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NZ626950B2 - Bisarylsulfonamides useful in the treatment of inflammation and cancer - Google Patents
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NZ626950B2 - Bisarylsulfonamides useful in the treatment of inflammation and cancer - Google Patents

Bisarylsulfonamides useful in the treatment of inflammation and cancer Download PDF

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Publication number
NZ626950B2
NZ626950B2 NZ626950A NZ62695012A NZ626950B2 NZ 626950 B2 NZ626950 B2 NZ 626950B2 NZ 626950 A NZ626950 A NZ 626950A NZ 62695012 A NZ62695012 A NZ 62695012A NZ 626950 B2 NZ626950 B2 NZ 626950B2
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NZ
New Zealand
Prior art keywords
amino
sulfonyl
hydroxybenzoate
methyl
alkyl
Prior art date
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NZ626950A
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NZ626950A (en
Inventor
Katarina Farnegardh
Mattias Jonsson
Jessica Martinsson
Rune Ringom
Original Assignee
Kancera Ab
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Publication date
Application filed by Kancera Ab filed Critical Kancera Ab
Priority claimed from PCT/EP2012/076836 external-priority patent/WO2013093095A1/en
Publication of NZ626950A publication Critical patent/NZ626950A/en
Publication of NZ626950B2 publication Critical patent/NZ626950B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
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    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

compound of formula (I), useful for the treatment of cancer, inflammation and inflammatory disorders, and a pharmaceutical composition containing the compound. An example of the compound is methyl 4-{[(3-bromophenyl)sulfonyl]amino}-2-hydroxybenzoate.

Description

2012/076836 BISARYLSULFONAMIDES USEFUL IN THE TREATMENT OF INFLAMMATION AND CANCER TECHNICAL FIELD The t invention s to novel sulfonamide derivatives, to pharmaceutical composi- tions comprising these derivatives, to processes for their preparation and to sulfonamide de- rivatives for use in a diagnostic method, profylaxis, or in therapy, e.g. for the treatment of inflammation and cancer.
BACKGROUND OF THE INVENTION In the 1920s Otto g first proposed non-oxidative metabolism of glucose as a unique feature oftumors rg, (1930) Ueber den stoffwechsel der tumoren (London: Consta- ble); Warburg, (1956) Science 123, 4). This esis 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 18F lucose uptake as a diagnostic tool for solid tumors.
Lately, energy processing of cancer cells has been given new attention (e.g. Vander Heiden, et al., 2009, Science 324, 1029). The hypoxic microenvironment and consequential lactate ac- cumulation resulting from altered tumor metabolism are reported predictive for both metastat- ic potential and therapy resistance, and thus survival of cancer patients (Brown, (1999) Can- cer Res. 59, 5863-5870; Walenta& Mueller-Klieser, (2004) Semin. Radiat. Oncol. 14, 267- 274; Walentaet al., (2004) Curr.Med. Chem. 11, 2195-2204). Targeting of hypoxic and/or acidotic tumor areas has therefore drawn attention as a complement to anti-proliferative treatments (see e.g. Pan &Mak, (2007) Sci. STKE 381, pe14; Bache et al., (2008) Curr. Med.
Chem. 15, 322-338 for reviews).
Known inhibitors of ysis include among others 2-deoxyglucose and o-puruvate targeting hexokinase (Liu et al., (2001) Biochemistry 40, 5542-5547; Liu et al. (2002) Bio- chem. 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-P2) plays a regulatory role in glucose metabolism by relieving ATP inhibition of phospho fructo- kinase-l. The levels of F-2,6-P2 are ted by the tional enzyme family 6- phosphofructokinase/fructose-2,6-bisphosphatase (PFKFB1-4).
Out of these four isozymes, mainly PFKFB3 and PFKFB4 are of particular interest for play- ing a role in cancer. Anti-sense treatment against PFKFB3 was shown to reduce tumor growth rate in viva (Chesney et al., (1999) Proc.Natl. Acad. Sci. USA 96, 3047-3052). Similarly, a decreased anchorage independent growth was shown for siRNA treated fibroblasts (Telang et al., (2006) Oncogene 25, 7225-7234). A link between inflammation and ed glycolysis and a possible potential for PFKFB3 inhibitors to act as a anti-inflammatory agents was indi- cated by a report that the ILSTAT3 pathway may enhance ysis through the induction ofPFKFB3 (Ando et al. J Nippon Med Sch (2010), 77, (2), 97-105). This possibility was further supported by a recent study using a small molecule; 3-(3 -pyridinyl)(4-pyridinyl) propen—1-one (3P0), previously shown to reduce F-2,6-P2 sis, glucose uptake and pro- liferation in transformed cells (see below). Telang et al. demonstrated that 3P0 ates the tion of T cells in vitro and suppresses T cell dependent immunity in vivo, indicating that small molecule inhibitors of PFKFB3 may prove effective as T cell immunosuppressive agents (Telang et al., (2012) Journal of ational Medicine 2012, . Moreover, hy- poxia is a prominent feature in rheumatoid arthritis (RA) synovium and induces significant changes in the sion of PFKFB3 and PFKFB4 (Del Rey et al., (2010) Arthritis & Rheu- matism 62, 3584—3594).
The PFKFB4 n was reported to be strongly responsive to hypoxia (Minchenko et al., (2004) FEBS Lett. 576, 14-20); Minchenko et al., (2005), mie 87, 1005-1010; Bo- barykina et al., (2006), Acta Biochemica Polonica 3, 789-799). US2010/0267815 A1). Min- chenko et al. trated an increased expression of PFKFB4 mRNA in malignant breast and colon s, as ed to corresponding non-malignant tissue counterparts. Recent- ly, Telang et al. showed decreased levels of F-2,6-P2 and lactate as well as decreased tumor growth following siRNA silencing of PFKFB4 (Telang, S. et a], (2010). Further support for PFKFB4 as a potential target for the development of antineoplastic agents came from a fianc- tional metabolic screen that identified PFKFB4 as an important regulator in prostate cancer (Ros et al. (2012) Cancer Discov. 2(4):328-43).
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 phos- phate, was used as a tool to igate the binding sites of the kinase and phosphatase do- mains ofPFKFB3 and 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 re- spect to F6P but a non-competitive inhibitor with respect to ATP. Analogues of this com- pound, N-(2-methoxyethyl)-bromoacetamide, N-(2-ethoxyethyl)-bromoacetamide and N-(3- methoxypropyl)-bromoacetamide, have demonstrated in viva activity with increased survival rate of P388 transplant BDF1 mice (Hirata et al. (2000) . Biotechnol. Biochem. 64, 2047-2052).
A l structure of the PFKFB3 *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 PFKFB3 *AMPPCP*fructose-6 phosphate complex in which thylene- adenosine 5’-triphosphate (AMPPCP) constituted a non-hydrolysable ATP-analogue. Recent- ly, small molecule PFKFB3 inhibitors identified by virtual screening were bed (Chrochet et al. (2011), Anal. Biochem. 418, 8; Seo et al., (2011), Plosone, 9, e24179 & Lee et al. (2012) US 2012/0302631). The identified PFKFB3 inhibitors were shown to re- duce the levels of F-2,6-P2, resulting in decreased tumor growth and increased cell death.
A drug-like compound was described (Clem et al. (2008) Mol. Cancer Ther. 7, 0; Chesney et al. (2008) ) where 3-(3-pyridinyl)(4-pyridinyl)propen one (3PO), by computational methods, was fied as a PFKFB3 tor. stration of 3PO reduced the intracellular concentration of F-2,6-P2, glucose uptake, and growth of established tumors in viva. Recently, substituted doles were bed as inhibitors of PFKFB3. The benzindoles were shown to inhibit proliferation in several cancer cell lines, inhibit glucose uptake as well as to reduce tumor growth in vivo in tumor models (Chand et al. (2011) WO2011/103557A1).
SUMMARY OF THE INVENTION One object of the present invention is to provide compounds for use in a diagnostic method, prophylaxis and treatment of inflammation or .
Another obj ect of the present invention is to provide compounds for use in the inhibition of the metabolism of cancer cells and immune ent cells to modulate disease.
Another obj ect of the present invention is to provide compounds for use in the inhibition of the glucose metabolism of cancer cells and immune competent cells to modulate disease.
One object of the present invention is to provide compounds affecting the F-2,6-P2 levels in cells. 4 2012/076836 Thus, according to a first aspect, there is ed a compound according to formula (1) H O .A N ” rl ‘ 3 ('85 / R n' (I) RbOOC R2 wherein n is 0 or 1; A is o, s, -CR4=CR4- or -CR4=N-; R1 is selected from H; halogen; Cl-C6 alkyl, optionally substituted with at least one halogen; and Cl-C6 alkoxy, optionally substituted with at least one halogen; R2 and R3 are each independently selected from H; halogen; Cl-C6 alkyl; Cl-C6 alkoxy; car- bamoyl; secondary or tertiary Cl-C6 alkylamido; carbocyclylcarbonylamino-C0-C2 alkyl; 5- or 6-membered cyclic aminocarbonyl optionally containing a r atom in the ring; C 1 -C6 alkylcarbonylamino; C 1 -C6 alkylsulfonyl; hydroxy-CO-C6 alkyl, C 1 -C6 alkylcarbon— yl; carboxy; C1-C6 alkoxycarbonyl; cyano; carbocyclyloxy; heterocyclyloxy; carbocyclyl- C0-C3 alkyl; carbocyclyl-C2-C3 l; heterocyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl or cyclyl is 5- or 6-membered monocyclyl or 9- or lO-membered bicyclyl; and any car- bocyclyl or heterocyclyl is optionally substituted with at least one R5 ; or R2 and R3 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 R5 ; ed that R1, R2 and R3 are not all hydrogen; each R4 is independently selected from H, halogen, monocyclic C3-C6 carbocyclyl and C1- C6 alkyl, wherein any alkyl is optionally substituted with at least one halogen; each R5 is independently selected from halogen; C1-C6 alkyl; C1-C6 alkoxy; phenoxy; ami- no; cyano; nitro; ary or tertiary Cl-C6 alkylamino; 5- or 6-membered cyclic amino, optionally containing at least one further heteroatom in the ring; Cl-C6 alkylcarbonylamino; carbanioyl; secondary or tertiary C1-C6 alkylaniido; 5- or 6-membered cyclic aminocarbonyl; C 1 -C6 alkoxycarbonylamino; hydroxy-CO-C6 alkyl; C l -C6-alkylthio; carboxy-CO-C6-alkyl; C 1 -C6 alkoxycarbonyl; C 1 -C6 alkylcarbonyl; C l -C6-alkylsulfonyl; and C 1 -C6 alkylsulfonyl— amino; n any alkyl is optionally substituted with at least one halogen; Ra is selected from H and Cl-C6 alkylcarbonyl; Rb is selected from H, Cl-C6 alkyl, Cl-C6 alkyl substituted with at least one R6; carbocyclyl- CO-CS alkyl; and cyclyl-CO-CS alkyl; wherein any carbocyclyl and heterocyclyl is 5- or 6- membered and is optionally substituted with at least one R7 and optionally comprises at least one oxo group in the ring; provided that R81 and Rb are not both H; each R6 is independently selected from y; Cl-C6 alkoxy; hydroxy-Cl-C6 alkoxy; C1- C6 alkylcarbonyloxy; Cl-C6 alkoxycarbonyloxy; 5- or 6-membered carbocyclylcarbonyl or heterocyclylcarbonyl; amino; secondary or tertiary Cl-C6 alkylaniino; secondary or tertiary hydroxy-Cl-C6 alkylaniino; 5- or 6-membered cyclic amino optionally containing at least one further heteroatoni in the ring and n the ring is optionally substituted with at least one C 1 -C6 alkyl; C 1 -C6 alkylcarbonylaniino; C 1 -C6 alkoxycarbonylaniino; (C 1 -C6 alkoxycar- bonyl)(Cl-C6 alkyl)an1ino; (Cl-C6 alkoxycarbonyl)(5- or 6-membered carbocyclyl or heterocyclyl )an1ino; (Cl-C6 alkylcarbonyl)(Cl-C6 alkyl)an1ino; carbanioyl; ary or tertiary Cl-C6 niido wherein any alkyl is optionally substituted by OH or CONHZ; 5- or 6- ed yclyl— or heterocyclylcarbanioyl; 5- or 6-membered cyclic aminocarbonyl, optionally containing at least one further heteroatoni in the ring, and wherein the ring is optionally substituted with at least one Cl-C6 alkyl; 5-orn1en1bered carbocyclylaniino or heterocyclylamino ; and -n1en1bered carbocyclyloxy or heterocyclyloxy; wherein any alkyl is optionally substituted with at least one halogen and any 5- or 6-membered carbocyclyl or heterocyclyl is optionally substituted with at least one R8; each R7 and R8 is independently selected from Cl-C6 alkyl; hydroxy—CO-C3 alkyl; Cl-C6 alkoxy-CO-C3 alkyl; Cl-C6 alkoxycarbonyl; yclyl-C0-C4 alkyl; heterocyclyl-C0-C4 alkyl; Cl-C6 alkylsulfinyl; amino; nitro; Cl-C6 secondary or ry amino; halogen; carbanioyl ; secondary or tertiary Cl-C6 alkylamido-CO-C3 alkyl; Cl-C6 alkylcarbonylaniino; and 5- or 6-membered cyclic amino, optionally containing at least one fiarther heteroatoni in the ring and wherein the ring is optionally substituted with at least one Cl-C6 alkyl; wherein any alkyl is optionally substituted with at least one halogen; wherein any carbocyclyl and het- erocyclyl is 5- or 6- membered; or a pharmaceutically acceptable salt thereof, provided that the compound is not -(N-(3-hydroxy(methoxycarbonyl)phenyl)sulfamoyl)methoxybenzoic acid, methyl 2-hydroxy(4-propylphenylsulfonamido)benzoate, methyl 4-(4-ethylphenylsulfonamido)hydroxybenzoate, methyl 4-(4-butylphenylsulfonamido)hydroxybenzoate, methyl 4-(3-bromophenylsulfonamido)hydroxybenzoate, methyl 4-(4-(tert-butyl)phenylsulfonamido)hydroxybenzoate, methyl 4-(3 hlorophenylsulfonamido)hydroxybenzoate, methyl oxy—4-(3-methylphenylsulfonamido)benzoate, methyl 4-(3-fluorophenylsulfonamido)hydroxybenzoate, ethyl 4-(4-acetamidophenylsulfonamido)hydroxybenzoate, methyl 4-(4-acetamidophenylsulfonamido)hydroxybenzoate, phenyl 2-hydroxy(4-methylphenylsulfonamido)benzoate, phenyl 4-(4-chlorophenylsulfonamido)hydroxybenzoate, methyl 2-hydroxy—4-(4-(4-oxo- l ,4-dihydropyrazolo[ l ,5-a] [l ,3 ,5]triazin—8- yl)phenylsulfonamido)benzoate, methyl oxy(4-methylphenylsulfonamido)benzoate, 2-acetoxy(4-methylphenylsulfonamido)benzoic acid, methyl 2-hydroxy—4-(3-(methylcarbamoyl)phenylsulfonamido)benzoate, methyl oxy—4-(3-(piperidine- l -carbonyl)phenylsulfonamido)benzoate, methyl 4-(3-bromo(trifluoromethyl)phenylsulfonamido)hydroxybenzoate, 3-(N-(3-hydroxy(methoxycarbonyl)phenyl)sulfamoyl)benzoic acid, methyl 4-((3-bromophenyl)methylsulfonamido)hydroxybenzoate, or methyl 4-(4,5-dichlorothiophenesulfonamido)hydroxybenzoate.
In one ment, A is O, S, -CR4=CR4- or -; and when A is -CR4=CR4- or - CR4=N-, one of R2 and R3, e.g. R2, is selected from carbocyclyl-C0-C3 alkyl; carbocyclyl- C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any car- bocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or lO-membered bicyclyl; and any carbocyclyl or heterocyclyl is ally substituted with at least one R5; or R2 and R3 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 R5.
In another embodiment, A is O, S, -CR4=CR4- or -CR4=N-; and when A is O or S, R2 and R3 are each independently selected from H; halogen; Cl-C6 alkyl; Cl-C6 ; carbamoyl; secondary or tertiary Cl-C6 alkylamido; carbocyclylcarbonylamino-CO-C2 alkyl; 5- or 6- membered cyclic aminocarbonyl optionally containing a fiarther atom in the ring; C1- C6 alkylcarbonylamino; Cl-C6 alkylsulfonyl; hydroxy-CO-C6 alkyl, Cl-C6 alkylcarbonyl; carboxy; Cl-C6 alkoxycarbonyl; cyano; wherein any alkyl is optionally substituted with at least one halogen.
In another embodiment, R3 is selected from H; halogen; and Cl-C6 alkyl, wherein any alkyl is optionally substituted with at least one halogen; or R2 and R3 form, er with the car- bon atoms to which they are attached, a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R5.
In another ment, R2 is ed from H; halogen; Cl-C6 alkyl; carbocyclyl-C0-C3 al- kyl; 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 het- erocyclyl is 5- or 6-membered monocyclyl or 9- or lO-membered bicyclyl; and any carbocy- clyl or heterocyclyl is optionally substituted with at least one R5; or R2 and R3 form, together with the carbon atoms to which they are attached, a 5- or 6-membered carbocyclic or hetero- cyclic ring, which ring is optionally substituted with at least one R5.
In another ment, R2 is selected from carbocyclyl-C0-C3 alkyl; yclyl-C2-C3 l; heterocyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; n any alkyl is optionally substituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6- membered monocyclyl or 9- or lO-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R5; or R2 and R3 form, together with the carbon atoms to which they are attached, a 5- or ered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R5.
The disclaimed compounds within the scope of formula (I) were found in a database search using the Internet search tool SciFinder. However, for most of these compounds, no particular use was found to be indicated; in particular, there was no indication that they had ever been used in therapy, with a few exceptions: Therefore, another object ofthe ion is to provide a compound of formula (I) as defined herein above, for use in therapy, provided that the compound is not: ethyl 4-(4-acetamidophenylsulfonamido)hydroxybenzoate, methyl 4-(4-acetamidophenylsulfonamido)hydroxybenzoate, phenyl 2-hydroxy(4-methylphenylsulfonamido)benzoate, or methyl 2-hydroxy—4-(4-(4-oxo- l ,4-dihydropyrazo lo[ 1 ,5 -a] [l ,3 ,5 ]triazinyl)phenyl- sulfonamido)benzoate.
Another object of the invention is to provide a compound of formula (I) as defined herein above, for use in the treatment of inflammation, inflammatory disorders or cancer, ed that the compound is not methyl 2-hydroxy—4-(4-(4-oxo-l,4-dihydropyrazolo[l,5-a][l ,3,5]— triazinyl)phenylsulfonamido)benzoate.
Furthermore, a pharmaceutical composition is provided, comprising a compound as defined herein, and ally at least one ceutically acceptable excipient.
Thus, the present invention provides a method of diagnosis, profylaxis and treatment of can- cer and inflammation, by the modulation of F-2,6-P2 levels, and a compound for use in such a method.
The compounds of the t invention may act as modulators of F-2,6-P2 levels. In some embodiments, the compounds ofthe above formula can exhibit a F-2,6-P2 level modulating activity corresponding to an IC50 of from about SOnM to about 25 uM; e. g., from about lOOnM to about lOuM, from about 200nM to about SuM, or from about SOOnM to about 1 uM or a lower tration 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 F-2,6-P2 level modulating activity, can be used, e.g., for the treatment or prevention of cancer and inflammation, and/or in treatment of disorders d to cancer and inflammation. icular interest are tumors with elevated glucose uptake compared to normal nontumor tissues, fied by for example PET studies. These tumors include, but are not d to breast cancer, lung cancer, prostate cancer, ctal cancers, pancreatic cancers, haemato- logical cancers and melanoma.
A further object of this invention relates to compounds of formula (I) for use as a medica- ment, especially for the treatment of cancer and inflammation.
In a r aspect the present invention relates to a method for the treatment or prophylaxis of a disease, disorder, or condition related to undesired level of F-2,6-P2 (e. g., inflammatory dis- order and cancer). 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 de- scribed herein) an ive amount of a compound of a I or a pharmaceutically ac- ceptable salt or prodrug f.
In one aspect, this invention relates to a method for the treatment or prophylaxis of cancer and inflammation, which includes administering to a subject (e.g., a subject in need of such treat- ment as described herein) an effective amount of a compound of formula I or a pharmaceuti- cally acceptable salt or g thereof W0 93095 10 2012/076836 In another , this invention relates to a method for the treatment or prophylaxis (e.g., treatment) of cancer, which includes administering to a subject (e. g., a subject in need of such treatment as described ) an effective amount of a compound of formula I or a pharma- ceutically acceptable salt or prodrug thereof.
In some embodiments, the subject can be a subject 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 ive (e.g. measurable by a test or diagnostic method). In some embodiments, the subject can be a . In certain embodiments, the subject is a human.
In a r aspect, this invention relates to the use of a compound of formula I (e.g., as a me- dicament or) in the manufacture of a medicament containing a compound of formula I for a diagnostic method, treatment or laxis (e.g., treatment) of a disease, er, or condi- tion related to undesired levels of F-2,6-P2 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 nd (in- cluding a pharmaceutically acceptable salt thereof) of any of the formulae delineated herein (e.g., a compound having formula I, or subgenera f), including the specific compounds described herein). In some embodiments, the composition or formulation can further include a pharmaceutically acceptable adjuvant, carrier or t. Any such compound can be used in the methods described herein.
BRIEF DESCRIPTION OF THE DRAWINGS Figure l is a chart enting the growth inhibitory effect of the compound of Example 27 in combination with cisplatin, on cell proliferation in the gastric tumor cell line NUGC-3 (72h).
Figure 2 is a chart representing the growth inhibitory effect of the compounds of Example 27 and Example 82, tively, on cell proliferation in the gastric tumor cell line NUGC-3 (72h).
W0 2013/093095 11 Figure 3 is a chart representing the tumour growth inhibitiory effect of the compound of Ex- ample 183 on Mia-Paca 2 afts in NMRI nude mice.
Figure 4 is a bar chart representing the unbound plasma concentration of Example 183, 30 s after IP administration.
DETAILED DESCRIPTION OF THE INVENTION The following ions shall apply throughout the specification and the appended claims.
“Pharmaceutically acceptable” means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use. ment” as used herein includes prophylaxis of the named disorder or condition, or amelioration or ation of the disorder once it has been established.
“Diagnostic” as used herein includes a systematic/diagnostic method used to identify the ce of an entity where multiple alternatives are possible; either to help select the patients likely to benefit from the treatment, or to help define a combination of substances/therapies likely to be beneficial for a specific patient.
“An effective amount” refers to an amount of a compound that s a therapeutic effect on the treated subject. The therapeutic effect may be ive (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
Reference to compounds of "formula I" in embodiments herein also includes compounds of any of the formulae delineated herein.
The recitation of a listing of al groups in any definition of a variable herein includes definitions of that le as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof As used herein, the term “carbocyclyl” refers to a cyclic moiety ning only carbon atoms in the ring structure, 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, sul- phur or oxygen atom. For the purpose of the present invention and unless otherwise indicated W0 93095 12 or apparent from the context, the terms “carbocyclyl” and “heterocyclyl” should not be con- strued 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 contain- ing two rings, fused to each other.
The term “oxo group” as used herein refers to a moiety of formula A cyclic moiety containing an oxo group in the ring comprises at least one ring carbon atom which is the carbon atom of an oxo group.
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 heterocy- clic) 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 , as ed to , 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 s 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 ic heterocyclyl (or heterocycle or heterocyclic moiety, etc.), as ed to herein, one or both of the rings may contain one or l, e.g. l, 2, 3 or 4 heteroatoms. By heteroa- tom according to the invention is meant N, O and S.
An n-membered cyclic moiety as ed to herein contains 11 ring (or cyclic) atoms.
W0 2013/093095 13 Examples of aromatic heterocyclic moieties ing to the invention are pyrrolyl, pyrazolyl, imidazolyl, filryl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrazinyl, dinyl, pyridazinyl, benzothiazolyl, benzoxadiazolyl , benzimidazolyl, indazolyl, benzothiadizolyl, uryl, benzoxazolyl, hienyl , isoquinolinyl, naphthyridinyl, quinolinyl, phthalazinyl, quinazolinyl, quinolinyl, alinyl, cinnolinyl, inyl, 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) ably selected from N, O and S, such as a dihydropyrrolyl, dioxolanyl, dithiolanyl, imidazolidinyl, imidazolinyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuryl, 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 con- taining one aromatic and one non-aromatic ring, e.g. indolinyl, chromanyl, thiochromanyl, obenzo filryl, l,2,3,4-tetrahydroisoquinolyl, etc.
The term Cn refers to a radical or moiety ning 11 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 Cl-C6 alkyl refers to an alkyl radical that may contain 1, 2, 3, 4, 5 or 6 carbon atoms.
The term C0 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 Cl-C6 alkyl) may be branched or linear, e. g. selected from , ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec- butyl, tert—butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3- methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
Any Cl-C6 alkyl ing to the invention more particularly may be selected from Cl-C5 alkyl, e. g. from Cl-C4 alkyl, from Cl-C3 alkyl, from Cl-C2 alkyl, or from methyl.
W0 2013/093095 14 An l moiety according to the ion is a straight or branched hydrocarbyl compris- ing at least one double bond between any two adjacent carbon atoms, e.g. a straight or ed hydrocarbyl sing 1 double bond.
As used herein, and unless otherwise specified, the term “halogen” (or “halo”) means fluorine (F), chlorine (Cl), bromine (Br) or iodine (1).
Any halogen according to the invention in particular may be selected from F, Cl, and Br, e. g. from F and Cl, or from F.
The term carbocyclyloxy refers to a radical of the type RO-, wherein R is a carbocyclyl moie- ty. 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-, n R is an alkyl moiety.
The term Cl-C6 alkoxy-CO-C3 alkyl refers to Cl-C6 alkoxy (when C0-C3 alkyl is C0 alkyl) or to a Cl-C3 alkyl radical substituted by a Cl-C6 alkoxy.
The term alkoxycarbonyl refers to a radical of the type ROC(O)-, wherein R is an alkyl moie- The term carboxy refers to the radical HO(O)C-.
The term alkylthio refers to a radical of the type RS-, wherein R is an alkyl .
The term amino refers to the radical H2N—.
The term hydroxy refers to the radical HO-.
The term hydroxy-CO-C6 alkyl refers to a radical selected from hydroxy (Viz. hydroxy—CO alkyl) and a Cl-C6 alkyl l 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 ex- ample, hydroxy-Cl alkyl is hydroxymethyl.
The term secondary or tertiary hydroxy-C 1 -C6 alkylamino refers to secondary or tertiary al- kylamino wherein at least one alkyl is substituted by a hydroxy group.
The term hydroxy-Cl-C6 alkoxy refers to a Cl-C6 alkoxy wherein the alkyl moiety is substi- tuted with a hydroxy group.
The term hydroxy-Cl-C6 alkoxy—Cl-C6 alkyl refers to a Cl-C6 alkyl substituted with a hy- droxy—C 1 -C6 alkoxy group.
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 tuted with at least one halogen” is meant an alkyl radical of the formula CnXpH(2n+1_p)-, wherein Xp refers to p independently selected halogen atoms, replacing p hy- drogen atoms of the alkyl radical CannH- at the same or different carbon atoms. An example of an alkyl substituted with at least one n is trifluoromethyl. The alkyl substituted with at least one halogen may be a moiety forming a part of another radical, such as in ro- y or difluoromethoxy.
The term trifluoromethyl refers to the radical CF3-.
The term trifluoromethoxy refers to the radical CF30-.
The term difluoromethoxy refers to the radical CHFzO-.
The term ary alkylamino refers to a radical of the type RHN—, wherein R is an alkyl moiety.
The term tertiary alkylamino refers to a l of the type RR'N—, n R and Rare each an independently selected alkyl moiety.
W0 2013/093095 16 2012/076836 The term carbamoyl refers to the radical NH2C(O)-.
The term secondary alkylamido refers to l 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 l of the type RC(O)NH-, wherein R is an alkyl moiety.
The term alkoxylcarbonylamino refers to a radical of the type NH-, wherein R is an alkyl moiety.
The term (Cl-C6 carbonyl)(Cl-C6 alkyl)amino refers to a radical of the type R/OW/ N£3 wherein R and R’ are independently selected C1-C6 alkyl moieties.
The term (Cl-C6 alkoxycarbonyl)(5- or 6-membered carbocyclyl or heterocyclyl)amino refers to a radical of the type wherein R is a C1-C6 alkyl moiety and R’ is a 5- or 6-membered carbocyclyl or heterocyclyl.
The term (Cl-C6 alkoxycarbonyl)(phenyl)amino refers to a radical ofthe type /0 N. R r 5‘5 wherein R is a Cl-C6 alkyl moiety.
The term benzoyl refers to the radical The term carbocyclylcarbonylamino refers to a radical of the type RC(O)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 y- clylcarbonylamino (Viz. carbocyclylcarbonylamino-C0 alkyl), carbocyclylcarbonylaminomethyl (Viz. carbocyclylcarbonylamino-Cl alkyl) or carbocyclylcarbonylaminoethyl (Viz. carbocyclylcarbonylamino-C2 alkyl).
The term 5- or 6-membered carbocyclylamino refers to a radical of the type RNH-, wherein R is a carbocyclyl as defined herein above, and is 5- or 6-membered. An e is phenyla- mino, i.e. the radical The term 5- or 6-membered or heterocyclylamino refers to a radical of the type RHN-, where- in R is a heterocyclyl as defined herein above, and is 5- or ered. An example is pyri- mino.
The term arbonyl 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 CH3C(O)-.
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 en-containing cycle. An example of a cyclic amino is piperidin-l-yl.
The term cyclic amino optionally containing at least one further heteroatom in the ring 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 and wherein at least one of R and R' con- tains a heteratom, e.g. O or N, that forms part of the ring. Examples of cyclic amino contain- ing a further heteroatom in the ring are morpho lino and piperazinyl. When the further heteroa- W0 2013/093095 18 tom is nitrogen, this nitrogen may be substituted by C1-C6 alkyl, e. g. Cl-C3 alkyl, e.g. me- thyl.
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(O)2-, wherein R is an alkyl .
The term alkylsulfonylamino refers to a radical of the type RS(O)2NH-, wherein R is an alkyl The term nitro refers to the radical -N02.
The term carboxy-CO-C6 alkyl refers to a carboxy (i.e. carboxy-CO alkyl) and a Cl-C6 alkyl substituted with a carboxy.
The term Cl-C6 alkylcarbonyloxy refers to a radical of the type wherein R is Cl-C6 alkyl.
The term Cl-C6 alkoxycarbonyloxy refers to a l of the type wherein R is Cl-C6 alkyl.
The term (Cl-C6 alkylcarbonyl)(Cl-C6 alkyl)amino refers to a radical ofthe type wherein R and R’ are independently selected Cl-C6 alkyl moieties.
The term Cl-C6 carbonylamino refers to a radical of the type W0 2013/093095 19 wherein R is C1-C6 alkyl.
