General procedure 4

2-hydroxy-4-({[5-(trifluoromethyl)biphenyl-3-yl]sulfonyl}ami no)benzoic acid

OH

A mixture of 3-bromo-5-(trifluoromethyl)benzenesulfonyl chloride (30 mg, 0.09 mmol) and 4-aminosalicylic acid (15 mg, 0.1 mmol) in CH ₂ CI ₂ (2 mL) and pyridine (80 μί) was heated at 60 °C for 5 h. The solvent was evaporated and the crude product was purified on silica gel (CHCI ₃ with acetone (10%) and formic acid (1%) as eluent) and gave 29 mg 5-({[3-bromo-5- (trifluoromethyl)phenyl]sulfonyl}amino)-2-hydroxybenzoic acid.

The crude 5-({[3-bromo-5-(trifluoromethyl)phenyl]sulfonyl}amino)-2-hyd roxybenzoic acid (29 mg) was mixed with phenylboronic acid (10 mg, 0.08 mmol), K ₂ CO ₃ (30 mg, 0.22 mmol) and Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (8 mg, 0.01 mmol) in dioxane (1 mL) and H ₂ 0 (250 μΐ,) and the resulting mixture was heated at 145°C for 900 s in a microwave reactor. The reaction mixture was concentrated and the crude product was purified by preparative HPLC (ACE C8, 5u 21x50mm, flow 25ml/min, 50 mM NH ₄ Ac in H ₂ 0/ MeCN) to give 9.4 mg (32% over two steps) of the title compound. 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 6.52 - 6.62 (m, 2 H) 7.48 - 7.56 (m, 3 H) 7.58 (d, J=8.30 Hz, 1 H) 7.71 - 7.75 (m, 2 H) 8.03 (s, 1 H) 8.27 (s, 2 H) 10.67 (br. s., 1 H); MS (ESI+) calcd for C ₂ oHi ₄ F ₃ N0 ₅ S 437.054478, found 437.040098 . Example 10

4-{[(4,6-difluorobiphenyl-3-yl)sulfonyl]amino}-2-hydroxybenz oic acid

A mixture of 5-bromo-2,4-difluorobenzenesulfonyl chloride (30 mg, 0.09 mmol) and 4- aminosalicylic acid (20 mg, 0.14 mmol) in CH ₂ CI ₂ (2 mL) and pyridine (80μί) was heated at 60°C over night. The solvent was evaporated and the crude product was dissolved in EtOAc and then washed with 1 M HC1. Drying and evaporation gave 24 mg of the intermediate 5- {[(5-bromo-2,4-difluorophenyl)sulfonyl]amino}-2-hydroxybenzo ic.

The 5-{[(5-bromo-2,4-difluorophenyl)sulfonyl]amino}-2-hydroxyben zoic acid (24 mg) was reacted with phenylboronic acid (10 mg, 0.08 mmol) according to General procedure 4, de- scribed in Example 9 (second step, i.e. Suzuki coupling). Purification (XTerra Prep MS C18 5mm 19x50mm, flow 25ml/min, 50 mM pHIO NH ₄ HC0 ₃ / MeCN) gave 6.2 mg (15% over two steps) of the title compound. 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 6.55 - 6.67 (m, 2 H) 7.44 - 7.55 (m, 5 H) 7.61 (d, J=8.55 Hz, 1 H) 7.69 (t, J=10.13 Hz, 1 H) 7.94 (t, J=8.18 Hz, 1 H) 11.08 (br. s., 1 H). MS (ESI+) calcd for Ci ₉ Hi ₃ F ₂ N0 ₅ S 405.04825, found 405.04891 . Example 11

2-hydroxy-4-{[(6-methoxybiphenyl-3-yl)sulfonyl]amino}benzoic acid

The product was prepared according to the General procedure 4, described in Example 9, with 3-bromo-4-methoxy-benzenesulfonyl chloride (30 mg, 0.11 mmol) and 4-aminosalicylic acid (15 mg, 0.1 mmol) which gave 33 mg of the intermediate 5-{[(3-bromo-4- methoxyphenyl)sulfonyl]amino}-2-hydroxybenzoic acid. The 5-{[(3-bromo-4- methoxyphenyl)sulfonyl]amino}-2-hydroxybenzoic acid was reacted with phenylboronic acid (15 mg, 0.12 mmol), K ₂ C0 ₃ (35 mg, 0.25 mmol) and Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (6 mg, 0.007 mmol). Purification gave 10.4 mg (30% over two steps) of the title compound. MS (ESI+) calcd for C ₂₀ Hi ₇ NO ₆ S 399.077658, found 399.078258 .

Example 12

4-{[(5-chloro-4-phenyl-2-thienyl)sulfonyl]amino}-2-hydroxybe nzoic acid

4-{[(4-Bromo-5-chloro-2-thienyl)sulfonyl]amino}-2-hydroxy benzoic acid (Intermediate 2) was reacted with phenylboronic acid (15 mg, 0.12 mmol), K ₂ C0 ₃ (35 mg, 0.25 mmol) and Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (6 mg, 0.007 mmol) according to the General procedure 4, described in Example 9 (second step, i.e. Suzuki coupling). Purification (XTerra Prep MS CI 8 5mm 19x50mm, flow 25ml/min, 50 mM pHIO NH ₄ HC0 ₃ /MeCN) gave 9.9 mg (32% over two steps) of the title compound. 1H NMR (400 MHz, METHANOL-d4) δ ppm 6.60 (dd, J=8.41, 2.13 Hz, 1 H) 6.68 (d, J=2.13 Hz, 1 H) 7.35 - 7.49 (m, 5 H) 7.50 (s, 1 H) 7.73 (d, J=8.41 Hz, 1 H); MS (ESI+) calcd for Ci ₇ Hi ₂ ClN0 ₅ S ₂ 408.984542, found 408.985932 . Example 13

2-hydroxy-4-({[2'-(hydroxymethyl)biphenyl-3-yl]sulfonyl}amin o)benzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with l-hydroxy-2, l-benzoxaborolane (9 mg, 0.07 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol),

Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4- {[(3-bromophenyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 1) (19 mg, 0.05 mmol) and gave 10 mg (50%) of the title compound. MS (ESI+) calcd for CzoHnNOgS 399.077658, found 399.078658 .

Example 14

4- { [(3 '-fluorobi henyl-3-yl)sulfonyl] amino}-2-hydroxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with (3-fluorophenyl)boronic acid (10 mg, 0.07 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol),

Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4- {[(3-bromophenyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 1) (19 mg, 0.05 mmol) and gave 10 mg (52%) of the title compound. MS (ESI+) calcd for Ci ₉ Hi ₄ FN0 ₅ S 387.057672, found 387.058082 .

Example 15

-{[(2',6'-difluorobiplienyl-3-yl)sulfonyl]amino}-2-liydroxyb enzoic acid

The product was prepared according to the General procedure 3, described in Example 4, 2,6-difluorophenylboronic acid (1 1 mg, 0.07 mmol), K ₂ C0 ₃ (20 mg, 0.15 mmol),

Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4- {[(3-bromophenyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 1) (19 mg, 0.05 mmol) and gave 0.7 mg (3%) of the title compound. MS (ESI+) calcd for Ci9Hi ₃ F ₂ N0 ₅ S 405.04825, found 405.04837 .

Example 16

2-hydroxy-4-({[3'-(isopropoxycarbonyl)biphenyl-3-yl]sulfonyl }amino)benzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 3-(isopropoxycarbonyl)phenyl]boronic acid (15 mg, 0.07 mmol), K ₂ C0 ₃ (20 mg, 0.15 mmol), Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4-{[(3-bromophenyl)sulfonyl]-amino}-2- hydroxybenzoic acid (Intermediate 1) (19 mg, 0.05 mmol) and gave 8 mg (35%) of the title compound. MS (ESI+) calcd for C ₂₃ H ₂ iN0 ₇ S 455.103873, found 455.104263 .

Example 17

4- 3-(2,3-dihydro-l-benzofuran-5-yl)phenyl]sulfonyl}amino)-2-hy droxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with

2,3-dihydro-l-benzofuran-5-ylboronic acid (11 mg, 0.07 mmol), K ₂ C0 ₃ (20 mg, 0.15 mmol) Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4-{[(3-bromophenyl)sulfonyl]-amino}-2- hydroxybenzoic acid (Intermediate 1) (19 mg, 0.05 mmol) and gave 4 mg (19%) of the title compound. MS (ESI+) calcd for C ₂ iHi ₇ N0 ₆ S 411.077658, found 411.077988 . Example 18

4-{[(3 ^, -fluoro-4'-hydroxybiphenyl-3-yl)sulfonyl]amino}-2-hydr oxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 3-fluoro-4-hydroxyphenyl)boronic acid (1 1 mg, 0.07 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol), Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4- {[(3-bromophenyl)sulfonyl]-amino}-2- hydroxybenzoic acid (Intermediate 1) (19 mg, 0.05 mmol) and gave 4 mg (20%) of the title compound. MS (ESI+) calcd for Ci ₉ Hi ₄ FN0 ₆ S 403.052586, found 403.052636 .

Example 19

2-hydroxy-4-{[(3-quinolin-6-ylphenyl)sulfonyl]amino}benzo ic acid

The product was prepared according to the General procedure 3, described in Example 4, with quinolin-6-ylboronic acid (12 mg, 0.07 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol),

Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4- {[(3-bromophenyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 1) (19 mg, 0.05 mmol) and gave 4.2 mg (20%) of the title compound. MS (ESI+) calcd for C ₂ 2Hi ₆ N ₂ 0 ₅ S 420.077992, found 420.078712 .

Example 20

4- { [(3 '-aminobiphenyl-3-yl)sulfonyl] amino}-2-hydroxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with (3-aminophenyl)boronic acid (10 mg, 0.07 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol),

Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4- {[(3-bromophenyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 1) (19 mg, 0.05 mmol) and gave 4 mg (21%) of the title compound. MS (ESI+) calcd for Ci ₉ Hi ₆ N ₂ 0 ₅ S 384.077992, found 384.078172.

Example 21

2-hydroxy-4-({[3-(2-methyl-l,3-thiazol-4-yl)phenyl]sulfonyl} amino)benzoic acid

The product was prepared according to the General procedure 1 , described in Example 1 , with 4-amino-2-hydroxybenzoic acid (9 mg, 0.06 mmol), 3-(2 -methyl- 1 ,3-thiazo 1-4-yl)- benzenesulfonyl chloride (18 mg, 0.066 mmol) and pyridine (24 μΐ) in CH ₂ CI ₂ (200 μΐ) and gave 4.6 mg (18%) of the title compound. MS (ESI+) calcd for Ci ₇ Hi ₄ N ₂ 0 ₅ S ₂ 390.034413, found 390.034453.

Example 22

-{[(5-chloro-2-thienyl)sulfonyl]amino}-2-hydroxybenzoic acid

The product was prepared according to the General procedure 1 , described in Example 1 , with 4-amino-2-hydroxybenzoic acid (50 mg, 0.33 mmol), 5-chlorothiophene-2-sulfonyl chloride (106 mg, 0.49 mmol) and pyridine (132 μΕ, 1.63 mmol) in CH ₂ CI ₂ (1.5 mL) and gave 23 mg (21%) of the title compound. MS (ESI+) calcd for CnH ₈ ClN0 ₅ S ₂ 332.953241 , found 332.952771. Example 23

4-({[5-chloro-4-(2,3-dihydro-l-benzofuran-5-yl)-2-thienyl]su lfonyl}amino)-2- h droxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 2,3-dihydro-l-benzofuran-5-ylboronic acid (11 mg, 0.065 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol), Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4-{[(4-bromo-5-chloro-2-thienyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 2) (20 mg, 0.05 mmol) and gave 6.1 mg (27%) of the title compound. 1H NMR (400 MHz, METHANOL-^) δ ppm 3.29 - 3.35 (m, 2 H, partially obscured by solvent peak) 4.87 - 4.92 (m, 2 H, partially obscured by solvent peak) 6.59 (dd, J=8.41, 2.13 Hz, 1 H) 6.67 (d, J=2.01 Hz, 1 H) 7.02 - 7.11 (m, 2 H) 7.39 - 7.47 (m, 2 H) 7.73 (d, J=8.28 Hz, 1 H). MS (ESI+) calcd for CigHnClNOgSz 450.995106, found 450.995606 .

Example 24

4-({[5-chloro-4-(3-fluoro-4-hydroxyphenyl)-2-thienyl]sulf onyl}amino)-2-hydroxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with (3-fluoro-4-hydroxyphenyl)boronic acid (10 mg, 0.065 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol), Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4- {[(4-bromo-5-chloro-2-thienyl)- sulfonyl]amino} -2-hydroxybenzoic acid (Intermediate 2) (20 mg, 0.05 mmol) and gave 3.3 mg (15%) of the title compound. MS (ESI+) calcd for C _I7 H _{I I} C1FN0 ₆ S ₂ 442.970034, found 442.971404 . Example 25

4-{[(5-chloro-4-quinolin-6-yl-2-thienyl)sulfonyl]amino}-2-hy droxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with quinolin-6-ylboronic acid (11 mg, 0.065 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol),

Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]- amino}-2-hydroxybenzoic acid (Intermediate 2) (20 mg, 0.05 mmol) and gave 4.3 mg (19%) of the title compound. MS (ESI+) calcd for C ₂ oHi ₃ Cl ₂ 0 ₅ S ₂ 459.995441, found 459.995861 .

Example 26

4- 4-(l,3-benzodioxol-5-yl)-5-chloro-2-thienyl]sulfonyl}amino)- 2-hydroxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with l,3-benzodioxol-5-ylboronic acid (11 mg, 0.065 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol), Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]- amino}-2-hydroxybenzoic acid (Intermediate 2) (20 mg, 0.05 mmol) and gave 4.7 mg (21%) of the title compound. MS (ESI+) calcd for C ₁₈ H ₁₂ CINO ₇ S ₂ 452.974371, found 452.974591 .

Example 27

4-({[5-chloro-4-(4-hydroxy-3,5-dimethylphenyl)-2-thienyl]sul fonyl}amino)-2- h droxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with (4-hydroxy-3,5-dimethylphenyl)boronic acid (11 mg, 0.065 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol), Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4-{[(4-bromo-5-chloro-2-thienyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 2) (20 mg, 0.05 mmol) and gave 8 mg (35%) of the title compound. MS (ESI+) calcd for Ci ₉ Hi ₆ ClN0 ₆ S2 453.010756, found 453.012276 .

Example 28

4- 5-chloro-4-(2,4-difluorophenyl)-2-thienyl]sulfonyl}amino)-2- hydroxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with (2,4-difluorophenyl)boronic acid (10 mg, 0.065 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol),

Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]- amino}-2-hydroxybenzoic acid (Intermediate 2) (20 mg, 0.05 mmol) and gave 4.5 mg (20%) of the title compound. MS (ESI+) calcd for Ci ₇ HioClF ₂ N0 ₅ S2 444.965698, found 444.966838

Example 29

4-({[4-(3-acetylphenyl)-5-chloro-2-thienyl]sulfonyl}amino)-2 -hydroxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with (3-acetylphenyl)boronic acid (10 mg, 0.065 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol),

Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]- amino}-2-hydroxybenzoic acid (Intermediate 2) (20 mg, 0.05 mmol) and gave 7.5 mg (33%) of the title compound. MS (ESI+) calcd for C ₁₉ H ₁₄ CINO ₆ S ₂ 450.995106, found 450.995136 . Example 30

4- [({5-chloro-4- [2-(hydroxymethyl)phenyl] -2-thienyl}sulfonyl)amino] -2-hydroxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with l-hydroxy-2, l-benzoxaborolane (9 mg, 0.07 mmol), K ₂ CO ₃ (20 mg, 0. 15 mmol),

Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4- {[(4-bromo-5-chloro-2-thienyl)sulfonyl]- amino} -2-hydroxybenzoic acid (Intermediate 2) (20 mg, 0.05 mmol) and gave 1 .4 mg (6%) of the title compound. MS (ESI+) calcd for 438.995 106, found 438.995506 . Example 31

4-({[5-chloro-4-(3-fluorophenyl)-2-thienyl]sulfonyl}amino)-2 -hydroxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with (3-fluorophenyl)boronic acid (10 mg, 0.07 mmol), K ₂ CO ₃ (20 mg, 0. 15 mmol),

Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4- {[(4-bromo-5-chloro-2-thienyl)sulfonyl]- amino} -2-hydroxybenzoic acid (Intermediate 2) (20 mg, 0.05 mmol) and gave 3.3 mg (15%) of the title compound. MS (ESI+) calcd for CI ₇ HI IC1FN0 ₅ S ₂ 426.975 12, found 426.97622 . Example 32

4- [({5-chloro-4- [3-(isopropoxycarbonyl)phenyl] -2-thienyl}sulfonyl)amino] -2- h droxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with [3-(isopropoxycarbonyl)phenyl]boronic acid (15 mg, 0.07 mmol), K ₂ CO ₃ (20 mg,

0.15 mmol), Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4- {[(4-bromo-5-chloro-2-thienyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 2) (20 mg, 0.05 mmol) and gave 4 mg (16%) of the title compound. MS (ESI+) calcd for C ₂ iHi ₈ ClN0 ₇ S ₂ 495.021321 , found 495.021531 .

Example 33

4-({[5-chloro-4-(3,5-difluorophenyl)-2-thienyl]sulfonyl}amin o)-2-hydroxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with

[2-(3,5-difluorophenyl)-5,5-dimethyl-l ,3,2-dioxaborinane (16 mg, 0.07 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol), Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4- {[(4-bromo-5-chloro-2- thienyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 2) (20 mg, 0.05 mmol) and gave 2.6 mg (12%) of the title compound. MS (ESI+) calcd for Ci ₇ Hi ₀ ClF ₂ NO ₅ S2

444.965698, found 444.965858 . Example 34

4-({[5-chloro-4-(6-ethoxypyridin-3-yl)-2-thienyl]sulfonyl}am ino)-2-hydroxyben

The product was prepared according to the General procedure 3, described in Example 4, with 2-ethoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyri dine (9 mg, 0.07 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol), Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4- {[(4-bromo-5-chloro-2- thienyl)sulfonyl]amino} -2-hydroxybenzoic acid (Intermediate 2) (20 mg, 0.05 mmol) and gave 2.4 mg (10%) of the title compound. MS (ESI+) calcd for C _{I 8} H _{I 5} C1N ₂ 0 ₆ S ₂ 454.006005, found 454.006105 . Example 35

4-({ [4-(3-aminophenyl)-5-chloro-2-thienyl] sulfonyl}amino)-2-hydroxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 3-aminophenylboronic acid (9.6 mg, 0.07 mmol), K ₂ CO ₃ (20 mg, 0.15 mmol),

Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (4 mg, 0.005 mmol) and 4- {[(4-bromo-5-chloro-2-thienyl)sulfonyl]- amino} -2-hydroxybenzoic acid (Intermediate 2) (20 mg, 0.05 mmol) and gave 1.8 mg (8%) of the title compound. MS (ESI+) calcd for C _I7 H _I3 C1N ₂ 0 ₅ S ₂ 423.995441 , found 423.99551 1 . Example 36

4-({[5-chloro-4-(4-methoxyphenyl)-2-thienyl]sulfonyl}amino)- 2-hydroxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 4-methoxyphenylboronic acid (15 mg, 0.10 mmol), K ₂ CO ₃ (30 mg, 0.22 mmol),

Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (6 mg, 0.007 mmol) and 4- {[(4-bromo-5-chloro-2-thienyl)sulfonyl]- amino}-2-hydroxybenzoic acid (Intermediate 2) (30 mg, 0.07 mmol). Repurification by preparative HPLC (ACE C8 5 μπι, 0.1% TFA in H ₂ 0/ MeCN) gave 6.0 mg (14%) of the title compound. MS (ESI+) calcd for 438.995106, found 438.996026 . Example 37

4-({[4-(4-aminophenyl)-5-chloro-2-thienyl]sulfonyl}amino)-2- hydroxybenzoic acid tri- fluoroacetate (salt)

The product was prepared according to the General procedure 3, described in Example 4, with 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)aniline (21 mg, 0.10 mmol), K ₂ CO ₃ (30 mg, 0.22 mmol), Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (6 mg, 0.007 mmol) and 4- {[(4-bromo-5-chloro-2- thienyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 2) (30 mg, 0.07 mmol). Repurification by preparative HPLC (ACE C8 5 μιη, 0.1% TFA in H ₂ 0/ MeCN) gave 4.8 mg (9%) of the title compound. MS (ESI+) calcd for Ci ₇ Hi ₃ Cl ₂ 0 ₅ S2 423.995441 , found 423.996591 . Example 38

4-({[5-chloro-4-(4-hydroxyphenyl)-2-thienyl]sulfonyl}amino)- 2-hydroxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 4-hydroxy-phenylboronic acid (13 mg, 0.10 mmol), K ₂ CO ₃ (30 mg, 0.22 mmol),

Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (6 mg, 0.007 mmol) and 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]- amino} -2-hydroxybenzoic acid (Intermediate 2) (30 mg, 0.07 mmol). Repurification by preparative HPLC (ACE C8 5 μπι, 0.1% TFA in H ₂ 0/ MeCN) gave 4.9 mg (12%) of the title compound. MS (ESI+) calcd for C _I7 H _I2 C1N0 ₆ S ₂ 424.979456, found 424.979226 . Example 39

4- [({5-chloro-4- [3-(hydroxymethyl)phenyl] -2-thienyl}sulfonyl)amino] -2-hydroxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with

3-(hydroxymethyl)phenylboronic acid (15 mg, 0.10 mmol), K ₂ CO ₃ (30 mg, 0.22 mmol), Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (6 mg, 0.007 mmol) and 4-{[(4-bromo-5-chloro-2-thienyl)- sulfonyl] amino} -2-hydroxybenzoic acid (Intermediate 2) (30 mg, 0.07 mmol). Repurification by preparative HPLC (ACE C8 5 μπι, 0.1% TFA in H ₂ 0/ MeCN) gave 6.3 mg (14%) of the title compound. MS (ESI+) calcd for Ci ₈ Hi ₄ ClN0 ₆ S ₂ 438.995106, found 438.995466 . Example 40

4- [({5-chloro-4- [4-(hydroxymethyl)phenyl] -2-thienyl}sulfonyl)amino] -2-hydroxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 4-(hydroxymethyl)phenylboronic acid (15 mg, 0.10 mmol), K ₂ CO ₃ (30 mg, 0.22 mmol), Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (6 mg, 0.007 mmol) and 4- {[(4-bromo-5-chloro-2-thienyl)- sulfonyl] amino} -2-hydroxybenzoic acid (Intermediate 2) (30 mg, 0.07 mmol). Repurification by preparative HPLC (ACE C8 5 μπι, 0.1% TFA in H ₂ 0/ MeCN) gave 1.8 mg (4%) of the title compound. MS (ESI+) calcd for 438.995106, found 438.996176 .

Example 41

4-({[4-(3-amino-4-methoxyphenyl)-5-chloro-2-thienyl]sulfonyl }amino)-2-hydroxybenzoic acid trifluoroacetate (salt)

The product was prepared according to the General procedure 3, described in Example 4, with 3-amino-4-methoxyphenylboronic acid (16 mg, 0.10 mmol), K ₂ CO ₃ (30 mg, 0.22 mmol), Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (6 mg, 0.007 mmol) and 4- {[(4-bromo-5-chloro-2-thienyl)- sulfonyl] amino} -2-hydroxybenzoic acid (Intermediate 2) (30 mg, 0.07 mmol). Repurification by preparative HPLC (ACE C8 5 μπι, 0.1% TFA in H ₂ 0/ MeCN) gave 2.3 mg (4%) of the title compound. MS (ESI+) calcd for CisHisClNzOgSz 454.006005, found 454.006735 . Example 42

4-{[(5-chloro-4-{4-[(methylsulfonyl)amino]phenyl}-2-thienyl) sulfonyl]amino}-2- hydroxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with (4-methylsulfonylaminophenyl)boronic acid (21 mg, 0.10 mmol), K ₂ CO ₃ (30 mg, 0.22 mmol), Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (6 mg, 0.007 mmol) and 4-{[(4-bromo-5-chloro-2-thienyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 2) (30 mg, 0.07 mmol). Repurification by preparative HPLC (ACE C8 5 μπι, 0.1% TFA in H ₂ 0/ MeCN) gave 2.1 mg (4%) of the title compound. MS (ESI+) calcd for CisHisClNzOySs 501.972991, found 501.973191 .

Example 43

4-{[(7-chloro-3-methyl-l-benzothien-2-yl)sulfonyl]amino}-2-h ydroxybenzoic acid

The product was prepared according to the General procedure 1 , described in Example 1 , with 4-amino-2-hydroxybenzoic acid (9 mg, 0.06 mmol), 7-chloro-3-methyl-l-benzothiophene-2- sulfonyl chloride (Intermediate 4) (19 mg, 0.066 mmol) and pyridine (24 μΕ) in CH ₂ C1 ₂ (200 μΐ,) and gave 4.4 mg (10%) of the title compound. MS (ESI+) calcd for C16H12CINO5S2

396.984542, found 396.983932 . Example 44

4-{[(5-chloro-3-methyl-l-benzothien-2-yl)sulfonyl]amino}-2-h ydroxybenzoic acid

The product was prepared according to the General procedure 1 , described in Example 1 , with 4-amino-2-hydroxybenzoic acid (9 mg, 0.06 mmol), 5-chloro-3-methyl-l-benzothiophene-2- sulfonyl chloride (19 mg, 0.066 mmol) and pyridine (24 μΐ,) in CH ₂ CI ₂ (200 μί) and gave 7 mg (17%) of the title compound. MS (ESI+) calcd for Ci6Hi ₂ ClN0 ₅ S ₂ 396.984542, found 396.984952 .

Example 45, General procedure 5

2-hydroxy-4-{[(3-piperidin-l-ylphenyl)sulfonyl]amino}benz oic acid

A tube charged with Pd ₂ (dba) ₃ (0.4576 mg, 0.005 mmol), 2-dicyclohexylphosphino-2 ^' -(N,N- dimethylamino)biphenyl (0.47 mg, 0.0012 mmol) and piperidine (10 mg, 0.12 mmol) was sealed and flushed with N ₂ (Harris et al, (2002) Org. Lett. 4, 2885-2888). A solution of 4- {[(3-bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (37 mg, 0.1 mmol) in dry THF and LiHMDS (1 M in THF, 120μί) was added via syringe. The reaction was heated at 130°C for 1000 s in microwave reactor. The reaction mixture was concentrated and the crude product was purified by preparative HPLC (ACE C8, 5u 21x50mm, flow 25ml/min, 50 mM NH ₄ Ac in H ₂ 0/ MeCN) to give 3.9 mg (10%) of the title compound. MS

(ESI+) calcd for Ci ₈ H ₂ oN ₂ 0 ₅ S 376.109292, found 376.109812 . Example 46

4-{[(3-acetylphenyl)sulfonyl]amino}-2-hydroxybenzoic acid

The product was prepared according to General procedure 1, described in Example 1 , with 3- acetylbenzenesulfonyl chloride (14 mg, 0.066 mmol) and 4-amino-2-hydroxybenzoic acid (9 mg, 0.06 mmol) and gave 3.3 mg (15%) of the title compound. MS (ESI+) calcd for

CisHisNOgS 335.046358, found 335.045738 .

Example 47

4-{[(3-tert-butylphenyl)sulfonyl]amino}-2-hydroxybenzoic acid

The product was prepared according to General procedure 1, described in Example 1 , with 3- tert-butylbenzenesulfonyl chloride (15 mg, 0.066 mmol) and 4-amino-2-hydroxy-benzoic acid (9 mg, 0.06 mmol) and gave 3.5 mg (15%) of the title compound. MS (ESI+) calcd for Ci ₇ Hi ₉ N0 ₅ S 349.098393, found 349.099143 .

Example 48

2-hydroxy-4-{[(4-phenyl-2-thienyl)sulfonyl]amino}benzoic acid

A mixture of 4- {[(5-chloro-4-phenylthiophen-2-yl)sulfonyl]amino}-2-hydroxyb enzoic acid (Example 12) (20 mg, 0.05 mmol), palladium on charcoal (10%, 0.2 g) and triethylamine (15 μΕ, 0.1 1 mmol) in MeOH (15 mL) was placed under hydrogen gas from a balloon and was stirred for 2 hours at room temperature. The mixture was filtered through celite, which was rinsed several times with MeOH. The organic solution was concentrated and the crude product was purified by reversed phase preparative HPLC (ACE C8, 50 mM NH ₄ OAc (pH 7) - CH ₃ CN) to give 3.0 mg (16%) the title compound. 1H NMR (400 MHz, METHANOL-^) δ ppm 6.59 (dd, J=8.41, 2.13 Hz, 1 H) 6.69 (d, J=2.26 Hz, 1 H) 7.27 - 7.32 (m, 1 H) 7.36 - 7.41 (m, 2 H) 7.57 (m, 2 H) 7.70 (d, J=8.53 Hz, 1 H) 7.85 (d, J=1.70 Hz,l H) 7.88 (d, j=1.70 Hz, 1H). MS (ESI+) calcd for Ci ₇ Hi ₃ N0 ₅ S ₂ 375.023514, found 375.024094 .

Example 49

2-hydroxy-4- [ [3-(piperidine- l-carbonyl)phenyl] sulfonylamino] benzoic acid

A solution of (4-(3-carboxy-benzenesulfonylamino)-2-hydroxy-benzoic acid methyl ester (Intermediate 5) (25 mg, 0.07 mmol), diisopropylethylamine (35 μί, 2.8 mmol), 1- propanephosphonic acid cyclic anhydride (50%> in EtOAc, 85 μί, 0.14 mmol) and piperidine (21 μΕ, 0.21 mmol) in THF (3 mL) was placed in a screw capped tube and shaken over night. The reaction mixure was diluted with CH ₂ C1 ₂ and washed with 1 M HC1. The organic phase was dried (NaS0 ₄ ) and evaporated and gave 30 mg of 2-hy droxy-4- [3 -(piperidine- 1- carbonyl)benzenesulfonyl-amino]-benzoic acid methyl ester (yield 99%). A mixture of the methyl ester (30 mg, 0.07 mmol), LiOH*H ₂ 0 (13 mg, 0.28 mmol) in THF (3 mL) and H ₂ 0 (1 mL) was heated at 60 °C over night. The solvent was evaporated and the crude product was purified by preparative HPLC (ACE C8, 5u 21x50mm, flow 25ml/min, 50 mM NH ₄ Ac in H ₂ 0/ MeCN) to give 23.9 mg (60%) of the title compound. MS (ESI+) calcd mass for Ci ₉ H ₂ oN ₂ 0 ₆ S 404.104207, found 404.104407 .

Example 50

2-hydroxy-4- [ [3-(methylcarbamoyl)phenyl] sulfonylamino] benzoic acid

A solution of (4-(3-carboxy-benzenesulfonylamino)-2-hydroxy-benzoic acid methyl ester (Intermediate 5) (25 mg, 0.07 mmol), diisopropylethylamine (35 μί, 2.8 mmol), 1- propanephosphonic acid cyclic anhydride (50% in EtOAc, 170 μί, 0.28 mmol) and methyla- mine (2 M in THF, 13 mL, 26 mmol) was placed in a screw capped tube and shaken over night. The reaction mixture was diluted with CH2CI2 and washed with 1 M HCl. The organic phase was dried (NaS0 ₄ ) and evaporated and gave 98 mg crude 2-hydroxy-4-(3- methylcarbamoyl-benzenesulfonylamino)-benzoic acid methyl ester.

A mixture of the crude methyl ester, LiOH*I¾C) (16 mg, 0.4 mmol) in THF (3 mL) and ¾0 (1 mL) was heated at 60 °C over night. The solvent was evaporated and the crude product was purified by preparative HPLC (ACE C8, 5u 21x50mm, flow 25ml/min, 50 mM NH ₄ Ac in H ₂ 0/ MeCN) to give 10.3 mg (42%) of the title compound over two steps. MS (ESI+) calcd mass for C15H14N206S 350.057257, found 350.057807 .

Example 51

2-hydroxy-4-[[3-(4-methylsulfonylphenyl)phenyl]sulfonylamino ] benzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with (4-methylsulfonylphenyl)boronic acid (13 mg 0.065 mmol) and 4-{[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (18.7 mg, 0.050 mmol) and gave 6.6 mg (29%) of the title compound. MS (ESI+) calcd mass for C20H17NO7S2 447.044643, found 447.046553 .

Example 52

4- [ [3-(3-ethoxyphenyl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with (3-ethoxyphenyl)boronic acid (11.6 mg 0.065 mmol) and 4-{[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (18.7 mg, 0.050 mmol) and gave 16.6 mg (80%) of the title compound. MS (ESI+) calcd mass for C ₂ iHi ₉ N0 ₆ S 413.093308, found 413.094308 .

Example 53

4- [ [3-(3-acetamidophenyl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with (3-acetamidophenyl)boronic acid (11.6 mg 0.065 mmol) and 4-{[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (18.7 mg, 0.050 mmol) and gave 6.7 mg (31%) of the title compound. MS (ESI+) calcd mass for C ₂ iHi ₈ N ₂ 0 ₆ S 426.088557, found 426.089457 . Example 54

4- [ [3-(3,4-dichlorophenyl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared according to the General procedure 1 , described in Example 1 , with 4-amino-2-hydroxybenzoic acid (7.7 mg, 0.05 mmol), 3-(3,4-dichlorophenyl)phenyl sulfonyl chloride (17.7 mg, 0.055 mmol) and pyridine (24 μΕ) in CH ₂ C1 ₂ (100 μί) and gave 13.4 mg (61%) of the title compound. MS (ESI+) calcd for Ci9Hi ₃ Cl ₂ N0 ₅ S 436.989149, found 436.988099 . Example 55

4- [ [3-(3-carbamoylphenyl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with (3-carbamoylphenyl)boronic acid (10.7 mg 0.065 mmol) and 4- {[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (18.7 mg, 0.050 mmol) and gave 4.1 mg (20%) of the title compound. MS (ESI+) calcd mass for C ₂ oHi ₆ N ₂ 0 ₆ S 412.072907, found 412.073737 .

Example 56

4- [ [3-(3-cyanophenyl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with (3-cyanophenyl)boronic acid (9.6 mg 0.065 mmol) and 4- {[(3-bromophenyl)sulfonyl]- amino}-2-hydroxybenzoic acid (Intermediate 1) (18.7 mg, 0.050 mmol) and gave 7.3 mg (37%) of the title compound. MS (ESI+) calcd mass for C ₂ oHi4N ₂ 0 ₅ S 394.062342, found 394.063762 .

Example 57

2-hydroxy-4- [ [3-(4-nitrophenyl)phenyl] sulfonylamino] benzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 4,4,5, 5-tetramethyl-2-(4-nitrophenyl)-l,3,2-dioxaborolane (17.4 mg 0.065 mmol) and 4-{[(3- bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (18.7 mg, 0.050 mmol) and gave 9.3 mg (45%) of the title compound. MS (ESI+) calcd mass for C19H14N2O7S 414.052171, found 414.053101 .

Example 58

2-hydroxy-4- [ [3- [3-(trifluoromethyl)phenyl] phenyl] sulfonylamino] benzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with (3-trifluoromethylphenyl)boronic acid (12.3 mg 0.065 mmol) and 4-{[(3-bromo- phenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (18.7 mg, 0.050 mmol) and gave 11.4 mg (52%) of the title compound MS (ESI+) calcd mass for C20H14F3NO5S

437.054478, found 437.055158 .

Example 59

2-hydroxy-4- [ [3-(4-methylsulfanylphenyl)phenyl] sulfonylamino] benzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with (4-methylsulfanylphenyl)boronic acid (10.9 mg 0.065 mmol) and 4-{[(3- bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (18.7 mg, 0.050 mmol) and gave 7.3 mg (35%>) of the title compound. MS (ESI+) calcd mass for C20H17NO5S2 415.054814, found 415.055224 . Example 60

2-hydroxy-4- [ [3- [4-(trifluoromethoxy)phenyl] phenyl] sulfonylamino] benzoic acid

The product was prepared according to the General procedure 2, described in Example 3, with 4-trifluoromethoxyphenyl boronic acid (10.8 mg, 0.052 mmol) and 4- {[(3-bromo- phenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (15 mg, 0.040 mmol) and gave 3.7 mg (20.4%) of the title compound. MS (ESI+) calcd mass for C ₂₀ H ₁₄ F ₃ NO ₆ S 453.049392, found 453.049792 .

Example 61

4- [ [3-(2-acetylphenyl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 2-acetylphenyl boronic acid (1 1.5 mg, 0.07 mmol) and 4- {[(3-bromophenyl)sulfonyl]- amino}-2-hydroxybenzoic acid (Intermediate 1) (15 mg, 0.040 mmol) and gave 13.3 mg (65%) of the title compound. MS (ESI+) calcd mass for C ₂ iHi ₇ N0 ₆ S: 41 1.077658, found 41 1.078548 .

Example 62

2-hydroxy-4- [ [3-(4-phenoxyphenyl)phenyl] sulfonylamino] benzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with (4-phenoxyphenyl)boronic acid (13.9 mg 0.065 mmol) and 4-{[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (18.7 mg, 0.050 mmol) and gave 11 mg (48%) of the title compound. MS (ESI+) calcd mass for C ₂ 5Hi ₉ N0 ₆ S 461.093308, found 461.093818 .

Example 63

2-hydroxy-4- [ [3-(4-hydroxy-3-methoxy-phenyl)phenyl] sulfonylamino] benzoic acid

The product was prepared according to the General procedure 2, described in Example 3, with 4-hydroxy-3-methoxyphenyl boronic acid (13.1 mg, 0.052 mmol) and 4-{[(3-bromo- phenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (15 mg, 0.040 mmol) and gave 1.2 mg (7.2%) of the title compound. MS (ESI+) calcd mass for C20H17NO7S:

415.072573, found 415.073303 .

Example 64

2-hydroxy-4- [(3-methylsulfonylphenyl)sulfonylamino] benzoic acid

The product was prepared according to General procedure 1, described in Example 1, with 3- (methylsulfonyl)benzenesulfonyl chloride (26 mg, 0.10 mmol) and 4-amino salicylic acid (30 mg, 0.20 mmol) and gave 10.7 mg (29%>) of the title compound. MS (ESI+) calcd mass for

C14H13NO7S2 371.013343, found 371.013433 . Example 65

4- [3-(benzofuran-2-yl)phenyl] sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared according to the General procedure 2, described in Example 3, with benzofuran-2-boronic acid (8.5 mg, 0.052 mmol) and 4-{[(3-bromophenyl)sulfonyl]-amino}- 2-hydroxybenzoic acid (Intermediate 1) (15 mg, 0.040 mmol) and gave 5.2 mg (32%) of the title compound. MS (ESI+) calcd mass for C ₂ iHi ₅ N0 ₆ S 409.062008, found 409.062548 .

Example 66

2-hydroxy-4- [ [3- [4-(methoxycarbonylamino)phenyl] phenyl] sulfonylamino] benzoic acid

The product was prepared according to the General procedure 2, described in Example 3, with 4-methoxycarbonylaminophenyl boronic acid (10.2 mg, 0.052 mmol) and 4-{[(3- bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (15 mg, 0.040 mmol) and gave 3.3 mg (19%) of the title compound. MS (ESI+) calcd mass for C ₂ iHi ₈ N ₂ 0 ₇ S 442.083472, found 442.084762 .

Example 67

4- [(5-fluoro-2-methylbenzene)sulfonamido] -2-hydroxybenzoic acid

The product was prepared according to General procedure 1, described in Example 1, with 5- fluoro-2-methylbenzene sulfonyl chloride (20 mg, 0.10 mmol) and 4-amino salicylic acid (15 mg, 0.10 mmol). The title compound was obtained in 21% yield (6.7 mg). MS (ESI+) calcd mass for Ci ₄ Hi ₂ FN0 ₅ S 325.042021, found 325.041161 .

Example 68

4- [(2-bromo-4-iodobenzene)sulfonamido] -2-hydroxybenzoic acid

The product was prepared according to General procedure 1 , described in Example 1 , with 2- bromo-4-iodo-benzene sulfonyl chloride (37 mg, 0.10 mmol) and 4-amino salicylic acid (15 mg, 0.10 mmol). The title compound was obtained in 17% yield (8.5 mg). MS (ESI+) calcd mass for Ci ₃ H ₉ BrIN0 ₅ S 496.842949, found 496.843709 .

Example 69

2-hydroxy-4- [(2,4,5-trichlorobenzene)sulfonamido] benzoic acid

The product was prepared according to General procedure 1 , described in Example 1 , with 2,4,5-trichloro-benzene sulfonyl chloride (27 mg, 0.10 mmol) and 4-amino salicylic acid (15 mg, 0.10 mmol). The title compound was obtained in 11% yield (4.5 mg). MS (ESI+) calcd mass for Ci ₃ H ₈ Cl ₃ N0 ₅ S 394.918876, found 394.919576 .

Example 70

2-hydroxy-4-{[4-(l,3-oxazol-5-yl)benzene]sulfonamido}benzoic acid

The product was prepared according to General procedure 1 , described in Example 1 , using 4- (l,3-oxazol-5-yl)benzenesulfonyl chloride (24 mg, 0.10 mmol) and 4-aminosalicylic acid (15 mg, 0.10 mmol). The title compound was obtained in 4% yield (1.4 mg). MS (ESI+) calcd mass for 360.041607, found 360.042747 . Example 71

4-(2,l,3-benzothiadiazole-4-sulfonamido)-2-hydroxybenzoic acid

A mixture of 2,l,3-benzothiadiazole-4-sulfonyl chloride (37 mg, 0.158 mmol), 4-aminosalicylic acid (20 mg, 0.130 mmol) and pyridine (32 μΕ, 3 equivs) in CH ₂ CI ₂ was stirred at 60°C over night and then at room temperature for additional 24h. The reaction mixture was concentrated and the crude product was purified by preparative HPLC (ACE C8, 5μιη, gradient: H ₂ O+0.1% TFA/MeCN). The title compound was obtained as a pink solid (8 mg, 18%). MS (ESI+) calcd for C13H9N3O5S2 350.998362, found mass 350.999342 .

Example 72

4-(2,l,3-benzoxadiazole-4-sulfonamido)-2-hydroxybenzoic acid

A mixture of 2,l,3-benzoxadiazole-4-sulphonyl chloride (34 mg, 0.156 mmol), 4- aminosalicylic acid (20 mg, 0.130 mmol) and pyridine (32 μΕ, 3 equivs) in CH ₂ CI ₂ was stirred at 60°C over night and then at room temperature for additional 24h. The reaction mix- ture was concentrated and the crude product was purified by preparative HPLC (ACE C8, 5μιη, gradient: H ₂ O+0.1% TFA/MeCN) . The title compound was obtained in 44% yield (6 mg, offwhite solid). MS (ESI+) calcd mass for CnHgNsOgS 335.021206, found 335.021636 . Example 73

4-{[3-(4-chlorophenyl)benzene]sulfonamido}-2-hydroxybenzoic acid

The product was prepared according to General procedure 1 , described in Example 1 , with [3- (4-chlorophenyl)phenyl]sulfonyl chloride (16 mg, 0.55 mmol) and 4-amino salicylic acid (8 mg, 0.052 mmol) using a prolonged reaction time (60 °C, over night) and 5 equiv. pyridine (24 μΕ). The title compound was obtained in 57% yield (12 mg). MS (ESI+) calcd mass for

CI ₉ HI ₄ C1N0 ₅ S 403.028121 , found 403.029061 .

Example 74

2-hydroxy-4-({3- [4-(trifluoromethyl)phenyl] benzene] sulfonamido)benzoic acid

The product was prepared according to General procedure 1 , described in Example 1 , with {3- [4-(trifluoromethyl)phenyl]phenyl}sulfonyl chloride (18 mg, 0.55 mmol) and 4- aminosalicylic acid (8 mg, 0.052 mmol) using a prolonged reaction time (60 °C, over night) and 5 equiv. pyridine (24 μΕ). The title compound was obtained in 53% yield (12 mg). MS (ESI+) calcd mass for C ₂ oHi ₄ F ₃ N0 ₅ S 437.054478, found 437.055228 .