The term phenylcarbamoyl refers to the radical The term Cl-C6 alkylsulfinyl refers to the radical R \SELSI‘v n R is Cl-C6 alkyl. ing to one aspect, the t invention provides a compound of formula (I) N W RbOOC R2 as defined herein above, or a pharmaceutically acceptable salt thereof In some embodiments, in a compound of formula (1), R1, R2, R3, R81 and n is as defined herein above, and Rb is selected from H, Cl-C6 alkyl, Cl-C6 alkyl substituted with at least one R6; carbocyclyl- CO-CS alkyl; and heterocyclyl-CO-CS alkyl; wherein any carbocyclyl and heterocyclyl is 5- or 6- membered and is optionally substituted with at least one R7 and optionally comprises at least one oxo group in the ring; provided that R81 and Rb are not both H; each R6 is independently selected from hydroxy; C1-C6 alkoxy; hydroxy-Cl-C6 alkoxy; C1- C6 alkylcarbonyloxy; C1-C6 alkoxycarbonyloxy; 5- or 6-membered carbocyclylcarbonyl or W0 2013/093095 20 heterocyclylcarbonyl; amino; ary or tertiary C1-C6 alkylamino; secondary or tertiary hydroxy-Cl-C6 alkylamino; 5- or 6-membered cyclic amino ally containing at least one r heteroatom in the ring and wherein the ring is optionally substituted with at least one C 1 -C6 alkyl; C 1 -C6 alkylcarbonylamino; C 1 -C6 alkoxycarbonylamino; (C 1 -C6 alkoxycar- bonyl)(Cl-C6 alkyl)amino; (Cl-C6 alkoxycarbonyl)(5- or 6-membered carbocyclyl or heterocyclyl )amino; (Cl-C6 alkylcarbonyl)(Cl-C6 alkyl)amino; carbamoyl; secondary or tertiary Cl-C6 alkylamido wherein any alkyl is optionally substituted by OH or CONH2; 5- or 6- membered carbocyclyl— or heterocyclylcarbamoyl; and 5- or ered cyclic aminocar- bonyl, optionally containing at least one further heteroatom in the ring, and wherein the ring is optionally substituted with at least one Cl-C6 alkyl; wherein any alkyl is optionally substi- tuted with at least one halogen and any 5- or 6-membered carbocyclyl or heterocyclyl is op- tionally substituted with at least one R8; and each R7 and R8 is independently selected from Cl-C6 alkyl; y—CO-C3 alkyl; Cl-C6 alkoxy; Cl-C6 alkylsulfinyl; amino; nitro; Cl-C6 secondary or tertiary amino; halogen; car- bamoyl; secondary or tertiary Cl-C6 alkylamido-CO-C3 alkyl; Cl-C6 alkylcarbonylamino; and 5- or 6-membered cyclic amino, optionally containing at least one fiarther heteroatom in the ring and wherein the ring is ally substituted with at least one Cl-C6 alkyl; wherein any alkyl is optionally substituted with at least one halogen.
In a compound of formula (I), the ring containing the moiety A (“the A-ring”) is linked to the R810, RbOOC- disubstituted phenyl ring through a amide moiety -NHS(O)2(CH)n- .
Depending on the point of attachment of the sulfonamide moiety to the A-ring, the compound of formula (I) may be represented by either a (Ia) or (Ib): H9?N? H? N? /_A O 0 RbOOC R2 RbOOC (Ia) (lb) In some embodiments, the compound of formula (I) is a compound of formula (Ia).
In some other ments, the nd of a (I) is a compound of formula (Ib).
In some embodiments, A is S and the compound of formula (I) may then be represented by formula (IA) W0 2013/093095 21 H O 8 Mg 7 / R3 II n R OOCb R2 (IA) In some embodiments, the compound of formula (IA) is represented by formula (IAa) NOII R OOCb (IAa) In some other embodiments, the compound a (IA) is represented by a (IAb) 0:0)20 RbOOC 0R61 (IAb) In some embodiments, A is O and the compound of formula (I) may then be represented by formula (IB) H O .O N ‘5 r : R3 n RbOOC R2 OR61 (”3) In some embodiments, the compound of formula (IB) is represented by formula (IBa) N9N‘s| R OOCb OR61 (IBa) W0 2013/093095 22 In some other embodiments, the compound of formula (IB) is represented by formula (IBb) (IBb) In some embodiments, in a compound of formula (I) as defined herein above, A is 4 and the compound of formula (I) may then be represented by a (IC) R1 R4 N‘fiiii/II \If \ RbOOC (IC) In some embodiments, the compound of formula (IC) is represented by a (ICa) HON\II Rbooc (ICa) In some other embodiments, the compound of formula (IC) is represented by formula (ICb) H?N? RbOOC (ICb) In some embodiments, in a compound of formula (I) as defined herein above, A is N=CR4 and the compound of formula (I) may then be represented by formula (ID) H o \N R4 N\|I35%K. \ RbOOC (ID) or by formula (IE) R1 R4 H52 RN O [1%R3 RbOOC (IE) In some embodiments, the compound of a (ID) is represented by formula (IDa) ('5 n / R3 Rbooc (IDa) In some other embodiments, the compound of formula (ID) is represented by formula (IDb) H9 N ('5 n / R4 Rbooc (IDb) In some embodiments, the compound of formula (IE) is represented by formula (IEa) W0 2013/093095 24 N\|SO|H \ N H n \ / R3 Rbooc R1 (IEa) In some other embodiments, the compound of formula (IE) is represented by formula (IEb) (IEb) It should be understood that for the e of the present invention, unless otherwise speci- fied or apparent from the t, any reference to a compound of formula (I) is meant to in- clude a compound of any of the above formulas (Ia) or (lb) or any of the embodiments of said formulas, as represented by formulas (IA), (IB), (IC), (ID) and (IE), or any of the embodi- ments thereof.
In some embodiments, the nd of formula (I) is a nd of formula (IA), (IB) or (IC). In some embodiments, the compound of formula (I) is a compound of formula (IA) or (IB), e. g. a compound of formula (IA). In still other embodiments, the compound of formula (I) is a compound of formula (IA) or (IC).
In some other embodiments, the compound of formula (I) is a nd of formula (IC), (ID) or (IE), e. g. a compound of formula (IC) or (IE), or a compound of formula (IC). In still other embodiments, the compound of formula (I) is a compound of formula (ID) or (IE), in particular a compound of formula (IE). For example, in some embodiments, the compound is a compound of formula (IDb) or (IEa), in particular a compound of formula (IEa). In some other embodiments, the compound is a compound of formula (IDa) or (IEa).
In some embodiments, the compound of formula (I) is a compound of formula (IAa), (IAb), (IBa), (IBb), (ICa), (ICb), (IDa) or (IEa). In some other embodiments, the compound of for- mula (I) is a compound of formula (IAa), (IAb), (IBa), (IBb), (ICa), (ICb), or (IEa). In some other embodiments, the nd of a (I) is a compound of formula (IAa), (IBa), (ICa) or (IEa). In some other embodiments, the compound of formula (I) is a compound of formula (IAa), (IBa) or (ICa). In still other embodiments, the compound of formula (I) is a compound of formula (IAa) or (ICa).
In some other embodiments, the compound of formula (I) is a compound of formula (IAb) or (IBb).
In formula (I), the moiety C that links the ring containing the moiety A (“the A ring”) to the disubstituted phenyl ring, may be a moiety )2- (i.e. n is 0) or -NHS(O)2CH2- (i.e. n is l). Preferably, n is 0, in which case formula (I) is represented as In some embodiments, n is l, in which case a (I) is represented as For example, in some embodiments of a nd of formula (IC), such as a compound of a (ICa), n is 1.
In some embodiments of a compound of formula (I), 11 may be 1 only when the compound is a compound of formula (IC).
In some embodiments of a compound of formula (I), 11 may be 1 only when the compound is a compound of formula (ICa).
W0 2013/093095 26 In a compound of formula (I), R1 is selected from H; n, Cl-C6 alkyl, e. g. Cl-C3 alkyl, such as methyl, optionally substituted with at least one halogen; and Cl-C6 alkoxy optionally substituted with at least one n, e.g. Cl-C3 alkoxy ally tuted with at least one halogen, e.g. methoxy or trifluoromethoxy.
In some embodiments, R1 is selected from H, halogen and C1-C6 alkyl, e. g. Cl-C3 alkyl, such as methyl, wherein the alkyl is optionally substituted with at least one halogen. For ex- ample, R1 may be H, halogen, CH3 or CF3; e.g. H, Cl, Br, CH3 and CF3.
In some embodiments, R1 is selected from H and Cl-C6 alkyl, e. g. Cl-C3 alkyl, such as me- thyl. For example, R1 may be H or methyl, e.g. H.
In some embodiments, e. g. when A is S or O, in particular S, R1 is selected from H and halo- gen.
In some ments, e. g. when A is S or O, in ular S, R1 is selected from halogen and Cl-C6 alkyl, optionally substituted with at least one halogen; such as n and Cl-C3 alkyl, optionally substituted with at least one halogen; e. g. Cl, Br, CH3, and CF3; or Cl, Br, and CH3.
In some embodiments, e. g. when A is -CR4=CR4- or -CR4=N-, R1 is selected from H, F, Cl, CH3 and CF3; e.g. R1 is H.
In some embodiments, R1 is Cl-C6 alkyl. For example, in some embodiments of a compound of formula (IA) or (IB), e. g. formula (IAa) or formula (IBa), R1 is Cl-C6 alkyl; and R2 and R3 form, together with the carbon atoms to which they are attached, a 5- or 6-membered carbo- cyclic or heterocyclic ring, e.g. a benzene ring, which ring is optionally substituted with at least one R5.
In a compound of formula (I), R2 and R3 are each independently ed from H; halogen; Cl-C6 alkyl; Cl-C6 alkoxy; oyl; secondary or tertiary Cl-C6 alkylamido; carbocy- clylcarbonylamino-CO-C2 alkyl; 5- or 6-membered cyclic aminocarbonyl optionally contain- ing a further heteroatom in the ring; Cl-C6 alkylcarbonylamino; Cl-C6 alkylsulfonyl; hydroxy —CO-C6 alkyl, Cl-C6 alkylcarbonyl; carboxy; Cl-C6 alkoxycarbonyl; cyano; y- clyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl- CO-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 lO-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R5; or R2 and R3 form, er with the carbon atoms to which they are at- tached, a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally substi- tuted with at least one R5.
In some embodiments, R2 and R3 are each ndently selected from H; n; Cl-C6 alkyl; Cl-C6 alkoxy; carbamoyl; carbocyclylcarbonylamino-C0-C2 alkyl; 5- or 6-membered cyclic aminocarbonyl optionally containing a further heteroatom in the ring; Cl-C6 alkylcarbonylamino ; C 1 -C6 alkylsulfonyl; hydroxy-CO-C6 alkyl, C 1 -C6 arbonyl; C 1 -C6 alkoxycarbonyl; cyano; carbocyclyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl; carbocy- clyl-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 lO-membered bicyclyl; and any carbocyclyl or heterocy- clyl is optionally substituted with at least one R5; or R2 and R3 form, er with the carbon atoms to which they are attached, a 5- or 6-membered yclic or heterocyclic ring, which ring is optionally substituted with at least one R5.
For example, R2 and R3 may each be independently selected from H; halogen, such as F, Cl, and Br, in particular F and Cl; Cl-C6 alkyl, such as Cl-C4 alkyl, or Cl-C3 alkyl, in particular methyl; Cl-C6 alkoxy, such as Cl-C4 alkoxy, or Cl-C3 alkoxy, e. g. methyl; carbamoyl; sec- ondary or tertiary Cl-C6 alkylamido, e.g. secondary or tertiary Cl-C4 alkylamido, such as secondary or tertiary Cl-C3 alkylamido, e.g. methylamido or dimethylamido; carbocyclylcarbonylamino-CO-C2 alkyl, e.g. carbocyclylcarbonylamino-C0-Cl alkyl, or carbocyclylcar- mino; 5- or ered cyclic aminocarbonyl optionally containing a fiarther heteroa- tom in the ring, e.g 5- or 6-membered cyclic aminocarbonyl optionally ning an oxygen atom in the ring; Cl-C6 alkylcarbonylamino, e.g. Cl-C4 alkylcarbonylamino, or Cl-C3 al- kylcarbonylamino, such as acetamido; Cl-C6 alkylsulfonyl, such as Cl-C4 alkylsulfonyl, or Cl-C3 ulfonyl, e. g. methylsulfonyl; hydroxy-CO-C6 alkyl, such as hydroxy-CO-C4 al- kyl, or hydroxy—CO-C3 alkyl, e.g. hydroxy-CO-Cl alkyl, e.g. hydroxy; Cl-C6 alkylcarbonyl, such as Cl-C4 alkylcarbonyl, or Cl-C3 alkylcarbonyl Cl-C6 alkoxy- , e.g. acetyl; carboxy; carbonyl, such as Cl-C4 alkoxycarbonyl, or Cl-C3 alkoxycarbonyl, e. g. methoxycarbonyl; cyano; yclyloxy, such as phenyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl, such as carbocyclyl-C0-C2 alkyl, or carbocyclyl-CO-Cl alkyl, e. g. phenyl or benzyl; carbocyclyl- C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl, such as cyclyl-C0-C2 alkyl, or heterocyclyl- W0 2013/093095 28 2012/076836 C0-C1 alkyl, e. g. heterocyclyl; and heterocyclyl-C2-C3 alkenyl; wherein any alkyl is option- ally substituted with at least one halogen, e.g. l, 2 or 3 ns; any carbocyclyl or heterocy- clyl is 5- or 6-membered monocyclyl, e.g. phenyl or 5- or 6-membered aromatic or non- aromatic heterocyclyl; or 9- or lO-membered bicyclyl, e.g. naphthyl or 9- or lO-membered aromatic or non-aromatic heterocyclyl; and any carbocyclyl or heterocyclyl is optionally sub- stituted with at least one R5, e.g. 1-5 R5, or 1-4 R5, such as l, 2 or 3 R5; or R2 and R3 form, together with the carbon atoms to which they are attached, a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally tuted with at least one R5.
In some ments, R2 and R3 are each independently selected from H; halogen; Cl-C6 alkyl; Cl-C6 alkoxy; carbamoyl; secondary or tertiary Cl-C6 alkylamido; carbocyclylcar- bonylamino-CO-C2 alkyl; 5- or 6-membered cyclic aminocarbonyl optionally containing a further heteroatom in the ring; Cl-C6 alkylcarbonylamino; Cl-C6 alkylsulfonyl; hydroxy-CO- C6 alkyl, Cl-C6 alkylcarbonyl; carboxy; Cl-C6 alkoxycarbonyl; cyano; carbocyclyloxy; het- erocyclyloxy; 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 lO-membered bicyclyl; and any carbocyclyl or cyclyl is optionally substituted with at least one R5; or R2 and R3 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 R5.
In some ments, R2 and R3 are each independently selected from H; halogen; Cl-C6 alkyl; Cl-C6 alkoxy; carbamoyl; secondary or tertiary Cl-C6 alkylamido; carbocyclylcar- bonylamino-CO-Cl alkyl; 6-membered cyclic aminocarbonyl optionally ning a further heteroatom in the ring; Cl-C6 alkylcarbonylamino; Cl-C6 alkylsulfonyl; hydroxy-CO-C6 alkyl, C1-C6 alkylcarbonyl; carboxy; Cl-C6 alkoxycarbonyl; cyano; carbocyclyloxy; carbo- cyclyl; and heterocyclyl; n any alkyl is optionally substituted with at least one halogen; any yclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or lO-membered bicy- clyl; and any yclyl or heterocyclyl is optionally substituted with at least one R5; or R2 and R3 form, together with the carbon atoms to which they are attached, a 5- or 6-membered carbocyclic or cyclic ring, which ring is optionally substituted with at least one R5.
In some ments, R2 and R3 are each independently ed from H; halogen; Cl-C6 alkyl; Cl-C6 alkoxy; carbocyclylcarbonylamino-C0-C2 alkyl; Cl-C6 alkylcarbonylamino; hydroxy-CO-C6 alkyl, Cl-C6 arbonyl; Cl-C6 alkoxycarbonyl; cyano; carbocyclyloxy; W0 2013/093095 29 cyclyloxy; carbocyclyl-C0-C3 alkyl; and heterocyclyl-C0-C3 alkyl, wherein any alkyl is optionally substituted with at least one halogen; any carbocyclyl or cyclyl is 5- or 6- ed monocyclyl or 9- or lO-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R5; or R2 and R3 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 R5.
In some embodiments, R2 and R3 are each independently selected from H; halogen; Cl-C6 alkyl; Cl-C6 alkoxy; carbocyclylcarbonylamino-CO-Cl alkyl; alkylcarbonylamino; hydroxy- C0-C6 alkyl, Cl-C6 alkylcarbonyl; Cl-C6 alkoxycarbonyl; cyano; carbocyclyloxy; heterocy- clyloxy; and carbocyclyl-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 ally substituted with at least one R5; or R2 and R3 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 R5.
In some embodiments, R2 and R3 are each independently selected from H; halogen; Cl-C6 alkyl; Cl-C6 alkoxy; oyl; secondary or tertiary Cl-C6 alkylamido; carbocyclylcar- bonylamino-CO-C2 alkyl; 5- or 6-membered cyclic aminocarbonyl optionally containing a further heteroatom in the ring; Cl-C6 alkylcarbonylamino; Cl-C6 alkylsulfonyl; y-CO- C6 alkyl, Cl-C6 alkylcarbonyl; carboxy; Cl-C6 alkoxycarbonyl; cyano; carbocyclyloxy; het- erocyclyloxy; wherein any alkyl is optionally tuted with at least one halogen; any car- bocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or lO-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R5; or R2 and R3 form, together with the carbon atoms to which they are attached, a 5- or 6-membered carbo- cyclic or heterocyclic ring, which ring is ally substituted with at least one R5.
In some embodiments, R2 and R3 are each independently selected from H; halogen; Cl-C6 alkyl; Cl-C6 alkoxy; carbamoyl; secondary or tertiary Cl-C6 alkylamido; Cl-C6 alkylcar- mino; Cl-C6 alkylsulfonyl; hydroxy-CO-C6 alkyl, Cl-C6 arbonyl; carboxy; C1- C6 alkoxycarbonyl; cyano; wherein any alkyl is optionally substituted with at least one halo- gen; or R2 and R3 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 R5.
W0 2013/093095 30 In some embodiments, R2 and R3 are each independently selected from H; n; Cl-C6 alkyl; Cl-C6 alkoxy; hydroxy-CO-C6 alkyl, Cl-C6 alkylcarbonyl; Cl-C6 alkoxycarbonyl; cyano; carbocyclyloxy; and carbocyclyl-CO-C3 alkyl; wherein any alkyl is optionally substi- tuted with at least one halogen; any yclyl or heterocyclyl is 5- or 6-membered monocy- clyl or 9- or lO-membered yl; and any carbocyclyl or heterocyclyl is optionally substi- tuted with at least one R5; or R2 and R3 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 R5.
In some embodiments, R2 and R3 are independently selected from H, n, Cl-C6 alkyl, Cl-C6 alkoxy, carbocyclyl-C0-C3 alkyl, heterocyclyl-C0-C3 alkyl; wherein any alkyl is op- tionally substituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6- membered monocyclyl or 9- or bered bicyclyl; and any carbocyclyl or heterocyclyl is optionally tuted with at least one R5; or R2 and R3 form, er 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 R5.
In some embodiments, R2 and R3 are independently selected from H, halogen, Cl-C6 alkyl, Cl-C6 alkoxy, wherein any alkyl is optionally substituted with at least one halogen; or R2 and R3 form, together with the carbon atoms to which they are attached, a 5- or 6-membered car- bocyclic or heterocyclic ring, which ring is optionally substituted with at least one R5.
In some other embodiments, one of R2 and R3, e.g. R2, is selected from carbocyclyl-C0-C3 alkyl; yclyl-C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is 5- or ered monocyclyl or 9- or 10- membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R5; or R2 and R3 form, er with the carbon atoms to which they are attached, a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally tuted with at least one R5.
In some embodiments, the compound of formula (I) is a compound of formula (IA) or (IE), in particular a compound of formula (IA), e.g. a compound of formula (IAa) and one of R2 and R3, e.g. R2, is selected from yclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocy- 0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is - or 6-membered monocyclyl or 9- or lO-membered bicyclyl; and any carbocyclyl or hetero- W0 2013/093095 31 2012/076836 cyclyl is optionally substituted with at least one R5; or R2 and R3 form, together with the car- bon atoms to which they are attached, a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R5.
In some other embodiments, the compound of formula (I) is a compound of formula (IC), (ID) or (IE), in particular a compound of formula (IC), e.g. a compound of formula (IC) and one of R2 and R3, e.g. R2, is selected from carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; cyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or lO-membered bicyclyl; and any car- bocyclyl or cyclyl is optionally substituted with at least one R5; or R2 and R3 form, to- gether 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 R5.
In some other ments, R2 and R3 are independently selected from H, halogen, and C1- C6 alkyl, wherein any alkyl is optionally substituted with at least one halogen; or R2 and R3 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 R5.
In still some other embodiments, R2 and R3 are independently selected from H and halogen; or R2 and R3 form, together with the carbon atoms to which they are attached, a 5- or 6- membered carbocyclic or heterocyclic ring, which ring is optionally tuted with at least one R5.
With respect to R2 and R3, in any of the above embodiments, any halogen e. g. may be select- ed from F, Cl and Br, or F and Cl; and any Cl-C6 alkyl e.g. may be selected from Cl-C4 al- kyl, or C1-C3 alkyl, e.g. methyl; any C0-C3 alkyl e.g. may be ed from C0-C2 alkyl, or CO-Cl alkyl, such as CO alkyl (i.e. a direct bond).
It should be understood that for the purpose of the present invention, and unless otherwise indicated or apparent from the context, any alkyl that is optionally substituted with at least one halogen may optionally be part of a l, i.e. an alkoxy or alkylcarbonyl. Thus, R2 and R3 may be e.g. a nated alkyl, a halogenated alkoxy or a nated alkylcarbonyl etc.
The number of halogen atoms attached to any one alkyl may be e. g. l, 2 or 3 and may be in- dependently ed from e.g. F and Cl. For example, any alkyl may be substituted by l, 2 or 3 halogens that are all fluoro, such as in trifluoromethyl, trifluoromethoxy or difluorometh- oxy.
W0 2013/093095 32 It also should be understood that for the e of the present invention, and unless other- wise indicated or apparent from the context, the reference to “any carbocyclyl or heterocy- clyl” as being 5- or 6-membered monocyclyl or 9- or lO-membered bicyclyl also inludes the carbocyclyl and heterocylyl, respectively, when present as a moiety of a radical such as e.g. yclyloxy or carbocyclyl-C2-C3 alkenyl.
In some embodiments, when either R2 or R3 is carbocyclyl or heterocyclyl optionally substi- tuted by at least one R5, or a radical comprising a carbocyclyl or heterocyclyl moiety optional- ly tuted by at least one R5, such carbocyclyl is aromatic and/or any heterocyclyl is het- eroaromatic. For example, any carbocyclyl may be selected from phenyl and yl, and any heterocyclyl may be selected from 5-lO-membered heterocyclyl comprising one or sever- al heteroatoms selected from N, O and S l, 2, 3 or 4 heteroatoms selected from N, O and S, such as dihydrobenzo filryl, dinyl, pyridinyl, benzo filryl, thiazolyl, quinolinyl, or thienyl.
In some embodiments, any carbocyclyl is an aryl and any heterocyclyl is a aryl.
In some embodiments, when either R2 or R3 is bicyclic 9- or lO-membered carbocyclyl or heterocyclyl, ally substituted with at least one R5, said bicyclic carbocyclyl or heterocy- clyl 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 e, this other ring may be phenyl or a het- erocyclic, non-aromatic or aromatic 5- or 6-membered ring, e. g. sing 1-3 heteroatoms, e.g. l or 2 heteroatoms selected from N, O and S, e.g. N and O.
In some embodiments, either R2 or R3 is phenyl substituted with at least one R5, e.g. from 1 to 4 R5; or from 1 to 4 R5; e.g. or 1, 2 or 3 R5, in ular 1 or 2 R5.
In some embodiments, either R2 or R3 is selected from phenyl, 2-hydroxyphenyl, 2- (hydroxymethyl)phenyl, 2-nitrophenyl, 2-hydroxyfluorophenyl, ophenyl, 3- chlorophenyl, 3-aminophenyl, 3-ethoxyphenyl, 3-(isopropoxycarbonyl)phenyl, 3- acetylphenyl, 3-carbamoylphenyl, 3-acetamidophenyl, 3-cyanophenyl, 3- (methylsulfonyl)phenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4- trifluoromethoxyphenyl, 4-(methylsulfonamido)phenyl, 4-carbamoylphenyl, 4- (dimethylamino)phenyl, 4-(methylthio)phenyl, 4-(dimethylcarbamoyl)phenyl, 2-fluoro methoxyphenyl, 2,5-difluorophenyl, 5-chloromethoxyphenyl, 3-fluorohydroxyphenyl, 3-fluoromethoxyphenyl, omethylphenyl, 3,5-difluorophenyl, 4-hydroxy-3,5- dimethylphenyl, 4-methoxy-3,5-dimethylphenyl, 2-methylthiazolyl, 5-acetylthiophenyl, W0 2013/093095 33 pyridinyl, e. g. pyridinyl, pyridinyl, ridinyl, 6-methoxypyridinyl, 6- ypyridinyl, hydrobenzofuran—5-yl, benzofuranyl, and quinolinyl.
In some embodiments, R2 and R3 are not both selected from a group that is cyclic (carbocyclic or heterocyclic) or comprises a cyclic moiety. Thus, in some embodiments, R2 is a radical that is or comprises a cyclic moiety, and R3 is not such a radical, while in some other embodi- ments, R3 is a radical that is or comprises a cyclic moiety and R2 is not such a radical.
For example, in some embodiments of a compound of formula (ICa), R2 is a radical that is or comprises a cyclic moiety and R3 is not such a radical. Likewise, in some ments of a compound of a (IAa), R2 is a radical that is or comprises a cyclic moiety and R3 is not such a radical.
In some embodiments of a compound of a (ICa), R3 is not (an ally substituted) phenyl. For example, in some embodiments of a compound of formula (ICa), when R1, R2, and each R4 are hydrogen, R3 is not (an ally tuted) phenyl. In some other embod- iments of a compound of a (ICa), when R1, R2, and each R4 are hydrogen and n is 0, R3 is not an optionally substituted . In some embodiments, when the compound is a com- pound of formula (IC), the A-ring is not monosubstituted in para-position with respect to the sulfonamide moiety. In some other embodiments, when the compound is a compound of formula (IC), and n is 0, the A-ring is not monosubstituted in para-position with respect to the sulfonamide moiety.
In some embodiments, e. g. in a compound of formula (ICa), R2 is as defined herein above, and R3 is selected from H; halogen; C1-C6 alkyl; Cl-C6 alkoxy; carbamoyl; secondary or tertiary Cl-C6 alkylamido; carbocyclylcarbonylamino-C0-C2 alkyl; 5- or 6-membered cyclic aminocarbonyl optionally containing a fiarther heteroatom in the ring; Cl-C6 alkylcarbonyla- mino; C 1 -C6 alkylsulfonyl; hydroxy-CO-C6 alkyl, C 1 -C6 alkylcarbonyl; carboxy; C 1 -C6 alkoxycarbonyl; cyano; carbocyclyloxy; heterocyclyloxy; wherein any alkyl is optionally sub- stituted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6-membered mono- cyclyl or 9- or lO-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally sub- stituted with at least one R5; or R2 and R3 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 R5.
W0 2013/093095 34 In some embodiments, e. g. in a compound of formula (ICa), R2 is as defined herein above, and R3 is selected from H, halogen, Cl-C6 alkyl, and carbocyclyl-C0-C3 alkyl; n any alkyl is optionally substituted with at least one halogen; any carbocyclyl is 5- or ered monocyclyl or 9- or lO-membered bicyclyl; and any carbocyclyl is optionally substituted with at least one R5; or R2 and R3 form, together with the carbon atoms to which they are ed, a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R5.
In some particular embodiments, e. g. in a compound of formula (ICa), R2 is as defined herein above, and R3 is ed from H, halogen, and Cl-C6 alkyl, wherein any alkyl is optionally substituted with at least one halogen; or R2 and R3 form, together with the carbon atoms to which they are ed, a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is ally substituted with at least one R5.
In some ments, e.g. in a compound of formula (ICa), R2 is as defined herein above, and R3 is selected from H and halogen.
In some embodiments, e. g. in a nd of formula (ICa), R2 is as defined herein above, and R3 is H.
In some embodiments, e. g. in a compound of formula (ICa), R3 is as defined herein above, and R2 is selected from carbocyclyloxy, heterocyclyloxy, carbocyclyl-C0-C3 alkyl, carbocy- clyl-C2-C3 alkenyl, heterocyclyl-C0-C3 alkyl, and heterocyclyl-C2-C3 alkenyl; in particular from carbocyclyl-C0-C3 alkyl and heterocyclyl-C0-C3 alkyl; e. g. fiom carbocyclyl alkyl and heterocyclyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or lO-membered bicyclyl; and any yclyl or heterocyclyl is optionally substituted with at least one R5. In these embodiments, R3 e. g. may be selected from R3 is selected from H, halo- gen, Cl-C6 alkyl, Cl-C6 alkoxy, carbamoyl, secondary or ry Cl-C6 alkylamido, Cl-C6 alkylcarbonylamino, Cl-C6 alkylsulfonyl, hydroxy-CO-C6 alkyl, Cl-C6 alkylcarbonyl, car- boxy, Cl-C6 alkoxycarbonyl, and cyano; or from H, halogen, and Cl-C6 alkyl; from H and halogen, or from H and Cl-C6 alkyl.
In some embodiments of compound of formula (IA) or (IE), in particular formula (IA), R2 is as defined herein above, and R3 is selected from H; halogen; Cl-C6 alkyl; Cl-C6 alkoxy; carbamoyl; secondary or tertiary Cl-C6 alkylamido; carbocyclylcarbonylamino-C0-C2 alkyl; - or 6-membered cyclic aminocarbonyl optionally ning a filrther heteroatom in the ring; C1-C6 arbonylamino; Cl-C6 alkylsulfonyl; hydroxy-CO-C6 alkyl, Cl-C6 alkyl- carbonyl; carboxy; C 1 -C6 alkoxycarbonyl; cyano; yclyloxy; heterocyclyloxy; carbocy- clyl-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 car- yl or heterocyclyl is 5- or ered monocyclyl or 9- or lO-membered yl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R5; or R2 and R3 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 R5.
In some embodiments of a nd of formula (IA) or (IE), in particular formula (IA), R2 is as defined herein above, and R3 is selected from H; halogen; Cl-C6 alkyl; Cl-C6 alkoxy; carbamoyl; ary or tertiary Cl-C6 alkylamido; carbocyclylcarbonylamino-C0-C2 alkyl; - or 6-membered cyclic aminocarbonyl optionally containing a fiarther heteroatom in the ring; Cl-C6 alkylcarbonylamino; Cl-C6 ulfonyl; hydroxy-CO-C6 alkyl, Cl-C6 alkylcarbonyl ; carboxy; Cl-C6 alkoxycarbonyl; cyano; wherein any alkyl is optionally substituted with at least one n; any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or lO-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R5; or R2 and R3 form, together with the carbon atoms to which they are at- tached, a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally substi- tuted with at least one R5.
In some embodiments of a compound of formula (IA) or (IE), in ular formula (IA), R2 is as defined herein above, and R3 is selected from H, halogen, Cl-C6 alkyl, yclylcar- bonylamino-CO-C2 alkyl, and carbocyclyl-C0-C3 alkyl; wherein any alkyl is optionally sub- stituted with at least one halogen; any carbocyclyl is 5- or 6-membered monocyclyl or 9- or lO-membered bicyclyl; and any carbocyclyl is optionally substituted with at least one R5; or R2 and R3 form, together with the carbon atoms to which they are attached, a 5- or 6- membered carbocyclic or heterocyclic ring, which ring is optionally tuted with at least one R5.