Example 75

4-{[3-(4-fluorophenyl)benzene]sulfonamido}-2-hydroxybenzoic acid

The product was prepared according to General procedure 1 , described in Example 1 , with [3- (4-fluorophenyl)phenyl]sulfonyl chloride (15 mg, 0.55 mmol) and 4-amino salicylic acid (8 mg, 0.052 mmol) using a prolonged reaction time (60 °C, over night) and 5 equiv. pyridine (24 μΕ). The title compound was obtained in 50% yield (10 mg). MS (ESI+) calcd mass for Ci ₉ Hi ₄ FN0 ₅ S 387.057672, found 387.058552 .

Example 76

4-{[3-(3,5-dichlorophenyl)benzene]sulfonamido}-2-hydroxybenz oic acid

The product was prepared according to General procedure 1 , described in Example 1 , with [3- (3,5-dichlorophenyl)phenyl]sulfonyl chloride (18 mg, 0.55 mmol) and 4-aminosalicylic acid (8 mg, 0.052 mmol) using a prolonged reaction time (60 °C, over night) and 5 equiv. pyridine (24 μΕ). The title compound was obtained in 57% yield (13 mg). MS (ESI+) calcd mass for Ci9Hi ₃ Cl ₂ N0 ₅ S 436.989149, found 436.989369 .

Example 77

2-hydroxy-4-{[3-(4-methoxyphenyl)benzene]sulfonamido}benz oic acid

The product was prepared according to General procedure 1 , described in Example 1 , with [3- (4-methoxyphenyl)phenyl]sulfonyl chloride (16 mg, 0.55 mmol) and 4-aminosalicylic acid (8 mg, 0.052 mmol) using a prolonged reaction time (60 °C, over night) and 5 equiv. pyridine (24 μΕ). The title compound was obtained in 58%> yield (12 mg). MS (ESI+) calcd mass for C ₂ oHi ₇ N0 ₆ S 399.077658, found 399.077298 . Example 78

2-hydroxy-4-{[3-(4-methylphenyl)benzene]sulfonamido}benzoic acid

The product was prepared according to General procedure 1 , described in Example 1 , with [3- (4-methylphenyl)phenyl]sulfonyl chloride (15 mg, 0.55 mmol) and 4-amino salicylic acid (8 mg, 0.052 mmol) using a prolonged reaction time (60 °C, over night) and 5 equiv. pyridine (24 μΕ). The title compound was obtained in 50% yield (10 mg). MS (ESI+) calcd mass for C ₂ oHi ₇ N0 ₅ S 383.082743, found 383.082693 .

Example 79

2-hydroxy-4-{[3-(trifluoromethyl)benzene]sulfonamido}benz oic acid

The product was prepared according to General procedure 1 , described in Example 1 , with 3- trifluoromethylbenzenesulfonyl chloride (16 mg, 0.66 mmol) and 4-amino salicylic acid (9 mg, 0.058 mmol) using a modified reaction time (room temperature, over night) and 5 equiv. pyridine (24 μΕ). The title compound was obtained in 24% yield (5 mg). MS (ESI+) calcd mass for Ci ₄ HioF ₃ N0 ₅ S 361.023178, found 361.024648 .

Example 80

4-(l-benzothiophene-2-sulfonamido)-2-hydroxybenzoic acid

The product was prepared according to General procedure 1 , described in Example 1 , with 1- benzothiophene-2-sulfonyl chloride (15 mg, 0.66 mmol) and 4-amino salicylic acid (9 mg, 0.058 mmol) using a modified reaction time (room temperature, over night) and 5 equiv. pyridine (24 μΐ,). The title compound was obtained in 14% yield (2.9 mg). MS (ESI+) calcd mass for Ci ₅ H„N0 ₅ S ₂ 349.007864, found 349.007174 .

Example 81

2-hydroxy-4-(5-methyl-l-benzothiophene-2-sulfonamido)benz oic acid

The product was prepared according to General procedure 1, described in Example 1, with 5- methyl-l-benzothiophene-2-sulfonyl chloride (16 mg, 0.66 mmol) and 4-aminosalicylic acid (9 mg, 0.058 mmol) using a modified reaction time (room temperature, over night) and 5 equiv. pyridine (24 μΐ,). The title compound was obtained in 15% yield (3.2 mg). MS (ESI+) calcd mass for Ci6Hi ₃ N0 ₅ S ₂ 363.023514, found 363.023204 .

Example 82

2-hydroxy-4-(7-methoxy-3-methyl-l-benzothiophene-2-sulfonami do)benzoic acid

The product was prepared according to General procedure 1 , described in Example 1 , with 7- methoxy-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (Intermediate 7) (18 mg, 0.66 mmol) and 4-aminosalicylic acid (9 mg, 0.058 mmol) using a modified reaction time (room temperature, over night) and 5 equiv. pyridine (24 μΕ). The title compound was obtained in 17% yield (3.9 mg). MS (ESI+) calcd mass for Ci ₇ Hi ₅ N0 ₆ S ₂ 393.034079, found 393.034069 Example 83

2-hydroxy-4-(5-methoxy-3-methyl-l-benzothiophene-2-sulfonami do)benzoic acid

The product was prepared according to General procedure 1, described in Example 1 , with 5- methoxy-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (Intermediate 8) (18 mg, 0.66 mmol) and 4-amino salicylic acid (9 mg, 0.058 mmol) using a modified reaction time (room temperature, over night) and 5 equiv. pyridine (24 μΐ,). The title compound was obtained in 26% yield (6 mg). MS (ESI+) calcd mass for Ci ₇ Hi ₅ N0 ₆ S2 393.034079, found 393.033809 .

Example 84

2-hydroxy-4-[3-methyl-5-(propan-2-yl)-l-benzofuran-2-sulf onamido]benzoic acid

The product was prepared according to General procedure 1 , described in Example 1 , with 5- isopropyl-3-methyl-benzofuran-2-sulfonyl chloride (Intermediate 9) (18 mg, 0.66 mmol) and 4-aminosalicylic acid (9 mg, 0.058 mmol) using a modified reaction time (room temperature, over night) and 5 equiv. pyridine (24 μΕ). The title compound was obtained in 30%> yield (6.8 mg). MS (ESI+) calcd mass for Ci ₉ Hi ₉ N0 ₆ S 389.093308, found 389.093208 .

Example 85

4-(5-fluoro-3-methyl-l-benzothiophene-2-sulfonamido)-2-hydro xybenzoic acid

The product was prepared according to General procedure 1 , described in Example 1 , with 5- fluoro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (Intermediate 10) (17 mg, 0.66 mmol) and 4-amino salicylic acid (9 mg, 0.058 mmol) using a modified reaction time (room temperature, over night) and 5 equiv. pyridine (24 μΕ). The title compound was obtained in 32% yield (7.1 mg). MS (ESI+) calcd mass for Ci6Hi ₂ FN0 ₅ S ₂ 381.014092, found 381.013732 .

Example 86

4-{[3-(2H-l,3-benzodioxol-5-yl)benzene]sulfonamido}-2-hydrox ybenzoic acid

The product was prepared according to the General procedure 2, described in Example 3, with (3,4-methylenedioxyphenyl)boronic acid (8.7 mg, 0.052 mmol) and 4- {[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (15 mg, 0.040 mmol). The title compound was obtained in 45% yield (7.4 mg). MS (ESI+) calcd mass for C ₂ oHi ₅ NOyS 413.056923, found 413.057473 .

Example 87

4-{[3-(2,4-difluorophenyl)benzene]sulfonamido}-2-hydroxyben

The product was prepared according to the General procedure 2, described in Example 3, with 2,4-difluorobenzeneboronic acid (8.3 mg, 0.052 mmol) and 4- {[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (15 mg, 0.040 mmol). The title compound was obtained in 30%> yield (4.8 mg). MS (ESI+) calcd mass for

405.048250, found 405.047980 . Example 88

2-hydroxy-4-{[3-(2-nitrophenyl)benzene]sulfonamido}benzoic acid

The product was prepared according to the General procedure 2, described in Example 3, with 2-nitrobenzeneboronic acid (8.8 mg, 0.052 mmol) and 4-{[(3-bromophenyl)-sulfonyl]amino}- 2-hydroxybenzoic acid (Intermediate 1) (15 mg, 0.040 mmol). The title compound was obtained in 16% yield (2.6 mg). MS (ESI+) calcd mass for C19H14N2O7S 414.052172, found 414.052582 .

Example 89

2-hydroxy-4-{[3-(4-hydroxy-3,5-dimethylphenyl)benzene]sul fonamido}benzoic acid

The product was prepared according to the General procedure 2, described in Example 3, with 2,6-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) phenol (13 mg, 0.052 mmol) and 4-{[(3-bromophenyl)-sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (15 mg, 0.040 mmol). The title compound was obtained in 43% yield (7.1 mg). MS (ESI+) calcd mass for C ₂ iHi ₉ N0 ₆ S 413.093308, found 413.093778 .

Example 90

4-{[3-(4-butylphenyl)benzene]sulfonamido}-2-hydroxybenzoic acid

The product was prepared according to the General procedure 2, described in Example 3, with 4-n-butylbenzeneboronic acid (9.3 mg, 0.052 mmol) and 4-{[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (15 mg, 0.040 mmol). The title compound was obtained in 11% yield (1.8 mg). MS (ESI+) calcd mass for C ₂₃ H ₂₃ NO ₅ S 425.129694, found 425.130924 .

Example 91

4-({3-[4-(ethanesulfonyl)phenyl]benzene}sulfonamido)-2-hydro xybenzoic acid

The product was prepared according to the General procedure 2, described in Example 3, with 4-(ethylsulfonyl)phenylboronic acid (11 mg, 0.052 mmol) and 4-{[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (15 mg, 0.040 mmol). The title compound was obtained in 7% yield (1.3 mg). MS (ESI+) calcd mass for C21H19NO7S2 461.060293, found 461.060683 .

Example 92

2-hydroxy-4-{[3-(4-methoxy-3-methylphenyl)benzene]sulfona mido}benzoic acid

The product was prepared according to the General procedure 2, described in Example 3, with 4-methoxy-3-methylphenylboronic acid (8.7 mg, 0.052 mmol) and 4-{[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (15 mg, 0.040 mmol). The title compound was obtained in 7% yield (1.1 mg). MS (ESI+) calcd mass for C21H19NO6S 413.093308, found 413.094848 . Example 93

2-hydroxy-4-{[3-(3-hydroxyphenyl)benzene]sulfonamido}benzoic acid

The product was prepared according to the General procedure 2, described in Example 3, with 3-hydroxyphenylboronic acid (7.2 mg, 0.052 mmol) and 4-{[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (15 mg, 0.040 mmol). The title compound was obtained in 12% yield (1.9 mg). MS (ESI+) calcd mass for C19H15NO6S 385.062008, found 385.062348 .

Example 94

2-hydroxy-4-{[3-(3-methanesulfonylphenyl)benzene]sulfonam ido}benzoic acid

The product was prepared according to the General procedure 2, described in Example 3, with

3- (methylsulfonyl)phenylboronic acid (10.5 mg, 0.052 mmol) and 4-{[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (15 mg, 0.040 mmol). The title compound was obtained in 10% yield (1.8 mg). MS (ESI+) calcd mass for C20H17NO7S2 447.044643, found 447.046523 .

Example 95

4- ({3-[4-(dimethylcarbamoyl)phenyl]benzene}sulfonamido)-2-hydr oxybenzoic acid

The product was prepared according to the General procedure 2, described in Example 3, with 4-(N,N-dimethylaminocarbonyl)phenylboronic acid (10.1 mg, 0.052 mmol) and 4- {[(3- bromophenyl)-sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (15 mg, 0.040 mmol). The title compound was obtained in 16% yield (2.8 mg). MS (ESI+) calcd mass for C22H20N2O6S 440.104207, found 440.105047 .

Example 96

4-{[3-(4-ethylphenyl)benzene]sulfonamido}-2-hydroxybenzoi c acid

The product was prepared according to the General procedure 2, described in Example 3, with 4-ethylbenzeneboronic acid (7.9 mg, 0.052 mmol) and 4- {[(3-bromophenyl)-sulfonyl]amino}- 2-hydroxybenzoic acid (Intermediate 1) (15 mg, 0.040 mmol). The title compound was obtained in 16% yield (2.5 mg). MS (ESI+) calcd mass for C ₂ iHi ₉ N0 ₅ S 397.098393, found 397.098823 .

Example 97

4-[(3-{4-[bis(propan-2-yl)carbamoyl]phenyl}benzene)sulfonami do]-2-hydroxyben acid

The product was prepared according to the General procedure 2, described in Example 3, with 4-(N,N-diisopropylaminocarbonyl)phenylboronic acid (13 mg, 0.052 mmol) and 4- {[(3- bromophenyl)-sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (15 mg, 0.040 mmol). The title compound was obtained in 7% yield (1.4 mg). MS (ESI+) calcd mass for C26H28N2O6S 496.166807, found 496.167547 . Example 98

4-{[3-(4-acetylphenyl)benzene]sulfonamido}-2-hydroxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 4-acetylphenylboronic acid (1 1 mg, 0.065 mmol) and 4- {[(3-bromophenyl)-sulfonyl]amino}- 2-hydroxybenzoic acid (Intermediate 1) (19 mg, 0.051 mmol). The title compound was obtained in 36% yield (7.5 mg). MS (ESI+) calcd mass for C ₂ iHi ₇ N0 ₆ S 41 1.077658, found 41 1.079168 .

Example 99

4-{[3-(2,3-dimethoxyphenyl)benzene]sulfonamido}-2-hydroxyben zoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 2,3-dimethoxyphenylboronic acid (12 mg, 0.065 mmol) and 4- {[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (19 mg, 0.051 mmol). The title compound was obtained in 32% yield (6.9 mg). MS (ESI+) calcd mass for C ₂ iHi ₉ N0 ₇ S: 429.088223, found mass: 429.089453 .

Example 100

4-{[3-(4-fluoro-2-methoxyphenyl)benzene]sulfonamido}-2-hydro xybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 4-fluoro-2-methoxyphenylboronic acid (11 mg, 0.065 mmol) and 4-{[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (19 mg, 0.051 mmol). The title compound was obtained in 47% yield (10 mg). MS (ESI+) calcd mass for C ₂₀ H ₁₆ FNO ₆ S 417.068236, found 417.068566 .

Example 101

2-hydroxy-4-{[3-(2,3,6-trifluorophenyl)benzene]sulfonamido}b enzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 2,3,6-trifluoro-phenylboronic acid (11 mg, 0.065 mmol) and 4-{[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (19 mg, 0.051 mmol). The title compound was obtained in 3% yield (0.7 mg). MS (ESI+) calcd mass for C ₁₉ H ₁₂ F ₃ NO ₅ S: 423.038828, found 423.040308.

Example 102

4-({3- [4-(2-carboxyethyl)phenyl] benzene} sulfonamido)-2-hydroxyben

The product was prepared according to the General procedure 3, described in Example 4, with 4-(2-carboxyethyl)benzeneboronic acid (12.6 mg, 0.065 mmol) and 4-{[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (19 mg, 0.051 mmol). The title compound was obtained in 28% yield (6.2 mg). MS (ESI+) calcd mass for C ₂₂ H ₁₉ NO ₇ S: 441.088223, found 441.089663. Example 103

2-hydroxy-4-{[3-(3-methylphenyl)benzene]sulfonamido}benzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 3-methylphenylboronic acid (9.5 mg, 0.070 mmol) and 4-{[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (19 mg, 0.051 mmol). The title compound was obtained in 58% yield (11.3 mg). MS (ESI+) calcd mass for C20H17NO5S 383.082743, found 383.083453.

Example 104

4-{[3-(3,5-difluorophenyl)benzene]sulfonamido}-2-hydroxyben

The product was prepared according to the General procedure 3, described in Example 4, with 3,5-difluorobenzeneboronic acid neopentyl glycol ester (16 mg, 0.070 mmol) and 4-{[(3- bromophenyl)-sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (19 mg, 0.051 mmol). The title compound was obtained in 93% yield (19.2 mg). MS (ESI+) calcd mass for Ci9Hi ₃ F ₂ N0 ₅ S 405.048250, found mass: 405.048950.

Example 105

2-hydroxy-4-{[3-(4-methoxy-3,5-dimethylphenyl)benzene]sulfon amido}benzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 3,5-dimethyl-4-methoxyphenylboronic acid (12.6 mg, 0.070 mmol) and 4-{[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (19 mg, 0.051 mmol). The title compound was obtained in 53% yield (11.6 mg). MS (ESI+) calcd mass for C22H21NO6S 427.108958, found 427.109048.

Example 106

2-hydroxy-4-{[3-(2-methylphenyl)benzene]sulfonamido}benzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 2-methylphenylboronic acid (9.5 mg, 0.070 mmol) and 4-{[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (19 mg, 0.051 mmol). The title compound was obtained in 51% yield (10 mg). MS (ESI+) calcd mass for C20H17NO5S 383.082743, found 383.083343.

Example 107

2-hydroxy-4-{[3-(2-propoxypyridin-3-yl)benzene]sulfonamid o}benzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 2-propoxy-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-p yridine (18.4 mg, 0.070 mmol) and 4-{[(3-bromophenyl)-sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (19 mg,

0.051 mmol). The title compound was obtained in 51% yield (6.8 mg). MS (ESI+) calcd for C21H20N2O6S 428.104207, found 428.104527. Example 108

4-{[3-(6-ethoxypyridin-3-yl)benzene]sulfonamido}-2-hydroxybe nzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 2-ethoxypyridine-5-boronic acid pinacol ester (17.4 mg, 0.070 mmol) and 4-{[(3- bromophenyl)-sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (19 mg, 0.051 mmol). The title compound was obtained in 29% yield (6.2 mg). MS (ESI+) calcd mass for C ₂ oHi ₈ N ₂ 0 ₆ S 414.088557, found 414.089097.

Example 109

2-hydroxy-4-({3-[4-(propan-2-yloxy)phenyl]benzene}sulfona mido)benzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 4-isopropoxyphenylboronic acid (12.6 mg, 0.070 mmol) and 4-{[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (19 mg, 0.051 mmol). The title compound was obtained in 39% yield (8.5 mg). MS (ESI+) calcd mass for C ₂₂ H ₂ iN0 ₆ S 427.108958, found 427.109898. Example 110

4-{[3-(4-butoxyphenyl)benzene]sulfonamido}-2-hydroxybenzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 4-n-butoxyphenylboronic acid (13.6 mg, 0.070 mmol) and 4-{[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (19 mg, 0.051 mmol). The title compound was obtained in 22% yield (5.0 mg). MS (ESI+) calcd mass for C ₂₃ H ₂₃ NO ₆ S 441.124608, found 441.125528.

Example 111

4-{[3-(3,4-dimethoxyphenyl)benzene]sulfonamido}-2-hydroxyben

The product was prepared according to the General procedure 3, described in Example 4, with 3,4-dimethoxyphenylboronic acid (13 mg, 0.070 mmol) and 4-{[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (19 mg, 0.051 mmol). The title compound was obtained in 78% yield (17.0 mg). 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 3.80 (s, 3 H) 3.84 (s, 3 H) 6.55 - 6.67 (m, 2 H) 7.08 (d, J=8.55 Hz, 1 H) 7.15 (d, J=2.20 Hz, 1 H) 7.17 (dd, J=8.55, 2.20 Hz, 1 H) 7.60 (d, J=8.30 Hz, 1 H) 7.63 (t, J=8.00 Hz, 1 H) 7.74 (ddd, J=8.06, 1.60, 0.98 Hz, 1 H) 7.91 (ddd, J=8.00, 1.60, 0.98 Hz, 1 H) 7.99 (t, J=1.60 Hz, 1 H) 10.67 (br. s., 1 H). MS (ESI-) 428 [M-H]. Example 112

2-hydroxy-4-{[3-(6-methoxypyridin-3-yl)benzene]sulfonamido}b enzoic acid

The product was prepared according to the General procedure 3, described in Example 4, with 2-methoxy-5-pyridineboronic acid (10.7 mg, 0.070 mmol) and 4- {[(3-bromophenyl)- sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (19 mg, 0.051 mmol). The title compound was obtained in 46% yield (9.3 mg). MS (ESI+) calcd mass for C19H16N2O6S 400.072907, found 400.073217.

Example 113

2-hydroxy-4-{[3-(morpholin-4-yl)benzene]sulfonamido}benzo ic acid

The product was prepared according to the General procedure 5, described in Example 45, with morpholine (10 mg, 0.12 mmol) and 4- {[(3-bromophenyl)-sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 1) (37 mg, 0.10 mmol) to give the title compound. MS (ESI+) calcd mass for 378.088557, found 378.088907.

Example 114

2-hydroxy-4-(5-phenyl-2,3-dihydro-l-benzofuran-7-sulfonamido )benzoic acid

The product was prepared according to the General procedure 4, described in Example 9, with 5-bromo-2,3-dihydrobenzo[b]furan-7-sulphonyl chloride (30 mg, 0.09 mmol) and 4- aminosalicylic acid (15 mg, 0.1 mmol) giving the intermediate 4-(5-bromo-2,3-dihydro- benzofuran-7-sulfonylamino)-2-hydroxy-benzoic acid (25 mg). The 4-(5-bromo-2,3-dihydro- benzofuran-7-sulfonylamino)-2-hydroxy-benzoic acid was let react with phenyl boronic acid (10 mg, 0.08 mmol) according to the General Procedure 4. The title compound was obtained in 15% yield over two steps (5.6 mg). MS (ESI+) calcd mass for C ₂ iHi ₇ N0 ₆ S 411.077658, found 411.078438.

Example 115

4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-2-hydroxyben zoic acid

The title compound was obtained as described for Intermediate 2 (0.64 g, 43%). 1H NMR (500 MHz, DMSO-dg) δ ppm 6.71 (d, J=2.20 Hz, 1 H) 6.75 (dd, J=8.55, 2.20 Hz, 1 H) 7.72 (d, J=8.55 Hz, 1 H) 7.80 (s, 1 H) 11.26 (br. s., 1 H) 11.39 (br. s., 1 H); MS (ESI+) 412

[M+H].

Example 116

4-(5-Bromo-6-chloro-pyridine-3-sulfonylamino)-2-hydroxy-benz oic acid

The title compound was obtained as described for Intermediate 6 (0.59 g, 38%>). 1H NMR (500 MHz, DMSO-dg) δ ppm 6.68 (d, J=2.20 Hz, 1 H) 6.73 (dd, J=8.67, 2.08 Hz, 1 H) 7.69 (d, J=8.55 Hz, 1 H) 8.55 (d, J=2.20 Hz, 1 H) 8.80 (d, J=2.20 Hz, 1 H) 11.12 (br. s., 1 H) 11.37 (br. s., 1 H); MS (ESI+) 407 [M+H]. Example 117

4-(4,5-Dichloro-thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid

A mixture of methyl 4-amino-salicylate (0.84 g, 5 mmol), 2,3-dichlorothiophene-5-sulfonyl chloride (1.38 g, 5.5 mmol) and pyridine (0.79 g, 10 mmol) in 100 mL MeCN was heated at 80 °C over night. The solvent was removed under reduced pressure giving a bright red residue, which was dissolved in 100 mL toluene and 100 mL 1 M HC1. The organic phase was washed with 1 M HC1 (3x100 ml), H ₂ 0 and Brine and then dried over MgSC^, filtered and concentrated. The residue was recrystallized from toluene/heptane giving 1.57 g (82%) of 4- (4,5-dichloro-thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid methyl ester.

The 4-(4,5-dichloro-thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid methyl ester was dissolved in 1 M NaOH (10 mL) and heated at 60 °C for 2 h. The reaction mixture was washed with DCM (2x 50 mL) and acidified by addition of H3P04 giving a white precipitate. EtOAc (100 mL) was added to the mixture. The organic phase was washed with 1 M HC1 (2x 50 ml), H ₂ 0 and Brine and then dried over MgSC^, filtered and concentrated giving the crude product as a white solid. The crude product was refluxed in H ₂ 0/MeOH and after cooling the precipitate was collected by filtration giving the title compound as a white solid (0.43 g, 75%). 1H NMR (500 MHz, METHANOL-^) δ ppm 6.70 (dd, J=8.55, 2.20 Hz, 1 H) 6.75 (d, J=1.95 Hz, 1 H) 7.52 (s, 1 H) 7.78 (d, J=8.55 Hz, 1 H); MS (ESI+) 368 [M+H].

Example 118, General procedure 6

4-(3-Bromo-thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid

A mixture of 4-amino salicylic acid (1.16 g, 7.6 mmol) and 3-bromothiophene-2-sulfonyl chloride (1.0 g, 3.8 mmol) in aqueous dioxane (95 mL dioxane, 5 mL H ₂ 0) was stirred at room temperature for 8 weeks. 100 mL EtOAc was added. The organic phase was washed with 1 M HC1 (3x 50 ml), H ₂ 0 and Brine and then dried over MgS0 ₄ , filtered and concentrated. The brown residue was crystallized from H ₂ 0/MeOH at 60 °C. The precipitate was collected by filtration and dried in vacuum giving the title compound as a light brown solid (0.55 g, 38%). 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 6.69 (d, J=2.20 Hz, 1 H) 6.71 (dd, J=8.55, 2.20 Hz, 1 H) 7.28 (d, J=5.13 Hz, 1 H) 7.67 (d, J=8.55 Hz, 1 H) 8.00 (d, J=5.13 Hz, 1 H) 11.35 (br. s., 1 H) 11.43 (s, 1 H). MS (ESI+) 378 [M+H].

Example 119

4-(5-Bromo-thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid

The product was prepared according to the General procedure 6, described in Example 118. 4- aminosalicylic acid (1.16 g, 7.6 mmol) and 5-bromothiophene-2-sulfonyl chloride (1.0 g, 3.8 mmol) were stirred at room temperature for 7 weeks giving 0.64 g of the title compound as light brown solid (45%). 1H NMR (500 MHz, DMSO-d ₆ ) d ppm 6.70 (d, J=l .95 Hz, 1 H) 6.72 (dd, J=8.55, 2.20 Hz, 1 H) 7.33 (d, J=4.15 Hz, 1 H) 7.52 (d, J=4.15 Hz, 1 H) 7.70 (d, J=8.79 Hz, 1 H) 11.11 (s, 1 H); MS (ESI+) 378 [M+H].

Example 120

4-(4-Chloro-3-nitro-benzenesulfonylamino)-2-hydroxy-benzoic acid

The product was prepared according to the General procedure 6, described in Example 118, using a slightly modified workup procedure. 4-aminosalicylic acid (1.16 g, 7.6 mmol) and 4- chloro-3-nitrobenzenesulfonyl chloride (0.97 g, 3.8 mmol) were stirred at room temperature for 4 weeks. 1 M Na ₂ C0 ₃ was added until pH~9 followed by 100 ml of EtOAc. The aqueous phase was washed with 3x 50 mL of EtOAc and then acidified with cone. H ₃ PO ₄ until pH ~3. 100 mL EtOAc was added. The organic solution and the crude product were thereafter treated according to the General procedure 6 described in Example 118. 1.19 g of the title compound was obtained as light brown solid (84%). 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 6.59 - 6.74 (m, 2 H) 7.65 (d, J=8.55 Hz, 1 H) 7.87 (d, J=8.55 Hz, 1 H) 8.01 (dd, J=8.55, 2.20 Hz, 1 H) 8.41 (d, J=2.20 Hz, 1 H); MS (ESI+) 373 [M+H].

Example 121

4-(4-Bromo-2,5-dichloro-thiophene-3-sulfonylamino)-2-hydr oxy-benzoic acid

The product was prepared according to the General procedure 6, described in Example 118 with a slightly modified workup procedure. 4-aminosalicylic acid (0.15 g, 1.0 mmol) and 4- bromo-2,5-dichlorothiophene-3-sulfonyl chloride (0.33 g, 1.0 mmol) were stirred at room temperature for 3 weeks. 100 ml H ₂ 0 and 100 mL EtOAc were added. The pH was adjusted with 1 M Na ₂ C03 to ~10. The aqueous phase was washed with 2x 100 ml of EtOAc and acidified with cone. H ₃ PO ₄ to pH~2. 100 mL EtOAc was added. The organic solution and the crude product were thereafter treated according to the General procedure 6, described in Example 118, giving 60 mg of the title compound as light brown solid (13%). 1H NMR (500 MHz, METHANOL-^) δ ppm 6.55 - 6.76 (m, 2 H) 7.74 (d, J=8.55 Hz, 1 H); MS (ESI+) 446 [M+H].

Example 122

4-(3-Difluoromethoxy-benzenesulfonylamino)-2-hydroxy-benzoic acid

The product was prepared according to the General procedure 6, described in Example 118, with a slightly modified workup procedure. 4-aminosalicylic acid (0.15 g, 1.0 mmol) and 3- (difluoromethoxy)benzene sulfonyl chloride (0.31 g, 1.28 mmol) were stirred at room temperature for 13 days. 100 ml H ₂ 0 and 200 mL EtOAc were added. The pH was adjusted with 1 M Na ₂ C0 ₃ to ~10. The aqueous phase was washed with 2x 100 ml of EtOAc and acidified with cone. H ₃ PO ₄ to pH~2. 200 mL EtOAc was added. The organic solution and the crude product were thereafter treated according to the General procedure 6, described in Example 118, giving 62 mg of the title compound as light brown solid (17%). 1H NMR (500 MHz, METHANOL-d4) δ ppm 6.65 (dd, J=8.67, 2.20 Hz, 1 H) 6.69 (d, J=2.20 Hz, 1 H) 6.87 (t, J=73.12 Hz, 1 H) 7.38 (dd, J=8.28, 2.44 Hz, 1 H) 7.56 (dd, J=8.28, 7.92 Hz, 1 H) 7.61 (dd, J=2.42, 1.73 Hz, 1 H) 7.70 (d, J=8.67 Hz, 1 H) 7.71 (ddd, J=7.92, 1.73, 0.98 Hz, 1 H); MS (ESI+) 360 [M+H].

Example 123

2-Hydroxy-4-(3-methoxy-benzenesulfonylamino)-benzoic acid

The product was prepared according to the General procedure 6, described in Example 118 with a slightly modified workup procedure. 4-aminosalicylic acid (0.15 g, 1.0 mmol) and 3- methoxybenzene sulfonyl chloride (0.21 g, 1.0 mmol) were stirred at room temperature for 15 days. 100 mL H ₂ 0 and 200 mL EtOAc were added. The pH was adjusted with 1 M Na ₂ C0 ₃ to ~10. The aqueous phase was washed with 2x 100 mL of EtOAc and acidified with cone. H ₃ PO ₄ to pH~2. 200 mL EtOAc was added. The organic solution and the crude product were thereafter treated according to the General procedure 6, described in Example 118, giving 71 mg of the title compound as light brown solid (21%). 1H NMR (500 MHz, METHA- NOL- 4) δ ppm 3.81 (s, 3 H) 6.64 (dd, J=8.67, 2.20 Hz, 1 H) 6.69 (d, J=2.20 Hz, 1 H) 7.12 - 7.17 (m, 1 H) 7.35 - 7.37 (m, 1 H) 7.41 - 7.45 (m, 2 H) 7.69 (d, J=8.67 Hz, 1 H); MS (ESI+) 324 [M+H]. Example 124, General procedure 7

4- [5-(Benzoylamino-methyl)-thiophene-2-sulfonylamino] -2-hydroxy-benzoic acid

A mixture of 4-amino salicylic acid (8 mg, 0.050 mmol) and 5-[benzoylamino)methyl]- thiophene-2-sulfonyl chloride (32 mg,0.100 mmol) in aqueous dioxane (400 μΐ, dioxane, 50 H ₂ 0) was shaken at room temperature for 4 days. The reaction mixture was diluted using approx. 1.25 mL MeOH, 150 μΐ, H ₂ 0 and 150 μΐ, TFA. The crude product was purified by reversed phase chromatography (ACE C8, 5mm, 21x50mm, flow 25 ml/min, gradient:

H ₂ O+0.1% TFA/MeCN over 6 minutes) giving 10.9 mg of the title compound (50%). 1H NMR (500 MHz, DMSO-d ₆ ) δ ppm 4.61 (d, J=5.62 Hz, 2 H) 6.69 (d, J=2.19 Hz, 1 H) 6.70 (dd, J=8.30, 2.19 Hz, 1 H) 7.05 (dt, J=3.87, 0.85 Hz, 1 H) 7.45 - 7.50 (m, 2 H) 7.53 - 7.57 (m, 1 H) 7.54 (d, J=3.87 Hz, 1 H) 7.66 (dd, J=8.30, 0.65 Hz, 1 H) 7.82 - 7.86 (m, 2 H) 9.24 (t, J=5.91 Hz, 1 H) 10.94 (s, 1 H) 11.39 (br. s., 1 H) 13.74 (br. s., 1 H); MS (ESI+) 433 [M+H].

Example 125

-(3-Chloro-4-methyl-benzenesulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from 4-amino salicylic acid (8 mg, 0.050 mmol) and 3-chloro-4- methylbenzenesulphonyl chloride (23 mg, 0.100 mmol) according to the General procedure 7, described in Example 124. 7.5 mg of the title compound was obtained (44%). 1H NMR (500 MHz, DMSO-dg) δ ppm 2.37 (s, 3 H) 6.63 (d, J=2.14 Hz, 1 H) 6.67 (dd, J=8.62, 2.10 Hz, 1 H) 7.58 (d, J=8.06 Hz, 1 H) 7.64 (d, J=8.62 Hz, 1 H) 7.68 (dd, J=8.06, 1.95 Hz, 1 H) 7.81 (d, J=1.95 Hz, 1 H) 10.86 (s, 1 H) 11.50 (br. s., 1 H) 13.74 (br. s., 1 H); MS (ESI+) 342 [M+H]. Example 126

2-Hydroxy-4-(4-methyl-3-nitro-benzenesulfonylamino)-benzoic acid

The product was prepared from 4-amino salicylic acid (8 mg, 0.050 mmol) and 4-methyl-3- nitrobenzenesulphonyl chloride (24 mg, 0.100 mmol) according to the General procedure 7, described in Example 124. 6.8 mg of the title compound was obtained (39%). MS (ESI+) 353 [M+H].

Example 127

4-(4-Bromo-benzenesulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from 4-amino salicylic acid (8 mg, 0.050 mmol) and 4- bromobenzenesulphonyl chloride (40 mg, 0.157 mmol) according to the General procedure 7, described in Example 124. 6.6 mg of the title compound was obtained (35%). MS (ESI+) 372 [M+H]. Example 128

4-(3-Fluoro-benzenesulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from 4-amino salicylic acid (8 mg, 0.050 mmol) and 3- fluorobenzenesulphonyl chloride (19.5 mg, 0.100 mmol) according to the General procedure 7, described in Example 124. 7.5 mg of the title compound was obtained (49%>). MS (ESI+) 312 [M+H]. Example 129

4-(2,5-Dichloro-thiophene-3-sulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from 4-amino salicylic acid (8 mg, 0.050 mmol) and 2,5-dichloro- thiophene-3-sulfonyl chloride (26 mg, 0.100 mmol) according to the General procedure 7, described in Example 124. 9.5 mg of the title compound was obtained (52%). 1H NMR (500 MHz, DMSO-dg) δ ppm 6.65 (d, J=2.20 Hz, 1 H) 6.68 (dd, J=8.55, 2.20 Hz, 1 H) 7.43 (s, 1 H) 7.69 (d, J=8.55 Hz, 1 H) 11.26 (br. s., 1 H) 11.52 (br. s., 1 H) 13.76 (br. s., 1 H); MS (ESI+) 368 [M+H].

Example 130

2-Hydroxy-4-(2,3,4-trichloro-benzenesulfonylamino)-benzoic acid

The product was prepared from 4-amino salicylic acid (12 mg, 0.078 mmol) and 2,3,4- trichlorobenzenesulphonyl chloride (42 mg, 0.150 mmol) according to the General procedure 7, described in Example 124. After 6 days of stirring another portion of trichlorobenzenesul- phonyl chloride (10 mg, 0.036 mmol) was added in order to obtain full conversion. The title compound was obtained as a light brown solid (7.6 mg, 25%). 1H NMR (500 MHz, METHANOL-^) δ ppm 6.63 (dd, J=8.55, 2.20 Hz, 1 H) 6.66 (d, J=2.20 Hz, 1 H) 7.69 (d, J=8.67 Hz, 1 H) 7.71 (d, J=8.79 Hz, 1 H) 8.12 (d, J=8.67 Hz, 1 H); MS (ESI+) 396 [M+H]. Example 131

2-Hydroxy-4-(4-methyl-naphthalene-l-sulfonylamino)-benzoic acid

The product was prepared from 4-amino salicylic acid (8 mg, 0.050 mmol) and 4-methyl-l- napthalene sulfonyl chloride (26 mg, 0.100 mmol) according to the General procedure 7, described in Example 124. A 2: 1 mixture of dioxane/H ₂ 0 was used as solvent (600 total volume). 9.0 mg of the title compound was obtained (50%). 1H NMR (500 MHz, METHANOL-^) δ ppm 2.74 (d, J=0.94 Hz, 3 H) 6.51 (dd, J=8.67, 2.20 Hz, 1 H) 6.56 (d, J=2.20 Hz, 1 H) 7.45 (dq, J=7.57, 0.94 Hz, 1 H) 7.56 (d, J=8.67 Hz, 1 H) 7.65 (ddd, J=8.38, 6.88, 1.31 Hz, 1 H) 7.71 (ddd, J=8.60, 6.88, 1.48 Hz, 1 H) 8.16 (ddd, J=8.38, 1.48, 0.67 Hz, 1 H) 8.22 (d, J=7.57 Hz, 1 H) 8.75 (ddd, J=8.60, 1.31, 0.67 Hz, 1 H); MS (ESI+) 358 [M+H].

Example 132

4-(4-Fluoro-naphthalene-l-sulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from 4-amino salicylic acid (8 mg, 0.050 mmol) and 4-fluoro-l- napthalene sulfonyl chloride (24 mg, 0.100 mmol) according to the General procedure 7, described in Example 124. A 2: 1 mixture of dioxane/H ₂ 0 was used as solvent (600 total volume). 9.6 mg of the title compound was obtained (53%). 1H NMR (500 MHz, METHANOL-^) δ ppm 6.53 (dd, J=8.56, 2.20 Hz, 1 H) 6.57 (d, J=2.20 Hz, 1 H) 7.31 (dd, J=9.89, 8.30 Hz, 1 H) 7.59 (d, J=8.65 Hz, 1 H) 7.72 (ddd, J=8.42, 7.00, 1.07 Hz, 1 H) 7.80 (ddd, J=8.77, 7.00, 1.34 Hz, 1 H) 8.20 (d, J=8.42 Hz, 1 H) 8.35 (dd, J=8.30, 5.37 Hz, 1 H) 8.75 - 8.78 (m, 1 H); MS (ESI+) 362 [M+H]. Example 133

4-(5-Dimethylamino-naphthalene-l-sulfonylamino)-2-hydroxy-be nzoic acid

The product was prepared from 4-amino salicylic acid (8 mg, 0.050 mmol) and dansyl chlo- ride (28 mg, 0.100 mmol) according to the General procedure 7, described in Example 124. 6.2 mg of the title compound was obtained (32%). 1H NMR (500 MHz, METHANOL-^) δ ppm 2.88 (s, 6 H) 6.55 (dd, J=8.67, 2.20 Hz, 1 H) 6.59 (d, J=2.20 Hz, 1 H) 7.31 (d, J=7.61 Hz, 1 H) 7.58 (dd, J=8.52, 7.35 Hz, 1 H) 7.59 (d, J=8.67 Hz, 1 H) 7.62 (dd, J=8.67, 7.61 Hz, 1 H) 8.33 (dd, J=7.35, 1.22 Hz, 1 H) 8.41 (d, J=8.67 Hz, 1 H) 8.55 (dt, J=8.52, 1.22 Hz, 1 H); MS (ESI+) 387 [M+H].

Example 134

4-(5-Chloro-3-methyl-benzo [b] thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from 4-amino salicylic acid (22 mg, 0.14 mmol) and 5-chloro-3- methylbenzo[b]thiophene-2-sulfonyl chloride (20 mg, 0.071 mmol) according to the General procedure 7, described in Example 124 with a slightly modified procedure using 5% aqueous dioxane (950 dioxane, 50 H ₂ 0) and 4 weeks reaction time. 15 mg of the title compound was obtained (53%). 1H NMR (500 MHz, METHANOL-^) δ ppm 2.60 (s, 3 H) 6.67 (dd, J=8.55, 2.20 Hz, 1 H) 6.74 (d, J=2.20 Hz, 1 H) 7.48 (dd, J=8.67, 2.08 Hz, 1 H) 7.69 (d, J=8.79 Hz, 1 H) 7.87 (dd, J=8.79, 0.49 Hz, 1 H) 7.89 (dd, J=1.95, 0.49 Hz, 1 H); MS (ESI+) 398 [M+H]. Example 135, General procedure 8

2-Hydroxy-4-(3-pyridin-4-yl-benzenesulfonylamino)-benzoic acid

A mixture of 4-{[(3-bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (11 mg, 0.030 mmol), 4-pyridineboronic acid (4 mg, 0.033 mmol), 0.5 M Na ₂ C0 ₃ (300 μΐ,, 0.150 mmol) and Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (2 mg, 0.003 mmol) in dioxane (0.9 mL) was heated at 80 °C under N ₂ atmosphere over night. The reaction mixture was acidified by addition of 50 of 50% aqueous TFA. After being allowed to settle overnight the reaction mixture was filtered, diluted with MeOH and purified by reversed phase chromatography (ACE C8, 5mm, 21x50mm, flow 25 ml/min, gradient: H ₂ O+0.1% TFA/MeCN over 6 minutes) to give 4 mg of the title compound (36%). MS (ESI+) 371 [M+H].

Example 136

4-(4 '-Fluoro-3 '-methyl-biphenyl-3-sulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from 4-{[(3-bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (11 mg, 0.030 mmol) and (4-fluoro-3-methylphenyl)boronic acid (5 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 7.7 mg of the title compound was obtained (64%). MS (ESI+) 402 [M+H]. Example 137

4-(3 '-Chloro-biphenyl-3-sulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from 4-{[(3-bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (11 mg, 0.030 mmol) and 3-chlorophenylboronic acid (5.2 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 6.7 mg of the title compound was obtained (55%). MS (ESI+) 404 [M+H].

Example 138

4-(4'-Carbamoyl-biphenyl-3-sulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from 4-{[(3-bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (11 mg, 0.030 mmol) and 4-aminocarbonylphenyl boronic acid (5.4 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 8.9 mg of the title compound was obtained (72%). MS (ESI+) 413 [M+H].

Example 139

4-(3 '-Fluoro-4 '-methoxy-biphenyl-3-sulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from 4-{[(3-bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (11 mg, 0.030 mmol) and 3-fluoro-4-methoxyphenylboronic acid (5.6 mg, 0.033 mmol) according to the general procedure 8, described in Example 135. 4.9 mg of the title compound was obtained (39%). MS (ESI+) 418 [M+H]. Example 140

4-[6-Chloro-5-(4-hydroxy-phenyl)-pyridine-3-sulfonylamino]-2 -hydroxy-benzoic acid

The product was prepared from 4-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-2-hydroxy- benzoic acid (Intermediate 6) (12 mg, 0.030 mmol) and 4-hydroxyphenylboronic acid (4.6 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 4.3 mg of the title compound was obtained (34%). MS (ESI+) 421 [M+H].

Example 141

4-[6-Chloro-5-(3-hydroxy-phenyl)-pyridine-3-sulfonylamino]-2 -hydroxy-benzoic acid

The product was prepared from 4-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-2-hydroxy- benzoic acid (Intermediate 6) (12 mg, 0.030 mmol) and 3-hydroxyphenylboronic acid (4.6 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 5.5 mg of the title compound was obtained (44%). MS (ESI+) 421 [M+H]. Example 142

4- [5-(3- Amino-phenyl)-6-chloro-pyridine-3-sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared from 4-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-2-hydroxy- benzoic acid (Intermediate 6) (12 mg, 0.030 mmol) and 3-(4,4,5,5-Tetramethyl-l,3,2- dioxaborolan-2-yl)aniline (7.2 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 6.5 mg of the title compound was obtained (52%). MS (ESI+) 420 [M+H].

Example 143

4- [6-Chloro-5-(lH-pyrazol-4-yl)-pyridine-3-sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared from 4-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-2-hydroxy- benzoic acid (Intermediate 6) (12 mg, 0.030 mmol) and 4-(4,4,5,5-Tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (6.4 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 0.5 mg of the title compound was obtained (4%). MS (ESI+) 395 [M+H].