In still other embodiments of a compound of formula (IA) or (IE), in particular formula (IA), R2 is as defined herein above, and R3 is selected from H, halogen, and Cl-C6 alkyl, wherein any alkyl is ally substituted with at least one halogen; or R2 and R3 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 R5.
W0 2013/093095 36 In still other ments of a compound of formula (IA) or (IE), in particular formula (IA), R2 is as defined herein above, and R3 is selected from H and halogen. For example, both R2 and R3 may be selected from H and halogen.
R2 and R3 ably should not both be H. In some embodiments, R2 is as defined herein above, but R2 is not H.
In some embodiments, R2 and R3 are as defined herein above, but R2 and R3 do not form, to- gether with the carbon atoms to which they are attached, a 5- or 6-membered carbocyclic or heterocyclic ring.
In some other embodiments, R2 and R3, together with the carbon atoms to which they are at- tached, form a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R5. For example, R2 and R3 together with the carbon atoms to which they are ed may form a 5- or 6-membered carbocyclic or heterocyclic ic ring. For example, in some embodiments, the ring formed by R2 and R3 is a carbocyclic aro- matic ring, e.g. a benzene ring. In some other embodiments, the ring formed by R2 and R3 is a 5- or 6-membered heterocyclic, aromatic or non-aromatic ring containing 1-4, e. g. l, 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 l,2,5-oxadiazole, or a tetrahydrofuran ring.
In some embodiments, when R2 and R3, together with the carbon atoms to which they are at- tached, form a 6-membered heterocyclic ring, said ring is not pyridine.
In some embodiments, when R2 and R3, er with the carbon atoms to which they are at- tached, form a 5- or 6-membered carbocyclic or cyclic ring, which ring is optionally substituted with at least one R5, said ring is a phenyl ring or a 5-membered heterocyclic ring.
In some embodiments, when R2 and R3, together with the carbon atoms to which they are at- tached, form a 5- or 6-membered carbocyclic or heterocyclic ring, the nd of formula (I) is a compound of a (IA) or (IE).
In some other embodiments, when R2 and R3, together with the carbon atoms to which they are attached, form a 5- or 6-membered carbocyclic or heterocyclic ring, the compound of formula (I) is a compound of formula (IC), in particular a compound of formula (ICb).
When the compound of formula (I) is a compound of formula (IC), (ID) or (IE), it comprises either one or two groups R4, independently selected from H; n, e.g. F, Cl and Br; mon- ocyclic C3-C6 carbocyclyl, e.g. phenyl; and Cl-C6 alkyl, such as C1-C4 alkyl, or Cl-C3 alkyl , e.g. methyl; wherein any alkyl is optionally substituted with at least one halogen, e. g. l, 2 or 3 halogen, such as l, 2, or 3 F. In some embodiments, each R4 is selected from H, halogen, and Cl-C6 alkyl, wherein any alkyl is optionally substituted with at least one halogen. In some embodiments, each R4 is selected from H and halogen. In still other embodiments, each R4 is selected from H and Cl-C6 alkyl. In some embodiments, each R4 is selected from H, F, Cl, Br, CH3 and CF3. In some embodiments, each R4 is H.
When R2 and/or R3 is a cyclic moiety or R2 and R3, 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 R5, e. g. 1-5 R5, or 1-4 R5, in particular 1, 2 or 3 R5. Each R5 is independently se- lected from halogen, e.g. F and Cl; C1-C6 alkyl, e. g. Cl-C4 alkyl, such as methyl, ethyl, n- propyl, isopropyl and n-butyl; Cl-C6 alkoxy, e.g. Cl-C4 alkoxy, such as y, ethoxy, n- propoxy, isopropoxy and n-butoxy; phenoxy; amino; cyano; nitro; secondary or tertiary C1- C6 mino, e.g. secondary or tertiary Cl-C4 alkylamino, such as dimethylamino; 5- or 6- membered cyclic amino, optionally containing at least one r heteroatom in the ring; C1- C6 arbonylamino, such as Cl-C4 alkylcarbonylamino, e. g. acetylamido; carbamoyl; secondary or tertiary Cl-C6 alkylamido,such as secondary or tertiary C1-C4 mido, e.g. dimethylcarbamoyl and diisopropylcarbamoyl; 5- or 6-membered cyclic aminocarbonyl; C1- C6 alkoxycarbonylamino, such as Cl-C4 alkoxycarbonylamino; hydroxy-CO-C6 alkyl e. g. hydroxy-CO-C4 alkyl, such as hydroxy and hydroxymethyl; Cl-C6-alkylthio such as Cl-C4 alkylthio, e.g. methylthio; carboxy-CO-C6-alkyl, e.g. y—CO-C4 alkyl, such as y; Cl-C6 alkoxycarbonyl, such as Cl-C4 alkoxycarbonyl, e.g. ycarbonyl and iso- propoxycarbonyl; Cl-C6 alkylcarbonyl such as Cl-C4 alkylcarbonyl, e. g. acetyl; Cl-C6 al- kylsulfonyl, such as Cl-C4 alkylsulfonyl, e. g. sulfonyl; and Cl-C6 alkylsulfonyla- mino, such as Cl-C4 alkylsulfonylamino, e.g. methylsulfonamido; wherein any alkyl is op- tionally substituted with at least one halogen; such as in trifluoromethyl or trifluoromethoxy.
In some embodiments, when A is 4 and n is 0, neither R2 nor R3 is selected from 4- hydroxypyrazolo[ l ,5-a] - l ,3 ,5-triazinyl and 2,4-dihydroxypyrazolo[ l ,5 -a] - l ,3 ,5-triazin W0 2013/093095 38 In some embodiments, each R5 is independently selected from halogen; Cl-C6 alkyl; Cl-C6 alkoxy; phenoxy; amino; cyano; nitro; secondary or tertiary Cl-C6 alkylamino; 5- or 6- membered cyclic amino, ally ning at least one fiarther heteroatom in the ring; C 1- C6 alkylcarbonylamino; carbamoyl; 5- or 6-membered cyclic aminocarbonyl; Cl-C6 alkoxycarbonylamino; hydroxy-CO-C6 alkyl; C l -C6-alkylthio; C 1 -C6 alkoxycarbonyl; C 1 -C6 alkylcarbonyl; Cl-C6-alkylsulfonyl; and Cl-C6 alkylsulfonylamino; wherein any alkyl is optionally substituted with at least one halogen.
In some embodiments, each R5 is independently selected from halogen, e.g. F and Cl; Cl-C6 alkyl, e. g. Cl-C4 alkyl, such as methyl, ethyl, yl, isopropyl and l; Cl-C6 alkoxy, e. g. Cl-C4 alkoxy, such as methoxy, ethoxy, oxy, isopropoxy and n-butoxy; amino; cyano; nitro; ary or tertiary Cl-C6 alkylamino, e.g. secondary or tertiary Cl-C4 alkyl- amino, such as dimethylamino; Cl-C6 alkylcarbonylamino, such as Cl-C4 arbonyla- mino, e. g. acetylamido; carbamoyl; secondary or tertiary Cl-C6 alkylamido,such as second- ary or tertiary Cl-C4 alkylamido, e.g. dimethylcarbamoyl and diisopropylcarbamoyl; hy- droxy—CO-C6 alkyl e.g. hydroxy-CO-C4 alkyl, such as hydroxy and hydroxymethyl; Cl-C6- alkylthio such as Cl-C4 alkylthio, e. g. methylthio; Cl-C6 alkoxycarbonyl, such as Cl-C4 alkoxycarbonyl, e.g. methoxycarbonyl and isopropoxycarbonyl; Cl-C6 alkylcarbonyl such as Cl-C4 alkylcarbonyl, e.g. acetyl; Cl-C6 alkylsulfonyl, such as Cl-C4 alkylsulfonyl, e.g. me- thylsulfonyl; and Cl-C6 alkylsulfonylamino, such as Cl-C4 ulfonylamino, e.g methyl- amido; wherein any alkyl is optionally substituted with at least one halogen; such as in trifluoromethyl or trifluoromethoxy.
In some embodiments, each R5 is independently selected from halogen, e.g. F and Cl; Cl-C6 alkyl, e.g. Cl-C4 alkyl, such as methyl and isopropyl; Cl-C6 alkoxy, e.g. Cl-C4 alkoxy, such as methoxy, ethoxy, and isopropoxy; amino; cyano; nitro; secondary or tertiary Cl-C6 alkyl- amino, e.g. secondary or tertiary Cl-C4 alkylamino, such as dimethylamino; Cl-C6 alkylcar- mino, such as Cl-C4 alkylcarbonylamino, e.g. acetylamido; carbamoyl; secondary or tertiary Cl-C6 alkylamido, such as ary or tertiary Cl-C4 mido, e.g. dimethylcar- bamoyl; hydroxy-CO-C6 alkyl e. g. hydroxy—CO-C4 alkyl, such as hydroxy and hydroxymethyl ; Cl-C6-alkylthio such as Cl-C4 alkylthio, e. g. methylthio; Cl-C6 alkoxycarbonyl, such as Cl-C4 alkoxycarbonyl, e. g. isopropoxycarbonyl; Cl-C6 alkylcarbonyl such as Cl-C4 al- kylcarbonyl, e.g. acetyl; Cl-C6 alkylsulfonyl, such as Cl-C4 alkylsulfonyl, e.g. methylsulfonyl ; and Cl-C6 alkylsulfonylamino, such as Cl-C4 alkylsulfonylamino, e.g methyl- W0 2013/093095 39 sulfonamido; wherein any alkyl is optionally tuted with at least one halogen; such as in trifluoromethyl or trifluoromethoxy.
In some embodiments, each R5 is selected from hydroxy, C1-C6 alkoxy and halogen, e. g. hy- droxy, Cl-C3 alkoxy and halogen, such as hydroxy, methoxy and F, in particular hydroxy and F. For example, R2 or R3, in particular R2, is phenyl substituted by l or 2, in ular 2, of said moeities, e. g. 2 moieties ed from OH and halogen, in ular OH and F. In some embodiments, R2 or R3, in particular R2, is phenyl substituted by any such R5 in 2- and 5- position, e.g. R2 or R3, in particular R2, is 5-fluorohydroxyphenyl or fluorophenyl, in particular 5-fluorohydroxyphenyl.
The moiety Ra is selected from H and Cl-C6 alkylcarbonyl. In some embodiments, Ra is se- lected from H and Cl-C4 alkylcarbonyl. In some other ments, R81 is selected from H and Cl-C3 alkylcarbonyl, e.g from H and acetyl. In some embodiments, R81 is H. In these em- bodiments, Rb is not H.
In some embodiments, Ra is Cl-C6 alkylcarbonyl, e.g. Cl-C4 alkylcarbonyl, or Cl-C3 alkyl- carbonyl, e.g. acetyl. In these embodiments, Rb may be H or different from H, e. g. Rb is dif- ferent from H.
Rb is selected from H, Cl-C6 alkyl, Cl-C6 alkyl substituted with at least one R6; carbocyclyl- C0-C5 alkyl; and heterocyclyl-C0-C5 alkyl; wherein any carbocyclyl and heterocyclyl is 5- or 6- membered and is optionally substituted with at least one R7 and optionally comprises at least one oxo group in the ring.
When Rb is an alkyl substituted by at least one R6, said alkyl may be substituted by e.g. l, 2 or 3 R6, e.g. 1 R6.
When Rb is 5- or 6- membered yclyl-C0-C5 alkyl or heterocyclyl-C0-C5 alkyl compris- ing at least one oxo group in the ring, it e. g. may be heterocyclyl C0-C5 alkyl comprising at least one oxo group in the ring, e. g. heterocyclyl- C0-C5 alkyl comprising one oxo group in the ring. In some embodiments, Rb may comprise l or 2 oxo groups in the ring, or I oxo group in the ring. For example, the ring may be l,3-dioxolyl. In some embodiments, Rb does not comprise any oxo group in the ring.
In some embodiments, Rb is selected from Cl-C6 alkyl, Cl-C6 alkyl substituted with at least one R6; carbocyclyl-C0-C5 alkyl; and heterocyclyl-C0-C5 alkyl; wherein any carbocyclyl and W0 93095 40 heterocyclyl is 5- or 6-membered and is optionally substituted with at least one R7 and op- tionally comprises at least one oxo group in the ring.
In some embodiments, Rb is selected from H and Cl-C6 alkyl optionally substituted with at least one R6, e.g. Cl-C6 alkyl optionally substituted with at least one R6.
When Rb is Cl-C6 alkyl or Cl-C6 alkyl substituted with at least one R6, said Cl-C6 alkyl e. g. may be Cl-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl or n-butyl, e.g. Cl-C3 alkyl, such as methyl or ethyl, e.g. methyl.
In some embodiments, when Rb is Cl-C6 alkyl, it is unsubstituted, e.g. in some embodiments, Rb is Cl-C6 alkyl, or Cl-C4 alkyl, or Cl-C3 alkyl, such as methyl.
In some embodiments, Rb is ed from carbocyclyl-CO-CS alkyl, e. g. phenyl-CO-CS alkyl; heterocyclyl-CO-CS alkyl, e.g. tetrahydrofiaryl—CO-CS alkyl, pyrrolyl-CO-CS alkyl or imidazolyl-CO-CS alkyl; Cl-C6 alkyl; and Cl-C6 alkyl substituted with at least one R6, e.g. l or 2 R6, e.g. one R6, n each R6 is independently selected from Cl-C6 alkoxy, e.g. Cl-C3 alkoxy; and 5- or 6-membered cyclic amino optionally containing at least one fiarther heteroa- tom in the ring and wherein the ring is optionally substituted with at least one, e.g. l or 2, e. g. l, substituent selected from Cl-C6 alkyl, e.g. at least one Cl-C3 alkyl.
In some embodiments, Rb is selected from carbocyclyl-CO-CS alkyl, e. g. phenyl-CO-CS alkyl; cyclyl-CO-CS alkyl, e.g. tetrahydrofiaryl—CO-CS alkyl, pyrrolyl-CO-CS alkyl, imidazolyl- CO-CS alkyl, pyrrolidinyl-CO-CS alkyl, piperidinyl-CO-CS alkyl; Cl-C6 alkyl; and Cl-C6 alkyl substituted with at least one R6, e. g. l or 2 R6, e. g. one R6, wherein each R6 is inde- pendently selected from Cl-C6 alkoxy, e. g. Cl-C3 ; and 5- or 6-membered cyclic ami- no optionally containing at least one fiarther heteroatom in the ring and wherein the ring is optionally substituted with at least one, e.g. l or 2, e.g. l, tuent selected from Cl-C6 alkyl, e.g. at least one Cl-C3 alkyl.
When Rb is carbocyclyl-CO-CS alkyl, optionally substituted with at least one R7 and optional- ly comprising at least one oxo group in the ring, it e.g. may be carbocyclyl-CO-C4 alkyl, car- bocyclyl-CO-C3 alkyl, carbocyclyl-CO-C2 alkyl, or yclyl-CO-Cl alkyl substituted with at least one R7 and optionally comprising at least one oxo group in the ring, wherein the car- yl e.g. may be phenyl.
W0 2013/093095 41 In some embodiments, when Rb is carbocyclyl-CO-CS alkyl, optionally substituted with at least one R7, Rb is -CO-CS alkyl, -C0-C4 alkyl, phenyl-C0-C3 alkyl, or phenyl- CO-C2 alkyl, e.g. benzyl or phenyl, wherein the phenyl ring is optionally substituted with at least one R7.
In some embodiments, Rb is phenyl, optionally substituted with at least one R7. In some other embodiments, Rb is benzyl, optionally substituted with at least one R7.
When Rb is heterocyclyl-CO-CS alkyl, ally substituted with at least one R7 and optional- ly comprising at least one oxo group in the ring, it e. g. may be heterocyclyl-C0-C4 alkyl, het- erocyclyl-C0-C3 alkyl, heterocyclyl-CO-C2 alkyl, or heterocyclyl-CO-Cl alkyl optionally sub- stituted with at least one R7 and optionally comprising at least one oxo group in the ring. In this case, the heterocyclyl e. g. may contain 1-4 atoms, selected from N, O and S, e. g. N and O. For e, the heterocyclyl may be tetrahydrofuryl, pyrrolyl, imidazolyl, or dioxol- yl, optionally comprising an oxo group in the ring, such as in l,3-dioxolyl. In other embodiments, the heterocyclyl is selected from tetrahydrofuryl, pyrrolyland olyl. In other embodiments, the heterocyclyl is selected from tetrahydrofuryl, pyrrolyl, imidazolyl, e.g imidazol-l-yl, pyrrolidinyl and dinyl. In one particular embodiment, the heterocyclyl is selected from yl and imidazolyl. In another particular embodiment, the heterocyclyl is tetrahydrofuryl In some embodiments, Rb is 2-nitro-lH-imidazol-S-yl—CO-C3 alkyl or 2-(methylsulfinyl)-lH- imidazol-S-yl)-C0-C3 alkyl, e.g. (2-nitro-lH-imidazol-S-yl)methyl or 2-(methylsulfinyl)-lH- imidazol-S-yl)methyl. In some ments, the lH-imidazol-S-yl is substituted by a group R7 in l-position, e.g. a group R7 selected from Cl-C6 alkyl, such as a Cl-C3 alkyl, e. g. me- thyl. For example, Rb may be l-methylnitro-lH-imidazol-S-yl—CO-C3 alkyl, e.g. l-methyl- 2-nitro - l H-imidazo l-5 -ylmethyl.
In some embodiments, Rb is lH-imidazolyl. In other embodiments, Rb is lH-imidazol-S-yl.
In some embodiments, when Rb is carbocyclyl-CO-CS alkyl or heterocyclyl-CO-CS alkyl, op- tionally substituted with at least one R7, said cyclyl does not contain any oxo group in the ring.
W0 2013/093095 42 In some embodiments, Rb is ed from H, carbocyclyl-CO-CS alkyl; and heterocyclyl-C0- CS alkyl; wherein any carbocyclyl and heterocyclyl is optionally substituted with at least one R7 and optionally comprises at least one oxo group in the ring.
In some other embodiments, Rb is selected from H, and carbocyclyl-CO-CS alkyl; n any carbocyclyl is optionally substituted with at least one R7 and optionally comprises at least one oxo group in the ring. In other embodiments, Rb is carbocyclyl-CO-CS alkyl; wherein any car- bocyclyl is optionally substituted with at least one R7 and optionally comprises at least one oxo group in the ring In some embodiments, Rb is selected from H and heterocyclyl-CO-CS alkyl; wherein any car- yl is optionally substituted with at least one R7 and optionally comprises at least one oxo group in the ring, e. g. Rb is heterocyclyl-CO-CS alkyl. In other embodiments, Rb is hetero- cyclyl-CO-CS alkyl, e.g. Rb is heterocyclyl-CO-CS alkyl.
In some ments, Rb is selected from H; Cl-C6 alkyl; Cl-C6 alkyl substituted with at least one moiety R6 selected from Cl-C6 alkoxy, hydroxy, hydroxy—Cl-C6 alkoxy, secondary or tertiary Cl-C6 alkylamino, secondary or tertiary hydroxy-Cl-C6 alkylamino, 5- or 6- membered cyclic amino optionally containing at least one further atom in the ring and wherein the ring is optionally substituted with at least one Cl-C6 alkyl, and carbamoyl; phe- -CS alkyl, wherein the phenyl is optionally substituted with at least one R7, and 5- or 6- membered heterocyclyl-CO-CS alkyl, n the heterocyclyl is optionally substituted with at least one R7 and optionally contains an oxo group in the ring.
In some embodiments, Rb is selected from H; Cl-C6 alkyl; Cl-C6 alkyl substituted with at least one moiety R6 selected from Cl-C6 alkoxy, hydroxy, hydroxy-Cl-C6 , Cl-C6 alkoxycarbonylamino, secondary or tertiary Cl-C6 alkylamino, secondary or tertiary hy- droxy—Cl-C6 alkylamino, 5- or 6-membered cyclic amino optionally containing at least one further heteroatom in the ring and n the ring is optionally substituted with at least one Cl-C6 alkyl, and carbamoyl; phenyl-CO-CS alkyl, wherein the phenyl is optionally substitut- ed with at least one R7; 5- or 6-membered heterocyclyl-CO-CS alkyl; 5-ormembered carbo- amino; -membered heterocyclylamino; 5-or—6-membered carbocyclyloxy; and 5- ormembered heterocyclyloxy; wherein any carbocyclyl or heterocyclyl is optionally - tuted with at least one R7 and optionally contains an oxo group in the ring.
W0 2013/093095 43 For e, Rb may be selected from H, , ethyl, n—propyl, isopropyl, l, n- pentyl, n—hexyl, 2-hydr0xyetyl, 2-meth0xyethyl, 2-eth0xyethyl, 3-hydr0xypr0pyl, 2-(2- hydroxyethoxy)ethyl, tetrahydrofilranyl, (tetrahydrofilranyl)methyl, 3- dimethylaminopropyl, 4-dimethylamin0butyl, 2-amin00X0ethyl, 3-morpholinopr0pyl, 3-(4- methylpiperazin— l -yl)pr0pyl, (5 -methyl0X0- l ,3-dioxolyl)methyl, 2- [bis(2- yethyl)amino] ethyl, 3 -( l H-pyrrol— l -yl)pr0pyl, 3 -( l H-imidazo l- l -yl)pr0pyl, 2-( l H- pyrrol-l-yl)ethyl, phenyl, and benzyl.
For example, Rb may be selected from H, methyl, ethyl, n—propyl, isopropyl, n—butyl, n- pentyl, n—hexyl, 2-hydr0xyetyl, 2-meth0xyethyl, 2-eth0xyethyl, 3-hydr0xypr0pyl, 2-(2- hydroxyethoxy)ethyl, tetrahydrofilranyl, (tetrahydrofilranyl)methyl, 3- dimethylaminopropyl, 4-dimethylamin0butyl, 2-amin00X0ethyl, 3-(tertbutoxycarbonyl )amin0)pr0pyl, 3-morpholin0propyl, 4-m0rpholin0butyl, l-methyl morpholinopropyl, 3-(2,6-dimethylmorpholino)pr0pyl, 3-(4-methylpiperazin— l -yl)pr0pyl, lmethylpiperidinyl , l -methylpyrrolidin-3 -yl, 2-meth0xy- l -methylethyl, l - (methoxymethyl)propyl, 2-eth0xy— l -(eth0xymethyl)ethyl, 2-methoxybutyl, 2-methoxy— l - (methoxymethyl)ethyl, (5-methyloxo-l,3-di0xolyl)methyl, 2-[bis(2- hydroxyethyl)amino] ethyl, 3 -( l H-pyrrol— l -yl)pr0pyl, 3 -( l azo l- l -yl)pr0pyl, 2-( l H- pyrrol- l -yl)ethyl, (l -methylnitr0- l H-imidazo l-5 -yl)methyl, l -benzylpyrrolidin-3 -yl, l - (tert-butoxycarbonyl)pyrr0lidinyl, chlor0pyridin—3-yl)0xy]ethyl, 2-[3- (methoxymethyl)phen0xy]ethyl, 2-(3-carbamoylphen0xy)ethyl, 3-(pyridin—3-ylamino)pr0pyl, 3-[(l-methyl-lH-pyrazol—S-yl)amin0]pr0pyl, 3-[(5-methylis0xazolyl)amin0]propyl, 2- phenoxyethyl, phenyl, and benzyl.
More particularly, Rb may be selected from , ethyl, yl, isopropyl, n—butyl, n- pentyl, n—hexyl, 2-meth0xyethyl, 2-ethoxyethyl, tetrahydrofuran—3-yl, (tetrahydrofuran—3- yl)methyl, 3-m0rpholinopr0pyl, 3-(4-methylpiperazin— l -yl)propyl, 3 -( l H-pyrro l- l -yl)pr0pyl, 3-( l H-imidazol— l -yl)pr0pyl, 2-( l H-pyrrol— l -yl)ethyl, , and benzyl.
More ularly, Rb may be selected from , ethyl, n—propyl, pyl, n—butyl, n- pentyl, l, 2-hydr0xyetyl, 2-meth0xyethyl, 2-eth0xyethyl, 3-hydr0xypr0pyl, tetrahydro- furan—3-yl, (tetrahydrofilranyl)methyl, 3-(tert-butoxycarb0nyl)amino)pr0pyl, 3- morpholinopropyl, 4-m0rpholin0butyl, l-methylm0rpholinopropyl, 3-(2,6- dimethylmorpholino)pr0pyl, 3-(4-methylpiperazin-l-yl)propyl, ylpiperidinyl, l- methylpyrrolidin—3-yl, 2-methoxy—l-methylethyl, l-(methoxymethyl)pr0pyl, 2-ethoxy—l- W0 93095 44 (ethoxymethyl)ethyl, 2-methoxybutyl, 2-methoxy- l -(methoxymethyl)ethyl, 3 -( l H-pyrrol- l - yl)propyl, 3 -( l H-imidazo l- l -yl)propyl, 2-( l H-pyrrol- l -yl)ethyl, (l -methylnitro- l H- imidazo l-5 -yl)methyl, l -benzylpyrro lidin-3 -yl, l -butoxycarbonyl)pyrrolidin-3 -yl, 2- [(6- chloropyridin-3 -yl)oxy] ethyl, 2- [3-(methoxymethyl)phenoxy] ethyl, 2-(3 - carbamoylphenoxy)ethyl, 3-(pyridinylamino)propyl, 3 - [( 1 -methyl- 1 H-pyrazol-5 - yl)amino]propyl, 3 - [(5 -methylisoxazo l-3 -yl)amino ]propyl, 2-phenoxyethyl, phenyl, and .
In some embodiments, Rb is selected from H, C1-C6 alkyl and C1-C6 alkyl substituted with Cl-C6 alkoxy, e.g. H, Cl-C6 alkyl and Cl-C6 alkyl substituted with Cl-C4 alkoxy, or with Cl-C3 alkoxy, such as y or ethoxy. For example, Rb may be selected from H, Cl-C6 alkyl, such as Cl-C4 alkyl, or Cl-C3 alkyl, in particular methyl; and Cl-C6 alkyl, such as C1- C4 alkyl, or Cl-C3 alkyl, in particular ethyl, substituted with Cl-C6 alkoxy, e. g. with Cl-C4 alkoxy, or with Cl-C3 alkoxy, e.g. y or ethoxy.
In some embodiments, Rb is selected from Cl-C6 alkyl and C1-C6 alkyl substituted with C1- C6 alkoxy, e.g. H, Cl-C6 alkyl and Cl-C6 alkyl substituted with Cl-C4 alkoxy, or with C1- C3 alkoxy, such as methoxy or ethoxy. For example, Rb may be selected from H, Cl-C6 al- kyl, such as Cl-C4 alkyl, or Cl-C3 alkyl, in particular methyl; and Cl-C6 alkyl, such as C1- C4 alkyl, or Cl-C3 alkyl, in particular ethyl, substituted with Cl-C6 alkoxy, e. g. with Cl-C4 alkoxy, or with Cl-C3 alkoxy, e.g. methoxy or ethoxy.
In some embodiments, Rb is selected from H and C1-C6 alkyl substituted with C1-C6 alkoxy; e. g. H and Cl-C6 alkyl tuted with C1-C4 alkoxy or with Cl-C3 alkoxy, such as meth- oxy or ethoxy. For example, Rb may be selected from H and Cl-C6 alkyl, such as Cl-C4 alkyl, or Cl-C3 alkyl, e.g. ethyl, substituted with Cl-C6 alkoxy, e.g. with Cl-C4 , or with Cl-C3 alkoxy, e.g. methoxy or ethoxy. In these embodiments, the alkyl moiety may be substituted either by one or by several alkoxy moieties, e.g. 1 or 2 alkoxy moieites. Thus, Rb e. g. may be selected from C2-C5 alkyl, e. g. C2-C4 alkyl, substituted by 1 or 2 methoxy or ethoxy groups, such as in 2-methoxyethyl, oxypropanyl, l-methoxybutanyl, 2- ybutyl, l,3-dimethoxypropanyl, l,3-diethoxypropanyl, etc.
In some ments, Rb is selected from H and C1-C6 alkyl substituted with hydroxy. For example, Rb may be selected from H and Cl-C6 alkyl, e.g. C2-C6 alkyl, such as C2-C5 alkyl, or C2-C4 alkyl, e. g. ethyl or propyl, substituted with one or l hydroxy groups, e. g. l or 45 2012/076836 2 hydroxy groups, in particular 1 hydroxy group. In some ments, Rb is hydroxy-Cl-C6 alkyl, such as hydroxy-C2-C6 alkyl, or y-C2-C5 alkyl, e.g. y-C2-C4 alkyl, such as hydroxyethyl or hydroxypropyl.
In some embodiments, Rb is as defined herein above, but is not H.
For example, Rb may be selected from, Cl-C6 alkyl and Cl-C6 alkyl substituted with Cl-C6 alkoxy, e. g. Cl-C6 alkyl and Cl-C6 alkyl substituted with Cl-C4 alkoxy, or with Cl-C3 alkoxy, such as methoxy or ethoxy. In particular, Rb may be ed from Cl-C6 alkyl, such as Cl-C4 alkyl, or Cl-C3 alkyl, in particular methyl; and Cl-C6 alkyl, such as Cl-C4 alkyl, or Cl-C3 alkyl, in particular ethyl, substituted with Cl-C6 alkoxy, e. g. with Cl-C4 alkoxy, or with C1-C3 alkoxy, e.g. methoxy or ethoxy.
In a compound of formula (I), each R6 is independently selected from hydroxy; Cl-C6 alkoxy; hydroxy-Cl-C6 alkoxy; C1-C6 alkylcarbonyloxy; Cl-C6 alkoxycarbonyloxy; 5- or 6- membered carbocyclylcarbonyl or heterocyclylcarbonyl; amino; secondary or ry C 1 -C6 alkylamino; secondary or tertiary hydroxy-Cl-C6 alkylamino; 5- or 6-membered cyclic amino optionally containing at least one further heteroatom in the ring and wherein the ring is optionally substituted with at least one Cl-C6 alkyl; Cl-C6 alkylcarbonylamino; Cl-C6 alkoxycarbonylamino; (C 1 -C6 alkoxycarbonyl)(C 1 -C6 alkyl)amino; (C 1 -C6 alkoxycarbon— yl)(5- or 6-membered carbocyclyl or cyclyl)amino; (Cl-C6 alkylcarbonyl)(Cl-C6 alkyl )amino; carbamoyl; secondary or tertiary Cl-C6 alkylamido wherein any alkyl is optional- ly substituted by OH or CONHZ; 5- or 6-membered carbocyclyl— or heterocyclylcarbamoyl; 5- or 6-membered cyclic aminocarbonyl, ally containing at least one further heteroatom in the ring, and wherein the ring is optionally substituted with at least one Cl-C6 alkyl; 5-or membered carbocyclylamino or heterocyclylamino; and 5-or 6-membered carbocyclyloxy or heterocyclyloxy; n any alkyl is optionally substituted with at least one halogen and any 5- or 6-membered carbocyclyl or heterocyclyl is optionally substituted with at least one R8.