Example 144

4-[6-Chloro-5-(4-fluoro-3-methyl-phenyl)-pyridine-3-sulfonyl amino]-2-hydroxy-benzoic acid

The product was prepared from 4-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-2-hydroxy- benzoic acid (Intermediate 6) (12 mg, 0.030 mmol) and 4-fluoro-3-methylphenylboronic acid (5 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 4.9 mg of the title compound was obtained (37%). MS (ESI+) 437 [M+H]. Example 145

4- [6-Chloro-5-(3-chloro-phenyl)-pyridine-3-sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared from 4-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-2-hydroxy- benzoic acid (Intermediate 6) (12 mg, 0.030 mmol) and 3-chloro-phenylboronic acid (5.2 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 4.8 mg of the title compound was obtained (36%). MS (ESI+) 439 [M+H].

Example 146

4- [6-Chloro-5-(2-fluoro-3-methoxy-phenyl)-pyridine-3-sulfonyla mino] -2-hydroxy benzoic acid

The product was prepared from 4-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-2-hydroxy- benzoic acid (Intermediate 6) (12 mg, 0.030 mmol) and 2-fluoro-3-methoxyphenylboronic acid (5.6 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 2.1 mg of the title compound was obtained (15%). MS (ESI+) 453 [M+H]. Example 147

4- [5-(4-Carbamoyl-phenyl)-6-chloro-pyridine-3-sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared from 4-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-2-hydroxy- benzoic acid (Intermediate 6) (12 mg, 0.030 mmol) and 4-aminocarbonylphenyl boronic acid (5.4 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 5.6 mg of the title compound was obtained (42%). MS (ESI+) 448 [M+H].

Exampel 148

4- [6-Chloro-5-(3-fluoro-phenyl)-pyridine-3-sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared from 4-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-2-hydroxy- benzoic acid (Intermediate 6) (12 mg, 0.030 mmol) and 3 -fluorophenyl boronic acid (4.6 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 4.4 mg of the title compound was obtained (35%). MS (ESI+) 423 [M+H].

Example 149

4- [6-Chloro-5-(3-fluoro-4-methoxy-phenyl)-pyridine-3-sulfonyla mino] -2-hydroxy benzoic acid

The product was prepared from 4-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-2-hydroxy- benzoic acid (Intermediate 6) (12 mg, 0.030 mmol) and 3-fluoro-4-methoxyphenylboronic acid (5.6 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 5.1 mg of the title compound was obtained (38%). MS (ESI+) 453 [M+H]. Example 150

4-(6-Chloro-5-quinolin-6-yl-pyridine-3-sulfonylamino)-2-hydr oxy-benzoic acid

The product was prepared from 4-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-2-hydroxy- benzoic acid (Intermediate 6) (12 mg, 0.030 mmol) and 6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline (8.4 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 2.5 mg of the title compound was obtained (18%). MS (ESI+) 456 [M+H].

Example 151

4-(5-Chloro-4-pyridin-3-yl-thiophene-2-sulfonylamino)-2-hydr oxy-benzoic acid

The product was prepared from 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 2) (12 mg, 0.030 mmol) and 3-pyridineboronic acid (4.0 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 1.0 mg of the title compound was obtained (8%). MS (ESI+) 411 [M+H]. Example 152

4- [5-Chloro-4-(3-hydroxy-phenyl)-thiophene-2-sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared from 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 2) (12 mg, 0.030 mmol) and 3-hydroxyphenylboronic acid (4.6 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 2.5 mg of the title compound was obtained (20%). MS (ESI+) 426 [M+H].

Example 153

4-[5-Chloro-4-(4-hydroxy-3-methoxy-phenyl)-thiophene-2-sulfo nylamino]-2-hydroxy benzoic acid

The product was prepared from 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 2) (12 mg, 0.030 mmol) and 4-hydroxy-3- methoxyphenylboronic acid pinacol ester (8.2 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 4.1 mg of the title compound was obtained (30%). MS (ESI+) 456 [M+H].

Example 154

4- [5-Chloro-4-(3-chloro-phenyl)-thiophene-2-sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared from 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 2) (12 mg, 0.030 mmol) and 3-chloro-phenylboronic acid (5.2 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 0.5 mg of the title compound was obtained (4%). MS (ESI+) 444 [M+H].

Example 155

4-[4-(4-Carbamoyl-phenyl)-5-chloro-thiophene-2-sulfonylamino ]-2-hydroxy-benzoic acid

The product was prepared from 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 2) (12 mg, 0.030 mmol) and 4-aminocarbonylphenyl bo- ronic acid (5.4 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 2.7 mg of the title compound was obtained (20%). MS (ESI+) 453 [M+H].

Example 156

4-[5-Chloro-4-(3-fluoro-4-methoxy-phenyl)-thiophene-2-sulfon ylamino]-2-hydroxy- benzoic acid

The product was prepared from 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 2) (12 mg, 0.030 mmol) and 3-fluoro-4- methoxyphenylboronic acid (5.6 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 2.2 mg of the title compound was obtained (16%). MS (ESI+) 458 [M+H]. Example 157

4- [4-(4- Amino-3-methoxy-phenyl)-5-chloro-thiophene-2-sulfonylamino] -2-hydroxy benzoic acid

The product was prepared from 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 2) (12 mg, 0.030 mmol) and 2-methoxy-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (8.2 mg, 0.033 mmol) according to the General procedure 8, described in Example 135. 1.6 mg of the title compound was obtained (12%). 1H NMR (500 MHz, METHANOL-^) δ ppm 3.87 (s, 3 H) 6.73 (dd, J=8.79, 2.20 Hz, 1 H) 6.79 (d, J=2.20 Hz, 1 H) 6.86 (d, J=8.06 Hz, 1 H) 6.92 - 6.96 (m, 1 H) 6.97 (d, J=1.71 Hz, 1 H) 7.56 (s, 1 H) 7.78 (d, J=8.79 Hz, 1 H); MS (ESI+) 455 [M+H].

Example 158, General procedure 9

3'-(4-Carboxy-3-hydroxy-phenylsulfamoyl)-biphenyl-2-carboxyl ic acid methyl ester

A mixture of 4-{[(3-bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (18.6 mg, 0.050 mmol), 2-methoxycarbonylphenylboronic acid (10 mg, 0.055 mmol), DI- PEA(26 mg, 0.200 mmol) and Pd(dppf)Cl ₂ ^' CH ₂ Ci ₂ (2 mg, 0.003 mmol) in aqueous dioxane (0.9 mL dioxane, 0.1 mL ¾0) was heated at 80 °C under N ₂ atmosphere over night. The reaction mixture was acidified by addition of 50 neat TFA. After being allowed to settle over- night the reaction mixture was filtered, diluted with MeOH and purified by reversed phase chromatography (ACE C8, 5mm, 21x50mm, flow 25 ml/min, gradient: H ₂ O+0.1%

TFA/MeCN over 6 minutes) to give 14 mg of the title compound (67%). 1H NMR (500 MHz,

METHANOL-d4) δ ppm 3.50 (s, 3 H) 6.66 (dd, J=8.64, 2.14 Hz, 1 H) 6.69 (d, J=2.14 Hz, 1 H) 7.32 (ddd, J=7.60, 1.25, 0.49 Hz, 1 H) 7.51 (td, J=7.60, 1.25 Hz, 1 H) 7.51 (ddd, J=7.75, 1.74, 1.20 Hz, 1 H) 7.57 (td, J=7.75, 0.51 Hz, 1 H) 7.61 (td, J=7.60, 1.45 Hz, 1 H) 7.70 (d, J=8.64 Hz, 1 H) 7.74 (ddd, J=1.94, 1.74, 0.51 Hz, 1 H) 7.86 (ddd, J=7.60, 1.45, 0.49 Hz, 1 H) 7.86 (ddd, J=7.75, 1.94, 1.20 Hz, 1 H); MS (ESI+) 428 [M+H].

Example 159

4-(5'-Chloro-2'-methoxy-biphenyl-3-sulfonylamino)-2-hydro xy-benzoic acid

The product was prepared from 4-{[(3-bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (18.6 mg, 0.050 mmol) and 5-chloro-2-methoxyphenylboronic acid (10 mg, 0.055 mmol) according to the General procedure 9, described in Example 158. 15 mg of the title compound was obtained (70%). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.75 (s, 3 H) 6.67 - 6.72 (m, 2 H) 7.17 (d, J=8.91 Hz, 1 H) 7.31 (d, J=2.69 Hz, 1 H) 7.45 (dd, J=8.85, 2.69 Hz, 1 H) 7.64 (t, J=7.81 Hz, 1 H) 7.65 (d, J=8.54 Hz, 1 H) 7.76 (ddd, J=7.85, 1.68, 1.16 Hz, 1 H) 7.82 (ddd, J=7.85, 1.95, 1.16 Hz, 1 H) 7.95 (dd, J=1.95, 1.68 Hz, 1 H); MS (ESI+) 434 [M+H].

Example 160

4-(2',5'-Difluoro-biplienyl-3-sulfonylamino)-2-liydroxy-benz oic acid

The product was prepared from 4-{[(3-bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (18.6 mg, 0.050 mmol) and 2,5-difluorophenylboronic acid (8.7 mg, 0.055 mmol) according to the General procedure 9, described in Example 158. 14 mg of the title compound was obtained (71%). 1H NMR (500 MHz, METHANOL-d4) δ ppm 6.66 (dd, J=8.65, 2.18 Hz, 1 H) 6.71 (d, J=2.18 Hz, 1 H) 7.14 - 7.19 (m, 1 H) 7.21 (ddd, J=8.97, 5.98, 3.11 Hz, 1 H) 7.25 (ddd, J=9.90, 9.02, 4.62 Hz, 1 H) 7.64 (td, J=7.85, 0.37 Hz, 1 H) 7.70 (d, J=8.65 Hz, 1 H) 7.78 (dddd, J=7.85, 1.70, 1.70, 1.27 Hz, 1 H) 7.89 (ddd, J=7.85, 1.89, 1.10 Hz, 1 H) 8.02 (dddd, J=1.89, 1.80, 1.30, 0.49 Hz, 1 H); MS (ESI+) 406 [M+H].

Example 161

2-Hydroxy-4-(2 '-methoxy-biphenyl-3-sulfonylamino)-benzoic acid

The product was prepared from 4-{[(3-bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (18.6 mg, 0.050 mmol) and 2-methoxyphenylboronic acid (8.3 mg, 0.055 mmol) according to the General procedure 9, described in Example 158. 14 mg of the title compound was obtained (69%). 1H NMR (500 MHz, METHANOL-d4) δ ppm 3.77 (s, 3 H) 6.66 (dd, J=8.97, 2.18 Hz, 1 H) 6.73 (d, J=2.18 Hz, 1 H) 7.02 (ddd, J=7.57, 7.45, 0.85 Hz, 1 H) 7.08 (d, J=8.29 Hz, 1 H) 7.23 (dd, J=7.57, 1.67 Hz, 1 H) 7.36 (ddd, J=8.29, 7.45, 1.67 Hz, 1 H) 7.55 (t, J=7.75 Hz, 1 H) 7.70 (ddd, J=7.80, 1.70, 1.16 Hz, 1 H) 7.70 (d, J=8.97 Hz, 1 H) 7.80 (ddd, J=7.80, 1.93, 1.16 Hz, 1 H) 7.99 (dd, J=1.93, 1.70 Hz, 1 H); MS (ESI+) 400

[M+H].

Example 162

4-(2 '-Fluoro-3 '-methoxy-biphenyl-3-sulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from 4-{[(3-bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (18.6 mg, 0.050 mmol) and 2-fluoro-3-methoxyphenylboronic acid (9.3 mg, 0.055 mmol) according to the General procedure 9, described in Example 158. 14 mg of the title compound was obtained (67%). 1H NMR (500 MHz, METHANOL-d4) δ ppm 3.91 (s, 3 H) 6.66 (dd, J=8.67, 2.18 Hz, 1 H) 6.71 (d, J=2.18 Hz, 1 H) 6.95 (ddd, J=7.55, 6.55, 1.90 Hz, 1 H) 7.14 (ddd, J=8.23, 7.95, 1.60 Hz, 1 H) 7.19 (ddd, J=8.23, 7.53, 1.22 Hz, 1 H) 7.61 (t, J=7.85 Hz, 1 H) 7.70 (d, J=8.67 Hz, 1 H) 7.76 (dddd, J=7.85, 1.61, 1.26 Hz, 1 H) 7.86 (ddd, J=7.85, 1.86, 1.10 Hz, 1 H) 7.99 (ddd, J=1.88, 1.61, 1.30 Hz, 1 H); MS (ESI+) 418 [M+H]. Example 163

2-Hydroxy-4-(2'-hydroxy-biphenyl-3-sulfonylamino)-benzoic acid

The product was prepared from 4-{[(3-bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (18.6 mg, 0.050 mmol) and 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan -2- yl)phenol (12 mg, 0.055 mmol) according to the General procedure 9, described in Example 158. 10 mg of the title compound was obtained (50%). 1H NMR (500 MHz, METHANOL- d4) δ ppm 6.67 (dd, J=8.63, 2.20 Hz, 1 H) 6.71 (d, J=2.20 Hz, 1 H) 6.88 - 6.93 (m, 2 H) 7.17 - 7.22 (m, 2 H) 7.53 (t, J=7.81 Hz, 1 H) 7.70 (d, J=8.63 Hz, 1 H) 7.77 (ddd, J=7.81, 1.89, 1.10 Hz, 1 H) 7.80 (ddd, J=7.81, 1.73, 1.10 Hz, 1 H) 8.09 (dd, J=1.89, 1.73 Hz, 1 H); MS (ESI+) 386 [M+H].

Example 164

4-(2 '- Amino-biphenyl-3-sulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from 4-{[(3-bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (18.6 mg, 0.050 mmol) and 2-aminophenylboronic acid hydrochloride (7.7 mg, 0.055 mmol) according to the General procedure 9, described in Example 158. 11 mg of the title compound was obtained (56%). 1H NMR (500 MHz, METHANOL-d4) δ ppm 6.66 (dd, J=8.67, 2.20 Hz, 1 H) 6.71 (d, J=2.20 Hz, 1 H) 6.76 (ddd, J=7.56, 7.32, 1.10 Hz, 1 H) 6.82 (dd, J=8.06, 1.10 Hz, 1 H) 6.97 (dd, J=7.56, 1.56 Hz, 1 H) 7.12 (ddd, J=8.06, 7.32, 1.56 Hz, 1 H) 7.60 (dd, J=7.84, 7.76 Hz, 1 H) 7.68 (ddd, J=7.76, 1.70, 1.31 Hz, 1 H) 7.70 (d, J=8.67 Hz, 1 H) 7.83 (ddd, J=7.84, 1.98, 1.31 Hz, 1 H) 7.90 (dd, J=1.98, 1.70 Hz, 1 H); MS (ESI+) 385 [M+H].

Example 165

4-(5 '-Fluoro-2 '-methoxy-biphenyl-3-sulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from 4-{[(3-bromophenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Intermediate 1) (18.6 mg, 0.050 mmol) and 5-fluoro-2-methoxyphenylboronic acid (9.3 mg, 0.055 mmol) according to the General procedure 9, described in Example 158. 11 mg of the title compound was obtained (51%). 1H NMR (500 MHz, METHANOL-d4) δ ppm 3.75 (s, 3 H) 6.66 (dd, J=8.67, 2.11 Hz, 1 H) 6.73 (d, J=2.11 Hz, 1 H) 7.02 (dd, J=8.79, 2.56 Hz, 1 H) 7.04 - 7.12 (m, 2 H) 7.57 (t, J=7.85 Hz, 1 H) 7.69 - 7.72 (m, 1 H) 7.71 (d, J=8.67 Hz, 1 H) 7.83 (ddd, J=7.85, 1.94, 1.08 Hz, 1 H) 8.01 (dd, J=1.94, 1.70 Hz, 1 H); MS (ESI+) 418

[M+H]. Example 166

4-[5-Chloro-4-(5-chloro-2-methoxy-phenyl)-thiophene-2-sulfon ylamino]-2-hydroxy- benzoic acid

The product was prepared from 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 2) (20.6 mg, 0.050 mmol) and 5-chloro-2- methoxyphenylboronic acid (10 mg, 0.055 mmol) according to the General procedure 9, described in Example 158. 9 mg of the title compound was obtained (36%). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.73 (s, 3 H) 6.73 (d, J=2.09 Hz, 1 H) 6.76 (dd, J=8.59, 2.09 Hz, 1 H) 7.16 (d, J=8.91 Hz, 1 H) 7.37 (d, J=2.69 Hz, 1 H) 7.47 (dd, J=8.91, 2.69 Hz, 1 H) 7.67 (s, 1 H) 7.72 (d, J=8.59 Hz, 1 H) 11.17 (br. s., 1 H); MS (ESI+) 474 [M+H].

Example 167

4- [5-Chloro-4-(2,5-difluoro-phenyl)-thiophene-2-sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared from 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 2) (20.6 mg, 0.050 mmol) and 2,5-difluorophenylboronic acid (8.7 mg, 0.055 mmol) according to the General procedure 9, described in Example 158. 7 mg of the title compound was obtained (33%). 1H NMR (500 MHz, DMSO-d6) δ ppm 6.73 (d, J=2.08 Hz, 1 H) 6.76 (dd, J=8.67, 2.08 Hz, 1 H) 7.34 - 7.46 (m, 3 H) 7.71 (d, J=8.67 Hz, 1 H) 7.79 (d, J=1.22 Hz, 1 H) 11.22 (br. s., 1 H); MS (ESI+) 446 [M+H].

Example 168

4- [5-Chloro-4-(2-methoxy-phenyl)-thiophene-2-sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared from 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 2) (20.6 mg, 0.050 mmol) and 2-methoxyphenylboronic acid (8.3 mg, 0.055 mmol) according to the General procedure 9, described in Example 158. 8 mg of the title compound was obtained (34%). 1H NMR (500 MHz, METHANOL-d4) δ ppm 3.75 (s, 3 H) 6.72 (dd, J=8.67, 2.16 Hz, 1 H) 6.79 (d, J=2.16 Hz, 1 H) 7.00 (td, J=7.52, 1.05 Hz, 1 H) 7.07 (dd, J=8.38, 0.49 Hz, 1 H) 7.26 (dd, J=7.52, 1.71 Hz, 1 H) 7.38 (ddd, J=8.38, 7.52, 1.71 Hz, 1 H) 7.51 (s, 1 H) 7.78 (d, J=8.67 Hz, 1 H); MS (ESI+) 440 [M+H]. Example 169

4-[5-Chloro-4-(2-fluoro-3-methoxy-phenyl)-thiophene-2-sulfon ylamino]-2-hydroxy- benzoic acid

The product was prepared from 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 2) (20.6 mg, 0.050 mmol) and 2-fluoro-3- methoxyphenylboronic acid (9.3 mg, 0.055 mmol) according to the General procedure 9, described in Example 158. 10 mg of the title compound was obtained (43%). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.87 (s, 3 H) 6.74 (d, J=1.99 Hz, 1 H) 6.78 (dd, J=8.65, 1.99 Hz, 1 H) 6.99 (ddd, J=7.57, 6.16, 1.95 Hz, 1 H) 7.21 - 7.25 (m, 1 H) 7.27 (td, J=8.11, 1.95 Hz, 1 H) 7.72 (d, J=8.65 Hz, 1 H) 7.73 (s, 1 H) 11.23 (s, 1 H) 11.37 (br. s., 1 H); MS (ESI+) 458

[M+H].

Example 170

4- [4-(2- Amino-phenyl)-5-chloro-thiophene-2-sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared from 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 2) (20.6 mg, 0.050 mmol) and 2-aminophenylboronic acid hydrochloride (7.7 mg, 0.055 mmol) according to the General procedure 9, described in Example 158. 3 mg of the title compound was obtained (12%). 1H NMR (500 MHz, DMSO-d6) δ ppm 6.58 (ddd, J=7.58, 7.24, 1.24 Hz, 1 H) 6.71 (d, J=2.15 Hz, 1 H) 6.74 (dd, J=8.65, 2.15 Hz, 1 H) 6.75 (dd, J=8.16, 1.21 Hz, 1 H) 6.91 (dd, J=7.58, 1.60 Hz, 1 H) 7.09 (ddd, J=8.16, 7.24, 1.60 Hz, 1 H) 7.56 (s, 1 H) 7.70 (d, J=8.65 Hz, 1 H) 11.07 (br. s., 1 H); MS (ESI+) 425 [M+H]. Example 171

4-[5-Chloro-4-(5-fluoro-2-methoxy-phenyl)-thiophene-2-sulfon ylamino]-2-hydroxy- benzoic acid

The product was prepared from 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-2- hydroxybenzoic acid (Intermediate 2) (20.6 mg, 0.050 mmol) and 5-fluoro-2- methoxyphenylboronic acid (9.3 mg, 0.055 mmol) according to the General procedure 9, described in Example 158. 10 mg of the title compound was obtained (45%). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.71 (s, 3 H) 6.74 (d, J=2.15 Hz, 1 H) 6.76 (dd, J=8.67, 2.15 Hz, 1 H) 7.14 (dd, J=9.17, 4.56 Hz, 1 H) 7.22 (dd, J=9.03, 3.16 Hz, 1 H) 7.27 (ddd, J=9.17, 8.26, 3.16 Hz, 1 H) 7.67 (s, 1 H) 7.72 (d, J=8.67 Hz, 1 H) 11.18 (br. s., 1 H); MS (ESI+) 458

[M+H].