In some embodiments, each R6 is independently selected from hydroxy; Cl-C6 alkoxy; hy- droxy-C 1 -C6 alkoxy; C 1 -C6 alkylcarbonyloxy; C 1 -C6 alkoxycarbonyloxy; 5- or 6-membered carbocyclylcarbonyl or heterocyclylcarbonyl; amino; ary or tertiary Cl-C6 alkylamino; ary or tertiary y-Cl-C6 mino; 5- or 6-membered cyclic amino optionally containing at least one fiarther heteroatom in the ring and wherein the ring is optionally substi- tuted with at least one Cl-C6 alkyl; Cl-C6 alkylcarbonylamino; Cl-C6 alkoxycarbonyla- W0 2013/093095 46 mino; (C1-C6 alkoxycarbonyl)(Cl-C6 alkyl)amino; (Cl-C6 alkoxycarbonyl)(5- or 6- membered carbocyclyl or heterocyclyl)amino; (C 1 -C6 arbonyl)(C 1 -C6 alkyl)amino; oyl; secondary or tertiary C1-C6 alkylamido wherein any alkyl is optionally substitut- ed by OH or CONHZ; 5- or 6-membered carbocyclyl- or heterocyclylcarbamoyl; and 5- or 6- membered cyclic aminocarbonyl, optionally containing at least one further heteroatom in the ring, and wherein the ring is ally substituted with at least one Cl-C6 alkyl; wherein any alkyl is optionally substituted with at least one halogen and any 5- or 6-membered carbocyclyl or heterocyclyl is optionally substituted with at least one R8.
In some embodiments, each R6 is independently selected from hydroxy; Cl-C6 alkoxy; hy- droxy—C 1 -C6 alkoxy; C 1 -C6 alkylcarbonyloxy; C 1 -C6 alkoxycarbonyloxy; benzoyl wherein the phenyl is optionally tuted with at least one R8; amino; secondary or tertiary Cl-C6 alkylamino; secondary or ry hydroxy-Cl-C6 alkylamino; 5- or 6-membered cyclic amino optionally containing at least one further heteroatom in the ring and wherein the ring is optionally substituted with at least one Cl-C6 alkyl; Cl-C6 alkylcarbonylamino; Cl-C6 alkoxycarbonylamino; (C 1 -C6 alkoxycarbonyl)(C 1 -C6 alkyl)amino; (C 1 -C6 alkoxycarbon— yl)(phenyl)amino n the phenyl is optionally substituted with at least one R8; (Cl-C6 arbonyl)(C 1 -C6 alkyl)amino; carbamoyl; secondary or tertiary C 1 -C6 alkylamido wherein any alkyl is optionally substituted by OH or CONHZ; phenylcarbamoyl wherein the phenyl is optionally substituted with at least one R8 ; and 5- or 6-membered cyclic aminocar- bonyl, optionally containing at least one r atom in the ring, and wherein the ring is optionally substituted with at least one Cl-C6 alkyl; wherein any alkyl is optionally substit- ued with at least one halogen.
In some embodiments, each R6 is independently selected from carbamoyl, amino, secondary or tertiary Cl-C6 alkylamino; secondary or tertiary hydroxy-Cl-C6 mino; 5- or 6- ed cyclic amino optionally containing at least one fiarther heteroatom in the ring and wherein the ring is optionally substituted with at least one Cl-C6 alkyl; hydroxy; Cl-C6 alkoxy; hydroxy-C 1 -C6 alkoxy, C 1 -C6 carbonylamino, (C 1 -C6 alkoxycarbonyl)(C l - C6 alkyl)amino, and Cl-C6 alkoxycarbonyloxy.
In some other embodiments, each R6 is independently selected from hydroxy; Cl-C6 alkoxy; hydroxy-Cl-C6 alkoxy; carbamoyl, secondary or tertiary Cl-C6 alkylamino; secondary or tertiary hydroxy-Cl-C6 alkylamino; and 5- or ered cyclic amino optionally contain- 47 2012/076836 ing at least one further heteroatom in the ring and n the ring is optionally substituted with at least one Cl-C6 alkyl.
In some embodiments, each R6 is hydroxy.
In some other embodiments, each R6 is independently selected from Cl-C6 alkoxy, e. g. C1- C3 alkoxy; and 5- or 6-membered cyclic amino optionally containing at least one further het- m in the ring and wherein the ring is optionally substituted with at least one, e.g. l or 2, e. g. l, tuent selected from Cl-C6 alkyl, e.g. at least one C1-C3 alkyl. Examples of such cyclic amino groups are morpholinyl and piperazinyl.
In some other embodiments, each R6 is ed from Cl-C6 alkylcarbonyloxy, 5- or 6- membered carbocyclylcarbonyl or heterocyclylcarbonyl; C 1 -C6 alkylcarbonylamino; C 1 -C6 alkoxy; C 1 -C6 alkoxycarbonylamino; (C 1 -C6 alkoxycarbonyl)(C 1 -C6 alkyl)amino; C 1 -C6 alkoxycarbonyloxy; and 5- or ered cyclic amino optionally containing at least one further heteroatom in the ring and wherein the ring is optionally substituted with at least one C1-C6 alkyl.
In one embodiment, each R6 is independently selected from hydroxy; Cl-C6 alkoxy; 5- or 6- membered cyclic amino optionally containing at least one further heteroatom in the ring and wherein the ring is optionally substituted with at least one Cl-C6 alkyl.
In another embodiment, each R6 is independently selected from y; Cl-C6 alkoxy; 5- or 6-membered cyclic amino optionally containing at least one further heteroatom in the ring and n the ring is optionally substituted with at least one Cl-C6 alkyl; Cl-C6 alkoxycar- bonylamino; 5-ormembered carbocyclylamino or heterocyclylamino; and 5-or 6-membered carbocyclyloxy or heterocyclyloxy.
In some embodiments, the 5- or 6-membered cyclic amino is morpholinyl, preferably attached to Rb by a bond to the nitrogen atom of the morpholinyl ring. For e, R6 is morpholinyl, preferably attached by the nitrogen atom of the morpholinyl ring, to a Cl-C5 alkyl, e. g. a C2- C5 alkyl, or a C3-C5 alkyl, in particular a C3-C4 alkyl; e.g. Rb is morpholinopropyl or morpholinobutyl.
In some other embodiments, each R6 is independently selected from C1-C6 arbonyla- mino; (Cl-C6 alkylcarbonyl)(Cl-C6 alkyl)amino; secondary or tertiary Cl-C6 alkylamido W0 2013/093095 48 wherein any alkyl is ally substituted by OH or CONHZ; 5- or 6-membered carbocyclyl- or heterocyclylcarbamoyl; and 5- or 6-membered cyclic aminocarbonyl.
In some ments, each R6 is independently selected from Cl-C6 alkoxy, e. g. Cl-C4 alkoxy, or Cl-C3 alkoxy, such as methoxy or ethoxy.
Each R7 and R8 is independently ed from Cl-C6 alkyl; hydroxy—CO-C3 alkyl; Cl-C6 alkoxy-CO-C3 alkyl; Cl-C6 carbonyl; carbocyclyl-C0-C4 alkyl; heterocyclyl-CO-C4 alkyl; Cl-C6 alkylsulfinyl; amino; nitro; Cl-C6 secondary or tertiary amino; halogen; car- bamoyl; secondary or tertiary Cl-C6 alkylamido-CO-C3 alkyl; Cl-C6 alkylcarbonylamino; and 5- or 6-membered cyclic amino, optionally containing at least one fiarther heteroatom in the ring and wherein the ring is ally substituted with at least one Cl-C6 alkyl; wherein any alkyl is optionally substituted with at least one halogen; wherein any carbocyclyl and het- erocyclyl is 5- or 6- membered.
In some embodiments, each R7 and R8 is independently ed from Cl-C6 alkyl, such as Cl-C4 alkyl, or Cl-C3 alkyl, e.g. methyl; hydroxy-CO-C3 alkyl, such as hydroxy C0-C2 al- kyl, e. g. hydroxy or hydroxymethyl; Cl-C6 alkoxy, such as Cl-C4 alkoxy, or Cl-C3 alkoxy, e. g. methoxy; Cl-C6 alkylsulfinyl, e.g. Cl-C4 alkylsufinyl, such as methylsulfinyl; amino; nitro; Cl-C6 secondary or tertiary amino, such as Cl-C4 secondary or tertiary amino, or Cl- C3 secondary or ry amino, e.g. methylamino or ylamino; halogen, such as F or Cl, e.g. F; carbamoyl; secondary or tertiary Cl-C6 alkylamido-CO-C3 alkyl, such as secondary or tertiary Cl-C4 alkylamido-CO-C3 alkyl, or Cl-C3 alkylamido-CO-C3 alkyl, wherein the C0- C3 alkyl moiety e.g. may be a CO-Cl moiety, or C0 (i.e. a direct bond); Cl-C6 alkylcarbonyl- amino; such as Cl-C4 arbonylamino, or Cl-C3 alkylcarbonylamino; e. g. acetamido; and 5- or 6-membered cyclic amino, optionally ning at least one fiarther heteroatom in the ring and wherein the ring is optionally substituted with at least one Cl-C6 alkyl, such as piperidinyl or morpholinyl optionally substituted with at least one Cl-C6 alkyl; wherein any alkyl is optionally substituted by at least one halogen.
When R7 or R8 is a 5- or 6-membered cyclic amino, optionally ning at least one further heteroatom in the ring, it e.g. may contain one further heteroatom in the ring. When the cyclic amino is substituted with at least one Cl-C6 alkyl it e. g. may be substituted with l, 2 or 3 Cl- C6 alkyl, e.g. one Cl-C6 alkyl, whereby any Cl-C6 alkyl may be e.g. e.g. a Cl-C3 alkyl, such as methyl.
W0 2013/093095 49 In some ments, any R7 and R8 is independently selected from C1-C6 alkyl, such as C1-C4 alkyl, or C1-C3 alkyl, e.g. methyl; hydroxy-CO-C3 alkyl, such as hydroxy C0-C2 al- kyl, e. g. hydroxy or hydroxymethyl; C1-C6 alkoxy, such as C1-C4 alkoxy, or C1-C3 alkoxy, e. g. methoxy; halogen, such as F or Cl, e. g. F; amino, and C1-C6 secondary or tertiary amino, such as C1-C4 secondary or tertiary amino, or C1-C3 secondary or ry amino, e.g. me- thylamino or ylamino.
In some embodiments, any R7 and R8 is independently selected from C1-C6 alkyl, such as C1-C4 alkyl, or C1-C3 alkyl, e.g. methyl; hydroxy-CO-C3 alkyl, such as y C0-C2 al- kyl, e.g. hydroxy or hydroxymethyl; C1-C6 alkoxy, such as C1-C4 alkoxy, or C1-C3 , e.g. methoxy; and halogen, such as F or Cl, e.g. F.
In some embodiments, any R7 and R8 is independently is selected from halogen and C1-C6 alkyl, such as C1-C4 alkyl, or C1-C3 alkyl, e.g. methyl.
In some embodiments, any R7 and R8 is independently is selected from C1-C6 alkyl, such as C1-C4 alkyl, or C1-C3 alkyl, e.g. methyl.
In some embodiments, R7 is absent. In some other embodiments, R8 is absent. In still other embodiments, both R7 and R8 are absent.
In one embodiment, a compound is provided, selected from the compounds according to EX- amples 1-4, 7-21, 24-26, 28-29, 31-35, 37-137, 140-144, 2, or from pharmaceutically acceptable salts thereof.
In one embodiment, a compound is provided, selected from the compounds ing to EX- amples 1-4, 7-21, 24-26, 28-29, 31-35, 38-49, 52-92, 94-111, 4, 136-137, 140, 142- 143, 149-150, 152-232, or from pharmaceutically acceptable salts thereof.
In one embodiment, a compound is provided for use in therapy, selected from any of the above-mentioned compounds, as well as from nds according to Examples 5, 6, 22, 23, 27, 30, 36, 138, 139 and 145, or from pharmaceutically acceptable salts thereof.
In one embodiment, a compound is provided for use in therapy, selected from any of the above-mentioned compounds, as well as from compounds according to Examples 5, 6, 22, 23, 27, 30 and 36, or from pharmaceutically acceptable salts thereof Depending on the process conditions the end products of formula (I) are obtained either in neutral or salt form. Both the free base and the free acid, as well as the salts of these end products are within the scope of the invention. Acid addition salts ofthe inventive compounds may in a manner known per se be transformed into the free base using basic agents such as alkali or by ion exchange. The free base obtained may also form salts with organic or n- ic acids. Alkali addition salts of the inventive compounds may in a manner known per se be transformed into the free acid by using acidic agents such as acid or by ion exchange. The free acid obtained may also form salts with organic or inorganic bases.
In the preparation of acid or base addition salts, preferably such acids or bases are used which form suitably therapeutically acceptable salts. Examples of such acids are hydrohalogen acids, sulfuric acid, oric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, roacetic acid, nic acid, succinic acid, filmaric acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, c acid, c acid, gluconic acid, p- hydroxybenzoic acid, embonic acid, methanesulfonic acid, sulfonic acid, hydroxyethanesulfonic acid, halogenbenzenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid. Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal ides, carbonates, bicarbonates, and the like, and organic bases such as alkoxides, alkyl amides, alkyl and aryl amines, and the like.
Examples of bases useful in preparing salts of the present invention include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, and the like.
Throughout the specification and the appended claims, a given chemical formula or name shall also encompass all salts, hydrates, solvates, N—oxides and prodrug forms thereof Fur- ther, a given chemical formula or name shall encompass all stereoisomeric forms thereof. Ste- reoisomers include enantiomers and diastereomers. Enantiomers can be present in their pure forms, or as racemic (equal) or unequal mixtures of two enantiomers. Diastereomers can be present in their pure forms, or as mixtures of diastereomers. Diastereomers also e geo- metric s, which can be present in their pure cis or trans forms or as mixtures of those.
The term "prodrug forms" means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug.
Reference is made to n and Gilman's, The Pharmacological basis of Therapeutics, 8th ed., -Hill, Int. Ed. 1992, "Biotransformation of Drugs", p. 13-15.
Pharmaceutical formulations are usually prepared by mixing the active substance, i.e. a compound of the invention, or a pharmaceutically acceptable salt f, with conventional ceutical excipients. The formulations can be fiarther 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, es, granules, powders, syrups, suspensions, suppositories or injections. Liquid formulations may be prepared by dissolving or suspending the active substance in water or other le vehicles. Tablets and granules may be coated in a conventional manner.
For clinical use, the nds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral, intravenous or other mode of administration. These ceutical preparations are a further object of the ion.
Usually the amount of active compounds is between 01-95% by weight ofthe preparation, preferably between 02-20% by weight in preparations for parenteral use and preferably between 1 and 50% by weight in preparations for oral stration.
The dose level and frequency of dosage of the specific compound will vary ing on a y of factors including the potency ofthe 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 t 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, intravenous, nasal or pulmonal administration may also be .
In the preparation of pharmaceutical ations 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, ose 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. 52 2012/076836 Soft ne 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 n the active compound in combination with solid powdered ingredients such as lactose, saccharose, ol, 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 ls and a mixture of ethanol, water, glycerol, ene glycol and polyethylene . If desired, such liquid ations 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 t prior to use.
Solutions for parenteral, e.g. intravenous, administration may be prepared as a solution of a nd of the ion 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 ing 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 ation to be reconstituted with a suitable solvent extemporaneously before use.
The compounds of the present invention may also be used or administered in combination with one or more additional therapeutically active agents, e. g. drugs useful in a diagnostic method, profylaxis or treatment of inflammation and inflammatory diseases or cancer. The components may be in the same formulation or in separate formulations for administration simultaneously or sequentially. Examples of combination therapies are, but not limited to; anti cancer therapy (such as gemcitabine, cisplatin, oxaliplatin, epirubicin, rexate, 5- FU, capecitabine, xel, vincristine, irinotecan, doxorubicin, velcade), or anti inflammatory therapy, e.g. with steroids (such as methotrexate, corticosteroids) or non- dal anti-inflammatory drugs / NSAIDs (such as aspirin, ibuprofen, naproxen).
Accordingly, in a further aspect of the invention, there is provided a combination product comprising: (A) a compound of the invention, as defined herein; and (B) r therapeutic agent, e.g. one that is useful in the treatment of, inflammation, in- ory diseases, or cancer; whereby (A) and (B) is ated in admixture with a pharmaceutically acceptable excipient.
Such ation products provide for the administration of a compound of the invention in ction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the inven- tion, and at least one comprises the other therapeutic agent, or may be presented (i.e. formu- lated) as a combined preparation (i.e. presented as a single formulation including a compound ofthe invention and the other eutic agent).
Thus, there is r provided: (1) a pharmaceutical formulation including a compound of the invention, as hereinbefore de- fined, another therapeutic agent, and a pharmaceutically acceptable excipient, e.g. an adju- vant, diluent or carrier; and (2) a kit of parts comprising, as components: (a) a pharmaceutical formulation including a compound of the invention, as d herein, in admixture with a pharmaceutically acceptable excipient, e.g. an adjuvant, diluent or carrier; (b) a pharmaceutical formulation including another therapeutic agent in admixture with a pharmaceutically acceptable excipient, e.g. an adjuvant, t or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other. 54 2012/076836 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.
Furthermore, a pharmaceutical composition is provided, comprising a compound of formula (I) as defined herein, and optionally at least one pharmaceutically acceptable excipient.
Another object of the present invention relates to modulation of P2 levels with the com- pounds of formula (1).
Thus, in one aspect, a compound as defined herein is provided for use in a diagnostic method treatment or profylaxis of a disorder related to or mediated the F-2,6-P2 levels.
In one aspect, a compound as defined herein is provided, for use in a diagnostic method, treatment or profylaxis of cancer, ation or an inflammatory disorder.
The use of a compound as defined herein in the manufacturing of a ment for a diagnos- tic method, treatment or axis of cancer, inflammation or an inflammatory disorder also is provided.
Finally, one object ofthe invention is to provide a method for the profylaxis or treatment of cancer, inflammation or an atory er in a mammal in need of such treatment by administering to said mammal a compound as defined herein.
The invention will now be further illustrated by the ing non-limiting Examples. The specific es below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Without filrther elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the t invention to its filllest 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 prepa- ration ofknown nds. All nces and ations cited herein are hereby incorpo- rated by reference in their entirety.
The compounds of the invention may be prepared according to known methods for those skilled in the art. Other reaction schemes, as well as a variety of different solvents, tempera- tures and other reaction conditions, could be readily devised by those skilled in the art.
W0 2013/093095 55 Substituted benzothiophenes were synthesized according to Scheme 1 as described by Ple et al. (Ple et al., (1988) J. Heterocyclic Chem. 25, 272). Alkylation of substituted thio- phenols with chloroacetone, followed by PPA-mediated cyclization of the ketones gave 5- substituted 3-methylbenzothiophenes.
Scheme 1 a) chloroacetone, K2C03, acetone, reflux b) polyphosphoric acid, benzene Substituted benzofuranes were synthesized from the corresponding phenols in three steps ac- cording to Scheme 2 (Xie et al., (2004) Tetrahedron Lett. 45, 6235-6237). Iodination of the phenols with N-iodosuccinimide followed by allylation with allylbromide gave l-allyloxy iodo-benzenes as intermediates, which were transformed to the tuted benzofuranes by palladium mediated Heck couplings.
SchemeZ or“ {10“ . <10“ . | | eo a) N—iodosuccinimide, p-TsOH, CHzClz, room temperature overnight b) allylbromide, K2C03, THF, reflux, 24 h. c) NBU3, ammonium formate, PdClz, lmetylimidazolium tetra- fluoroborate, 60 oC, overnight.
The preparation of some sulfonyl chlorides was performed by a two step procedure wherein the sulfonylation using SOg/dioxane complex or H2SO4/Acz0 (Graham et al., (1990) J. Med.
Chem. 33, 749-754) was ed by chlorination with POC13 or POClg/PCls. Alternatively, the sulfonylation was done using sulfonic acid (Scheme 3). ing the handling and use of SOg/dioxane-complex see Paquette, Encyclopedia ofReagentsfor c Synthesis and references therein.
Scheme 3 a) SOg/dioxane complex, l,2-dichloroethane, room temperature or stO4/ACZO, EtOAc, room temperature b) POClg, CHzClz, 60 °C or POClg/PCls/CHzClz, room temperature c) chlorosulfonic acid, CHzClz or CHClg, -20 °C to room temperature, ed by 35-50 °C.
A=O or S.
Sulfonyl chlorides of aryl-substituted thiophenes were ed via palladium-mediated Su- zuki couplings followed by sulfonylations using chlorosulfonic acid (Scheme 4).
Scheme 4 Brfl Ar\ /OH / + 3 ? —> Arfl b—> NH Cl OH a) DIPEA, Pd(dppf)C12:CH2Clz, aqueous dioxane, 80 oC overnight b) chlorosulfonic acid, CHClg, 0 °C.
The sulfonamides were, for example, synthesized from sulfonyl chlorides and methyl 4- aminosalicylate according to any of the methods illustrated in Scheme 5, wherein A corre- sponds to s, o, -CR4=CR4- or -CR4=N- ing to the Formula (1).
Scheme 5 o o 0 R10 0 A RO HO A W0 2013/093095 57 a) pyridine, CHzClz, 60 0C b) aqueous dioxane, room temperature c) pyridine, MeCN, tem- perature ranging from room ature to 80 °C.
For some of examples described below, the intermediate acids were obtained by alkaline hy- drolysis of the methyl esters (Scheme 6).
Scheme 6 a) aqueous NaOH, room temperature or 50 0C.
For some ofthe es described below, the desired ester or amide onalities were introduced by ng the corresponding acids with a coupling reagent (1 ,l ’-carbonyl- diimidazole) followed by addition of the appropriate alcohol or amine. Alternatively, the de- sired ester was obtained by esterification using conc. H2SO4 and excess of the alcohol, or Via formation of the intermediate acid chloride which was reacted with the riate alcohol (Scheme 7).
Scheme7 0 0 AL 8 R or JL OH —> a R OR or it R NRbRc R OH + RdOH _,b JOL R ORd i O + ReOH _, R OH RJLORE a) 1,1 ’-carbonyldiimidazole, pyridine, MeCN, room temperature or C b) H2SO4, excess alcohol, 60-80 0C. c) SOClz, MeCN, room temperature.
For some esters containing a basic moiety within the ester group an intermediate alkyl halide was prepared, which was subsequently reacted with an appropriate amine (Scheme 8). For WO 93095 58 amines with low nucleophilicity, the latter reaction was carried out in the presence of i- um iodide.
Scheme8 o o JOL b H0flvx 3—» i + i b R OH n R OHVX —> R R n n a) H2SO4, excess alcohol, 85 0C b) amine, (KI), MeCN at 60-80 0C.
The biaryl compounds (wherein A=S, -CR4=CR4- or -CR4=N-) were prepared by Suzuki cou- plings at 80 0C according to a modified procedure based on the method bed by Jiang et al. (Jiang et al., (2006) Tetrahedron Lett. 47, 197-200) (Scheme 9, step d). The same synthetic procedures should be applicable for biaryl compounds with A=O.
Scheme 9 o@NHZ O O +CI— _</ Br a, bore R10 OZUJZO </ R0@th 1 II A H 0 0 d H 1 N—§—</}Ar RO H o A a) pyridine, CHzClz, 60 0C b) aqueous dioxane, room temperature c) pyridine, MeCN, tem- perature ranging from room temperature to 80 CC d) aryl boronic acid, DIPEA or K2C03, Pd(dppf)Clz:CH2Clz, aqueous dioxane, 80 oC overnight or 145 0C, 900 s using microwave reactor. A=S, -CR4=CR4- or -CR4=N-.
Amine substituted benzothiophene analogues were sized from the corresponding bro- mides following the procedures described by Harris et. al (Harris et al., (2001) Org. Lett 3, 21, 3417-3419) (Scheme 10).
Scheme 10 O O _,a O 9 R10 HN—gflBr II A 1 N‘fi NR1R2 0 RO H o A a) amine, Pd2(dba)3, 2'-(dicyclohexylphosphino)-N,N—dimethyl[l,l'-biphenyl]amine, LiHMDS, THF, 100 0C in a microwave reactor. ent esters were prepared by nucleophilic substitution of the carboxylic acids using alkyl halides as the electrophiles (Scheme ll).
Scheme 11 a) NaHCOg, DMF, NaI, 50 ° C, overnight b) NaHCOg, DMF, room temperature, overnight. es described herein, containing acetylated phenols, were synthesized in 3-5 steps according to Schemes 12 and 13.
Scheme 12 o O o o / X JLd O / 8) followed by b) o 0 C) A 0\\ ll o N OH —> _, s H H2N 0 U N/ 0 ox H Ox a) AczO, ne, MeCN, 70 0C, 2 weeks b) TFA/CHzClz, room temperature, overnight c) ArSOzCl, pyridine, MeCN, room temperature.
W0 2013/093095 60 Scheme 13 80% ),b),C) o d) o. —» d WQ H H2N O o H O\ O 0 e) A \\S// do A/ \o —> S\ \ / ‘N Um O o H A 0% O a) 1,1 ’-carbonyldiimidazole, benzyl alcohol, pyridine, MeCN, 50 CC, ght b) acetyl chlo- ride, DIPEA, MeCN, overnight 0) zClz, room temperature, overnight d) l, pyridine, MeCN, 50 °C, 2 h e) Pd/C, H2, 2 h.
Some ofthe starting materials used for synthesis of aryloxy- and heteroaryloxy substituted esters were prepared according to the methods described by Nilsson et. al (2002) US6465467 and Nilsson et. al. (2000) WO 2000076984.
EXAMPLES NMR spectra were recorded on a Varian Inova 500 instrument equipped with a triple reso- nance probe, a Varian Inova 600 equipped with a triple resonance cold probe or a triple reso- nance probe, or a Bruker DRX400 ed with a QNP probe. All spectra were recorded using the residual solvent proton resonance or tetramethylsilane (TMS) as al standard. ical HPLC was carried out on an Agilent Series 1100 system using either an ACE C8 (3 um, 3.0X50 mm) column with 0.1% TFA in MilliQ water / MeCN as mobile phase (acidic system) or an XTerra (3.5um 3.0x50 mm) column with 10 mM leO NH4HCO3 / MeCN as mobile phase (basic system). Electrospray mass spectrometry (ES-MS) was performed using an Agilent 1100 Series Liquid Chromatograph/Mass Selective Detector (MSD) to obtain the pseudo molecular [M+H]+ ion of the target molecules. Preparative HPLC was performed on a Gilson 306 or Gilson 333 HPLC system using either an ACE C8 (5 um, 21x50 mm) column with 0.1%TFA in MilliQ H20 / MeCN as mobile phase (acidic system), an XTerra Prep MS W0 2013/093095 61 Cl 8 (5 um, 19x50 mm) column with 50 mM pH10 NH4HC03 / MeCN as mobile phase (basic system 1), a GeminiNX Prep MS C18 (5 um, 21x50 mm) column with 50 mM leO NH4HCO3 /MeCN (basic system 2) or an ACE C8 (5 um 21x50 mm) column with 50 mM NH4OAc in water/ MeCN (neutral system). Fractions were ted based on the UV-signal at 220 or 254 nm. Preparative flash chromatography was performed on Merck silica gel 60 00 mesh) or YMC gel 120 A S-l50 um. Accurate masses were measured using an Ag- ilent MSD-TOF connected to an Agilent 1100 HPLC . During the analyses the calibra- tion was checked by two masses and automatically corrected when needed. Spectra were ac- quired in positive electrospray mode. The ed mass range was m/z 100-1100. Profile detection of the mass peaks was used. Microwave reactions were performed with a Personal Chemistry Smith r using 0.5-2 mL or 2-5 mL Smith Process Vials fitted with aluminum caps and septa. The compounds were named using the software ACD Labs 6.0 or 10.0.
Intermediate 1 4-{[(4—Br0m0chlor0thi0phenyl)sulf0nyl] amin0}hydr0xybenz0ic acid A mixture of 4-aminosalicylic acid (0.57 g, 3.7 mmol) and 3-bromochlorothiophene sulfonyl chloride (1 .0 g, 3.4 mmol) in s dioxane (50 mL dioxane, 50 mL water) was stirred at room temperature for 3 days. EtOAc (100 mL) was added. The organic phase was washed with l M HCl (3 x 50 mL), water and brine and then dried with MgSO4, filtered and concentrated. The brown residue was crystallized from MeOH at 50 0C. 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-d6) 8 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, l H) 1126 (br. s., l H) 1139 (br. s., l H). MS (ESI+) m/z 412 [M+H]+.
Intermediate 2 4-({ [5-Chlor0(2,3-dihydr0benz0furanyl)thi0phenyl] sulfonyl}amin0)—2- hydroxybenzoic acid W0 2013/093095 62 S o A mixture of 4- {[(4-bromochlorothiophenyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 1) (150 mg, 0.36 mmol), 2,3-dihydrobenzofuranboronic acid (65 mg, 0.40 mmol), DIPEA (140 mg, 1.1 mmol) and Pd(dppf)C12'CH2C12 (15 mg, 0.018 mmol) in aqueous dioxane (5 mL dioxane, 1 mL water) was heated at 80 0C under N2 atmosphere overnight.
CHzClz (50 mL) followed by 1 M N32C03 (10 mL) were added to the reaction e. The aqueous phase was washed with CHzClz (2 x 50 mL) and then ed with conc. H3PO4.
EtOAc (100 mL) was added. The organic phase was washed with 1 M HCl (2 x 50 mL), water and brine, and dried with MgSO4, filtered and concentrated. The crude product was purified by preparative HPLC (acidic system). The title nd was obtained as a white solid (50 mg, 31%). 1H NMR (500 MHz, CDgOD) 8 ppm 3.24 (t, J=8.67 Hz, 2 H) 4.58 (t, J=8.67 Hz, 2 H) 6.72 (dd, J=8.55, 2.20 Hz, 1 H) 6.76 - 6.81 (m, 2 H) 7.22 (dd, J=8.18, 2.08 Hz, 1 H) 7.33 (d, J=1.46 Hz, 1 H) 7.54 (s, 1 H) 7.78 (d, J=8.79 Hz, 1 H). MS (ESI+) m/z 452 [M+H]+.
Intermediate 3 Methyl 4-{[(4-br0m0ch10r0thienyl)sulf0nyl] amin0}hydr0xybenz0ate A reaction mixture with methyl 4-amino-salicylate (330 mg, 2.0 mmol), 2-chloro bromothiophenesulfonyl chloride (590 mg, 2.0 mmol) and pyridine (1.58 g, 20 mmol) in MeCN (100 mL) was heated at 60 0C for 3 days. After l ofthe solvent under reduced pressure, EtOAc (100 mL) followed by 1 M HCl (100 mL) were added.
The organic phase was washed with 1 M HCl (3 x 100 mL), water and brine, then dried over MgSO4, filtered and trated. The residue was stirred in refluxing MeOH (50 mL). After cooling overnight the white impurity was removed by filtration. The mother-liquid was con- centrated to s giving a solid, which was recrystallized from toluene/heptane. The title W0 2013/093095 63 compound was obtained as a white solid (300 mg, 35%). 1H NMR (500 MHz, CDClg) 8 ppm 3.95 (s, 3 H) 6.69 (dd, J=8.67, 2.32 Hz, 1 H) 6.74 (d, J=2.44 Hz, 1 H) 6.91 (br. s., 1 H) 7.46 (s, 1 H) 7.80 (d, J=8.79 Hz, 1 H) 10.93 (s, 1 H). MS (ESI+) m/z 426 [M+H]+.
Intermediate 4, General Procedure 1 Methyl 4-{[(3-br0mophenyl)sulf0nyl]amin0}hydr0xybenzoate O\‘ /N So 0 OH 0\ A reaction mixture with methyl 4-amino-salicylate (1.3 g, 7.8 mmol), 3- bromobenzenesulfonyl de (2.0 g, 7.8 mmol) and pyridine (1.2 g, 15 mmol) in MeCN (100 mL) was stirred at 80 0C overnight. After removal of the solvent under reduced re, toluene (100 mL) followed by 1 M HCl (100 mL) were added. The organic phase was washed with 1 M HCl (3 x 100 mL), water and brine, then dried over MgSO4, filtered and concentrat- ed to a light brown oil. The crude product was tallized from MeOH/water giving the title compound as white solid (2.4 g, 79%). 1H NMR (500 MHz, CDClg) 8 ppm 3.92 (s, 3 H) 6.64 (dd, J=8.55, 2.20 Hz, 1 H) 6.68 (d, J=2.20 Hz, 1 H) 7.01 (s, 1 H) 7.37 (t, J=7.93 Hz, 1 H) 7.67 - 7.72 (m, 1 H) 7.74 (d, J=8.79 Hz, 1 H) 7.78 - 7.84 (m, 1 H) 8.04 (t, J=1.83 Hz, 1 H) .87 (s, 1 H). MS (ESI+) m/z 386 [M+H]+.
Intermediate 5 Methyl 4-({[3-br0m0(trifluoromethyl)phenyl] sulfonyl}amino)—2-hydr0xybenzoate F O\‘ /N F So 0 OH 0\ A reaction e with methyl 4-amino-salicylate (170 mg, 1.0 mmol), 3-bromo trifluoromethylbenzenesulphonyl chloride (320 mg, 1.0 mmol) and pyridine (156 mg, 2.0 mmol) in MeCN (50 mL) was heated at 70 0C overnight. After removal ofthe solvent under W0 2013/093095 64 d pressure, EtOAc (100 mL) followed by l M K2C03 (50 mL) were added. The organic phase was washed with l M K2C03, l M HCl, water and brine, then dried over MgSO4, fil- tered and concentrated. The residue was recrystallized from refluxing MeOH/water. The title compound was obtained as a white solid (280 mg, 61%). 1H NMR (500 MHz, CDClg) 8 ppm 3.93 (s, 3 H) 6.63 - 6.69 (m, 2 H) 6.92 (s, l H) 7.74 - 7.82 (m, l H) 7.96 (s, l H) 8.04 (s, l H) 8.18 (s, 1 H) 10.90 (s, 1 H). MS (ESI+) m/Z 454 [M+H]+.
Intermediate 6 4-{[(2,5-Dichlor0thi0phenyl)sulf0nyl]amin0}hydr0xybenzoic acid A mixture of 4-amino salicylic acid (1 .16 g, 7.6 mmol) and 2,5-dichlorothiophenesulfonyl chloride (0.95 g, 3.8 mmol) in aqueous dioxane (95 mL dioxane, 5 mL water) was stirred at room temperature for 2 weeks. The pH of the reaction mixture was adjusted to 10 by on of l M Na2C03, and then EtOAc (200 mL) followed by water (100 mL) were added. The aqueous phase was washed with EtOAc (2 x 100 mL) and then the pH was adjusted to 3 by addition of concentrated phosphoric acid. EtOAc (200 mL) was added and the organic phase was washed with l M HCl (3 x 100 mL) and brine, and then dried over MgSO4, filtered and trated. The brown residue was llized from water/MeOH at 60 0C. The precipitate was collected by filtration and dried in vacuum giVing the title compound as a light brown solid (0.58 g, 42%). 1H NMR (500 MHz, CDgOD) 8 ppm 6.67 (dd, , 2.26 Hz, 1 H) 6.70 (d, J=2.26 Hz, 1 H) 7.26 (s, l H) 7.74 (d, J=8.6l Hz, 1 H). MS (ESI+) m/z 368 [M+H]+.
Intermediate 7 4-{[(4,5-Dichlor0thi0phenyl)sulf0nyl]amin0}hydr0xybenzoic acid 0 H \‘ / S S\\ O CI \I The ediate methyl ester was prepared from methyl 4-amino-salicylate (0.84 g, 5 mmol) and 2,3-dichlorothiophenesulfonyl chloride (1 .38 g, 5.5 mmol) according to the General Procedure 1, described in Intermediate 4, using toluene for the extractive workup. The residue was recrystallized fiom refluxing e/heptane, giving the intermediate methyl 4- {[(4,5- dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate as a white solid (0.97 g). A sec- ond crop of 0.6 g was ted from the mother liquid giving a total yield of 82% (1.57 g) of the methyl 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} roxybenzoate. 1H NMR (500 MHz, CDClg) 8 ppm 3.94 (s, 3 H) 6.68 (dd, J=8.67, 2.32 Hz, 1 H) 6.73 (d, J=2.32 Hz, 1 H) 6.83 (br. s., l H) 7.42 (s, l H) 7.79 (d, J=8.67 Hz, 1 H) 10.92 (s, l H). MS (ESI+) m/Z 382 [M+H]+.
The methyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]-amino}hydroxybenzoate (0.6 g, 1.6 mmol) was ved in l M NaOH (10 mL) and stirred at 60 0C for 2 h. The aqueous reaction mixture was washed with CH2C12 (2 x 50 mL) and then acidified with phosphoric acid giving a white precipitate. EtOAc (100 mL) was added. The organic phase was washed with l M HCl (2 x 50 mL), water and brine and then dried over MgSO4, filtered and concentrated. The residue was refluxed in water/MeOH. After cooling, the title compound was collected by fil- tration (white solid, 0.43 g, 1.2 mmol, 75%). 1H NMR (500 MHZ, CDgOD) 8 ppm 6.70 (dd, J=8.55, 2.20 Hz, 1 H) 6.75 (d, J=l.95 Hz, 1 H) 7.52 (s, l H) 7.78 (d, J=8.55 Hz, 1 H). MS (ESI+) m/Z 368 [M+H]+.
Intermediate 8 Methyl 4-{[(5-br0mochloropyridinyl)sulf0nyl] amin0}hydr0xybenzoate B r O\\S/NH \ \\ | O o CI N OH O\ The product was prepared from methyl 4-amino-salicylate (401 mg, 2.4 mmol) and o- 2-chloropyridinesulfonyl chloride (698 mg, 2.4 mmol) according to the General Procedure 1, described in Intermediate 4, using toluene for the extractive workup. The solid collected after recrystallization was refluxed in EtOAc/heptane. After g, a white impurity was removed by filtration. The mother liquid was concentrated to dryness giving the title com- pound as an off-white solid (449 mg, 44%). 1H NMR (600 MHz, DMSO-d6) 8 ppm 3.83 (s, 3 W0 2013/093095 66 H) 6.72 (d, J=2.20 Hz, 1 H) 6.74 (dd, J=8.60, 2.20 Hz, 1 H) 7.69 (d, J=8.60 Hz, 1 H) 8.55 (d, J=2.20 Hz, 1 H) 8.80 (d, J=2.20 Hz, 1 H) 10.59 (s, 1 H) 11.15 (br. s., 1 H). MS (ESI+) m/Z 421 [M+H]+.
Intermediate 9, General Procedure 2 4-{[(5—Bromothiophenyl)sulfonyl]amino}hydroxybenzoic acid O\\ IN 0 s 0 \ OH A mixture of 4-amin0salicylic acid (1 .16 g, 7.6 mmol) and 0thi0phenesulfonyl chloride (1 .0 g, 3.8 mmol) in aqueous e (95 mL e, 5 mL water) was stirred at room temperature for 7 weeks. EtOAc (100 mL) was added. The organic phase was washed with l M HCl (3 x 50 mL), water and brine and then dried over MgSO4, filtered and concen- trated. The brown residue was crystallized from water/MeOH at 60 0C. The precipitate was collected by filtration and dried in vacuum giving the title compound as a light brown solid (0.64 g, 45%). 1H NMR (500 MHz, DMSO-d6) 8 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.l5 Hz, 1 H) 7.52 (d, J=4.l5 Hz, 1 H) 7.70 (d, J=8.79 Hz, 1 H) 11.11 (s, 1 H). MS (ESI+) m/z 378 [M+H]+. ediate 10, General Procedure 3 4-{[(3-Bromobenzyl)sulfonyl] amino}hydroxybenzoic acid 0° ,N o A mixture of methyl 4-aminosalicylate (67 mg, 0.400 mmol), 3-bromobenzylsulfonyl chloride (108 mg, 0.400 mmol) and pyridine (31 mg, 0.400 mmol) in MeCN (2 mL) was stirred at room temperature overnight. The solvent was d and the residue was dissolved in 5 M NaOH (1 mL, 5.0 mmol) and then heated at 60 0C for 30 minutes. The reaction mixture was acidified with cone. H3PO4 and extracted with EtOAc (2 x 3 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated. The residue was stirred in aqueous MeOH (1 mL MeOH, 5 mL water) at 60 0C. After cooling to room tem- re, the solid was collected by filtration and dried in vaccum. The title compound was obtained as a white solid (24 mg, 17%). 1H NMR (500 MHz, CDgOD) 8 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+) m/z 386 [M+H]+.
Intermediate 11 4-{[(4—Br0m0benzyl)sulf0nyl] amin0}hydr0xybenz0ic acid 0‘ ”mo 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 General ure 3, described in Intermediate 10. The title nd was obtained as a white solid (69 mg, 51%). 1H NMR (500 MHz, CDgOD) 8 4.47 (s, 2 H) 6.64 (dd, , 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+) m/z 386 [M+H].
Intermediate 12 4-{[(3-Br0m0phenyl)sulf0nyl] amin0}hydr0xybenz0ic acid O\‘ N 80 o The product was prepared from 4-aminosalicylic acid (0.57 g, 3.7 mmol) and 3- bromobenzenesulfonyl chloride (0.87 g, 3.4 mmol) according to the General Procedure 2, described in Intermediate 9, using a d reaction time (room temperature overnight).
The title compound was obtained as a light brown solid (0.41 g, 32%). 1H NMR (500 MHz, DMSO-d6) 5 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 W0 2013/093095 68 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+) m/Z 372 [M+H]+.
Intermediate 13 hlor0{[3-hydr0xy(methoxycarbonyl)phenyl] oyl}thiophenyl)benzoic acid 0 H CI 8 “S/N \ / \\ O O A reaction mixture containing methyl 4- {[(4-bromochlorothienyl)sulfonyl]amino} hydroxybenzoate (Intermediate 3) (128 mg, 0.30 mmol), 3-carboxyphenylboronic acid (50 mg, 0.30 mmol), DIPEA (155 mg, 1.2 mmol) and Pd(dppf)Clg‘CH2Clz (3 mg, 0.003 mmol) in aqueous dioxane (4 mL dioxane, 0.4 mL water) was heated at 80 0C under N2 atmosphere overnight. EtOAc (5 mL) and 0.5 M N32C03 (5 mL) were added to the reaction mixture. The aqueous phase was washed with EtOAc (2 x 5 mL) and then acidified to pH 3 by addition of cone. H3PO4. EtOAc (5 mL) was added. The organic phase was washed with 1 M H3PO4 (2 x mL) and brine, and then dried with MgSO4, filtered and concentrated giving the title com- pound in 80% purity (85 mg). An analytical sample ofthe crude product (14 mg) was purified by ative HPLC c system) to give the title compound in 100% purity (5.3 mg, 38%). 1H NMR (600 MHz, CDgOD) 8 ppm 3.91 (s, 3 H) 6.76 (dd, J=8.70, 2.20 Hz, 1 H) 6.82 (dd, J=2.20, 0.30 Hz, 1 H) 7.57 (td, J=7.78, 0.50 Hz, 1 H) 7.68 (s, 1 H) 7.73 (ddd, J=7.78, 1.88, 1.18 Hz, 1 H) 7.79 (dd, J=8.70, 0.30 Hz, 1 H) 8.06 (ddd, J=7.78, 1.65, 1.18 Hz, 1 H) 8.14 (ddd, J=1.88, 1.65, 0.50 Hz, 1 H). MS (ESI+) m/z 468 [M+H]+.
Intermediate 14 Methyl 4-[(tert-butoxycarbonyl)amin0]hydr0xybenzoate W0 2013/093095 69 Methyl 4-aminohydroxybenzenecarboxylate (3.0 g, 17.9 mmol) and BOC-anhydride (3.9 g, 17.9 mmol) were mixed neat and stirred at 70 0C for 2 days. The reaction was diluted with toluene and washed with water, 1 M H2S04 and brine. The organic phase was dried over MgSO4, filtered and concentrated. The brown oily residue was recrystallized fiom hep- tane/toluene. The title compound was obtained in 45% yield (2.13 g). 1H NMR (600 MHz, CDgOD) 5 ppm 1.52 (s, 9 H) 3.90 (s, 3 H) 6.90 (dd, J=8.79, 2.20 Hz, 1 H) 7.14 (d, J=2.20 Hz, 1 H) 7.70 (d, J=8.79 Hz, 1 H). MS (ESI+) m/z 268 .
Intermediate 15 3-({[3-Hydr0xy(methoxycarbonyl)phenyl] amin0}sulf0nyl)benzoic acid A mixture of 3-(chlorosulfonyl)benzoic acid (0.50 g, 2.3 mmol) and methyl 4-amino- salicylate (0.38 g, 2.3 mmol) was stirred at 60 0C for 3 days. The reaction was concentrated under reduced pressure. EtOAc and 0.5 M N32C03 were added. The aqueous phase was washed with EtOAc and then acidified with 1 M H3PO4 until pH ~3. EtOAc (100 mL) was added. The organic phase was washed with 1 M H3PO4 and brine, dried over MgSO4, filtered and concentrated to a light brown oil. The t was purified by flash chromatography (sil- ica, 50% hexane in 1% acetic acid). The title compound was ed in 22% yield (180 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 3.88 (s, 3 H) 6.68 (dd, J=8.70, 2.23 Hz, 1 H) 6.71 (dd, J=2.23, 0.31 Hz, 1 H) 7.64 (td, J=7.86, 0.55 Hz, 1 H) 7.69 (dd, J=8.70, 0.31 Hz, 1 H) 8.05 (ddd, J=7.86, 1.96, 1.15 Hz, 1 H) 8.21 =7.86, 1.67, 1.15 Hz, 1 H) 8.48 (ddd, J=1.96, 1.67, 0.55 Hz, 1 H) MS (ESI+) m/Z 352 [M+H]+.
Intermediate 16 4-{[(5'-Flu0r0-2'-hydr0xybiphenylyl)sulf0nyl] amin0}hydr0xybenz0ic acid A mixture of methyl 4- {[(3-bromophenyl)sulfonyl]amino}hydroxybenzoate (Intermediate 4) (1.05 g, 2.7 mmol), 5-fluorohydroxyphenylboronic acid (0.47 g, 3.0 mmol), DIPEA (1.05 g, 8.1 mmol) and Pd(dppf)C12‘CH2C12 (44 mg, 54 umol) in s dioxane (30 mL dioxane, 5 mL water) was heated at 80 0C under N2 atmosphere overnight. Water and EtOAc were added. The organic phase was washed with 1 M HC1 and brine, dried over MgSO4, fil- tered and concentrated. To the residue was added 1 M NaOH (20 mL). The on was stirred at room temperature for 3 h. A spoonful of charcoal was added. The mixture was stirred for 1 h and filtered throught a pad of celite. The mother liquid was washed twice with CH2C12 and acidified with conc. H3PO4. EtOAc was added. The organic phase was washed with 1 M HC1 and brine, dried over MgSO4, filtered and concentrated. The e was re- crystallized from water/MeOH. The title compound was obtained as a white solid (0.77 g, 70%). 1H NMR (600 MHz, CDgOD) 8 ppm 6.68 (dd, J=8.85, 2.14 Hz, 1 H) 6.72 (d, J=1.83 Hz, 1 H) 6.86 - 6.90 (m, 1 H) 6.92 - 6.99 (m, 2 H) 7.56 (t, J=7.78 Hz, 1 H) 7.70 (d, J=8.54 Hz, 1 H) 7.78-7.82 (m, 2 H) 7.81 (d, J=1.83 Hz, 1 H) 8.11 (t, J=1.68 Hz, 1 H). MS (ESI+) m/z 404 [M+H]+.
Intermediate 17 4-({[4-(1,3-Benzodioxol—5-yl)chlor0thienyl] sulfonyl}amino)—2-hydr0xybenzoic acid A mixture of methyl 4-({[4-(1,3-benzodioxolyl)chlorothienyl]sulfonyl}amino) hydroxybenzoate le 158) (62 mg, 0.13 mmol) in 2 ml of 1 M NaOH was d at 60 0C for 6 h. Water and EtzO was added. The aqueous phase was separated and acidified with conc. H3PO4. EtOAc was added. The organic phase was washed with 1 M H3PO4 and brine, dried over MgSO4, filtered and concentrated. The title compound was obtained in 85% yield (52 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 5.99 (s, 2 H) 6.72 (dd, J=8.54, 2.14 Hz, 1 H) 6.78 (d, J=2.14 Hz, 1 H) 6.89 (d, J=8.24 Hz, 1 H) 6.93 - 6.97 (m, 1 H) 6.98 (d, J=1.53 Hz, 1 H) 7.56 (s, 1 H) 7.78 (d, J=8.54 Hz, 1 H). MS (ESI+) m/z 454 [M+H]+.
Intermediate 18 2-Hydr0xy{[(2,4,5—trichlor0thienyl)sulf0nyl] amin0}benzoic acid CI H GIVEoé/N\\O OH Chlorosulfonic acid (285 uL, 4.3 mmol) was added to a solution of 2,3,5-trichlorothiophene (0.72 g, 3.8 mmol) in . After 1 h of stirring at room temperature additional chlorosul— fonic acid (1000 uL, 15.2 mmol) was added to the reaction mixture, which was then heated at reflux for 3 h followed by stirring at room temperature overnigth. The on was quenched by slow on of brine. The product was extracted with CHZClz. The organic phase was dried over MgSO4. Removal of the solvents gave the 2,4,5-trichlorothiophenesulfonyl chloride as a brown oil, which was used in the following step without further ation (0.90 g, 83% yield).
A mixture of methyl 4-aminosalicylate (263 mg, 1.57 mmol), the preformed 2,4,5- trichlorothiophenesulfonyl chloride (450 mg, 1.57 mmol) and ne (0.25 g, 3.1 mmol) in MeCN (7 mL) was heated at 60 0C for 3 days. The solvent was ated, and the crude product was partitioned between water and CHzClz . The organic phase was washed with brine, dried (MgSO4) and evaporated to yield a dark red sticky oil. The crude oil was dis- solved in toluene and washed with l M HCl followed by brine. Evaporation gave crude oily crystals which were tallized from MeOH/water to yield methyl 2-hydroxy {[(2,4,5- trichlorothienyl)sulfonyl]amino}benzoate (257 mg, 39%) as light brown crystals. MS (ESI+) m/Z 416 [M+H]+.
Methyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate (0.26 g, 0.62 mmol) was dissolved in l M NaOH (4 mL). The reaction was stirred at 60°C overnight. A few mL ofwater were added and the reaction mixture was washed with EtzO. The pH was adjust- ed to imately 2 by addition of l M HCl. The formed precipitate was filtered off and dried. The filtrate was extracted with EtOAc and evaporated. The two lots were pooled to yield the title compound in 85% yield (0.21 g). MS (ESI+) m/z 402 [M+H]+.
Intermediate 19 4-{[(2',5'-Diflu0robiphenylyl)sulf0nyl] amin0}hydr0xybenz0ic acid o o, ,H A mixture of methyl 4- {[(3-bromophenyl)sulfonyl]amino}hydroxybenzoate mediate 4) (0.74 g, 2.0 mmol), 2,5-difiuorophenylboronic acid (0.34 g, 2.2 mmol), DIPEA (1.1 g, 8.8 mmol) and Pd(dppf)C12‘CH2C12 (66 mg, 81 umol) in aqueous dioxane (20 mL dioxane, 3 mL water) was heated at 80 0C under N2 atmosphere overnight. Water and EtOAc were added.
The organic phase was washed with 1 M H3PO4, sat. NaHC03 and brine, dried over MgSO4, filtered and concentrated. To the e was added 1 M NaOH (20 mL). The on was stirred at room temperature for 3 h. A spoonful of charcoal was added. The mixture was stirred for 1 h and filtered throught a pad of celite. The mother liquid was washed twice with CHzClz and acidified with conc. H3PO4. EtOAc was added. The organic phase was washed with 1 M H3PO4 and brine, dried over MgSO4, filtered and concentrated. The residue was recrystallized fiom water/MeOH. The title compound was obtained as a white solid (0.54 g, 65%). 1H NMR (600 MHz, CDgOD) 8 ppm 6.66 (d, J=8.85 Hz, 1 H) 6.71 (s, 1 H) 7.09 - 7.30 (m, 3 H) 7.64 (t, J=7.78 Hz, 1 H) 7.70 (d, J=8.54 Hz, 1 H) 7.78 (d, J=7.93 Hz, 1 H) 7.89 (d, J=7.93 Hz, 1 H) 8.02 (s, 1 H). MS (ESI+) m/z 406 [M+H]+.
Intermediate 20 4-({[3-(2,3-Dihydr0benz0furanyl)phenyl]sulfonyl}amino)—2—hydr0xybenzoic acid 00 O“ A mixture of methyl 4- {[(3-bromophenyl)sulfonyl]amino}hydroxybenzoate (Intermediate 4) (0.74 g, 2.0 mmol), 2,3-dihydrobenzofuranboronic acid (0.36 g, 2.2 mmol), DIPEA (1.1 g, 8.8 mmol) and Pd(dppf)C12'CH2C12 (66 mg, 81 umol) in s dioxane (20 mL e, 3 mL water) was heated at 80 0C under N2 atmosphere overnight. Water and EtOAc were add- ed. The organic phase was washed with 1 M H3PO4, sat. NaHC03 and brine, dried over MgSO4, filtered and concentrated. To the residue was added 1 M NaOH (20 mL). The reac- tion was stirred at room temperature for 3 h. A spoonful of charcoal was added. The mixture was stirred for l h and filtered throught a pad of celite. The mother liquid was washed twice with CHzClz and acidified with conc. H3PO4. EtOAc was added. The organic phase was washed with l M H3PO4 and brine, dried over MgSO4, filtered and concentrated. The residue was recrystallized from water/MeOH. The title compound was ed as a white solid. 1H NMR (600 MHz, CDgOD) 8 ppm 3.26 (t, J=8.70 Hz, 2 H) 4.59 (t, J=8.54 Hz, 2 H) 6.66 (d, J=8.54 Hz, 1 H) 6.73 (s, l H) 6.80 (d, J=8.24 Hz, 1 H) 7.31 (d, J=8.24 Hz, 1 H) 7.39 (s, l H) 7.54 (t, J=7.93 Hz, 1 H) 7.70 (d, J=8.85 Hz, 1 H) .80 (m, 2 H) 7.95 (s, l H). MS (ESI+) m/Z 412 [M+H]+.
Intermediate 21 4-{[(3,5-Dichlor0phenyl)sulf0nyl] amin0}hydr0xybenz0ic acid 00 /H 8‘ O A e of 3,5-dichlorobenzene-sulfonyl chloride (1 .03 g, 4.2 mmol), methyl o- salicylate (0.65 g, 3.9 mmol) and pyridine (0.58 g, 7.3 mmol) was stirred in 50 mL of MeCN at 80 0C overnight. The solvent was removed under reduced presseure. Toluene and l M HCl was added. The organic phase was washed with l M HCl, water and brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in 20 mL of l M NaOH. The reaction mixture was stirred at 60 0C for 2 h. Water and CHzClz was added. The aqueous phase was washed twice with CH2C12. The alkaline solution was ed with orto-phosphoric acid to pH 2-3 giving lots of white precipitate. The precipitate was collected and washed with water.
The title compound was obtained as a white solid (1.11 g, 78%). 1H NMR (600 MHZ, CDgOD) 8 ppm 6.66 (dd, J=8.54, 2.14 Hz, 1 H) 6.69 (d, J=2.14 Hz, 1 H) 7.72 (t, J=l.83 Hz, 1 H) 7.74 (d, J=8.54 Hz, 1 H) 7.77 (d, J=l.83 Hz, 2 H). MS (ESI+) m/z 362 [M+H]+.
Intermediate 22 4-{[(4-Br0m0-2,5-dichlorothiophenyl)sulf0nyl]amin0}hydr0xybenz0ic acid Br O\‘ /N 218% O / \ 8 CI OH A mixture of 4-amino salicylic acid (0.15 g, 1.0 mmol) and 4-bromo-2,5-dichlorothiophene sulfonyl de (0.33 g, 1.0 mmol) in s dioxane (19 mL dioxane, 1 mL water) was stirred at room temperature for 3 weeks. Water (100 mL) and EtOAc (100 mL) were added and the pH was adjusted to about 10 by addition of 1 M N32C03. The aqueous phase was washed with EtOAc (2 x 100 mL) and then the pH was adjusted to about 2 by addition of concentrated phosphoric acid. EtOAc (100 mL) was added and the c phase was washed with 1 M HCl (2 x 50 mL) and brine, and then dried over MgSO4, filtered and concentrated.
The residue was crystallized from water/MeOH. The itate was collected by filtration and dried in vacuum giving the title compound as a light brown solid (60 mg, 13%). 1H NMR (500 MHz, CD3OD) 8 ppm 6.55 - 6.76 (m, 2 H) 7.74 (d, J=8.55 Hz, 1 H). MS (ESI+) m/z 446 [M+H]+.
Intermediate 23 Methyl 4-{[(5—br0m0ch10r0thienyl)sulf0nyl] amin0}hydr0xybenz0ate Chlorosulfonic acid (0.65 g, 5.6 mmol) in CHzClz (10 mL) was added to a cooled solution of 2-bromochlorothiophene (1.00 g, 5.1 mmol) in CHzClz (100 mL). After 20 minutes of stir- ring, additional chlorosulfonic acid (2.3 g, 20 mmol) was added to the reaction mixture, which was then heated at reflux overnight. The reaction was quenched by slow addition of water.
The organic phase was washed with water and brine, dried over MgSO4, filtered and concen- trated. The intermediate 5-bromochlorothiophenesulfonyl chloride was obtained as a light green solid which was used in the following step without filrther purification (1.2 g, 80%). 1H NMR (600 MHz, CDClg) 5 ppm 7.68 (s, 1 H).
W0 2013/093095 75 2012/076836 A reaction mixture with methyl 4-amino-salicylate (0.46 g, 2.8 mmol), 5-bromo chlorothiophenesulfonyl de (0.68 g, 2.3 mmol) and pyridine (0.36 g, 4.6 mmol) in MeCN (50 mL) was heated at 60 0C for 5 days. EtOAc and water was added. The organic phase was washed with 1 M H3PO4 and brine, dried over MgSO4, filtered and concentrated.
The residue was recrystallized from water/MeCN. The title compound was obtained in 61% yield (0.60 g). 1H NMR (600 MHz, CDC13) 8 ppm 3.95 (s, 3 H) 6.69 (dd, J=8.70, 2.29 Hz, 1 H) 6.74 (d, J=2.14 Hz, 1 H) 6.83 (br. s., 1 H) 7.41 (s, 1 H) 7.80 (d, J=8.54 Hz, 1 H) 10.93 (s, 1 H). MS (ESI+) m/z 426 [M+H]+.
Intermediate 24 4-({[5-Chlor0(5-fluor0hydroxyphenyl)thienyl] sulfonyl}amin0)hydr0xybenzoic acid S st/N ‘ O OH OH A reaction e containing methyl 4-({[5-chloro(5-fluorohydroxyphenyl) thienyl]sulfonyl}amino)hydroxybenzoate (Example 157) (3.2 g, 7.1 mmol) in 30 mL of 1 M NaOH was stirred at room temperature for 3 days. Conc. H3PO4 was added until acidic followed by EtOAc. The organic phase was washed with 1 M H3PO4 and brine, dried over MgSO4, filtered and concentrated. The residue was recrystallized from water/MeOH. The title compound was obtained in 79% yield (2.5 g). 1H NMR (600 MHz, CDgOD) 8 ppm 6.72 (dd, J: 8.85, 2.14 Hz, 1 H) 6.78 (d, J=2.14 Hz, 1 H) 6.87 (dd, J=9.00, 4.73 Hz, 1 H) 6.94 - 6.99 (m, 1 H) 7.01 (dd, J=9.15, 3.05 Hz, 1 H) 7.64 (s, 1 H) 7.77 (d, J=8.54 Hz, 1 H). MS (ESI+) m/z 444 .
Intermediate 25 3-Br0m0pr0pyl 4-{[(5'-flu0r0-2'-hydr0xybiphenylyl)sulf0nyl] amin0} hydroxybenzoate 00 /N OS\\ O OH O\/\/BIr A mixture of 4- {[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 16) (60 mg, 0.15 mmol), conc. H2S04 (15 uL) and 3-bromopropan—l-ol (0.60 mL) was heated at 85 0C overnight. The on mixture was diluted with MeCN and purified by preparative HPLC (acidid system). The title compound was ed in 62% yield (48 mg). MS (ESI+) m/Z 524 [M+H]+.
Intermediate 26 3-Br0m0pr0pyl 4-({[5-chlor0(5-fluor0hydroxyphenyl)thienyl]sulfonyl}amin0)—2- hydroxybenzoate S COS/N \ I 0m OH O\/\/Br A mixture of 4-({[5-chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoic acid (Intermediate 24) (42 mg, 0.095 mmol), conc. H2S04 (20 uL) and 3- ropan—ol (0.40 mL) was heated at 85 0C overnight. The reaction mixture was diluted with MeCN and d by preparative HPLC (acidid system). The title product was obtained in 60% yield (32 mg). MS (1351+) m/Z 564 [M+H]+.
Intermediate 27 4-{[(5-Chlor0phenylthienyl)sulf0nyl]amin0}hydr0xybenzoic acid W0 2013/093095 77 A e of 4- {[(4-bromochlorothiophenyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 1) (0.70 g, 1.7 mmol), phenylboronic acid (0.31 g, 2.5 mmol), sodium carbonate (0.5 M (aq), 0.90 g) and Pd(dppf)C12'CH2C12 (0.11 g, 0.14 mmol) in aqueous dioxane (35 mL dioxane, 3.5 ml water) was stirred at 80 0C overnight. The reaction mixture was trated.
The residue was slurried in water and filtered. Conc. HC1 was added to the e until acidic.
The precipitate was collected by filtration. The crude product was purified by preparative HPLC (acidic system). The title compound was obtained in 16% yield (0.11 g). 1H NMR (600 MHz, CDgOD) 8 ppm 6.73 (dd, , 2.14 Hz, 1 H) 6.79 (d, J=2.14 Hz, 1 H) 7.37-7.41 (m, 1 H) 7.42-7.46 (m, 2 H) 7.47 - 7.50 (m, 2 H) 7.61 (s, 1 H) 7.78 (d, J=8.85 Hz, 1 H). MS (ESI+) m/Z 410 [M+H]+.