Example 172

4- [5-Chloro-4-(2-hydroxy-phenyl)-thiophene-2-sulfonylamino] -2-hydroxy-benzoic acid

A mixture of 4-{[(4-bromo-5-chloro-2-thienyl)sulfonyl]amino}-2-hydroxyben zoic acid (Intermediate 2) (150 mg, 0.36 mmol), 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (87 mg, 0.40 mmol), DIPEA (140 mg, 1.1 mmol) and Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (15 mg, 0.018 mmol) in aqueous dioxane (5 mL dioxane, 1 mL ¾0) was heated at 80 °C under N ₂ atmosphere over night. 50 mL CH ₂ CI ₂ and 10 mL 1 M Na ₂ C0 ₃ were added to the reaction mixture. The aqueous phase was washed with CH ₂ CI ₂ (2x 50 mL) and then acidified with cone. H ₃ PO ₄ . 100 mL EtOAc was added. The organic phase was washed with 1 M HC1 (2x 50 mL) and Brine, dried over MgS0 ₄ , filtered and concentrated. The crude product was dissolved in H ₂ 0/MeOH and purified by reversed phase chromatography (ACE C8, 5mm, 21x50mm, flow 25 ml/min, gradient: H ₂ O+0.1% TFA/MeCN over 6 minutes). The title compound was obtained as a white solid (37 mg, 24%). 1H NMR (500 MHz, METHANOL-^) δ ppm 6.72 (dd, J=8.55, 2.20 Hz, 1 H) 6.78 (d, J=1.95 Hz, 1 H) 6.85 - 6.91 (m, 2 H) 7.19 - 7.24 (m, 2 H) 7.61 (s, 1 H) 7.77 (d, J=8.55 Hz, 1 H); MS (ESI+) 426 [M+H]. Example 173, General procedure 10

4-(2,3-Dichloro-benzenesulfonylamino)-2-hydroxy-benzoic acid

A mixture of methyl 4-aminosalicylate (8.5 mg, 0.050 mmol), 2,3-dichlorobenzene sulfonyl chloride (23 mg, 0.050 mmol) and pyridine (8 μί, 0.100 mmol) in MeCN (400 μί) were heated at 50 °C for 4 days. The solvent was removed and the residue redissolved in 1 M

NaOH (300 μί, 0.300 mmol) and then heated at 60 °C over night. The crude product was diluted with H ₂ 0/MeOH/DMSO. 50 μΐ, TFA was added and the product was purified by reversed phase chromatography (ACE C8, 5mm, 21x50mm, flow 25 ml/min, gradient:

H ₂ O+0.1% TFA/MeCN over 6 minutes). The title compound was obtained in 92% yield (16.7 mg). 1H NMR (500 MHz, METHANOL-^) δ ppm 6.63 (dd, J=8.67, 2.20 Hz, 1 H) 6.65 (d, J=2.20 Hz, 1 H) 7.48 (t, J=8.06 Hz, 1 H) 7.67 (d, J=8.67 Hz, 1 H) 7.78 (dd, J=8.06, 1.53 Hz, 1 H) 8.14 (dd, J=8.06, 1.53 Hz, 1 H); MS (ESI+) 362 [M+H].

Example 174

4- [(3-chloro-4-fluorobenzene)sulfonamido] -2-hydroxybenzoic acid

The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 3-chloro- 4-fluorobenzene sulfonyl chloride (7.1 μί, 0.050 mmol) according to the General procedure 10, described in Example 173. 18 mg of the title compound was obtained (100%). 1H NMR (500 MHz, METHANOL-^) δ ppm 6.63 (dd, J=8.67, 2.20 Hz, 1 H) 6.67 (d, J=2.20 Hz, 1 H) 7.41 (t, J=8.77 Hz, 1 H) 7.71 (d, J=8.67 Hz, 1 H) 7.81 (ddd, J=8.77, 4.33, 2.32 Hz, 1 H) 7.97 (dd, J=6.71, 2.32 Hz, 1 H); MS (ESI+) 346 [M+H].

Example 175

4-(4-Bromo-2,5-difluoro-benzenesulfonylamino)-2-hydroxy-b enzoic acid

The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 4-bromo- 2,5-difluorobenzene sulfonyl chloride (16 mg, 0.054 mmol) according to the General procedure 10, described in Example 173. 18.5 mg of the title compound was obtained (91%). 1H NMR (500 MHz, METHANOL-^) δ ppm 6.66 (dd, J=8.55, 2.20 Hz, 1 H) 6.68 (d, J=2.20 Hz, 1 H) 7.71 (dd, J=9.03, 5.25 Hz, 1 H) 7.72 (d, J=8.55 Hz, 1 H) 7.79 (dd, J=7.57, 5.98 Hz, 1 H); MS (ESI+) 408 [M+H].

Example 176

2-Hydroxy-4-(toluene-3-sulfonylamino)-benzoic acid

The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 3- toluenesulfonyl chloride (7.3 μί, 0.050 mmol) according to the General procedure 10, described in Example 173. 14.4 mg of the title compound was obtained (94%). 1H NMR (500 MHz, METHANOL-^) δ ppm 2.39 (s, 3 H) 6.62 (dd, J=8.55, 2.20 Hz, 1 H) 6.66 (d, J=2.20 Hz, 1 H) 7.40 (t, J=7.57 Hz, 1 H) 7.40 - 7.44 (m, 1 H) 7.63 - 7.67 (m, 1 H) 7.67 (d, J=8.55 Hz, 1 H) 7.67 - 7.69 (m, 1 H); MS (ESI+) 308 [M+H]. Example 177

4-(Biphenyl-4-sulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 4- biphenylsulfonyl chloride (13 mg, 0.054 mmol) according to the General procedure 10, described in Example 173. 8.8 mg of the title compound was obtained (48%). 1H NMR (500 MHz, METHANOL-^) δ ppm 6.66 (dd, J=8.67, 2.20 Hz, 1 H) 6.72 (d, J=2.20 Hz, 1 H) 7.36 - 7.41 (m, 1 H) 7.42 - 7.48 (m, 2 H) 7.63 - 7.66 (m, 2 H) 7.70 (d, J=8.67 Hz, 1 H) 7.76 - 7.80 (m, 2 H) 7.91 - 7.95 (m, 2 H); MS (ESI+) 370 [M+H]. Example 178, General procedure 11

4-(Benzo [b] thiophene-3-sulfonylamino)-2-hydroxy-benzoic acid

A mixture of methyl 4-aminosalicylate (10 mg, 0.060 mmol), l-benzothiophene-3-sulfonyl chloride (11.5 mg, 0.049 mmol) and pyridine (50 μί) in CH ₂ CI ₂ (1 mL) was heated in a sealed tube at 60 °C over night. The solvent was evaporated, and the residue was dissolved in THF (1 mL) and 1 M NaOH (200 μί, 0.200 mmol). The alkaline reaction mixture was heated at 60 °C for 4h. The crude product was purified by preparative HPLC (ACE C8, 5μιη, 21x50mm, flow 25 ml/min, gradient: H ₂ O+0.1% TFA/MeCN over 6 minutes). The title compound was obtained in 51% yield (over two steps, 8.9 mg). 1H NMR (500 MHz, METHA- NOL- 4) δ ppm 6.61 (dd, J=8.67, 2.20 Hz, 1 H) 6.67 (d, J=2.20 Hz, 1 H) 7.46 (ddd, J=8.14, 7.14, 1.28 Hz, 1 H) 7.52 (ddd, J=8.14, 7.17, 1.22 Hz, 1 H) 7.64 (d, J=8.67 Hz, 1 H) 7.95 (ddd, J=8.14, 1.22, 0.75 Hz, 1 H) 8.25 (ddd, J=8.14, 1.28, 0.75 Hz, 1 H) 8.50 (s, 1 H); MS (ESI+) 350 [M+H]. Example 179

4-(2,5-Dichloro-4-methyl-thiophene-3-sulfonylamino)-2-hydrox y-benzoic acid

The product was prepared from methyl 4-aminosalicylate (10 mg, 0.060 mmol) and 2,5- dichloro-4-methyl-thiophene-3-sulfonyl chloride (Intermediate 12) (13 mg, 0.049 mmol) according to the General procedure 11, described in Example 178 with a slightly modified reaction time (50 °C 4h, then room temperature over night). The title compound was obtained in 37% yield (over two steps, 6.0 mg). 1H NMR (500 MHz, METHANOL-^) δ ppm 2.37 (s, 3 H) 6.61 (dd, J=8.67, 2.20 Hz, 1 H) 6.65 (d, J=2.20 Hz, 1 H) 7.73 (d, J=8.67 Hz, 1 H); MS (ESI+) 382 [M+H].

Example 180

2-Hydroxy-4-(2,4,5-trichloro-thiophene-3-sulfonylamino)-benz oic acid

The product was prepared from methyl 4-aminosalicylate (10 mg, 0.060 mmol) and 2,4,5- trichloro-thiophene-3-sulfonyl chloride (Intermediate 13) (14 mg, 0.049 mmol) according to the General procedure 11, described in Example 178 with a slightly modified reaction time (50 °C 4h, then room temperature over night). The title compound was obtained in 26% yield (over two steps, 5.1 mg). 1H NMR (500 MHz, METHANOL-^) δ ppm 6.65 (dd, J=8.67, 2.20 Hz, 1 H) 6.69 (d, J=2.20 Hz, 1 H) 7.73 (d, J=8.67 Hz, 1 H); MS (ESI+) 402 [M+H]. Example 181

4-(2-Chloro-6-methyl-benzenesulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 2-chloro- 6-methylbenzenesulfonyl chloride (11 mg, 0.050 mmol) according to the General procedure 10, described in Example 173, using a modified reaction time (60 °C over night). 11.1 mg of the title compound was obtained (65% over two steps). 1H NMR (500 MHz, METHANOL- d4) δ ppm 2.76 (s, 3 H) 6.58 (dd, J=8.54, 2.20 Hz, 1 H) 6.58 - 6.60 (m, 1 H) 7.31 (dd, J=7.38, 1.83 Hz, 1 H) 7.37 (dd, J=8.00, 7.39 Hz, 1 H) 7.40 (dd, J=8.00, 1.83 Hz, 1 H) 7.64 - 7.68 (m, 1 H); MS (ESI+) 342 [M+H].

Example 182

2-Hydroxy-4-(3-trifluoromethoxy-benzenesulfonylamino)-benzoi c acid

The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 3- (trifluoromethoxy)benzenesulphonyl chloride (13 mg, 0.050 mmol) according to the General procedure 10, described in Example 173, using a modified reaction time (60 °C over night). 13.3 mg of the title compound was obtained (71% over two steps). 1H NMR (500 MHz, METHANOL-d4) δ ppm 6.63 (dd, J=8.67, 2.20 Hz, 1 H) 6.68 (d, J=2.20 Hz, 1 H) 7.50 - 7.54 (m, 1 H) 7.64 (t, J=8.00 Hz, 1 H) 7.70 (d, J=8.67 Hz, 1 H) 7.70 - 7.73 (m, 1 H) 7.84 (ddd, J=8.00, 1.46, 0.92 Hz, 1 H); MS (ESI+) 378 [M+H].

Example 183

4-(Benzofuran-2-sulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 1- benzofuran-2-sulfonyl chloride (10.8 mg, 0.050 mmol) according to the General procedure 10, described in Example 173. 13.1 mg of the title compound was obtained (79%). IH NMR (500 MHz, METHANOL-^) δ ppm 6.72 (dd, J=8.67, 2.20 Hz, 1 H) 6.79 (d, J=2.20 Hz, 1 H) 7.34 (ddd, J=7.90, 7.20, 0.98 Hz, 1 H) 7.48 (ddd, J=8.60, 7.20, 1.31 Hz, 1 H) 7.56 (dddd, J=8.60, 0.98, 0.86, 0.72 Hz, 1 H) 7.56 (d, J=0.86 Hz, 1 H) 7.71 (d, J=8.67 Hz, 1 H) 7.73 (ddd, J=7.90, 1.31, 0.72 Hz, 1 H); MS (ESI+) 334 [M+H].

Example 184

2-H droxy-4-(5-methyl-2-trifluoromethyl-furan-3-sulfonylamino)-b enzoic acid

The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 5- methyl-2-(trifluoromethyl)-3-furansulfonyl chloride (12.4 mg, 0.054 mmol) according to the General procedure 10, described in Example 173. 13 mg of the title compound was obtained (71%). IH NMR (500 MHz, METHANOL-^) δ ppm 2.55 (s, 3 H) 6.66 (dd, J=8.67, 2.20 Hz, 1 H) 6.71 (d, J=2.20 Hz, 1 H) 7.14 (q, J=1.10 Hz, 1 H) 7.77 (d, J=8.67 Hz, 1 H); MS (ESI+) 366 [M+H].

Example 185

-(3-Chloro-2-methyl-benzenesulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 3-chloro- 2-methylbenzenesulfonyl chloride (11.2 mg, 0.054 mmol) according to the General procedure 10, described in Example 173. 14 mg of the title compound was obtained (82%). IH NMR (500 MHz, METHANOL-^) δ ppm 2.70 (d, J=0.63 Hz, 3 H) 6.55 (dd, J=8.55, 2.20 Hz, 1 H) 6.59 (d, J=2.20 Hz, 1 H) 7.34 (tq, J=8.00, 0.63 Hz, 1 H) 7.63 (dd, J=8.00, 1.33 Hz, 1 H) 7.66 (d, J=8.55 Hz, 1 H) 8.00 (dd, J=8.00, 1.33 Hz, 1 H); MS (ESI+) 342 [M+H]. Example 186

-Hydroxy-4-(5-isopropyl-3-methyl-benzo [b] thiophene-2-sulfonylamino)-benzoic acid

The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 5- isopropyl-3-methyl-benzothiophene-2-sulfonyl chloride (Intermediate 11) (14.4 mg, 0.054 mmol) according to the General procedure 10, described in Example 173. 14.4 mg of the title compound was obtained (71%). 1H NMR (500 MHz, METHANOL-^) δ ppm 1.30 (d, J=6.92 Hz, 6 H) 2.62 (s, 3 H) 3.05 (spt, J=6.92 Hz, 1 H) 6.68 (dd, J=8.67, 2.20 Hz, 1 H) 6.75 (d, J=2.20 Hz, 1 H) 7.43 (dd, J=8.55, 1.65 Hz, 1 H) 7.69 (d, J=8.67 Hz, 1 H) 7.68 (d, J=1.65 Hz, 1 H) 7.78 (d, J=8.55 Hz, 1 H); MS (ESI+) 406 [M+H].

Example 187

4- [4-(2,3-Dihydro-benzofuran-5-yl)-thiophene-2-sulfonylamino] -2-hydroxy-benzoic acid

A mixture of 4-({[5-chloro-4-(2,3-dihydro-l-benzofuran-5-yl)-2-thienyl]su lfonyl}amino)-2- hydroxybenzoic acid (Example 23, 5 mg, 0.011 mmol) and Pd/C (10%, 10 mg) in MeOH was stirred at room temperature under ¾ atmosphere for 1 day. The reaction mixture was filtered and concentrated to give the title compound as a white solid (3.6 mg, 82%>). 1H NMR (500 MHz, METHANOL-^) δ ppm 3.22 (t, J=8.79 Hz, 2 H) 4.56 (t, J=8.67 Hz, 2 H) 6.69 - 6.80 (m, 3 H) 7.32 (dd, J=8.30, 2.20 Hz, 1 H) 7.44 (d, J=1.46 Hz, 1 H) 7.72 - 7.76 (m, 2 H) 7.85 (d, J=1.71 Hz, 1 H); MS (ESI+) 418 [M+H]. Example 188

2-Hydroxy-4-[3-(l-hydroxy-ethyl)-benzenesulfonylamino] -benzoic acid

A mixture of 4-{[(3-acetylphenyl)sulfonyl]amino}-2-hydroxybenzoic acid (Example 46, 12 mg, 0.036 mmol) and NaB¾ (5 mg, 0.132 mmol) in MeOH (1 mL) was stirred at room temperature for 1 h. 1 M HC1 (2 mL) was added. The product was extracted using EtOAc (3x 2 mL). The organic solution was concentrated in vaccum giving the crude product, which was dissolved in H ₂ 0/MeOH and purified by reversed phase chromatography (ACE C8, 5mm, 21x50mm, flow 25 ml/min, gradient: H ₂ O+0.1% TFA/MeCN over 6 minutes). The title com- pound was obtained in 70% yield (8.5 mg). 1H NMR (500 MHz, METHANOL-d4) d ppm

1.39 (d, J=6.47 Hz, 3 H) 4.83 - 4.89 (m, 1 H) 6.63 (dd, J=8.64, 2.18 Hz, 1 H) 6.66 (dd, J=2.18, 0.36 Hz, 1 H) 7.49 (ddd, J=7.81, 7.74, 0.57 Hz, 1 H) 7.59 (dddd, J=7.74, 1.72, 1.16, 0.63 Hz, 1 H) 7.67 (dd, J=8.64, 0.36 Hz, 1 H) 7.74 (ddd, J=7.81, 1.93, 1.16 Hz, 1 H) 7.89 (dddd, J=1.93, 1.72, 0.57, 0.57 Hz, 1 H); MS (ESI+) 338 [M+H]. Example 189

2-Hydroxy-4-(3-hydroxy-benzenesulfonylamino)-benzoic acid

A solution of 1 M BBr ₃ in CH ₂ C1 ₂ (0.1 mL, 0.100 mmol) was added to a solution of 2- hydroxy-4-(3-methoxy-benzenesulfonylamino)-benzoic acid (Example 123, 10 mg, 0.031 mmol) in CH ₂ C1 ₂ (0.5 mL). Within 30 minutes the reaction was complete and 1 mL H ₂ 0 and MeOH was added. The CH ₂ C1 ₂ was removed under vaccum. The residue was dissolved in H ₂ 0/MeOH and purified by reversed phase chromatography (ACE C8, 5mm, 21x50mm, flow 25 ml/min, gradient: H ₂ O+0.1% TFA/MeCN over 6 minutes). The title compound was obtained in 51% yield (4.9 mg). 1H NMR (500 MHz, METHANOL-d4) δ ppm 6.62 (dd, J=8.67,

2.20 Hz, 1 H) 6.68 (d, J=2.20 Hz, 1 H) 6.98 (ddd, J=7.30, 2.49, 1.77 Hz, 1 H) 7.25 (ddd, J=2.49, 1.50, 0.67 Hz, 1 H) 7.30 (ddd, J=7.66, 1.77, 1.50 Hz, 1 H) 7.32 (ddd, J=7.66, 7.30, 0.67 Hz, 1 H) 7.68 (d, J=8.67 Hz, 1 H); MS (ESI+) 310 [M+H].

Example 190

2-Hydroxy-4-(2-hydroxy-benzenesulfonylamino)-benzoic acid

2-Hydroxy-4-(2-methoxy-benzenesulfonylamino)-benzoic acid was prepared according to the General procedure 6, described in Example 118 with a slightly modified workup procedure. 4- aminosalicylic acid (0.15 g, 1.0 mmol) and 2-methoxybenzene-sulphonyl chloride (0.21 g, 1.0 mmol) were stirred at room temperature for 4 weeks. 100 ml H ₂ 0 and 100 mL EtOAc were added. The pH was adjusted with 1 M Na ₂ C0 ₃ to -10. The aqueous phase was washed with 2x 100 mL of EtOAc and acidified with cone. H ₃ P0 ₄ to pH~2. 100 mL EtOAc was added. The organic solution and the crude product were thereafter treated according to the General procedure 6, described in Example 118, giving 70 mg of 2-hydroxy-4-(2-methoxy- benzenesulfonylamino)-benzoic acid as light brown solid (22%). 1H NMR (500 MHz, METHANOL-d4) δ ppm 3.93 (s, 3 H) 6.62 (dd, J=8.54, 2.20 Hz, 1 H) 6.64 (dd, J=2.20, 0.44 Hz, 1 H) 7.06 (ddd, J=7.84, 7.45, 0.98 Hz, 1 H) 7.12 (dd, J=8.43, 0.98 Hz, 1 H) 7.56 (ddd, J=8.43, 7.45, 1.73 Hz, 1 H) 7.63 (dd, J=8.54, 0.44 Hz, 1 H) 7.91 (dd, J=7.84, 1.73 Hz, 1 H); MS (ESI+) 324 [M+H].

The ether group in 2-hydroxy-4-(2-methoxy-benzenesulfonylamino)-benzoic acid (10 mg, 0.031 mmol) was cleaved using 1 M BBr ₃ in CH ₂ C1 ₂ (0.1 mL, 0.1 mmol) according to the procedure described for Example 189. The title compound was obtained in 62% yield (5.9 mg). 1H NMR (500 MHz, METHANOL-d4) δ ppm 6.64 (dd, J=8.55, 2.19 Hz, 1 H) 6.66 (dd, J=2.19, 0.42 Hz, 1 H) 6.90 (ddd, J=8.24, 1.09, 0.37 Hz, 1 H) 6.92 (ddd, J=7.92, 7.34, 1.09 Hz, 1 H) 7.40 (ddd, J=8.24, 7.34, 1.73 Hz, 1 H) 7.63 (dd, J=8.55, 0.42 Hz, 1 H) 7.80 (ddd, J=7.92, 1.73, 0.37 Hz, 1 H); MS (ESI+) 310 [M+H]. Example 191

4-(4-Chloro-phenylmethanesulfonylamino)-2-hydroxy-benzoic acid

The product was prepared according to the General procedure 1 , described in Example 1 , with 4-amino-2-hydroxybenzoic acid (9.2 mg, 0.060 mmol), 4-chlorobenzylsulfonyl chloride (14.9 mg, 0.66 mmol) and pyridine (24 μΐ _^ , 0.3 mmol) reacting at room temperature over night in CH ₂ C1 ₂ (200 μΐ,). 3.4 mg of the title compound was obtained (16%). MS (ESI+) calcd for C _I4 H _I2 C1N0 ₅ S 341.012471 , found 341.012331.