Intermediate 28 4-({[5-Chlor0(3-flu0r0phenyl)—2-thienyl]sulfonyl}amino)—2-hydr0xybenzoic acid A mixture of 4- {[(4-bromochlorothiophenyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 1) (0.50 g, 1.2 mmol), 3-fiuorophenylboronic acid (0.24 g, 1.7 mmol), sodium carbonate (0.5 M (aq), 0.64 g) and Pd(dppf)C12'CH2C12 (0.079 g, 0.097 mmol) in aqueous dioxane (25 mL dioxane, 3 ml water) was stirred at 80 0C overnight. Conc. HCl was added until acidic. The reaction mixture was concentrated, redissolved in MeOH and filtered. The crude product was purified by preparative HPLC (acidic system). The title compound was obtained in 32% yield (0.17 g). 1H NMR (600 MHz, CDgOD) 8 ppm 6.73 (dd, J=8.54, 2.14 Hz, 1 H) 6.79 (d, J: 2.14 Hz, 1 H) 7.15 (td, J=8.32, 1.98 Hz, 1 H) 7.28 (dt, J=9.84, 2.10 Hz, 1 H) 7.31 (d, J=7.93 Hz, 1 H) 7.47 (td, J=8.09, 6.10 Hz, 1 H) 7.64 (s, 1 H) 7.78 (d, J=8.54 Hz, 1 H). MS (ESI+) m/Z 428 .
Intermediate 29 4-({[5-Chlor0(2-flu0r0meth0xyphenyl)—2-thienyl] sulfonyl}amin0) hydroxybenzoic acid s OoS/N \ 0 OH OH A mixture of 4- {[(4-bromochlorothiophenyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 1) (0.70 g, 1.7 mmol), 2-fluoromethoxyphenylboronic acid (0.35 g, 2.1 mmol), sodium ate (0.5 M (aq), 0.90 g) and Pd(dppf)C12'CH2C12 (0.11 g, 0.14 mmol) in aqueous dioxane (35 mL dioxane, 3.5 ml water) was stirred at 80 0C overnight. Water (50 mL) was added and the reaction mixture was filtered. The filtrate was acidified with cone.
HCl. The precipitate was collected by filtration and washed with water. The solid was dis- solved in MeOH and filtered through a plug of silica with 10% MeOH (aq) as eluent. The most pure fractions were evaporated and the residue filtered h a plug of silica using 5% MeOH in CH2C12 as eluent. The most pure fractions were evaporated and the residue recrys- tallized from CHzClz. The title nd was obtained in 29% yield (0.23 g). 1H NMR (600 MHz, CDgOD) 8 ppm 3.89 (s, 3 H) 6.71 (dd, J=8.55, 2.14 Hz, 1 H) 6.77 (d, J=2.14 Hz, 1 H) 6.89 - 6.93 (m, 1 H) 7.12 - 7.19 (m, 2 H) 7.53 (d, J=1.22 Hz, 1 H) 7.77 (d, J=8.54 Hz, 1 H).
MS (ESI+) m/Z 458 [M+H]+.
Example 1 Methyl 4-({[5-chlor0(3-flu0r0hydr0xyphenyl)—2-thienyl]sulfonyl}amin0)—2- hydroxybenzoate O H \/‘5 A solution of 4- {[(4-bromochlorothiophenyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 1) (40 mg, 0.097 mmol) in dioxane (2 mL) was added to a mixture of (3-fluoro- 4-hydroxyphenyl)boronic acid (24 mg, 0.15 mmol), K2C03 (40 mg, 0.29 mmol) and Pd(dppf)C12:CH2C12 (8 mg, 0.0097 mmol). Water (0.5 mL) was added and the on mix- ture was heated for 900 s at 145 CC in a microwave r. The reaction mixture was diluted with EtOAc. The organic phase was washed with 1 M HCl, dried and concentrated to give the crude 4-( {[5 -chloro(3-fluorohydroxyphenyl)thiophenyl]sulfonyl} amino) hydroxybenzoic acid.
H2S04 (500 uL) was added to a solution of the crude 4-({[5-chloro(3-fluoro hydroxyphenyl)thiophenyl]sulfonyl}amino)hydroxybenzoic acid (43 mg, 0.096 mmol) in dry MeOH (20 mL). The mixture was d for 24 h .The reaction mixture was diluted with EtOAc and the organic phase was washed with water, dried and concentrated. The crude product was purified by preparative HPLC (acidic system). The fractions were neutralized with aqueous NH4OAc (sat) before evaporation. The residue was dissolved in EtOAc. The organic solution was washed with diluted HCl to remove the salts, dried and concentrated.
The title compound was obtained in 24% yield (10.6 mg). 1H NMR (500 MHz, DMSO-d6) 8 ppm 3.83 (s, 3 H) 6.74 - 6.81 (m, 2 H) 7.03 (dd, , 8.42 Hz, 1 H) 7.22 (dd, J=8.42, 2.20 Hz, 1 H) 7.40 (dd, J=12.27, 2.20 Hz, 1 H) 7.71 (d, J=8.54 Hz, 1 H) 7.78 (s, 1 H) 10.26 (s, 1 H) 10.60 (s, 1 H) 11.21 (br. s., 1 H). MS (ESI+) m/z 458 .
Example 2 Methyl 4-({[5-chlor0(2,3-dihydr0benz0furanyl)thienyl]sulfonyl}amin0)—2- hydroxybenzoate W0 2013/093095 80 H2S04 (10 uL) was added to a solution of 4-({[5-chloro(2,3-dihydrobenzofuran yl)thiophenyl]sulfonyl}amino)hydroxybenzoic acid (Intermediate 2) (9.5 mg, 0.021 mmol) in MeOH (1 mL). The reaction mixture was heated at 60 CC for 2 days. After cooling to room temperature, the mixture was diluted using THF (250 uL) and water (100 uL). The crude product was d by preparative HPLC (acidic system). The title compound was obtained as a white solid (7.1 mg, 73%). 1H NMR (500 MHz, CDClg) 8 ppm 3.26 (t, J=8.79 Hz, 2 H) 3.93 (s, 3 H) 4.63 (t, J=8.79 Hz, 2 H) 6.71 (dd, J=8.67, 2.32 Hz, 1 H) 6.76 (d, J=2.20 Hz, 1 H) 6.84 (d, J=8.30 Hz, 1 H) 6.88 (s, 1 H) 7.22 (dd, J=8.30, 1.95 Hz, 1 H) 7.29 - 7.33 (m, 1 H) 7.55 (s, 1 H) 7.79 (d, J=8.79 Hz, 1 H) 10.91 (s, 1 H). MS (ESI+) m/Z 466 [M+H]+.
Example 3 Methyl 4-{[(4-br0m0-2,5-dichlor0thienyl)sulf0nyl] amin0}hydr0xybenzoate o N O Br S\\ O O\ /\ OH CI CI A on mixture with methyl 4-amino-salicylate (463 mg, 2.77 mmol), 4-bromo-2,5- dichlorothiophenesulfonyl chloride (913 mg, 2.76 mmol) and pyridine (450 uL, 5.58 mmol) in MeCN (20 mL) was d at room temperature for 5 days. After l ofthe solvent under reduced pressure, the residue was dissolved in EtOAc. The organic phase was washed with 2 M HCl twice, water twice and brine, and then dried over MgSO4, filtered and concentrated. The crude product was recrystallized from MeOH (45 mL)/water (20 mL) giv- ing the product as a white solid, which was purified filrther by refluxing in MeOH for 3 h.
The white solid was ted, washed with MeOH and then with heptane. The title com- pound was obtained as a white solid (0.54 g, 42%). 1H NMR (500 MHz, DMSO-d6) 8 ppm 3.83 (s, 3 H) 6.62 - 6.70 (m, 2 H) 7.69 (d, J=8.55 Hz, 1 H) 10.63 (s, 1 H) 11.60 (br. s., 1 H).
MS (ESI+) m/Z 460 [M+H]+.
Example 4 Methyl 4-{[(4-br0m0ch10r0thienyl)sulf0nyl] amin0}hydr0xybenz0ate W0 2013/093095 81 The product was prepared from methyl 4-amino-salicylate (330 mg, 2.0 mmol) and 2-chloro- 3-bromothiophenesulfonyl chloride (590 mg, 2.0 mmol) as described for Intermediate 3.
The title compound was obtained as a white solid (300 mg, 35%). 1H NMR (500 MHz, CDClg) 8 ppm 3.95 (s, 3 H) 6.69 (dd, J=8.67, 2.32 Hz, 1 H) 6.74 (d, J=2.44 Hz, 1 H) 6.91 (br. s., 1 H) 7.46 (s, 1 H) 7.80 (d, J=8.79 Hz, 1 H) 10.93 (s, 1 H). MS (ESI+) m/Z 426 [M+H]+.
Example 5 Methyl 4-{[(3-br0mophenyl)sulf0nyl] amin0}hydr0xybenz0ate O\‘ /N 80 o OH 0\ The t was prepared from methyl 4-amino-salicylate (l .3 g, 7.8 mmol) and 3- bromobenzenesulfonyl chloride (2.0 g, 7.8 mmol) as bed for Intermediate 4. The title nd was obtained as a white solid (2.4 g, 79%). 1H NMR (500 MHz, CDClg) 8 ppm 3.92 (s, 3 H) 6.64 (dd, J=8.55, 2.20 Hz, 1 H) 6.68 (d, J=2.20 Hz, 1 H) 7.01 (s, l H) 7.37 (t, J=7.93 Hz, 1 H) 7.67 - 7.72 (m, l H) 7.74 (d, J=8.79 Hz, 1 H) 7.78 - 7.84 (m, l H) 8.04 (t, J=1.83 Hz, 1 H) 10.87 (s, 1 H). MS (ESI+) m/Z 386 [M+H]+.
Example 6 Methyl 4-({[3-br0m0(trifluoromethyl)phenyl] sulfonyl}amino)—2-hydr0xybenzoate W0 2013/093095 82 2012/076836 The product was prepared from methyl 4-amino-salicylate (170 mg, 1.0 mmol) and 3-bromo- uoromethylbenzenesulphonyl chloride (320 mg, 1.0 mmol) as described for Intermedi- ate 5. The title compound was obtained as a white solid (280 mg, 61%). 1H NMR (500 MHz, CDClg) 8 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+) m/z 454 [M+H]+.
Example 7, General Procedure 4 Methyl 4-{[(2-chlor0fluorophenyl)sulf0nyl] amin0}hydr0xybenzoate CI OH O\ A mixture of methyl 4-aminosalicylate (8.5 mg, 0.050 mmol), 2-chlorofluoro- benzenesulfonyl chloride (11.4 mg, 0.050 mmol) and pyridine (8 uL, 0.100 mmol) in MeCN (400 uL) was heated at 55 0C overnight. The reaction mixture was diluted with MeCN/MeOH/water. TFA (50 uL) was added and the crude product was d by prepara- tive HPLC (acidic system). The title compound was obtained in 48% yield (8.6 mg). 1H NMR (500 MHz, CDC13) 8 ppm 3.89 (s, 3 H) 6.61 (dd, J=8.67, 2.32 Hz, 1 H) 6.68 (d, J=2.32 Hz, 1 H) 7.10 (ddd, J=8.87, 7.45, 2.44 Hz, 1 H) 7.20 (br. s., 1 H) 7.23 (dd, J=8.06, 2.44 Hz, 1 H) 7.69 (d, J=8.67 Hz, 1 H) 8.15 (dd, , 5.74 Hz, 1 H) 10.83 (s, 1 H). MS (ESI+) m/z 360 [M+H]+.
Example 8 Methyl 4-{[(3-chlor0methylphenyl)sulf0nyl] amin0}hydr0xybenzoate O\\ /N 8‘ 0 CI ‘0 OH O\ Methyl 4-aminosalicylate (9.1 mg, 0.054 mmol) and 3-chloromethylbenzenesulfonyl chlo- ride (8.4 mg, 0.037 mmol) were allowed to react according to the General Procedure 4, de- scribed in e 7 giVing 15.3 mg of the title compound. 1H NMR (500 MHz, CDClg) 8 W0 2013/093095 83 ppm 2.41 (s, 3 H) 3.91 (s, 3 H) 6.61 — 6.66 (m, 2 H) 6.84 (s, 1 H) 7.33 (d, J=8.06 Hz, 1 H) 7.64 (dd, J=8.06, 1.95 Hz, 1 H) 7.72 (d, J=8.79 Hz, 1 H) 7.85 (d, J=1.95 Hz, 1 H) 10.85 (s, 1 H). MS (ESI+) m/Z 356 [M+H]+.
Example 9 Methyl 4-[(1-benzofuran-Z-ylsulfonyl)amin0]hydr0xybenz0ate The t was prepared from methyl 4-aminosa1icy1ate (9.1 mg, 0.054 mmol) and 1- uransu1fony1 chloride (10.8 mg, 0.050 mmol) according to the General Procedure 4, described in Example 7. The title compound was obtained in 70% yield (12.1 mg). 1H NMR (500 MHz, CDC13) 8 ppm 3.89 (s, 3 H) 6.69 (dd, J=8.67, 2.32 Hz, 1 H) 6.79 (d, J=2.32 Hz, 1 H) 7.20 (br. s., 1 H) 7.32 (ddd, J=7.90, 7.16, 1.04 Hz, 1 H) 7.46 (ddd, J=8.37, 7.16, 1.29 Hz, 1 H) 7.51 (s, 1 H) 7.51 - 7.53 (m, 1 H) 7.66 (ddd, J=7.90, 1.29, 0.70 Hz, 1 H) 7.72 (d, J=8.67 Hz, 1 H) 10.85 (s, 1 H). MS (ESI+) m/Z 348 [M+H]+.
Example 10 Methyl 2-hydr0xy({[2-methyl(triflu0r0methyl)furanyl] sulfonyl}amin0)benz0ate The product was prepared from methyl osa1icy1ate (9.1 mg, 0.054 mo 1) and 2- methy1(trifluoromethy1)fi3ransu1fony1 chloride (12.4 mg, 0.054 mmol) ing to the General Procedure 4, described in Example 7. The title compound was obtained in 67% yield (12.8 mg). 1H NMR (500 MHz, CDC13) 8 ppm 2.59 (s, 3 H) 3.93 (s, 3 H) 6.62 (dd, J=8.67, 2.20 Hz, 1 H) 6.70 (d, J=2.20 Hz, 1 H) 6.90 - 6.92 (m, 1 H) 6.95 (br. s., 1 H) 7.77 (d, J=8.67 Hz, 1 H) 10.90 (s, 1 H). MS (ESI+) m/Z 380 [M+H]+.
W0 2013/093095 84 Example 11 Methyl 4-{[(3-chlor0methylphenyl)sulf0nyl] amin0}hydr0xybenz0ate CI 0 OH O\ The t was prepared from methyl 4-aminosa1icy1ate (9.1 mg, 0.054 mo 1) and 3-chloro- 2-methy1benzenesu1fony1 chloride (11.8 mg, 0.052 mmol) ing to the General Procedure 4, described in Example 7. The title compound was obtained in 70% yield (12.9 mg). 1H NMR (500 MHz, CDC13) 8 ppm 2.73 (s, 3 H) 3.90 (s, 3 H) 6.54 (dd, J=8.67, 2.32 Hz, 1 H) 6.60 (d, J=2.20 Hz, 1 H) 7.08 (s, 1 H) 7.28 (t, J=7.69 Hz, 1 H) 7.59 (dd, J=8.06, 0.98 Hz, 1 H) 7.70 (d, J=8.79 Hz, 1 H) 8.02 (dd, J=8.06, 0.98 Hz, 1 H) 10.85 (s, 1 H). MS (ESI+) m/z 356 [M+H]+.
Example 12 Methyl 4-{[(5-br0m0thienyl)sulfonyl] amin0}hydr0xybenz0ate The product was prepared from methyl 4-aminosa1icy1ate (9.1 mg, 0.054 mo 1) and 5- bromothiophenesu1fony1 de (13.8 mg, 0.053 mrnol) according to the l Proce- dure 4, described in Example 7. The title compound was obtained in 71% yield (14.7 mg). 1H NMR (500 MHz, CDC13) 8 ppm 3.93 (s, 3 H) 6.68 (dd, J=8.67, 2.32 Hz, 1 H) 6.73 (d, J=2.20 Hz, 1 H) 6.98 (s, 1 H) 7.02 (d, J=4.15 Hz, 1 H) 7.40 (d, J=4.15 Hz, 1 H) 7.77 (d, J=8.55 Hz, 1 H) 10.90 (s, 1 H). MS (ESI+) m/Z 392 [M+H]+.
Example 13 Methyl 4-{[(5—chlor0thienyl)sulf0nyl] amin0}hydr0xybenz0ate The product was prepared from methyl osalicylate (9.1 mg, 0.054 mmol) and 5- chlorothiophenesulfonyl chloride (10.9 mg, 0.050 mmol) according to the General Proce- dure 4, described in Example 7. The title compound was obtained in 76% yield (13.2 mg). 1H NMR (500 MHz, CDClg) 8 ppm 3.94 (s, 3 H) 6.68 (dd, J=8.55, 2.20 Hz, 1 H) 6.73 (d, J=2.20 Hz, 1 H) 6.88 (br. S., 1 H) 6.89 (d, J=4.15 Hz, 1 H) 7.44 (d, J=4.15 Hz, 1 H) 7.77 (d, J=8.55 Hz, 1 H) 10.90 (s, 1 H). MS (ESI+) m/Z 348 [M+H]+. e 14 Methyl 4-{[(5-br0mochloropyridinyl)sulf0nyl] amin0}hydr0xybenzoate o\ H \ / S“ O N \ O OH 0\ Br The product was prepared from methyl 4-aminosalicylate (9.1 mg, 0.054 mmol) and 5-bromo- 6-chloropyridinesulfonyl chloride (15.0 mg, 0.051 mmol) according to the General Proce- dure 4, described in Example 7. The title compound was obtained in 41% yield (8.9 mg). 1H NMR (500 MHz, CDClg) 8 ppm 3.75 (s, 3 H) 6.59 (dd, J=8.79, 2.20 Hz, 1 H) 6.65 (d, J=2.20 Hz, 1 H) 7.54 (d, J=8.79 Hz, 1 H) 8.22 (d, J=2.20 Hz, 1 H) 8.59 (d, J=2.20 Hz, 1 H) 10.55 (s, 1 H) 10.66 (s, 1 H). MS (ESI+) m/z 421 [M+H]+.
Example 15 Methyl 2-hydr0xy{[(5-isopr0pyl—3-methyl—1-benz0thienyl)sulf0nyl] amin0}benz0ate W0 2013/093095 86 The 5-isopropylmethylbenzothiophenesulfonyl chloride was prepared according to the following multistep procedure. A mixture of 4-isopropyl-thiophenol (5.0 g, 32.8 mmol), chloroacetone (7.0 mL, 88 mmol) and K2C03 (6.4 g, 46.3 mmol) in acetone (100 mL) was refluxed overnight. More K2C03 (2 g, 14.5 mmol) and chloroacetone (3.5 mL, 43 mmol) were added and the reaction mixture was heated for r 5 h. The on 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 hours (Ple et al., (1988) J. Heterocyclic Chem. 25, 1271-1272). The reaction mixture was diluted with CH2C12 and washed with water. The ed organic phases were dried and the t was evaporated. The crude t was purified on silica using heptane as eluent, giving 4.2 g of -isopropylmethylbenzothiophene as a colorless oil (67% over two steps). 1H NMR (400 MHz, CDC13) 8 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-dichloroethane (10 mL) was cooled on ice and dioxane (610 uL, 7.15 mmol) in 1,2-dichloroethane (1 mL) was added dropwise.
The resulting white e was stirred for 30 s at 0 0C. A solution of 5-isopropyl methylbenzothiophene (420 mg, 2.2 mmol) in 1,2-dichloroethane (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-isopropylmethylbenzothiophenesulfonic acid was collect- ed. 1H NMR (400 MHz, CDgOD) 8 ppm 1.32 (d, J=6.90 Hz, 6 H) 2.64 (s, 3 H) 3.05 (spt, J=6.90 Hz, 1 H) 7.32 (ddd, J=8.34, 1.70, 0.44 Hz, 1 H) 7.61 (dt, J=1.70, 0.70 Hz, 1 H) 7.72 (dd, J=8.34, 0.70 Hz, 1 H).
A mixture of 5-isopropylmethylbenzothiophenesulfonic acid (2.54 g, 9.4 mmol), POC13 (10 mL) and PC15 (4.0 g, 19.2 mmol) in CH2C12 (100 mL) was stirred at room temperature for 2 h. The reaction was quenched by addition of ice and water and stirred for 1 h. The organic phase was separated and dried. 1.74 g yl chloride was obtained as an oil after evapora- tion ofthe solvents. The crude product was purified on silica using CH2C12 as eluent giving 1.46 g (54%) of 5-isopropylmethylbenzothiophenesulfonyl chloride.
The title compound was prepared from methyl 4-aminosalicylate (9.1 mg, 0.054 mmol) and 5- isopropylmethylbenzothiophenesulfonyl chloride (15.4 mg, 0.053 mmol) according to the General Procedure 4, described in e 7. The title compound was obtained in 70% yield (15.5 mg). 1H NMR (500 MHz, CDClg) 8 ppm 1.30 (d, J=6.84 Hz, 6 H) 2.64 (s, 3 H) 3.03 (spt, J=6.84 Hz, 1 H) 3.88 (s, 3 H) 6.70 (dd, J=8.55, 2.20 Hz, 1 H) 6.72 (dd, J=2.20, 0.46 Hz, 1 H) 7.15 (s, 1 H) 7.38 (dd, J=8.42, 1.73 Hz, 1 H) 7.58 (dt, J=1.73, 0.65 Hz, 1 H) 7.70 (dd, J=8.55, 0.46 Hz, 1 H) 7.71 (dd, J=8.42, 0.65 Hz, 1 H) 10.82 (s, 1 H). MS (ESI+) m/z 420 [M+H]+.
Example 16 Methyl 2-hydr0xy({[4-(triflu0r0methyl)phenyl] sulfonyl}amin0)benz0ate The t was prepared from methyl 4-aminosalicylate (9.1 mg, 0.054 mmol) and 4- trifluoromethylbenzenesulfonyl chloride (12.5 mg, 0.051 mmol) according to the General Procedure 4, described in Example 7. The title compound was obtained in 65% yield (12.5 mg). 1H NMR (500 MHz, CDClg) 8 ppm 3.91 (s, 3 H) 6.62 (dd, , 2.32 Hz, 1 H) 6.69 (d, J=2.20 Hz, 1 H) 6.98 (s, 1 H) 7.72 (d, J=8.55 Hz, 1 H) 7.75 (m, 2 H) 8.00 (m, 2 H) 10.87 (s, 1 H). MS (ESI+) m/Z 376 [M+H]+.
Example 17 Methyl 4-{[(3-chlor0fluorophenyl)sulf0nyl] amin0}hydr0xybenz0ate F O\\ N S\\ 0 CI 0 The product was prepared from methyl 4-aminosalicylate (9.1 mg, 0.054 mmol) and 3-chloro- 2-fluorobenzenesulfonyl chloride (11.5 mg, 0.050 mmol) according to the General ure 4, bed in Example 7. The title compound was obtained in 72% yield (13.0 mg). 1H NMR (500 MHz, CDClg) 8 ppm 3.60 (s, 3 H) 6.43 (dd, J=8.67, 2.08 Hz, 1 H) 6.48 (d, J=2.20 Hz, 1 H) 6.98 (td, J=8.06, 0.98 Hz, 1 H) 7.35 (ddd, J=8.12, 6.53, 1.71 Hz, 1 H) 7.36 (d, W0 2013/093095 88 J=8.79 Hz, 1 H) 7.59 (ddd, J=7.87, 6.29, 1.71 Hz, 1 H) 10.48 (s, 1 H) 10.69 (s, 1 H). MS (ESI+) m/Z 360 [M+H]+.
Example 18 Methyl 4-{[(3-chlorophenyl)sulf0nyl] amin0}hydr0xybenz0ate The product was prepared from methyl 4-aminosa1icy1ate (9.1 mg, 0.054 mo 1) and 3- chlorobenzenesulfonyl chloride (11.7 mg, 0.055 mmol) ing to the General Procedure 4, described in Example 7. The title compound was obtained in 75% yield (13.8 mg). 1H NMR (500 MHz, CDC13) 8 ppm 3.91 (s, 3 H) 6.63 (d, J=8.55, 2.20 Hz, 1 H) 6.66 (d, J=2.20 Hz, 1 H) 6.86 (s, 1 H) 7.42 (t, J=7.93 Hz, 1 H) 7.54 (ddd, J=8.06, 2.20, 0.98 Hz, 1 H) 7.73 (d, J=8.55 Hz, 1 H) 7.74 (ddd, J=7.90, 1.71, 0.98 Hz, 1 H) 7.86 (t, J=1.95 Hz, 1 H) 10.86 (s, 1 H). MS (ESI+) m/Z 342 [M+H]+.
Example 19 Methyl 4-{[(2,5-dichlor0phenyl)sulf0nyl] amin0}hydr0xybenzoate O\\S/ N O CICL\‘0 The product was prepared from methyl 4-aminosa1icy1ate (9.1 mg, 0.054 mo 1) and 2,5- dichlorobenzenesulfonyl chloride (12.7 mg, 0.052 mmol) according to the General Procedure 4, described in Example 7. The title compound was obtained in 31% yield (6.0 mg). 1H NMR (500 MHz, CDC13) 8 ppm 3.73 (s, 3 H) 6.56 (dd, , 2.20 Hz, 1 H) 6.61 (d, J=2.20 Hz, 1 H) 7.25 (d, J=8.55 Hz, 1 H) 7.30 (dd, , 2.44 Hz, 1 H) 7.50 (d, J=8.79 Hz, 1 H) 7.98 (d, J=2.44 Hz, 1 H) 10.51 (s, 1 H) 10.63 (s, 1 H). MS (ESI+) m/z 376 .
Example 20 Methyl 4-{[(5-chlor0fluorophenyl)sulf0nyl] amin0}hydr0xybenzoate W0 2013/093095 89 The product was prepared from methyl 4-aminosalicylate (9.1 mg, 0.054 mmol) and 5-chloro- 2-fluorobenzenesulfonyl chloride (16.6 mg, 0.072 mmol) according to the General Procedure 4, described in Example 7. The title compound was obtained in 68% yield (13.3 mg). 1H NMR (500 MHz, CDClg) 8 ppm 3.90 (s, 3 H) 6.66 (dd, J=8.55, 2.20 Hz, 1 H) 6.68 (d, J=2.20 Hz, 1 H) 6.99 (s, 1 H) 7.13 (t, J=9.03 Hz, 1 H) 7.51 (ddd, J=8.85, 4.33, 2.69 Hz, 1 H) 7.72 (d, J=8.55 Hz, 1 H) 7.90 (dd, J=6.10, 2.69 Hz, 1 H) 10.85 (s, 1 H). MS (ESI+) m/z 360 [M+H]+.
Example 21 Methyl 4-{[(5-chlor0-2,4-diflu0r0phenyl)sulf0nyl]amin0}hydr0xybenz0ate So 0 OH 0\ CI The product was ed from methyl 4-aminosalicylate (9.1 mg, 0.054 mmol) and 5-chloro- 2,4-difluorobenzenesulfonyl chloride (16.6 mg, 0.067 mrnol) according to the General Proce- dure 4, described in Example 7. The title compound was ed in 66% yield (13.5 mg). 1H NMR (500 MHz, CDClg) 8 ppm 3.91 (s, 3 H) 6.65 (dd, J=8.55, 2.20 Hz, 1 H) 6.68 (d, J=2.20 Hz, 1 H) 7.03 (dd, J=9.28, 8.30 Hz, 1 H) 7.14 (s, 1 H) 7.73 (d, J=8.79 Hz, 1 H) 8.01 (t, J=7.57 Hz, 1 H) 10.87 (s, 1 H). MS (ESI+) m/Z 378 [M+H]+.
Example 22 Methyl ,5-dichlor0phenyl)sulfonyl] amin0}hydr0xybenzoate W0 2013/093095 90 The product was prepared from methyl 4-aminosalicylate (9.1 mg, 0.054 mmol) and 3,5- dichlorobenzenesulfonyl chloride (15.0 mg, 0.061 mmol) according to the General Procedure 4, described in Example 7. The title compound was obtained in 70% yield (14.2 mg). 1H NMR (500 MHz, CDClg) 8 ppm 3.92 (s, 3 H) 6.65 (dd, J=8.55, 2.20 Hz, 1 H) 6.66 (d, J=2.20 Hz, 1 H) 7.02 (s, 1 H) 7.54 (t, J=1.83 Hz, 1 H) 7.73 (d, J=1.95 Hz, 2 H) 7.76 (d, J=8.55 Hz, 1 H) 10.88 (s, 1 H). MS (ESI+) m/Z 376 [M+H]+.
Example 23 Methyl 4-{[(3-br0mobenzyl)sulf0nyl]amin0}hydr0xybenzoate S o OH O\ The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 3- bromobenzylsulfonyl chloride (13.5 mg, 0.050 mmol) according to the General Procedure 4, described in Example 7. The title compound was obtained in 45% yield (9.1 mg). 1H NMR (500 MHz, DMSO-d6:CD30D 7:1) 5 ppm 3.87 (s, 3 H) 4.61 (s, 2 H) 6.72 (dd, J=8.67, 2.20 Hz, 1 H) 6.74 (d, J=2.20 Hz, 1 H) 7.21 — 7.25 (m, 1 H) 7.30 (td, J=7.69, 0.61 Hz, 1 H) 7.44 (t, J=1.59 Hz, 1 H) 7.51 — 7.55 (m, 1 H) 7.72 (d, J=8.67 Hz, 1 H). MS (ESI+) m/Z 400 [M+H]+.
Example 24 Methyl -br0mobenzyl)sulf0nyl]amin0}hydr0xybenzoate \S/\O\©\( \ O OH 0\ The product was ed from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 4- enzylsulfonyl chloride (13.5 mg, 0.050 mmol) according to the General Procedure 4, described in Example 7. The title nd was obtained in 63% yield (12.7 mg). 1H NMR (500 MHz, 6:CD30D 7:1) 8 ppm 3.87 (s, 3 H) 4.58 (s, 2 H) 6.71 (dd, J=8.55, 2.20 Hz, 1 H) 6.73 (d, J=2.20 Hz, 1 H) 7.16 - 7.20 (m, 2 H) 7.51 - 7.56 (m, 2 H) 7.72 (d, J=8.55 W0 93095 91 Hz, 1 H). MS (ESI+) m/Z 400 [M+H]+.
Example 25 Methyl 4-{[(2,5-dichlor0thienyl)sulf0nyl]amin0}hydr0xybenz0ate o N O AO O\ CI CI The product was prepared from methyl 4-aminosa1icy1ate (12.0 mg, 0.072 mmol) and 2,5- dichlorothiophenesu1fony1 chloride (18.0 mg, 0.072 mmol) according to the General Pro- cedure 4, described in Example 7. The title compound was obtained in 68% yield (18.7 mg). 1H NMR (500 MHz, DMSO-d6:CD30D 6:1) 8 ppm 3.84 (s, 3 H) 6.70 (d, J=2.22 Hz, 1 H) 6.72 (dd, J=8.60, 2.22 Hz, 1 H) 7.39 (s, 1 H) 7.70 (d, J=8.60 Hz, 1 H). MS (ESI+) m/Z 382 [M+H]+.
Example 26 Methyl 0xy{[(4-methylnaphthyl)sulf0nyl] amin0}benz0ate OH O\ The product was prepared from methyl osa1icy1ate (12.0 mg, 0.072 mmol) and 4- methyl—1-naphtha1enesu1fony1 chloride (17.0 mg, 0.071 mmol) according to the General Pro- cedure 4, described in Example 7. The title compound was obtained in 70% yield (18.4 mg). 1H NMR (500 MHz, DMSO-d6CCD30D 6:1) 8 ppm 2.70 (d, J=1.00 Hz, 3 H) 3.77 (s, 3 H) 6.59 (d, J=2.20 Hz, 1 H) 6.61 (dd, J=8.67, 2.20 Hz, 1 H) 7.52 (dq, J=7.57, 1.00 Hz, 1 H) 7.55 (d, J=8.67 Hz, 1 H) 7.68 (ddd, J=8.36, 6.84, 1.28 Hz, 1 H) 7.74 (ddd, J=8.48, 6.84, 1.40 Hz, 1 H) 8.15 (ddd, J=8.36, 1.40, 0.70 Hz, 1 H) 8.21 (d, J=7.57 Hz, 1 H) 8.70 (ddd, J=8.48, 1.28, 0.70 Hz, 1 H). MS (ESI+) m/Z 372 [M+H]+.
Example 27 W0 2013/093095 92 Methyl 4-{[(4,5-dichlor0thienyl)sulf0nyl]amin0}hydr0xybenz0ate The product was ed from methyl 4-aminosa1icy1ate (12.0 mg, 0.072 mmol) and 2,3- dichlorothiophenesu1fony1 chloride (18.0 mg, 0.072 mmol) according to the l Pro- cedure 4, described in Example 7. The title nd was obtained in 60% yield (16.3 mg). 1H NMR (500 MHz, DMSO-d6:CD30D 6:1) 8 ppm 3.84 (s, 3 H) 6.75 (dd, J=2.20, 0.50 Hz, 1 H) 6.77 (dd, J=8.55, 2.20 Hz, 1 H) 7.73 (dd, J=8.55, 0.50 Hz, 1 H) 7.77 (s, 1 H). MS (ESI+) m/Z 382 [M+H]+.
Example 28 Methyl 2-hydr0xy[(1-naphthylsulf0nyl)amin0]benzoate O O\\S/N o O\O\ OH O\ The product was prepared from methyl 4-aminosa1icy1ate (8.5 mg, 0.050 mmol) and 1- naphthalenesulfonyl de (12.0 mg, 0.053 mmol) according to the General Procedure 4, described in Example 7. The title compound was obtained in 78% yield (13.9 mg). 1H NMR (500 MHz, CDC13) 8 ppm 3.87 (s, 3 H) 6.54 (dd, J=8.67, 2.20 Hz, 1 H) 6.57 (d, J=2.20 Hz, 1 H) 7.14 (br. s., 1 H) 7.53 (dd, J=8.25, 7.42 Hz, 1 H) 7.62 (ddd, J=8.19, 6.92, 1.12 Hz, 1 H) 7.61 (d, J=8.67 Hz, 1 H) 7.71 (ddd,J=8.65, 6.92, 1.35 Hz, 1 H) 7.94 (dddd,J=8.19, 1.35, 0.62, 0.62 Hz, 1 H) 8.05 - 8.09 (m, 1 H) 8.34 (dd, J=7.42, 1.27 Hz, 1 H) 8.65 (dddd, J=8.65, 1.12, 0.91, 0.62 Hz, 1 H) 10.77 (s, 1 H). MS (ESI+) m/z 358 [M+H]+.
Example 29 Methyl 4-{[(4-br0m0-2,5-diflu0r0phenyl)sulf0nyl] amin0}hydr0xybenz0ate W0 2013/093095 93 F 8°C F OH O\ The product was prepared from methyl osalicylate (8.5 mg, 0.050 mmol) and 4-bromo- 2,5-difluorobenzenesulphonyl chloride (16.1 mg, 0.055 mmol) according to the General Pro- cedure 4, described in Example 7. The title compound was obtained in 70% yield (14.7 mg). 1H NMR (500 MHz, CDC13) 5 ppm 3.91 (s, 3 H) 6.65 (dd, J=8.67, 2.32 Hz, 1 H) 6.69 (d, J=2.20 Hz, 1 H) 7.18 (br. s., 1 H) 7.43 (dd, J=8.79, 5.13 Hz, 1 H) 7.68 (dd, J=7.02, 6.04 Hz, 1 H) 7.73 (d, J=8.67 Hz, 1 H) 10.86 (s, 1 H). MS (ESI+) m/Z 422 [M+H]+.
Example 30 Methyl 2-hydr0xy{[(3-methylphenyl)sulf0nyl]amin0}benzoate The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 3- toluenesulfonyl de (9.5 mg, 0.050 mmol) according to the General Procedure 4, de- d in Example 7. The title compound was obtained in 88% yield (14.2 mg). 1H NMR (500 MHz, CDC13) 8 ppm 2.39 (s, 3 H) 3.90 (s, 3 H) 6.62 (dd, J=8.67, 2.20 Hz, 1 H) 6.64 (d, J=2.20 Hz, 1 H) 6.79 (br. s., 1 H) 7.34 - 7.39 (m, 2 H) 7.64 - 7.70 (m, 2 H) 7.69 (d, J=8.67 Hz, 1 H) 10.83 (s, 1 H). MS (ESI+) m/z 322 [M+H]+.
Example 31 Methyl 4-({[3-(difluoromethoxy)phenyl] sulfonyl}amino)—2-hydr0xybenzoate W0 2013/093095 94 The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 3- (difluoromethoxy)benzenesulfonyl chloride (12.1 mg, 0.050 mmol) according to the General Procedure 4, described in Example 7. The title compound was obtained in 78% yield (14.6 mg). 1H NMR (500 MHz, CDClg) 8 ppm 3.91 (s, 3 H) 6.52 (t, J=72.63 Hz, 1 H) 6.63 (dd, J=8.67, 2.32 Hz, 1 H) 6.66 (d, J=2.32 Hz, 1 H) 6.80 (br. s., 1 H) 7.31 - 7.35 (m, 1 H) 7.49 (dd, J=8.30, 7.89 Hz, 1 H) 7.62 (dd, , 1.78 Hz, 1 H) 7.71 (ddd,.]=7.89, 1.78, 0.97 Hz, 1 H) 7.73 (d, J=8.67 Hz, 1 H) 10.85 (s, 1 H). MS (ESI+) m/z 374 [M+H]+.
Example 32 Methyl 4-{[(3-chlor0fluorophenyl)sulf0nyl] amin0}hydr0xybenzoate S o ‘0\ CI OH O\ The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and ro- 4-fluorobenzenesulfonyl de (11.4 mg, 0.050 mmol) according to the General Procedure 4, described in Example 7. The title compound was obtained in 82% yield (14.8 mg). 1H NMR (500 MHz, CDClg) 8 ppm 3.91 (s, 3 H) 6.62 (dd, J=8.61, 2.26 Hz, 1 H) 6.67 (d, J=2.26 Hz, 1 H) 6.91 (br. s., 1 H) 7.24 (dd, J=8.72, 8.35 Hz, 1 H) 7.74 (d, J=8.61 Hz, 1 H) 7.76 (ddd, J=8.72, 4.31, 2.32 Hz, 1 H) 7.95 (dd, J=6.59, 2.32 Hz, 1 H) 10.87 (s, 1 H). MS (ESI+) m/z 360 [M+H]+.
Example 33 Methyl 4-{[(4-flu0r0naphthyl)sulf0nyl] hydr0xybenzoate 0 OH O\ The product was ed from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 4- fluoronaphthalenesulfonyl chloride (12.3 mg, 0.050 mmol) according to the General Pro- cedure 4, described in Example 7. The title compound was obtained in 77% yield (14.4 mg). 1H NMR (500 MHz, CDC13) 8 ppm 3.86 (s, 3 H) 6.51 (dd, , 2.20 Hz, 1 H) 6.55 (d, J=2.20 Hz, 1 H) 7.14 (br. s., 1 H) 7.18 (dd, J=9.40, 8.30 Hz, 1 H) 7.61 (d, J=8.67 Hz, 1 H) 7.68 (ddd, J=8.37, 6.93, 0.99 Hz, 1 H) 7.77 (ddd, J=8.76, 6.93, 1.34 Hz, 1 H) 8.19 — 8.23 (m, 1 H) 8.32 (dd, J=8.30, 5.25 Hz, 1 H) 8.62 — 8.66 (m, 1 H) 10.77 (s, 1 H). MS (1351+) m/Z 376 [M+H]+.
Example 34 Methyl 4-{[(2,3-dichlor0phenyl)sulf0nyl] amin0}hydr0xybenzoate O\\S/H 0 CI OH 0\ The product was ed from methyl osa1icy1ate (8.5 mg, 0.050 mmol) and 2,3- dichlorobenzenesulfonyl chloride (12.4 mg, 0.050 mmol) according to the General Procedure 4, described in Example 7. The title compound was obtained in 66% yield (12.4 mg). 1H NMR (500 MHz, CDC13) 8 ppm 3.89 (s, 3 H) 6.61 (dd, J=8.67, 2.20 Hz, 1 H) 6.70 (d, J=2.20 Hz, 1 H) 7.26 (br. s., 1 H) 7.35 (t, J=8.03 Hz, 1 H) 7.66 (dd, J=8.03, 1.56 Hz, 1 H) 7.69 (d, J=8.67 Hz, 1 H) 8.08 (dd, J=8.03, 1.56 Hz, 1 H) 10.83 (s, 1 H). MS (ESI+) m/z 376 [M+H]+.
Example 35 Methyl 4-[(biphenylylsulf0nyl)amin0]hydr0xybenzoate The product was prepared from methyl 4-aminosa1icy1ate (8.5 mg, 0.050 mo 1) and bi- pheny1su1fony1 chloride (12.9 mg, 0.051 mmol) according to the General ure 4, de- scribed in Example 7. The title compound was obtained in 56% yield (10.8 mg). 1H NMR (500 MHz, CDC13) 8 ppm 3.90 (s, 3 H) 6.65 (dd, J=8.67, 2.20 Hz, 1 H) 6.70 (d, J=2.20 Hz, 1 H) 6.94 (br. s., 1 H) 7.38 - 7.43 (m, 1 H) 7.43 - 7.48 (m, 2 H) 7.54 - 7.58 (m, 2 H) 7.66 - 7.70 W0 2013/093095 96 (m, 2 H) 7.71 (d, J=8.67 Hz, 1 H) 7.92 — 7.95 (m, 2 H) 10.85 (s, 1 H). MS (ESI+) m/Z 384 [M+H]+.
Example 36 Methyl 4-{[(4-tert-butylphenyl)sulf0nyl] hydr0xybenz0ate The product was prepared from methyl 4-aminosa1icy1ate (8.5 mg, 0.050 mo 1) and 4-tert- buty1benzenesu1fony1 chloride (12.5 mg, 0.053 mmol) according to the General Procedure 4, described in Example 7. The title compound was ed in 96% yield (17.4 mg). 1H NMR (500 MHz, CDC13) 5 ppm 1.31 (s, 9 H) 3.90 (s, 3 H) 6.64 (dd, J=8.67, 2.20 Hz, 1 H) 6.66 (d, J=2.32 Hz, 1 H) 6.87 (br. s., 1 H) 7.46 — 7.51 (m, 2 H) 7.70 (d, J=8.67 Hz, 1 H) 7.78 — 7.81 (m, 2 H) 10.84 (s, 1 H). MS (ESI+) m/Z 364 [M+H]+.
Example 37 Methyl 4-[(2,1,3-benzothiadiazol—4-ylsulf0nyl)amin0]hydr0xybenz0ate The product was prepared from methyl osa1icy1ate (8.3 mg, 0.050 mmol) and 2,1,3- benzothiadiazolesu1fony1 chloride (11.7 mg, 0.050 mmol) ing to the General Proce- dure 4, described in Example 7. DMSO was added to the reaction mixture prior to the purifi- cation in order to dissolve precipitated material. The title compound was obtained in 27% yield (4.9 mg). 1H NMR (600 MHz, CD3OD) 8 ppm 3.83 (s, 3 H) 6.65 (dd, J=8.75, 2.21 Hz, 1 H) 6.70 (d, J=2.21 Hz, 1 H) 7.58 (d, J=8.75 Hz, 1 H) 7.79 (dd, J=8.85, 7.02 Hz, 1 H) 8.27 (dd, J=8.85, 1.07 Hz, 1 H) 8.38 (dd, J=7.02, 1.07 Hz, 1 H). MS (ESI+) m/z 366 [M+H]+.
Example 38 Methyl 2-hydr0xy{[(4-phenoxyphenyl)sulf0nyl] amin0}benz0ate The product was prepared from methyl 4-aminosa1icy1ate (8.3 mg, 0.050 mo 1) and 4- phenoxybenzenesulfonyl chloride (13.4 mg, 0.050 mmol) according to the General ure 4, described in Example 7. The title compound was obtained in 78% yield (15.6 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 3.89 (s, 3 H) 6.66 (dd, J=8.70, 2.25 Hz, 1 H) 6.70 (dd, J=2.25, 0.31 Hz, 1 H) 6.99 - 7.03 (m, 2 H) 7.04 - 7.07 (m, 2 H) 7.20 - 7.24 (m, 1 H) 7.38 - 7.44 (m, 2 H) 7.68 (dd, J=8.70, 0.31 Hz, 1 H) 7.81 - 7.85 (m, 2 H). MS (ESI+) m/z 400 [M+H]+.
Example 39 Methyl 0xy[(naphthalen-Z-ylsulfonyl)amin0]benzoate The product was prepared from methyl osa1icy1ate (8.3 mg, 0.050 mo 1) and 2- naphthalenesulfonyl chloride (11.3 mg, 0.050 mmol) according to the General Procedure 4, described in Example 7. The title compound was obtained in 72% yield (12.8 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 3.85 (s, 3 H) 6.68 (dd, , 2.21 Hz, 1 H) 6.75 (dd, J=2.21, 0.31 Hz, 1 H) 7.62 (ddd, J=8.09, 6.89, 1.37 Hz, 1 H) 7.65 (dd, J=8.72, 0.31 Hz, 1 H) 7.66 (ddd, J=8.09, 6.89, 1.40 Hz, 1 H) 7.82 (dd, J=8.73, 1.93 Hz, 1 H) 7.92 - 7.95 (m, 1 H) 8.00 (d, J=8.73 Hz, 1 H) 8.01 - 8.04 (m, 1 H) 8.46 - 8.48 (m, 1 H). MS (ESI+) m/z 358 [M+H]+.
Example 40 Methyl 4-({[5-(dimethylamin0)naphthalenyl]sulfonyl}amino)—2-hydr0xybenzoate tri- fluoroacetate W0 2013/093095 98 \N S“ I O O o O\ FVLOH A mixture of methyl 4-aminosalicylate (8.3 mg, 0.050 mmol), 5-dimethylaminonaphthalene- onyl chloride (13.5 mg, 0.050 mmol) and pyridine (8 uL, 0.100 mmol) in MeCN (400 uL) was heated at 60 0C for 5 h. Due to low solubility of the reagents, MeCN (400 uL) was added and the mixture was heated at 60 0C overnight. A second portion of 5-dimethylamino- naphthalenesulfonyl chloride was added (13.6 mg, 0.05 mmol) and the e was heated at 60 0C for another 24 h. After 2 days, additional 5-dimethylaminonaphthalenesulfonyl chloride (6.7 mg, 0.025 mmol) was added and the reaction mixture was heated at 60 0C over- night. The reaction mixture was filtered and the clear solution obtained was diluted with eOH/water. TFA (50 uL) was added and the crude t was purified by prepara- tive HPLC (acidic system). The title compound was obtained in 42% yield (10.9 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 2.95 (s, 6 H) 3.84 (s, 3 H) 6.57 (dd, J=8.77, 2.21 Hz, 1 H) 6.61 (dd, J=2.21, 0.30 Hz, 1 H) 7.40 (d, J=7.70 Hz, 1 H) 7.58 (dd, J=8.77, 0.30 Hz, 1 H) 7.62 (dd, J=8.54, 7.40 Hz, 1 H) 7.66 (dd, J=8.54, 7.70 Hz, 1 H) 8.36 (dd, J=7.40, 1.04 Hz, 1 H) 8.48 (d, J=8.54 Hz, 1 H) 8.53 (dt, J=8.54, 1.04 Hz, 1 H). MS (ESI+) m/z 401 [M+H]+. e 41 Methyl 2-hydr0xy{[(5-{[(phenylcarbonyl)amin0] methyl}thi0phen yl)sulf0nyl] amin0}benz0ate O\\S,NH H OH o \\ \ I O O The product was prepared from methyl 4-aminosalicylate (8.3 mg, 0.050 mmol) and 5- [(benzoylamino)methyl]thiophenesulfonyl chloride (16.3 mg, 0.052 mmol) according to W0 2013/093095 99 the General Procedure 4, described in Example 7, with a modified reaction volume of 800 uL.
The title compound was obtained in 61% yield (13.7 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 3.89 (s, 3 H) 4.69 (d, J=0.90 Hz, 2 H) 6.69 (dd, J=8.71, 2.19 Hz, 1 H) 6.74 (dd, J=2.19, 0.29 Hz, 1 H) 7.01 (dt, J=3.83, 0.90 Hz, 1 H) 7.44 - 7.48 (m, 2 H) 7.50 (d, J=3.83 Hz, 1 H) 7.53 - 7.57 (m, 1 H) 7.69 (dd, J=8.71, 0.29 Hz, 1 H) 7.77 - 7.82 (m, 2 H). MS (ESI+) m/z 447 [M+H]+.
Example 42 Methyl —chlorophenyl)sulf0nyl] amin0}hydr0xybenz0ate \ o OH O\ The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 4- chlorobenzenesulfonyl chloride (11.6 mg, 0.050 mmol) according to the l Procedure 4, described in Example 7. The title compound was obtained in 68% yield (11.6 mg). 1H NMR (500 MHz, CDClg) 8 ppm 3.91 (s, 3 H) 6.61 (dd, J=8.67, 2.26 Hz, 1 H) 6.66 (d, J=2.26 Hz, 1 H) 6.86 (s, 1 H) 7.43 - 7.47 (m, 2 H) 7.71 (d, J=8.67 Hz, 1 H) 7.78 - 7.82 (m, 2 H) 10.86 (s, 1 H). MS (ESI+) m/Z 342 [M+H]+.
Example 43 Methyl 4-{[(2-chlor0methylphenyl)sulf0nyl] amin0}hydr0xybenzoate O\\ /N S\\ o CI OH O\ The t was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 2-chloro- 6-methylbenzenesulfonyl chloride (11.3 mg, 0.050 mrnol) ing to the General Procedure 4, bed in Example 7. The title compound was obtained in 30% yield (5.4 mg). 1H NMR (500 MHz, CDClg) 8 ppm 2.73 (s, 3 H) 3.89 (s, 3 H) 6.64 (dd, J=8.67, 2.20 Hz, 1 H) 6.68 (d, J=2.20 Hz, 1 H) 7.17 - 7.20 (m, 1 H) 7.29 (t, J=7.81 Hz, 1 H) 7.34 - 7.37 (m, 1 H) 7.38 (br. s., 1 H) 7.69 (d, J=8.67 Hz, 1 H) 10.81 (s, 1 H). MS (ESI+) m/z 356 [M+H]+.
W0 2013/093095 100 Example 44 Methyl 2-hydr0xy({[3-(triflu0r0meth0xy)phenyl]sulfonyl}amin0)benz0ate OH O\ The product was prepared from methyl 4-aminosa1icy1ate (8.5 mg, 0.050 mo 1) and 3- (trifluoromethoxy)benzenesulfony1 chloride (13.0 mg, 0.050 mmol) according to the General Procedure 4, bed in Example 7. The title compound was obtained in 66% yield (12.9 mg). 1H NMR (500 MHz, CDC13) 8 ppm 3.91 (s, 3 H) 6.63 (dd, J=8.54, 2.20 Hz, 1 H) 6.65 (d, J=2.20 Hz, 1 H) 6.74 (br. s., 1 H) 7.40 - 7.44 (m, 1 H) 7.54 (dd, J=8.27, 7.92 Hz, 1 H) 7.71 (br. s., 1 H) 7.73 (d, J=8.54 Hz, 1 H) 7.80 (ddd, , 1.71, 0.98 Hz, 1 H) 10.86 (s, 1 H).
MS (ESI+) m/Z 392 . e 45 Methyl 4-({[5-chlor0(2,5-diflu0r0phenyl)thienyl] sulfonyl}amino)—2- hydroxybenzoate F O\\ /N S o \ O OH O\ F CI A solution of 3-bromochlorothiophene (2.43 g, 12.3 mmol), 2,5-difluoropheny1boronic acid (2.91 g, 18.4 mmol), DIPEA (4.8 g, 37 mmol) and Pd(dppf)C12’CH2C12 (300 mg, 0.37 mmol) was stirred in dioxane (100 mL) and water (10 mL) at 80 0C for two days. Toluene (100 mL) was added. The organic phase was washed with 1 M NaOH, 1 M HC1 and brine, dried and concentrated to a brown oil. The brown oil was purified by distillation (twice) in a Kuge1rohr apparatus at 120 0C and ~10 mbar resulting in 0.73 g (26%) of the intermediate 2- chloro(2,5-difluoropheny1)thiophene. 1H NMR (500 MHZ, CDC13) 8 ppm 7.01 - 7.23 (m, 5 W0 2013/093095 101 A solution of 2-chloro(2,5-difluorophenyl)thiophene (0.73 g, 3.2 mmol) in CHzClz (100 mL) was cooled on ice. Chlorosulfonic acid (0.37 g, 3.2 mmol) in CH2C12 (50 mL) was add- ed dropwise over 1 h. The reaction was refluxed overnight. The reaction mixture was cooled and washed with water (2 x 100 mL) and brine, dried over MgSO4, filtered and concentrated to a dark brown oil. The oil was dissolved in e (50 mL) and stored in the fridge for 3 days. A black tar precipitated. The solution was decanted and concentrated to give the inter- mediate ro(2,5-difluorophenyl)thiophenesulfonyl chloride as a light brown oil (0.87 g, 21% over two steps). MS (ESI+) m/z 293 [M-Cl]+.
The title compound was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 5- chloro(2,5-difluorophenyl)thiophenesulfonyl chloride (16.5 mg, 0.050 mmol) according to the General Procedure 4, described in Example 7. The title nd was obtained in 47% yield (10.9 mg). 1H NMR (500 MHz, CDC13) 8 ppm 3.93 (s, 3 H) 6.71 (dd, J=8.67, 2.32 Hz, 1 H) 6.76 (d, J=2.32 Hz, 1 H) 6.95 (s, 1 H) 7.06 - 7.16 (m, 3 H) 7.58 (d, J=1.95 Hz, 1 H) 7.79 (d, J=8.67 Hz, 1 H) 10.91 (s, 1 H). MS (ESI+) m/z 460 [M+H]+.
Example 46 Methyl 2-hydr0xy({[3-(triflu0r0methyl)phenyl] sulfonyl}amin0)benzoate o\ R \S/ O OH O\ The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 3- trifluoromethylbenzenesulfochloride (12.2 mg, 0.050 mmol) according to the General Proce- dure 4, described in Example 7. The title compound was obtained in 76% yield (14.3 mg). 1H NMR (500 MHz, CDC13) 8 ppm 3.91 (s, 3 H) 6.64 (dd, J=8.54, 2.32 Hz, 1 H) 6.66 (d, J=2.32 Hz, 1 H) 6.94 (s, 1 H) 7.64 (t, J=7.87 Hz, 1 H) 7.73 (d, J=8.54 Hz, 1 H) 7.81 - 7.85 (m, 1 H) 8.02 - 8.06 (m, 1 H) 8.14 (s, 1 H) 10.86 (s, 1 H). MS (ESI+) m/z 376 [M+H]+. e 47 Methyl 4-{[(3-br0m0chlorothiophenyl)sulf0nyl] amin0}hydr0xybenzoate W0 2013/093095 102 The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 3-bromo- -chlorothiophenesulfonyl chloride (15.0 mg, 0.051 mmol) ing to the l Pro- cedure 4, described in Example 7. The title nd was obtained in 37% yield (8.0 mg). 1H NMR (500 MHz, CDC13) 8 ppm 3.92 (s, 3 H) 6.72 (dd, J=8.67, 2.20 Hz, 1 H) 6.75 (d, J=2.20 Hz, 1 H) 6.92 (s, 1 H) 7.35 (br. s., 1 H) 7.76 (d, J=8.67 Hz, 1 H) 10.88 (s, 1 H). MS (ESI+) m/Z 426 [M+H]+.
Example 48 Methyl 4-{[(5-chlor0methylthienyl)sulf0nyl] amin0}hydr0xybenzoate The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 5-chloro- 2-methylthiophenesulfonyl chloride (11.5 mg, 0.050 mmol) according to the General Pro- cedure 4, described in Example 7. The title compound was obtained in 17% yield (3.0 mg). 1H NMR (600 MHz, CDC13) 8 ppm 2.58 (s, 3 H) 3.92 (s, 3 H) 6.61 (dd, J=8.60, 2.26 Hz, 1 H) 6.65 (d, J=2.26 Hz, 1 H) 6.81 (br. s., 1 H) 7.06 (s, 1 H) 7.75 (d, J=8.60 Hz, 1 H) 10.89 (s, 1 H). MS (ESI+) m/Z 362 [M+H]+.
Example 49 Methyl 4-{[(5-br0m0-2,4-diflu0r0phenyl)sulf0nyl] amin0}hydr0xybenz0ate W0 2013/093095 103 The product was prepared from methyl 4-aminosalicylate (8.5 mg, 0.050 mmol) and 5-bromo- 2,4-difluorobenzenesulfonyl chloride (14.5 mg, 0.050 mmol) according to the l Pro- cedure 4, described in e 7. The title compound was obtained in 66% yield (14.0 mg). 1H NMR (600 MHz, CDC13) 5 ppm 3.91 (s, 3 H) 6.65 (dd, J=8.60, 2.23 Hz, 1 H) 6.68 (d, J=2.23 Hz, 1 H) 7.00 (dd, J=9.52, 7.69 Hz, 1 H) 7.06 (br. s., 1 H) 7.73 (d, J=8.60 Hz, 1 H) 8.15 (t, J=7.32 Hz, 1 H) 10.87 (s, 1 H). MS (ESI+) m/Z 422 [M+H]+.
Example 50 Methyl 4-{[(3-cyan0phenyl)sulf0nyl]amin0}hydr0xybenzoate The t was prepared from methyl 4-aminosalicylate (9.1 mg, 0.054 mmol) and 3- cyanobenzenesulfonyl chloride (10.4 mg, 0.052 mmol) according to the General Procedure 4, described in Example 7. The title compound was obtained in 64% yield (11.1 mg). 1H NMR (500 MHz, CDClg) 8 ppm 3.92 (s, 3 H) 6.64 (dd, J=8.35, 2.25 Hz, 1 H) 6.66 (dd, J=2.25, 0.60 Hz, 1 H) 7.06 (br. s., 1 H) 7.64 (ddd, J=8.04, 7.77, 0.55 Hz, 1 H) 7.74 (dd, J=8.35, 0.60 Hz, 1 H) 7.85 (ddd, J=7.77, 1.59, 1.16 Hz, 1 H) 8.08 (ddd,J=8.04, 1.89, 1.16 Hz, 1 H) 8.15 (ddd, J=1.89, 1.59, 0.55 Hz, 1 H) 10.88 (s, 1 H). MS (ESI+) m/z 333 [M+H]+.
Example 51 Methyl 2-hydr0xy({[3-(methylsulf0nyl)phenyl] sulfonyl}amin0)benz0ate The t was prepared from methyl 4-aminosalicylate (8.4 mg, 0.050 mmol) and 3- methylsulphonyl)benzenesulphonyl chloride (12.8 mg, 0.050 mmol) according to the General W0 2013/093095 104 Procedure 4, described in Example 7. The title compound was ed in 62% yield (11.9 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 3.13 (s, 3 H) 3.89 (s, 3 H) 6.69 (dd, J=8.70, 2.21 Hz, 1 H) 6.72 (dd, J=2.21, 0.42 Hz, 1 H) 7.71 (dd, J=8.70, 0.42 Hz, 1 H) 7.81 (td, J=7.85, 0.55 Hz, 1 H) 8.16 (ddd, J=7.85, 1.83, 1.07 Hz, 1 H) 8.18 (ddd,.]=7.85, 1.83, 1.07 Hz, 1H) 8.38 (td, J=1.83, 0.55 Hz, 1 H). MS (ESI+) m/z 386 [M+H]+.
Example 52 Methyl benzothienylsulf0nyl)amin0]hydr0xybenz0ate A mixture of methyl 4-aminosalicylate (10 mg, 0.060 mmol), 1-benzothiophenesulfonyl chloride (11.5 mg, 0.049 mmol) and pyridine (50 uL) in CHzClz (1 mL) was heated in a sealed tube at 60 0C overnight. The solvent was evaporated, and the crude product was puri- fied by preparative HPLC (acidic system). The title nd was obtained in 53% yield (11.6 mg). 1H NMR (500 MHz, CDgOD) 8 ppm 3.86 (s, 3 H) 6.64 (dd, , 2.20 Hz, 1 H) 6.70 (d, J=2.20 Hz, 1 H) 7.46 (ddd, J=8.20, 7.10, 1.20 Hz, 1 H) 7.52 (ddd, J=8.10, 7.10, 1.20 Hz, 1 H) 7.63 (d, J=8.79 Hz, 1 H) 7.95 (ddd, J=8.10, 1.20, 0.75 Hz, 1 H) 8.25 (ddd, J=8.20, 1.20, 0.75 Hz, 1 H) 8.51 (s, 1 H). MS (ESI+) m/z 364 [M+H]+.
Example 53, General Procedure 5 Methyl 4-{[(2,5-dichlor0methylthienyl)sulf0nyl] amin0}hydr0xybenzoate o N O MS\\O O\ CI CI Chlorosulfonic acid (52 uL, 0.77 mmol) was added to a solution of 2,5-dichloro methylthiophene (125 mg, 0.75 mmol) in CH2C12. After 1 h of ng at room temperature another portion of chlorosulfonic acid (52 uL, 0.77 mmol) was added. Complete conversion to the intermediate ic acid was observed after stirring at room temperature overnight.
W0 2013/093095 105 2012/076836 Chlorosulfonic acid (100 uL, 1.55 mmol) was added to the reaction mixture, which was then heated at 50 0C for 3 h followed by stirring at room temperature for 3 days. The reaction was quenched by slow on of water. The product was extracted with CH2C12. The organic phase was dried. Removal ofthe solvents gave the 2,5-dichloromethylthiophenesulfonyl chloride as a dark oil, which was used in the following step without filrther purification (119 mg).
A mixture of methyl 4-aminosalicylate (10 mg, 0.060 mmol), the preformed 2,5-dichloro methylthiophenesulfonyl chloride (13 mg, 0.049 mmol) and pyridine (50 uL) in CH2C12 (1 mL) was heated in a sealed tube at 50 0C overnight. The solvent was evaporated, and the crude t was purified by preparative HPLC (acidic system). The title nd was obtained in 18% yield (3.5 mg). 1H NMR (500 MHz, CDgOD) 8 ppm 2.37 (s, 3 H) 3.90 (s, 3 H) 6.63 (dd, J=8.67, 2.26 Hz, 1 H) 6.68 (d, J=2.26 Hz, 1 H) 7.72 (d, J=8.67 Hz, 1 H). MS (ESI+) m/Z 396 [M+H]+.