Example 192

4-(3-Bromo-phenylmethanesulfonylamino)-2-hydroxy-benzoic acid

The intermediate 4-(3-bromo-phenylmethanesulfonylamino)-2-hydroxy-benzoic acid methyl ester was prepared from methyl 4-amino salicylate (67 mg, 0.400 mmol) and 3- bromobenzylsulfonyl chloride (108 mg, 0.400 mmol) according to the General procedure 10, described in Example 173 with a modified temperature (room temperature over night). The intermediate ester was hydro lyzed with 5 M NaOH at 60 °C for 30 min. The reaction mixture was acidified by addition of cone. H ₃ PO ₄ , and then extracted with 2x EtOAc. The combined organic phases were washed with Brine, dried (MgS0 ₄ ), filtered and concentrated. The residue was dissolved in MeOH (1 mL) and precipitated by the addition of ~5 ml H ₂ 0. The mixture was heated with stirring at 60°C for 30 minutes (white precipitate). The solid was collected by filtration and dried in vaccum. The title compound was obtained as white solid (24 mg, 17%). 1H NMR (500 MHz, METHANOL-^) δ ppm 4.50 (s, 2 H) 6.65 (dd, J=8.55, 2.20 Hz, 1 H) 6.73 (d, J=2.20 Hz, 1 H) 7.22 - 7.26 (m, 2 H) 7.44 (br. s., 1 H) 7.47 - 7.52 (m, 1 H) 7.77 (d, J=8.55 Hz, 1 H). MS (ESI+) 386 [M+H]. Example 193

4-(4-Bromo-phenylmethanesulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from methyl 4-aminosalicylate (67 mg, 0.400 mmol) and 4- bromobenzylsulfonyl chloride (108 mg, 0.400 mmol) according to the experimental procedure described in Example 192. The title compound was obtained as a white solid (69 mg, 51%). IH NMR (500 MHz, METHANOL-^) δ ppm 4.47 (s, 2 H) 6.64 (dd, J=8.79, 2.20 Hz, 1 H) 6.72 (d, J=2.20 Hz, 1 H) 7.15 - 7.22 (m, 2 H) 7.45 - 7.53 (m, 2 H) 7.77 (d, J=8.55 Hz, 1 H). MS (ESI+) 386 [M+H]. Example 194

2-Hydroxy-4-(2'-hydroxy-biphenyl-4-ylmethanesulfonylamino)-b enzoic acid

The product was prepared from 4-(4-bromo-phenylmethanesulfonylamino)-2-hydroxy- benzoic acid (Intermediate 15) (12 mg, 0.030 mmol) and 2-hydroxyphenylboronic acid pina- col ester (8 mg, 0.036 mmol) according to the General procedure 9, described in Example 158. 12.8 mg of the title compound was obtained (100%). IH NMR (500 MHz, METHANOL-^) δ ppm 4.52 (s, 2 H) 6.69 (dd, J=8.67, 2.20 Hz, 1 H) 6.77 (d, J=2.20 Hz, 1 H) 6.86 - 6.90 (m, 2 H) 7.13 - 7.17 (m, 1 H) 7.18 - 7.21 (m, 1 H) 7.26 - 7.31 (m, 2 H) 7.49 - 7.53 (m, 2 H) 7.78 (d, J=8.67 Hz, 1 H). MS (ESI+) 400 [M+H]. Example 195

4-[4-(2,3-Dihydro-benzofuran-5-yl)-phenylmethanesulfonylamin o]-2-hydroxy-benzoic acid

The product was prepared from 4-(4-bromo-phenylmethanesulfonylamino)-2-hydroxy- benzoic acid (Intermediate 15) (12 mg, 0.030 mmol) and 2,3-dihydrobenzofuran-5-boronic acid (6 mg, 0.036 mmol) according to the General procedure 9, described in Example 158. 12.2 mg of the title compound was obtained (96%). 1H NMR (500 MHz, METHANOL-^) δ ppm 3.25 (t, J=8.70 Hz, 2 H) 4.51 (s, 2 H) 4.58 (t, J=8.70 Hz, 2 H) 6.65 (dd, J=8.67, 2.14 Hz, 1 H) 6.72 (d, J=2.14 Hz, 1 H) 6.77 (d, J=8.18 Hz, 1 H) 7.27 - 7.31 (m, 2 H) 7.30 (dd, J=8.18, 1.83 Hz, 1 H) 7.42 (d, J=1.83 Hz, 1 H) 7.45 - 7.50 (m, 2 H) 7.74 (d, J=8.67 Hz, 1 H). MS (ESI+) 426 [M+H].

Example 196

4-(2',5'-Difluoro-biphenyl-4-ylmethanesulfonylamino)-2-hydro xy-benzoic acid

The product was prepared from 4-(4-bromo-phenylmethanesulfonylamino)-2-hydroxy- benzoic acid (Intermediate 15) (12 mg, 0.030 mmol) and 2,5-difluorophenylboronic acid (6 mg, 0.036 mmol) according to the General procedure 9, described in Example 158. 11.9 mg of the title compound was obtained (95%). 1H NMR (500 MHz, METHANOL-^) δ ppm

4.56 (s, 2 H) 6.66 (dd, J=8.50, 2.00 Hz, 1 H) 6.73 (br. s., 1 H) 7.10 (dddd, J=8.95, 7.65, 3.54, 3.54 Hz, 1 H) 7.17 - 7.23 (m, 2 H) 7.36 - 7.41 (m, 2 H) 7.48 - 7.52 (m, 2 H) 7.76 (d, J=8.50 Hz, 1 H). MS (ESI+) 420 [M+H].

Example 197

4-(Biphenyl-4-ylmethanesulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from 4-(4-bromo-phenylmethanesulfonylamino)-2-hydroxy- benzoic acid (Intermediate 15) (12 mg, 0.030 mmol) and phenylboronic acid (4 mg, 0.036 mmol) according to the General procedure 9, described in Example 158. 10.3 mg of the title compound was obtained (90%). 1H NMR (500 MHz, METHANOL-^) δ ppm 4.54 (s, 2 H) 6.67 (dd, J=8.67, 1.83 Hz, 1 H) 6.74 (br. s., 1 H) 7.31 - 7.37 (m, 1 H) 7.33 - 7.37 (m, 2 H) 7.40 - 7.45 (m, 2 H) 7.54 - 7.58 (m, 2 H) 7.56 - 7.59 (m, 2 H) 7.76 (d, J=8.67 Hz, 1 H). MS (ESI+) 384 [M+H].

Example 198

4-[3-(2,3-Dihydro-benzofuran-5-yl)-phenylmethanesulfonylamin o]-2-hydroxy-benzoic acid

The product was prepared from 4-(3-bromo-phenylmethanesulfonylamino)-2-hydroxy- benzoic acid (Intermediate 14) (12 mg, 0.030 mmol) and 2,3-dihydrobenzofuran-5-boronic acid (6 mg, 0.036 mmol) according to the General procedure 9, described in Example 158. 9.2 mg of the title compound was obtained (72%). 1H NMR (500 MHz, METHANOL-^) δ ppm 3.23 (t, J=8.70 Hz, 2 H) 4.57 (t, J=8.70 Hz, 2 H) 4.56 (s, 2 H) 6.65 (dd, J=8.67, 2.20 Hz, 1 H) 6.70 (d, J=2.20 Hz, 1 H) 6.74 (d, J=8.30 Hz, 1 H) 7.20 - 7.25 (m, 2 H) 7.27 - 7.29 (m, 1 H) 7.31 (t, J=l .47 Hz, 1 H) 7.36 (t, J=7.80 Hz, 1 H) 7.50 (ddd, J=7.80, 1.47, 1.05 Hz, 1 H) 7.73 (d, J=8.67 Hz, 1 H). MS (ESI+) 426 [M+H].

Example 199

4-(2 ^, ,5'-Difluoro-biphenyl-3-ylmethanesulfonylamino)-2-hydr oxy-benzoic acid

The product was prepared from 4-(3-bromo-phenylmethanesulfonylamino)-2-hydroxy- benzoic acid (Intermediate 14) (12 mg, 0.030 mmol) and 2,5-difluorophenylboronic acid (6 mg, 0.036 mmol) according to the General procedure 9, described in Example 158. 10.1 mg of the title compound was obtained (80%). 1H NMR (500 MHz, METHANOL-^) δ ppm 4.59 (s, 2 H) 6.62 (dd, J=8.67, 2.20 Hz, 1 H) 6.69 (d, J=2.20 Hz, 1 H) 7.06 - 7.12 (m, 2 H) 7.19 (td, J=10.00, 4.52 Hz, 1 H) 7.34 (dt, J=7.75, 1.50 Hz, 1 H) 7.39 (q, J=1.50 Hz, 1 H) 7.43 (t, J=7.75 Hz, 1 H) 7.53 (dq, J=7.75, 1.50 Hz, 1 H) 7.71 (d, J=8.67 Hz, 1 H). MS (ESI+) 420 [M+H].

Example 200, General procedure 12

4-(3,5-Dibromo-thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid

A solution of 2,4-dibromothiophene (24 mg, 0.100 mmol) in CH ₂ CI ₂ (1.5 mL) was cooled to - 20 °C. To this was added a cold solution of chlorosulfonic acid (12 mg, 0.100 mmol) in CH ₂ CI ₂ (0.5 mL). The reaction was allowed to reach room temperature over 2 h, after which more chlorosulfonic acid was added (35 mg, 0.300 mmol). The reaction was stirred at 35 °C over night and was then poured through a column loaded with hydro matrix (3 g) and ¾0 (1 mL). The column was eluted with CH ₂ CI ₂ (2 mL). The eluate was concentrated to dryness under vacuum to give 3,5-dibromo-thiophene-2-sulfonyl chloride, which was dissolved in MeCN (0.5 mL) together with methyl 4-amino salicylate (16 mg, 0.100 mmol) and pyridine (15 mg, 0.200 mmol). The reaction mixture was allowed to react at 60 °C over night. The sol- vent was removed and the residue redissolved in 1 M NaOH (600 μί, 0.600 mmol) and then heated at 60 °C over night. The crude product was diluted with H ₂ 0/MeOH. 75 TFA was added and the product was purified by reversed phase chromatography (ACE C8, 5mm, 21x50mm, flow 25 ml/min, gradient: H ₂ O+0.1% TFA/MeCN over 6 minutes). The title compound was obtained in 39% yield (17.6 mg). 1H NMR (500 MHz, METHANOL- d ₄ ) δ ppm 6.71 (dd, J=8.58, 2.20 Hz, 1 H) 6.74 (d, J=2.20 Hz, 1 H) 7.24 (s, 1 H) 7.74 (d, J=8.58 Hz, 1 H); MS (ESI+) 456 [M+H].

Example 201

4-(3,4-Dibromo-thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid

The intermediate 3,4-dibromo-thiophene-2-sulfonyl chloride was prepared from 3,4- dibromothiophene (24 mg, 0.10 mmol) and chlorosulfonic acid (47 mg, 0.40 mmol) according to the General procedure 12, described in Example 200. The title compound was obtained by reacting the preformed 3,4-dibromo-thiophene-2-sulfonyl chloride with methyl 4- aminosalicylate (16 mg, 0.100 mmol) and pyridine (15 mg, 0.200 mmol) followed by hydrolysis according to the General procedure 12. 6.2 mg of the title compound was obtained (14%). 1H NMR (500 MHz, METHANOL-^) δ ppm 6.68 (dd, J=8.67, 2.20 Hz, 1 H) 6.73 (d, J=2.20 Hz, 1 H) 7.72 (d, J=8.67 Hz, 1 H) 7.93 (s, 1 H). MS (ESI+) 456 [M+H].

Example 202

4-(4,5-Dibromo-thiophene-2-sulfonylamino)-2-hydroxy-benzo ic acid

The product was prepared from methyl 4-aminosalicylate (9 mg, 0.050 mmol) and 4,5- dibromo-thiophene-2-sulfonyl chloride (22 mg, 0.065 mmol) according to the General procedure 10, described in Example 173. 14.7 mg of the title compound was obtained (64%>). 1H NMR (500 MHz, METHANOL-^) δ ppm 6.69 (dd, J=8.67, 2.20 Hz, 1 H) 6.75 (d, J=2.20 Hz, 1 H) 7.50 (s, 1 H) 7.78 (d, J=8.67 Hz, 1 H). MS (ESI+) 456 [M+H].

Example 203

4-(5-Bromo-4-methyl-thiophene-2-sulfonylamino)-2-hydroxy-ben zoic acid

The intermediate 5-bromo-4-methyl-thiophene-2-sulfonyl chloride was prepared from 2- bromo-3-methyl-thiophene (17.5 mg, 0.10 mmol) and chlorosulfonic acid (47 mg, 0.40 mmol) according to the General procedure 12, described in Example 200. The title compound was obtained by reacting the preformed 5-bromo-4-methyl-thiophene-2-sulfonyl chloride with methyl 4-aminosalicylate (16 mg, 0.100 mmol) and pyridine (15 mg, 0.200 mmol) followed by hydrolysis according to the General procedure 12. 17.1 mg of the title compound was obtained (44%). 1H NMR (500 MHz, METHANOL-^) δ ppm 2.16 (s, 3 H) 6.66 (dd, J=8.67, 2.20 Hz, 1 H) 6.72 (d, J=2.20 Hz, 1 H) 7.36 (s, 1 H) 7.74 (d, J=8.67 Hz, 1 H). MS (ESI+) 392 [M+H]. Example 204

4-(5-Chloro-4-methyl-thiophene-2-sulfonylamino)-2-hydroxy-be nzoic acid

The intermediate 5-chloro-4-methyl-thiophene-2-sulfonyl chloride was prepared from 2- chloro-3-methyl-thiophene (13.5 mg, 0.20 mmol) and chlorosulfonic acid (47 mg, 0.40 mmol) according to the General procedure 12, described in Example 200. The title compound was obtained by reacting the preformed 5-chloro-4-methyl-thiophene-2-sulfonyl chloride with methyl 4-aminosalicylate (16 mg, 0.100 mmol) and pyridine (15 mg, 0.200 mmol) followed by hydrolysis according to the General procedure 12. 20.8 mg of the title compound was obtained (60%). 1H NMR (500 MHz, METHANOL-^) δ ppm 2.16 (s, 3 H) 6.68 (dd, J=8.67, 2.20 Hz, 1 H) 6.74 (d, J=2.20 Hz, 1 H) 7.39 (s, 1 H) 7.75 (d, J=8.67 Hz, 1 H). MS (ESI+) 348 [M+H].

Example 205

4-(3,5-Dichloro-benzenesulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from methyl 4-aminosalicylate (9 mg, 0.050 mmol) and 3,5- dichloro-benzenesulfonyl chloride (15 mg, 0.061 mmol) according to the General procedure 10, described in Example 173. 12.8 mg of the title compound was obtained (71%). 1H NMR (500 MHz, METHANOL-^) δ ppm 6.66 (dd, J=8.67, 2.20 Hz, 1 H) 6.69 (d, J=2.20 Hz, 1 H) 7.72 (t, J=1.83 Hz, 1 H) 7.74 (d, J=8.67 Hz, 1 H) 7.77 (d, J=1.83 Hz, 2 H). ). MS (ESI+) 362 [M+H].

Example 206

4-(3-Bromo-5-trifluoromethyl-benzenesulfonylamino)-2-hydroxy -benzoic acid

4-(3-Bromo-5-trifluoromethyl-benzenesulfonylamino)-2-hydr oxy-benzoic acid methyl ester (Intermediate 16) (23 mg, 50 μιηοΐ) was dissolved in 1 M NaOH (300 μί) and shaken at 60 °C overnight. The reaction mixture was acidified with 50 μΐ of TFA, diluted to 2 mL with MeOH/H ₂ 0 and purified by reversed phase chromatography (ACE C8, 5mm, 21x50mm, flow 25 ml/min, gradient: 27-56% H ₂ O+0.1% TFA/MeCN over 6 minutes). 7 mg of the title compound was obtained (32%). 1H NMR (500 MHz, METHANOL-^) δ ppm 6.66 (dd, J=8.67, 2.20 Hz, 1 H) 6.69 (d, J=2.20 Hz, 1 H) 7.74 (d, J=8.67 Hz, 1 H) 8.04 - 8.06 (m, 1 H) 8.12 - 8.13 (m, 1 H) 8.21 - 8.23 (m, 1 H). MS (ESI+) 440 [M+H].

Example 207, General procedure 13 4-(2 ^, ,5 ^, -Difluoro-5-trifluoromethyl-biphenyl-3-sulfonylamino)- 2-hydroxy-benzoic acid

The product was prepared from 4-(3-bromo-5-trifluoromethyl-benzenesulfonylamino)-2- hydroxy-benzoic acid methylester (Intermediate 16) (23 mg, 0.050 mmol) and 2,5- difluorophenylboronic acid (9 mg, 0.060 mmol) according to the General procedure 9, described in Example 158. After complete Suzuki coupling reaction, most solvent was removed with a slow stream of air. 1 M NaOH (300 μί) was added and the reaction was shaken at 60 °C overnight. The title compound was obtained after purification according to the General procedure 9, described in Example 158 (19.2 mg, 81%). 1H NMR (500 MHz, METHANOL- d ₄ ) δ ppm 6.68 (dd, J=8.67, 2.20 Hz, 1 H) 6.72 (d, J=2.20 Hz, 1 H) 7.20 - 7.30 (m, 2 H) 7.30 (td, J=9.40, 4.52 Hz, 1 H) 7.74 (d, J=8.67 Hz, 1 H) 8.08 (br. s., 1 H) 8.13 (br. s., 1 H) 8.21 - 8.23 (m, 1 H). MS (ESI+) 474 [M+H].

Example 208

4-[3-(2,3-Dihydro-benzofuran-5-yl)-5-trifluoromethyl-benzene sulfonylamino]-2- hydroxy-benzoic acid

The product was prepared from 4-(3-bromo-5-trifluoromethyl-benzenesulfonylamino)-2- hydroxy-benzoic acid methylester (Intermediate 16) (23 mg, 0.050 mmol) and 2,3- dihydrobenzofuran-5-boronic acid (10 mg, 0.060 mmol) according to the General procedure 13, described in Example 207. The title compound was obtained in 83% yield (19.8 mg). 1H

NMR (500 MHz, METHANOL-^) δ ppm 3.27 (t, J=8.76 Hz, 2 H) 4.61 (t, J=8.76 Hz, 2 H) 6.68 (dd, J=8.67, 2.20 Hz, 1 H) 6.74 (d, J=2.20 Hz, 1 H) 6.84 (d, J=8.30 Hz, 1 H) 7.35 (ddt, J=8.30, 2.14, 0.70 Hz, 1 H) 7.42 (dt, J=2.14, 1.20 Hz, 1 H) 7.74 (d, J=8.67 Hz, 1 H) 7.98 (dq, J=1.68, 0.74 Hz, 1 H) 8.03 (dq, J=1.68, 0.74 Hz, 1 H) 8.14 (t, J=1.68 Hz, 1 H). MS (ESI+) 480 [M+H].

Example 209

2-Hydroxy-4-(2'-hydroxy-5-trifluoromethyl-biplienyl-3-sul fonylamino)-benzoic acid

The product was prepared from 4-(3-bromo-5-trifluoromethyl-benzenesulfonylamino)-2- hydroxy-benzoic acid methylester (Intermediate 16) (23 mg, 0.050 mmol) and 2- hydroxyphenylboronic acid pinacol ester (13 mg, 0.060 mmol) according to the General procedure 13, described in Example 207. The title compound was obtained in 72% yield (16.3 mg). 1H NMR (500 MHz, METHANOL-^) δ ppm 6.69 (dd, J=8.67, 2.18 Hz, 1 H) 6.73 (d, J=2.18 Hz, 1 H) 6.92 - 6.96 (m, 2 H) 7.22 - 7.27 (m, 2 H) 7.73 (d, J=8.67 Hz, 1 H) 8.00 (dq, J=l .76, 0.75 Hz, 1 H) 8.11 (dq, J=l .67, 0.78 Hz, 1 H) 8.29 (t, J=l .67 Hz, 1 H). MS (ESI+) 454 [M+H].

Example 210

4-(3-Chloro-2-fluoro-benzenesulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from methyl 4-aminosalicylate (9 mg, 0.050 mmol) and 3-chloro-2- fluoro-benzenesulfonyl chloride (7.5 μί, 0.050 mmol) according to the General procedure 10, described in Example 173. 11.8 mg of the title compound was obtained (68%).

1H NMR (500 MHz, METHANOL-^) δ ppm 6.65 (dd, J=8.67, 2.20 Hz, 1 H) 6.68 (d, J=2.20 Hz, 1 H) 7.33 (td, J=8.06, 1.22 Hz, 1 H) 7.69 (d, J=8.67 Hz, 1 H) 7.74 (ddd, J=8.06, 6.71, 1.68 Hz, 1 H) 7.89 (ddd, J=8.06, 6.32, 1.68 Hz, 1 H). MS (ESI+) 346 [M+H].

Example 211

4-(5-Chloro-2-fluoro-benzenesulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from methyl 4-aminosalicylate (9 mg, 0.050 mmol) and 5-chloro-2- fluoro-benzenesulfonyl chloride (16 mg, 0.072 mmol) according to the General procedure 10, described in Example 173. 12.9 mg of the title compound was obtained (75%>). MS (ESI+) 346 [M+H]. Example 212

4-(2,5-Dimethyl-furan-3-sulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from methyl 4-aminosalicylate (9 mg, 0.050 mmol) and 2,5- dimethyl-furan-3-sulfonyl chloride (7 μΐ,, 0.050 mmol) according to the General procedure 10, described in Example 173. 7.6 mg of the title compound was obtained (49%). 1H NMR (500 MHz, METHANOL-^) δ ppm 2.20 (d, J=1.10 Hz, 3 H) 2.44 (s, 3 H) 6.15 (q, J=1.10 Hz, 1 H) 6.62 (dd, J=8.67, 2.20 Hz, 1 H) 6.67 (d, J=2.20 Hz, 1 H) 7.72 (d, J=8.67 Hz, 1 H). MS (ESI+) 312 [M+H]. Example 213

4- [5-(2,5-Difluoro-phenyl)-thiophene-2-sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared from 4-(5-bromo-thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid (Intermediate 17) (19 mg, 0.050 mmol) and 2,5-difluorophenylboronic acid (9 mg, 0.060 mmol) according to the General procedure 9, described in Example 158. 15 mg of the title compound was obtained (74%). 1H NMR (500 MHz, METHANOL-^) δ ppm 6.72 (dd, J=8.63, 2.17 Hz, 1 H) 6.78 (d, J=2.17 Hz, 1 H) 7.15 (dddd, J=9.15, 7.53, 3.86, 3.16 Hz, 1 H) 7.27 (ddd, J=10.54, 9.15, 4.58 Hz, 1 H) 7.53 (ddd, J=9.15, 5.99, 3.16 Hz, 1 H) 7.52 (d, J=4.02 Hz, 1 H) 7.63 (dd, J=4.02, 1.40 Hz, 1 H) 7.75 (d, J=8.63 Hz, 1 H). MS (ESI+) 412 [M+H].

Example 214

4- [5-(2,3-Dihydro-benzofuran-5-yl)-thiophene-2-sulfonylamino] -2-hydroxy-benzoic acid

The product was prepared from 4-(5-bromo-thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid (Intermediate 17) (19 mg, 0.050 mmol) and 2,3-dihydrobenzofuran-5-boronic acid (10 mg, 0.060 mmol) according to the General procedure 9, described in Example 158. 15.2 mg of the title compound was obtained (73%). 1H NMR (500 MHz, METHANOL-^) δ ppm 3.23 (t, J=8.73 Hz, 2 H) 4.58 (t, J=8.73 Hz, 2 H) 6.70 (dd, J=8.67, 2.14 Hz, 1 H) 6.75 (d, J=8.31 Hz, 1 H) 6.78 (d, J=2.14 Hz, 1 H) 7.19 (d, J=4.03 Hz, 1 H) 7.37 (ddt, J=8.31, 2.08, 0.70 Hz, 1 H) 7.48 (dt, J=2.08, 1.15 Hz, 1 H) 7.54 (d, J=4.03 Hz, 1 H) 7.74 (d, J=8.67 Hz, 1 H). MS (ESI+) 418 [M+H].

Example 215

2-Hydroxy-4-(5-phenyl-thiophene-2-sulfonylamino)-benzoic acid

The product was prepared from 4-(5-bromo-thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid (Intermediate 17) (19 mg, 0.050 mmol) and phenylboronic acid (7 mg, 0.060 mmol) according to the General procedure 9, described in Example 158. 12.8 mg of the title compound was obtained (68%). MS (ESI+) 376 [M+H].

Example 216

2-Hydroxy-4- [5-(2-hydroxy-phenyl)-thiophene-2-sulfonylamino] -benzoic acid

The product was prepared from 4-(5-bromo-thiophene-2-sulfonylamino)-2-hydroxy-benzoic acid (Intermediate 17) (19 mg, 0.050 mmol) and 2-hydroxyphenylboronic acid pinacol ester (13 mg, 0.060 mmol) according to the General procedure 9, described in Example 158. 14.6 mg of the title compound was obtained (75%). MS (ESI+) 392 [M+H]. Example 217

2-hydroxy-4- [(4-phenoxybenzene)sulfonamido] benzoic acid

The product was prepared according to the General procedure 1 , described in Example 1 , with 4-amino-2-hydroxybenzoic acid (9.2 mg, 0.060 mmol), 4-phenoxy-benzenesulfonyl chloride (17 mg, 0.66 mmol) and pyridine (24 μΕ, 0.3 mmol) reacting at room temperature over night in CH ₂ C1 ₂ (200 μΐ,). 3.9 mg (17%) of the title compound was obtained. MS (ESI+) calcd for Ci ₉ Hi ₅ N0 ₆ S 385.062008, found 385.061508.

Example 218

4-(2,5-Dimethyl-thiophene-3-sulfonylamino)-2-hydroxy-benz oic acid

The title compound was commercially available from Aurora Fine Chemicals LLC, CAS [1094700-71-6].

Example 219

4-(4-Chloro-benzenesulfonylamino)-2-hydroxy-benzoic acid

The title compound was commercially available from Aurora Fine Chemicals LLC CAS [313496-24-1]. -benzoic acid

The title compound was commercially available from Aurora Fine Chemicals LLC CAS [59149-18-7].

Example 221

2-Hydroxy-4-(3-nitro-benzenesulfonylamino)-benzoic acid

The title compound was commercially available from Aurora Fine Chemicals LLC CAS [326610-63-3].

Example 222

2-Hydroxy-4-(naphthalene-l-sulfonylamino)-benzoic acid

The title compound was commercially available from Aurora Fine Chemicals LLC CAS [825601-10-3]. Example 223

2-Hydroxy-4-(naphthalene-2-sulfonylamino)-benzoic acid

The title compound was commercially available from Aurora Fine Chemicals LLC CAS [791786-80-6].

Example 224

4-(3-Carboxy-benzenesulfonylamino)-2-hydroxy-benzoic acid

The title compound was commercially available from Aurora Fine Chemicals LLC CAS [794552-84-4].

Example 225

4-(4-Carboxy-benzenesulfonylamino)-2-hydroxy-benzoic acid

The title compound was commercially available from Aurora Fine Chemicals LLC, CAS [22895-16-5]. Example 226

4-(2,5-Dichloro-benzenesulfonylamino)-2-hydroxy-benzoic acid

The title compound was commercially available from Aurora Fine Chemicals LLC CAS [714261-12-8].

Example 227

4-(3-Chloro-benzenesulfonylamino)-2-hydroxy-benzoic acid

The title compound was commercially available from Aurora Fine Chemicals LLC CAS [1039811-20-5].

Example 228

4-(3-Bromo-5-chloro-thiophene-2-sulfonylamino)-2-hydroxy-ben zoic acid

The product was prepared from methyl 4-aminosalicylate (9 mg, 0.050 mmol) and 3-bromo- 5-chlorothiophene-2-sulfonyl chloride (15 mg, 0.050 mmol) according to the General procedure 10, described in Example 173, with a modified reaction time (60 °C, overnight). 10 mg of the title compound was obtained (48%). MS (ESI+) 412 [M+H]. Example 229

4-(4-Bromo-thiophene-3-sulfonylamino)-2-hydroxy-benzoic acid

The product was prepared from methyl 4-aminosalicylate (9 mg, 0.050 mmol) and 4-bromo- 3-thiophenesulfonyl chloride (13 mg, 0.050 mmol) according to the General procedure 10, described in Example 173, with a modified reaction time (60 °C, overnight). 12 mg of the title compound was obtained (63%). MS (ESI+) 378 [M+H].

BIOLOGICAL TESTS

6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/BPase-2) is a bi-functional enzyme that catalyses the formation and degradation of fructose-2,6-bisphosphate (F-2,6-P ₂ ) (see e.g. Pilkis et al., (1995) Annu. Rev. Biochem. 64, 799-835; and Okar et al, (2001) Trends Biochem. Sci. 26, 30-5; for reviews). The relative kinase (formation) and phosphatase (degradation) activities of the bi-functional enzyme control the intracellular levels of this regulator (F-2,6-P ₂ ), which acts as an allosteric activator of glycolysis. Both the relative activities as well as the kinase to phosphatase ratios differ between the isoforms of the bi-functional enzymes, referred to as PFKFB1, PFKFB2, PFKFB3 and PFKFB4. Intracellular F-2,6-P ₂ levels are consequently controlled by variable tissue expression of these isoforms, including splice variants or post-translational modifications (see e.g. Rider et al. (2007) Biochem J. 381, 561-579). Methods for measurement of enzymatic activity of PFKFB3 and PFKFB4

The PFKFB3 (placenta form) and PFKFB4 were produced and purified to homogeneity from E. coli at Biovitrum and at Sprint Bioscience. All other reagents were purchased from commercial sources. Two independent methods have been used for determination of the kinase activity of PFKFB3 (Method A and Method B). Method B has been used for determination of the kinase activity of PFKFB4.

Method A: The kinase activity of the bi-functional enzyme is readily quantified based on the production of F-2,6-P ₂ as described by Van Schaftingen et al. (1982) Eur. J. Biochem. 129, 191-5. This sensitive assay is based on the potent activation of pyrophosphate dependent phosphofructokinase-1 (PPi-PFK) from potato tubers by F-2,6-P ₂ . The use of a series of coupled enzymes leads to a consumption of NADH (nicotinamide adenine dinucleotide) that can be followed spectrophotometrically (an updated protocol is available in Van Schaftingen, (1984) Methods of Enzymatic Analysis (Bergmeyer, H. U., ed.), 3rd edn., vol. 6, pp. 335-341, Verlag Chemie, Weinheim). A protocol for measurements in 96-well microtiter plate format is also available (Bruni et al., (1989) Anal. Biochem. 178, 324-6). These assay protocols have been adopted for the measurement of the kinase activity of PFKFB3 with some modifications as described in the protocol below. The assay was run in 96-well microtiter plates (Costar 3365 round bottom polypropylene) by consecutive additions of 30 μΐ each of a test compound solution (diluted from a DMSO stock solution), a PFKFB3 solution and a substrate (fructose-6-phosphate (F6P) and adenosine-5'- triphosphate (ATP)) containing solution. Controls in the absence of inhibitor (uninhibited activity) and 50 μΜ of an in- house inhibitor (completely inhibited kinase activity) were in- eluded in column 12 of the plate. The final concentrations of all reagents in a total assay volume of 90 μΐ per well were:

50 mM Tris-acetate at pH 8.0

0.1 mM EDTA (ethylene diamine tetraacetic acid)

10 mM MgCl ₂

5 mM Na ₂ HP0 ₄ (buffered by the Tris-acetate to a final pH of 8.0)

5 nM PFKFB3

4 μΜ ATP

100 mM F6P (acid treated and then neutralised to remove any contaminating F-2,6-P ₂ ; see Van Schaftingen, 1984)

1 mM dithiothreitol (DTT)

0.005% Tween-20

A test compound at various concentrations (which also added 0.83% DMSO to the final solution)

The enzymatic reaction was allowed to proceed for 10 minutes at room temperature while on a plate shaker at medium speed (750 RPM). The reaction was then terminated by the addition of 90 μΐ of a 0.4 M NaOH solution to all wells. The plate was then placed on the plateshaker at the same speed for two minutes to allow sufficient mixing. All samples were then diluted by a factor of 10 by transferring 20 μΐ from each well to the corresponding well of a new plate with 180 μΐ distilled water predispensed to all wells.

The next step in the protocol was quantification of the levels of F-2,6-P ₂ in each well of the microtiter plate. This was done by transferring 20 μΐ of the content in each well to the corresponding position in a new plate (Nunc 269620 transparent 96-well plate). The control samples representing uninhibited and completely inhibited (two each) reactions were placed in column 12 of the plate. To ensure that all measured values were within the linear range of the response (measured to be between 0-1 nM of F-2,6-P ₂ as also described by Van Schaftingen) the same volume of a 2.5 nM and a 5.0 nM standard sample were also added to column 12 (as all samples were diluted five-fold in the assay procedure this corresponds to 0.5 and 1.0 nM samples). The procedure then involved consecutive additions of three solutions with the following premixed components:

• Assay-mix (20 μΐ): Tris-acetate at pH 8.0, NADH and Mg(OAc) ₂

· PPi/F6P-mix (40 μΐ): Pyrophosphate and F6P

• Enzyme-mix (20 μΐ): Tris-acetate at pH 8.0, aldolase, triose phosphate isomer- ase, glycero 1-3 -phosphate dehydrogenase, pyrophosphate-dependent phosphofructokinase from potato tubers and bovine serum albumin (BSA)

The final concentrations of all reagents in a total assay volume of 100 μΐ per well were: 50 mM Tris-acetate at pH 8.0

0.15 mM NADH

2 mM Mg(OAc) ₂

1 mM F6P (acid treated and then neutralised to remove any contaminating F-2,6-P ₂ ; see Van

Schaftingen, 1984 in Methods of Enzymatic Analysis (Bergmeyer, H. U., ed.), 3rd edn., vol. 6, pp. 335-341, Verlag Chemie, Weinheim)

0.5 mM pyrophosphate

0.5 U/ml aldolase

5 U/ml triose phosphate isomerase

1.7 U/ml glycero 1-3 -phosphate dehydrogenase

0.01 U/ml pyrophosphate-dependent phosphofructokinase from potato tubers

0.2 mg/ml BSA Test samples containing variable F-2,6-P ₂ concentrations were diluted in NaOH (including also additional diluted components from the PFKFB3 reaction)

The coupled enzymatic reaction was allowed to proceed for 30 minutes at room temperature while on a plate shaker at medium speed (750 RPM). The reaction was then terminated by the addition of 20 μΐ of a 0.5M EDTA solution to all wells. The plate was then read in a Victor2 plate reader from Perkin-Elmer Life Sciences using the standard absorbance filter at 355 nm. The measured absorbance is proportional to the concentration of NADH, which in turn is proportional to the levels of F-2,6-P ₂ within the linear range. This was defined by the 0.5 and 1.0 nM controls together with the completely inhibited control (corresponding to 0 nM F-2,6-P ₂ ) on each plate. As described above controls were included on each plate to define the values for uninhibited and fully inhibited reactions and these values were used to calculate the % inhibition of the enzymatic reaction at any given compound concentration. The inhibitory potency or IC ₅₀ values of test compounds on the kinase activity of PFKFB3 were calculated using a four-parameter model (model 205) in XLfit (IDBS ActivityBase).

Method B: The kinase activity of the bi-functional enzyme is readily quantified based on the production of ADP and F-2,6-P ₂ from ATP and F6P. The ADP is detected with a kit, ADP- Glo™ Kinase Assay^ ^" ^, from Promega. The assay is a luminescent ADP detection assay that measures kinase activity by quantifying the amount of ADP produced during the kinase reaction. The assay is performed in two steps; first, after the kinase reaction, an equal volume of ADP-Glo™ Reagent is added to terminate the kinase reaction and deplete the remaining ATP. Second, the Kinase Detection Reagent is added to simultaneously convert ADP to ATP and allow the newly synthesized ATP to be measured using a luciferase/ luciferine reaction. The light generated is measured using a luminescence counter (1450 MicroBeta TriLux).

The assay was performed in white 384-well microtiter plates (OptiPlate, 6007299, Perki- nElmer) by consecutive additions of 0.1 μΙ_, of a test compound solution (serial diluted in DMSO from compound DMSO stock solution and dispensed by acoustic dispensing from UV-star 384-well plate 7360153, VWR), 5 μΙ_, of enzyme solution and 5 of a substrate (fructose-6-phosphate (F6P) and adenosine-5 '-triphosphate (ATP)) containing solution. Controls in the absence of inhibitor (uninhibited activity, only DMSO), 100 nM of an in- house inhibitor (QC, 50% inhibited kinase activity) and 49.5 μΜ of an in- house inhibitor (completely inhibited kinase activity) were included in column 23, 24 of the plate. Four reference dose response curves, one of them being the QC compound, were included in row 01-2, PI -2, and serial diluted as the test compounds. The final concentrations of all reagents in a total assay volume of 10.1 μΐ, per well were:

50 mM Tris-HCl at pH 8.0

10 mM MgCl ₂

5 mM Na ₂ HPO ₄ at pH 8.0

81.48 nM PFKFB3 or 145nM PFKFB4

8 μΜ ATP

100 μΜ F6P (acid treated and then neutralised to remove any contaminating F-

2,6-P ₂ ; see Van Schaftingen, 1984)

0.005% Tween-20

1 mM dithiothreitol (DTT)

A test compound at various concentrations or controls (final DMSO concentration 0.99%)

Enzyme, compounds and controls were pre-incubated at room temperature for 15 min before the addition of substrate solution. The enzymatic reaction was allowed to proceed for 20 min (PFKFB3) or 40 min (PFKFB4) at room temperature. The reaction was terminated by the addition of 10 of ADP-Glo™ Reagent to all wells and the plate was incubated for 40 min at room temperature. After addition of 20 μΐ _^ Kinase Detection Reagent to all wells the plate was incubated for 30 min at room temperature, followed by measurement in 1450 MicroBeta TriLux. All plates were centrifuged after each addition (room temperature, short spin, 500 RPM, Megafuge 1.0 Heraeus Instruments).

As described above controls were included on each plate to define the values for uninhibited and fully inhibited reactions and these values were used to calculate the % inhibition of the enzymatic reaction at any given compound concentration. The inhibitory potency or IC ₅₀ values of test compounds on the kinase activity of PFKFB3 or PFKFB4 were calculated using a four-parameter model (model 205) in XLfit (IDBS ActivityBase XE Runner).

Examples included herein have IC ₅₀ values in the range of 50 nM to 15 μΜ as measured using the above described assays Method A and/or Method B (see Table I and Table II for exemplary data). TABLE I. PFKFB3: IC50 values for representative compounds as measured by Method A and/or B.

TABLE II. PFKFB4: IC50 values for representative test compounds as measured by Method B

Example Example

Number IC50 (μΜ) Number IC50 (μΜ)

23 0.55 152 1.59

24 1.56 160 4.84

25 2.25 162 2.13

44 5.91 163 4.70

115 7.48 166 2.76

117 7.20 167 1.93

131 2.39 169 1.01

146 5.00 172 3.41 Method for quantification of F-2,6-P ₂ in the human pancreatic carcinoma cell line (PANC-1)

The relative kinase (formation) and phosphatase (degradation) activities of the bi- functional enzymes PFKFB3 and PFKFB4 control the intracellular levels of the regulator F-2,6-P ₂ , which acts as an allosteric activator of glycolysis. The levels of F-2,6-P ₂ have been determined in the pancreatic cancer cell line PANC-1 using the van Shaftingen assay. The assay protocols described under "Methods for measurement of enzymatic activity of PFKFB3 and PFKFB4, Method A" have been adapted for the measurement of the inhibitory effect of compounds on the kinase activity of the various iso forms of the bi-functional enzyme (endoge- nously expressed) in the human pancreatic carcinoma cell line (PANC-1). The modifications are described in the protocol below. All reagents were purchased from commercial sources or prepared inhouse.

Cells: PANC-1(ATCC-CRL-1469). Lot.no: 58564651.

Growth medium: Dulbecco 's Modified Eagle's Medium, DMEM, ATCC-30-2002

10% FBS, Invitrogen, 10106- 169

Starvation medium: DMEM/F12 without phenol red and glucose free, SVA, 991373

0.25% FBS, Invitrogen, 10106-169

Induction medium: DMEM/F12 without phenol red and glucose free, SVA, 991373

0.25% FBS, Invitrogen, 10106-169 (same as starvation medium) Cells were seeded in 96-well Corning Costar tissue culture plates (CLS3595, Sigma- Aldrich), at a concentration of 250 000 cells/mL in 100 growth medium (25 000 cells/well) and incubated over night at 37 °C and 5% C0 ₂ . Row A was left empty. Next day the growth medium was discarded and replaced with 100 starvation medium. The plates were incubated for 18 h at 37 °C and 5% C0 ₂ . After 18 h of starvation the cells were induced with 100 compound or control solutions. Compounds were either tested in two concentrations (50 μΜ and 10 μΜ) or in dose response curves starting from 50 μΜ and the final DMSO concentration in assay plates was 0.5%>. Also a dose response curve of a reference inhibitor was included in row H on each plate. All compounds were tested in duplicate plates. Compounds (in 96 well CLS 3365, Sigma-Aldrich) were serial diluted in DMSO from 10 mM compound DMSO stock solutions with Janus (automated liquid handling workstation from PerkinElmer). 5 μΐ _^ were transferred to a Greiner deep well plate (736-0155, VWR) with 495 μΐ, starvation medium. The final start concentration of compounds in the dilution plate was 100 μΜ, 1% DMSO. For compounds tested as single points, 10 mM compound solutions were diluted five fold in DMSO to 2 mM, followed by the transfer of 5 to separate dilution plates with 495 starvation medium. The final concentration of compounds in these dilution plates were 100 or 20 μΜ, respectively, and final concentration of DMSO was 1%. The plates were incubated at 37 °C and 5% C0 ₂ for 1 h, followed by the addition of 10 20 mM D-glucose in starvation medium. Controls, with and without 1 mM glucose, were included in row B. The final assay volume was 210 μί per well. After 2 h of incubation at 37 °C and 5% C0 ₂ , supematants were discarded and the cells were lysed by the addition of 25 μΙ_, 250 mM NaOH. The plates were incubated at 37 °C and 5% C0 ₂ for 5 min followed by an addition of 75 μί MilliQ dH ₂ 0. The supematants were further diluted with 210 μί MilliQ dH ₂ 0 to a final concentration of 20 mM NaOH. 200 μΐ, were transferred to NUNC 96-well plates (7322661, VWR) and the plates were sealed and stored at -20 °C until analysis.

The amount of F-2,6-P ₂ was quantified based on the coupled enzymatic reaction described by Van Schaftingen. If necessary the samples were further diluted in 20 mM NaOH before quan- tification. Plates stored at -20 °C were thawed and the F-2,6-P ₂ quantification was initiated by transferring 40 μί from each well of the NUNC plate to the corresponding position in a transparent 96-well SpectraPlate-MB (6005649, PerkinElmer). In order to ensure that all F-2,6-P ₂ measured values were within the linear range of response (between 0-1 nM final concentration of F-2,6-P ₂ as described by Van Schaftingen), the same sample volume (40 μΐ,) of an in- house produced F-2,6-P ₂ standard was included on each plate in row A.

The procedure described below involved consecutive additions of three solutions with the following premixed components:

• Assay-mix (40 μΐ.): Tris-acetate at pH 8.0, NADH and Mg(OAc) ₂

• Substrate-mix (80 μΐ,): Pyrophosphate and F6P

• Enzyme-mix (40 μί): Tris-acetate at pH 8.0, aldolase, triose phosphate isomerase, glycero 1-3 -phosphate dehydrogenase, pyrophosphate-dependent phosphofructokinase from potato tubers and bovine serum albumin (BSA)

The final concentrations of all reagents in a total assay volume of 200 μΐ _^ per well were:

50 mM Tris-acetate at pH 8.0

0.15 mM NADH

2 mM Mg(OAc) ₂ 1 mM F6P (acid treated and then neutralised to remove any contaminating F- 2,6-P ₂ ; see Van Schaftingen, 1984 in Methods of Enzymatic Analysis (Bergmeyer, H. U., ed.), 3rd edn., vol. 6, pp. 335-341, Verlag Chemie,

Weinheim)

0.5 mM pyrophosphate

0.45 U/mL aldolase

5 U/mL triose phosphate isomerase

1.7 U/mL glycero 1-3 -phosphate dehydrogenase

0.01 U/mL pyrophosphate-dependent phosphofructokinase from potato tubers 0.2 mg/mL BSA

Test samples containing variable concentrations of F-2,6-P ₂ diluted in NaOH

The coupled enzymatic reaction was allowed to proceed for 45 minutes at room temperature and the absorbance at 340 nm was continuously measured every 30 seconds (SpectraMax plate reader, Molecular Devices). The measured absorbance is proportional to the concentra- tion of NADH, which in turn is proportional to the levels of F-2,6-P ₂ within the linear range. This was defined by the 0 to 1.0 nM F-2,6-P ₂ controls in row A of the SpectraPlate. The IC ₅₀ values for test compounds were calculated using a four-parameter model (model 205) in XLfit (Excel).

Examples included herein have IC ₅₀ values in the range 1 to 15 μΜ (see Table III for exemplary data) as measured using the above described assay.

TABLE III. IC50 values for representative compounds in PANC-1 cells

based on quantification of F-2,6-P ₂

Example No. IC50 (μΜ)

163 6.0

166 4.1

167 4.2

168 4.4

169 2.3

171 3.8