Example 54 Methyl 2-hydr0xy{[(2,4,5-trichlor0thienyl)sulf0nyl] amin0}benz0ate 2,4,5-Trichlorothiophenesulfonyl chloride was prepared from 2,3,5-trichlorothiophene (138 mg, 0.74 mmol) and chlorosulfonic acid (First step: 2 x 52 uL, 2 x 0.77 mmol; second step: 100 uL, 1.55 mmol) according the General Procedure 5, described in e 53. 2,4,5- orothiophenesulfonyl chloride was obtained as a dark oil (165 mg).
The title nd was obtained by reacting the preformed 2,4,5-trichlorothiophene sulfonyl chloride (14 mg, 0.049 mmol) with methyl 4-aminosalicylate (10 mg, 0.060 mmol) according to the General Procedure 5, described in Example 53. The title compound was ob- tained in 16% yield (3.2 mg). 1H NMR (500 MHZ, CDgOD) 8 ppm 3.90 (s, 3 H) 6.66 (dd, J=8.67, 2.20 Hz, 1 H) 6.71 (d, J=2.20 Hz, 1 H) 7.72 (d, J=8.67 Hz, 1 H). MS (ESI+) m/z 416 [M+H]+.
Example 55, General Procedure 6 W0 2013/093095 106 2012/076836 Methyl 4-{[(3,5-dibromothiophenyl)sulf0nyl] amin0}hydr0xybenzoate A solution of bromothiophene (24 mg, 0.100 mmol) in CH2C12 (1.5 mL) was cooled to - 0C and a cold solution of chlorosulfonic acid (12 mg, 0.100 mmol) in CH2C12 (0.5 mL) was added. The reaction was allowed to reach room temperature over 2 h, after which more chlorosulfonic acid was added (35 mg, 0.300 mrno 1). The on mixture was stirred at 35 0C overnight and was then passed through a column loaded with hydromatrix (3 g) and water (1 mL). The column was eluted with CH2C12 (2 mL). The eluate was concentrated to dryness under vacuum to give 3,5-dibromothiophenesu1fonyl chloride, which was dissolved in MeCN (0.5 mL) together with methyl 4-aminosa1icy1ate (16 mg, 0.100 mmol) and pyridine (15 mg, 0.200 mmol). The reaction mixture was allowed to react at 60 0C overnight. The crude product was diluted with water/MeCN. TFA (50 uL) was added and the product was purified by preparative HPLC (acidic system). The title nd was obtained in 37% yield (17.5 mg). 1H NMR (500 MHz, CDC13) 8 ppm 3.92 (s, 3 H) 6.72 (dd, J=8.61, 2.20 Hz, 1 H) 6.75 (d, J=2.20 Hz, 1 H) 7.04 (s, l H) 7.32 (br. s., l H) 7.76 (d, J=8.61 Hz, 1 H) 10.88 (s, l H). MS (ESI+) m/Z 470 [M+H]+.
Example 56 Methyl 4-{[(5—chlor0methylthi0phenyl)sulf0nyl] hydr0xybenzoate The intermediate 5-chloromethy1thiophenesu1fony1 chloride was prepared from 2- chloromethy1thiophene (13.5 mg, 0.20 mmol) and chlorosulfonic acid (47 mg, 0.40 mmol) according to the General Procedure 6, described in Example 55. The title compound was ob- tained by reacting the preformed 5-chloromethylthiophenesu1fony1 de with methyl 4-aminosa1icy1ate (16 mg, 0.100 mmol) and pyridine (15 mg, 0.200 mmol) according to the W0 2013/093095 107 General Procedure 6. The title compound was obtained in 59% yield (21.4 mg). 1H NMR (500 MHz, CDClg) 8 ppm 2.16 (d, J=0.40 Hz, 3 H) 3.92 (s, 3 H) 6.67 (dd, J=8.67, 2.20 Hz, 1 H) 6.72 (d, J=2.20 Hz, 1 H) 6.90 (br. s., 1 H) 7.34 (q, J=0.40 Hz, 1 H) 7.76 (d, J=8.67 Hz, 1 H) .89 (s, 1 H). MS (ESI+) m/Z 362 [M+H]+.
Example 57 Methyl 4-{[(3,4-dibromothiophenyl)sulf0nyl] amin0}hydr0xybenzoate The intermediate 3,4-dibromothiophenesulfonyl de was prepared from 3,4- dibromothiophene (24 mg, 0.10 mmol) and chlorosulfonic acid (47 mg, 0.40 mmol) accord- ing to the General Procedure 6, described in Example 55. The title compound was obtained by reacting the preformed 3,4-dibromothiophenesulfonyl chloride with methyl 4- aminosalicylate (16 mg, 0.100 mmol) and pyridine (15 mg, 0.200 mmol) according to the General Procedure 6. The title nd was obtained in 13% yield (5.9 mg). 1H NMR (500 MHz, CDC13:DMSO-d6 6:1) 8 ppm 3.58 (s, 3 H) 6.45 (dd, J=8.67, 2.20 Hz, 1 H) 6.51 (d, J=2.20 Hz, 1 H) 7.36 (d, J=8.67 Hz, 1 H) 7.43 (s, 1 H) 10.47 (s, 1 H) 10.85 (s, 1 H). MS (ESI+) m/Z 470 [M+H]+.
Example 58 Methyl 4-{[(5-br0m0methylthi0phenyl)sulf0nyl]amin0}hydr0xybenzoate The ediate omethylthiophenesulfonyl chloride was prepared from 2- bromomethylthiophene (17.5 mg, 0.10 mmol) and chlorosulfonic acid (47 mg, 0.40 mmol) according to the General Procedure 6, described in Example 55. The title nd was ob- tained by reacting the preformed 5-bromomethylthiophenesulfonyl chloride with methyl W0 2013/093095 108 4-aminosalicylate (16 mg, 0.100 mmol) and pyridine (15 mg, 0.200 mmol) ing to the General Procedure 6. The title compound was obtained in 44% yield (17.9 mg). 1H NMR (500 MHz, CDClg) 8 ppm 2.16 (d, J=0.43 Hz, 3 H) 3.92 (s, 3 H) 6.67 (dd, J=8.67, 2.20 Hz, 1 H) 6.72 (d, J=2.20 Hz, 1 H) 6.91 (br. s., l H) 7.32 (q, J=0.43 Hz, 1 H) 7.76 (d, J=8.67 Hz, 1 H) .89 (s, 1 H). MS (ESI+) m/Z 406 .
Example 59, General Procedure 7 2-Meth0xyethyl 4-{[(2,5-dichlor0thienyl)sulf0nyl] amin0}hydr0xybenzoate A reaction mixture containing 4- {[(2,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18 mg, 0.050 mmol) mediate 6), l,l'-carbonyldiimidazole (16 mg, 0.100 mmol) and pyridine (8 mg, 0.100 mmol) in MeCN (0.5 mL) was stirred at room tem- perature for 45 min, and then 2-methoxyethanol (7.6 mg, 0.100 mmol) was added. The reac- tion e was stirred at room temperature ght, then acidified with TFA and diluted with MeCN/MeOH/water. The crude product was purified by preparative HPLC (acidic sys- tem). The title compound was obtained in 66% yield (14 mg). 1H NMR (500 MHz, DMSO- d6: CD30D 6:1)8 ppm 3.29 (s, 3 H) 3.61 - 3.65 (m, 2 H) 4.36 - 4.41 (m, 2 H) 6.70 (d, J=2.20 Hz, 1 H) 6.74 (dd, J=8.67, 2.20 Hz, 1 H) 7.40 (s, l H) 7.71 (d, J=8.67 Hz, 1 H). MS (ESI+) m/Z 426 [M+H]+.
Example 60, General Procedure 8 Ethyl 4-{[(4,5-dichlor0thienyl)sulf0nyl]amin0}hydr0xybenz0ate A reaction mixture containing 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18 mg, 0.050 mmol) (Intermediate 7), l,l'-carbonyldiimidazole (16 mg, W0 2013/093095 109 2012/076836 0.100 mmol) and ne (8 mg, 0.100 mmol) in MeCN (0.7 mL) was stirred at room tem- perature for 30 min, and then EtOH (50 uL, 0.858 mmol) was added. The reaction mixture was stirred at 55 0C for overnight, then acidified with TFA and diluted with MeCN/MeOH/water. The crude product was purified by ative HPLC (acidic system).
The title compound was obtained in 70% yield (139 mg). 1H NMR (500 MHz, CDClg) 8 ppm 1.40 (t, J=7.14 Hz, 3 H) 4.39 (q, J=7.14 Hz, 2 H) 6.69 (dd, J=8.6l, 2.26 Hz, 1 H) 6.74 (d, J=2.26 Hz, 1 H) 7.23 (br. s., l H) 7.41 (s, l H) 7.80 (d, J=8.61 Hz, 1 H) 11.01 (s, 1 H). MS (ESI+) m/Z 396 [M+H]+.
Example 61 2-(1H-Pyrrolyl)ethyl 4-{[(4,5-dichlorothiophenyl)sulf0nyl]amin0} hydroxybenzoate S S\ O CI \I OH O\/\N \7 The product was prepared from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18.4 mg, 0.050 mmol) (Intermediate 7), l,l'-carbonyldiimidazole (32.5 mg, 0.200 mmol), pyridine (16 mg, 0.200 mmol) and oxyethylpyrrole (22.4 mg, 0.200 mmol) according to the General Procedure 8, described in Example 60. The title compound was obtained in 60% yield (138 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 4.28 (t, J=5.34 Hz, 2 H) 4.54 (t, J=5.34 Hz, 2 H) 6.05 (t, J=2.14 Hz, 2 H) 6.71 (dd, J=8.70, 2.20 Hz, 1 H) 6.74 (t, J=2.14 Hz, 2 H) 6.76 (d, J=2.20 Hz, 1 H) 7.52 (s, l H) 7.74 (d, J=8.70 Hz, 1 H). MS (ESI+) m/Z 461 [M+H]+.
Example 62 3-(1H-Pyrrolyl)pr0pyl 4-{[(4,5-dichlorothiophenyl)sulf0nyl]amin0} hydroxybenzoate W0 2013/093095 110 O\‘ /H s 80 l :l (”fl 70 0 6/ OH0\/\/N The product was prepared from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18.4 mg, 0.050 mmol) (Intermediate 7), 1,1'-carbonyldiimidazole (32.5 mg, 0.200 mmol), pyridine (16 mg, 0.200 mmol) and 1-(3-hydroxypropyl)pyrrole (25.7 mg, 0.205 mmol) according to the General Procedure 8, described in e 60. The title com- pound was ed in 66% yield (15.7 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 2.16 - 2.24 (m, 2 H) 4.08 (t, J=6.64 Hz, 2 H) 4.26 (t, J=6.10 Hz, 2 H) 6.03 (t, J=2.14 Hz, 2 H) 6.69 (t, J=2.14 Hz, 2 H) 6.74 (dd, J=8.69, 2.21 Hz, 1 H) 6.77 (dd, J=2.2l, 0.31 Hz, 1 H) 7.54 (s, l H) 7.77 (dd, J=8.70, 0.31 Hz, 1 H). MS (ESI+) m/z 475 [M+H]+.
Example 63 3-M0rpholinylpr0pyl 4-{[(4,5—dichlorothiophenyl)sulf0nyl] amin0} ybenzoate trifluoroacetate The t was prepared from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18.4 mg, 0.050 mmol) (Intermediate 7), 1,1'-carbonyldiimidazole (32.5 mg, 0.200 mmol), pyridine (16 mg, 0.200 mmol) and 4-(3-hydroxypropyl)morpholine (29.1 mg, 0.200 mmol) according to the General Procedure 8, described in Example 60. The title compound was obtained in 50% yield (15.3 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 2.20 - 2.27 (m, 2 H) 3.32 (br. m., 2 H) 3.31 - 3.35 (m, 2 H) 3.47 (br. m., 2 H) 3.79 (br. m., 2 H) 4.04 (br. m., 2 H) 4.46 (t, J=6.03 Hz, 2 H) 6.76 - 6.79 (m, 2 H) 7.54 (s, l H) 7.82 - 7.85 (m, l H).
MS (ESI+) m/Z 495 [M+H]+.
Example 64 W0 2013/093095 111 3-(lH-Imidazol-l-yl)pr0pyl 4-{[(4,5-dichlorothiophen-Z-yl)sulfonyl]amin0} hydroxybenzoate trifluoroacetate O\‘ /H s o @N \l N\// OH O\/\/ CI 0 Faka The t was prepared from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18.4 mg, 0.050 mmol) mediate 7), l,l'-carbonyldiimidazole (32.5 mg, 0.200 mmol), pyridine (16 mg, 0.200 mmol) and 3-(lH-imidazol-l-yl)propan-l-ol (25.9 mg, 0.205 mmol) according to the General Procedure 8, described in Example 60. The title compound was obtained in 68% yield (20.2 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 2.36 - 2.43 (m, 2 H) 4.43 (t, J=5.85 Hz, 2 H) 4.44 (t, J=7.02 Hz, 2 H) 6.75 - 6.78 (m, 2 H) 7.55 (s, l H) 7.56 (t, J=l.64 Hz, 1 H) 7.72 (t, J=l.64 Hz, 1 H) 7.72 - 7.75 (m, l H) 8.99 (s, l H). MS (ESI+) m/Z 476 [M+H]+.
Example 65 3-(4-Methylpiperazinyl)pr0pyl 4-{[(4,5—dichlorothiophenyl)sulf0nyl] amin0} hydroxybenzoate trifluoroacetate O\‘ /N / 8 so 0 0 N\)KN CI \ I CI F F The product was prepared from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (184 mg, 0.050 mmol) (Intermediate 7), l,l'-carbonyldiimidazole (32.5 mg, 0.200 mmol), ne (16 mg, 0.200 mmol) and ydroxypropyl) methylpiperazine (32.6 mg, 0.206 mmol) according to the General Procedure 8, described in Example 60. The title compound was obtained in 47% yield (146 mg). 1H NMR (600 MHz, CDgOD) 5 ppm 1.99 - 2.06 (m, 2 H) 2.50 - 3.25 (br. m., 4 H) 2.74 (t, J=7.02 Hz, 2 H) 2.83 (s, W0 2013/093095 112 2012/076836 3 H) 3.21 (br. m., 4 H) 4.43 (t, J=6.33 Hz, 2 H) 6.76 (dd, J=8.54, 2.14 Hz, 1 H) 6.77 (dd, J=2.14, 0.31 Hz, 1 H) 7.54 (s, 1 H) 7.80 (dd, , 0.31 Hz, 1 H). MS (ESI+) m/Z 508 [M+H]+.
Example 66 2-Eth0xyethyl 4-{[(2,5-dichlor0thienyl)sulf0nyl]amin0}hydr0xybenz0ate o\\ ,N O O o / \ OH \\\ CI CI 8 o\\ The product was prepared from 4-{[(2,5-dichlorothiopheny1)sulfony1]amino} hydroxybenzoic acid (18 mg, 0.50 mmol) (Intermediate 6) and 2-ethoxyethanol (8 mg, 0.105 mmol) according to the General Procedure 7, described in Example 59. The title compound was obtained in 15% yield (3.4 mg). 1H NMR (500 MHZ, CDClg) 8 ppm 1.23 (t, J=7.08 Hz, 3 H) 3.58 (q, J=7.00 Hz, 2 H) 3.73 - 3.78 (m, 2 H) 4.44 - 4.49 (m, 2 H) 6.67 (dd, , 2.20 Hz, 1 H) 6.71 (d, J=2.20 Hz, 1 H) 7.17 (s, 1 H) 7.48 (s, 1 H) 7.81 (d, J=8.79 Hz, 1 H) 10.84 (s, 1 H). MS (ESI+) m/Z 440 [M+H]+.
Example 67 Tetrahydrofuranyl 4-{[(2,5-dichlor0thienyl)sulf0nyl] amin0}hydr0xybenz0ate The product was prepared from 4- {[(2,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18 mg, 0.50 mmol) (Intermediate 6) and 3-hydroxytetrahydrofuran (9 mg, 0.102 mmol) according to the General Procedure 7, described in e 59. The title compound was obtained in 64% yield (14.0 mg). 1H NMR (500 MHz, DMSO-d6) 8 ppm 2.01 - 2.09 (m, 1 H) 2.17 - 2.26 (m, 1 H) 3.75 (td, J=8.30, 4.52 Hz, 1 H) 3.80 - 3.88 (m, 2 H) 3.86 (dd, J=10.50, 4.27 Hz, 1 H) 5.43 - 5.47 (m, 1 H) 6.69 (d, J=2.20 Hz, 1 H) 6.72 (dd, J=8.67, 2.20 Hz, 1 H) 7.40 (s, 1 H) 7.71 (d, J=8.67 Hz, 1 H). MS (ESI+) m/z 438 [M+H]+.
W0 2013/093095 113 Example 68 Isopropyl ,5-dichlor0thienyl)sulf0nyl] amin0}hydr0xybenzoate o\ H \ / s\\ \QYO \ 0 CIa\ OH 0% The product was ed from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} ybenzoic acid (18 mg, 0.50 mmol) (Intermediate 7) and 2-propanol (50 uL, 0.654 mmol) according to the General Procedure 8, described in Example 60. The title compound was obtained in 80% yield (16.4 mg). 1H NMR (500 MHz, CDClg) 8 ppm 1.38 (d, J=6.23 Hz, 6 H) 5.27 (spt, J=6.27 Hz, 1 H) 6.67 (dd, J=8.67, 2.20 Hz, 1 H) 6.72 (d, J=2.20 Hz, 1 H) 6.95 (br. s., 1 H) 7.41 (s, 1 H) 7.79 (d, J=8.67 Hz, 1 H) 11.10 (s, 1 H). MS (ESI+) m/z 410 .
Example 69 2-Meth0xyethyl 4-{[(4,5-dichlor0thienyl)sulf0nyl] amin0}hydr0xybenzoate O\\S/N O / \ \‘O 0 CI \ S OH OJ The product was prepared from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18 mg, 0.50 mmol) (Intermediate 7) and 2-methoxyethanol (50 uL, 0.634 mmol) according to the General Procedure 8, described in Example 60. The title com- pound was obtained in 68% yield (14.6 mg). 1H NMR (500 MHz, CDClg) 8 ppm 3.42 (s, 3 H) 3.70 - 3.74 (m, 2 H) 4.47 - 4.50 (m, 2 H) 6.68 (dd, J=8.67, 2.32 Hz, 1 H) 6.73 (d, J=2.32 Hz, 1 H) 6.91 (br. s., 1 H) 7.41 (s, 1 H) 7.84 (d, J=8.67 Hz, 1 H) 10.86 (s, 1 H). MS (ESI+) m/z 426 [M+H]+.
Example 70 Butyl 4-{[(4,5-dichlor0thienyl)sulf0nyl] amin0}hydr0xybenzoate W0 2013/093095 114 O\\ /N \ 0 OH y The product was prepared from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18 mg, 0.50 mrnol) (Intermediate 7) and 1-butanol (50 uL, 0.546 mmol) according to the General Procedure 8, described in Example 60. The title compound was obtained in 60% yield (12.8 mg). 1H NMR (500 MHz, CDClg) 8 ppm 0.98 (t, J=7.45 Hz, 3 H) 1.43 - 1.51 (m, 2 H) 1.71 - 1.79 (m, 2 H) 4.34 (t, J=6.65 Hz, 2 H) 6.68 (dd, J=8.61, 2.26 Hz, 1 H) 6.72 (d, J=2.26 Hz, 1 H) 6.87 (br. s., 1 H) 7.42 (s, 1 H) 7.80 (d, J=8.61 Hz, 1 H) 11.02 (s, 1 H). MS (ESI+) m/z 424 [M+H]+.
Example 71 Benzyl 4-{[(4,5-dichlor0thienyl)sulfonyl]amin0}hydr0xybenzoate The product was prepared from 4- -dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18 mg, 0.50 mmol) (Intermediate 7) and benzyl alcohol (50 uL, 0.483 mmol) ing to the General Procedure 8, described in Example 60. The title compound was obtained in 55% yield (12.7 mg). 1H NMR (500 MHz, CDC13) 8 ppm 5.37 (s, 2 H) 6.67 (dd, J=8.67, 2.20 Hz, 1 H) 6.75 (d, J=2.20 Hz, 1 H) 7.03 (br. s., 1 H) 7.35 - 7.46 (m, 5 H) 7.42 (s, 1 H) 7.84 (d, J=8.67 Hz, 1 H) 10.92 (s, 1 H). MS (ESI+) m/z 458 [M+H]+.
Example 72 Hexyl ,5—dichlor0thienyl)sulf0nyl] amin0}hydr0xybenzoate l 15 The product was prepared from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18 mg, 0.50 mmol) (Intermediate 7) and 1-hexanol (50 uL, 0.398 mmol) according to the General Procedure 8, described in Example 60. The title compound was obtained in 71% yield (16.0 mg). 1H NMR (500 MHz, CDClg) 8 ppm 0.87 - 0.94 (m, 3 H) 1.29 - 1.38 (m, 4 H) 1.38 - 1.47 (m, 2 H) 1.72 - 1.80 (m, 2 H) 4.32 (t, J=6.71 Hz, 2 H) 6.68 (dd, J=8.61, 2.26 Hz, 1 H) 6.72 (d, J=2.26 Hz, 1 H) 6.87 (br. s., 1 H) 7.41 (s, 1 H) 7.79 (d, J=8.61 Hz, 1 H) 11.02 (s, 1 H). MS (ESI+) m/z 452 [M+H]+.
Example 73 Phenyl 4-{[(4,5—dichlor0thienyl)sulfonyl]amin0}hydr0xybenzoate The product was prepared from 4- -dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18 mg, 0.50 mrnol) mediate 7) and phenol (50 uL, 0.568 mrnol) according to the General Procedure 8, described in Example 60. The title compound was ob- tained in 75% yield (16.7 mg). 1H NMR (500 MHz, CDClg) 8 ppm 6.78 (dd, , 2.20 Hz, 1 H) 6.81 (d, J=2.20 Hz, 1 H) 7.17 - 7.21 (m, 2 H) 7.29 - 7.34 (m, 1 H) 7.33 (br. s., 1 H) 7.42 - 7.47 (m, 2 H) 7.45 (s, 1 H) 8.03 (d, J=8.67 Hz, 1 H) 10.66 (s, 1 H). MS (ESI+) m/z 444 [M+H]+.
Example 74 Tetrahydrofuranyl 4-{[(4,5-dichlor0thienyl)sulfonyl] amin0}hydr0xybenz0ate W0 2013/093095 116 The product was prepared from 4- -dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18 mg, 0.50 mmol) (Intermediate 7) and 3-hydroxytetrahydrofuran (50 uL, 0.619 mrnol) according to the General Procedure 8, described in Example 60. The title nd was obtained in 78% yield (17.0 mg). 1H NMR (500 MHz, CDClg) 8 ppm 2.12 - 2.19 (m, 1 H) 2.25 - 2.34 (m, 1 H) 3.92 (td, J=8.48, 4.39 Hz, 1 H) 3.95 - 4.03 (m, 3 H) 5.55 (dddd, J=6.27, 4.27, 2.01, 1.89 Hz, 1 H) 6.68 (dd, J=8.67, 2.32 Hz, 1 H) 6.75 (d, J=2.32 Hz, 1 H) 7.14 (br. s., 1 H) 7.42 (s, 1 H) 7.78 (d, J=8.67 Hz, 1 H) 10.85 (s, 1 H). MS (ESI+) m/z 438 [M+H]+.
Example 75 Tetrahydrofuranylmethyl 4-{[(4,5-dichlor0thienyl)sulf0nyl] amin0} hydroxybenzoate O\\ /N S\\ J30o \ 0 C. \ S 0 The product was prepared from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18 mg, 0.50 mmol) (Intermediate 7) and tetrahydrofuranmethanol (50 uL, 0.519 mrnol) according to the General Procedure 8, described in Example 60. The title compound was obtained in 72% yield (16.3 mg). 1H NMR (500 MHz, CDClg) 8 ppm 1.72 (dddd, J=12.68, 7.95, 6.95, 5.83 Hz, 1 H) 2.12 (dddd, J=12.68, 8.40, 7.73, 5.44 Hz, 1 H) 2.67 - 2.77 (m, 1 H) 3.68 (dd, J=8.97, 5.25 Hz, 1 H) 3.79 (ddd, J=8.58, 7.73, 6.95 Hz, 1 H) 3.89 (dd, , 7.07 Hz, 1 H) 3.92 (ddd, J=8.58, 7.95, 5.44 Hz, 1 H) 4.25 (dd, J=10.86, 7.81 Hz, 1 H) 4.34 (dd, J=10.86, 6.47 Hz, 1 H) 6.69 (dd, J=8.67, 2.26 Hz, 1 H) 6.74 (d, J=2.26 Hz, 1 H) 7.09 (br. s., 1 H) 7.42 (s, 1 H) 7.77 (d, J=8.67 Hz, 1 H) 10.88 (s, 1 H). MS (ESI+) m/z 452 [M+H]+.
Example 76 1 l7 2012/076836 2-Meth0xyethyl 4-({[5-chlor0(2,3-dihydr0benz0furanyl)—2- thienyl] sulfonyl}amino)—2-hydr0xybenz0ate The product was prepared from 4-({[5-chloro(2,3-dihydrobenzofuranyl)thiophen yl]sulfonyl} amino)hydroxybenzoic acid (13 mg, 0.022 mmol) (Intermediate 2), 1,1'- carbonyldiimidazole (16 mg, 0.100 mmol), pyridine (8 mg, 0.100 mmol) and 2- methoxyethanol (50 uL, 0.63 mmol) ing to the General Procedure 8, described in EX- ample 60, using 0.5 mL MeCN. The title compound was obtained in 91% yield (10 mg). 1H NMR (500 MHz, CDClg) 8 ppm 3.25 (t, J=8.73 Hz, 2 H) 3.41 (s, 3 H) 3.69 - 3.73 (m, 2 H) 4.45 - 4.49 (m, 2 H) 4.62 (t, J=8.73 Hz, 2 H) 6.71 (dd, J=8.67, 2.32 Hz, 1 H) 6.75 (d, J=2.32 Hz, 1 H) 6.83 (d, J=8.30 Hz, 1 H) 7.06 (s, l H) 7.19 - 7.23 (m, l H) 7.29 - 7.31 (m, l H) 7.54 (s, l H) 7.82 (d, J=8.67 Hz, 1 H) 10.84 (s, 1 H). MS (ESI+) m/z 510 [M+H]+.
Example 77 Methyl —chlor0[3-(methoxycarbonyl)phenyl]thiophen-Z-yl}sulfonyl)amin0] hydroxybenzoate CI 8 Q‘s/H \ / o ‘6 The product was prepared from 3-(2-chloro {[3-hydroxy (methoxycarbonyl)phenyl]sulfamoyl}thiophenyl)benzoic acid (14 mg, 0.030 mmol) (In- termediate l3), 1,1'-carbonyldiimidazole (16 mg, 0.100 mmol), pyridine (8 mg, 0.100 mmol) and MeOH (100 uL, 2.49 mmol) ing to the General Procedure 8, described in Example 60. The title compound was obtained in 72% yield (10.4 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.92 (s, 3 H) 3.94 (s, 3 H) 6.72 (dd, J=8.70, 2.29 Hz, 1 H) 6.76 (d, J=2.29 Hz, 1 H) 6.99 (br. s., l H) 7.52 (td,.]=7.77, 0.57 Hz, 1 H) 7.61 (s, l H) 7.67 (ddd,.]=7.77, 1.90, 1.21 Hz, 1 W0 93095 118 2012/076836 H) 7.79 (d, J=8.70 Hz, 1 H) 8.06 (ddd, J=7.77, 1.67, 1.21 Hz, 1 H) 8.13 (ddd, J=1.90, 1.67, 0.57 Hz, 1 H) 10.91 (s, 1 H). MS (ESI+) m/Z 482 [M+H]+.
Example 78 Methyl 4-{[(5-chlor0{3-[(1-methyleth0xy)carb0nyl]phenyl}thi0phen yl)sulf0nyl]amin0}hydr0xybenz0ate The product was prepared from 3-(2-chloro {[3-hydroxy (methoxycarbony1)pheny1]su1famoy1}thiophen—3-y1)benzoic acid (14 mg, 0.030 mmol) (In- termediate 13), 1,1'-carbony1diimidaz01e (16 mg, 0.100 mmol), ne (8 mg, 0.100 11111101) and 2-propanol (100 uL, 1.31 11111101) according to the General Procedure 8, described in EX- amp1e 60. The title nd was obtained in 42% yield (6.4 mg). 1H NMR (600 MHz, CDC13) 8 ppm 1.38 (d, J=6.26 Hz, 6 H) 3.92 (s, 3 H) 5.27 (spt, J=6.26 Hz, 1 H) 6.72 (dd, J=8.62, 2.25 Hz, 1 H) 6.77 (d, J=2.25 Hz, 1 H) 7.02 (br. s., 1 H) 7.51 (td, J=7.77, 0.55 Hz, 1 H) 7.62 (s, 1 H) 7.65 (ddd, J=7.77, 1.90, 1.18 Hz, 1 H) 7.79 (d, J=8.62 Hz, 1 H) 8.06 (ddd-, J=7.77, 1.65, 1.18 Hz, 1 H) 8.11 (ddd, J=1.90, 1.65, 0.55 Hz, 1 H) 10.91 (s, 1 H). MS (ESI+) m/Z 510 [M+H]+.
Example 79 3-Hydr0xypr0pyl 4-{[(4,5-dichlorothiophenyl)sulf0nyl]amin0}hydr0xybenzoate /\/\ 0‘, .,0do The product was prepared from 4- {[(4,5-dichlorothiopheny1)su1fony1]amino} hydroxybenzoic acid (18 mg, 0.050 mmol) (Intermediate 7) and 1-propanedi01 (158 mg, 2.1 W0 2013/093095 119 mmol) according to the General Procedure 8, described in Example 60. The title compound was obtained in 59% yield (12 mg). 1H NMR (600 MHz, CDClg) 5 ppm 2.03 (quin, J=6. 10 Hz, 2 H) 3.80 (t, J=5.95 Hz, 2 H) 4.52 (t, J=6.26 Hz, 2 H) 6.69 (dd, J=8.70, 2.29 Hz, 1 H) 6.74 (d, J=2.14 Hz, 1 H) 6.77 (br. s., l H) 7.43 (s, l H) 7.80 (d, J=8.55 Hz, 1 H) 10.91 (s, l H). MS (ESI+) m/Z 426 [M+H]+.
Example 80 3-(Dimethylamin0)pr0pyl 4-{[(4,5-dichlor0thienyl)sulf0nyl] amin0} hydroxybenzoate trifluoroacetate §3“EQTJW; A solution of 4- -dichlorothiophenyl)sulfonyl]amino}hydroxybenzoic acid (Inter- e 7) (18 mg, 0.050 mmol), pyridine (8 mg, 0.10 mmol) and 1,1’-carbonyldiimidazole (16 mg, 0.10 mmol) in 700 uL ofMeCN was prepared. After 30 minutes was 3- dimethylamino-l-propanol (50 uL, excess) added. The reaction was shaken at 50 0C over- night. The reaction was ed by addition of TFA, diluted with water/MeCN and purified by preparative HPLC (acidic system). The title compound was obtained in 56% yield (158 mg). 1H NMR (500 MHz,CDC13)8 ppm 2.26 - 2.35 (m, 2 H) 2.87 (s, 6 H) 3.15 - 3.23 (m, 2 H) 4.42 (t, J=6.10 Hz, 2 H) 6.68 (dd, J=8.67, 2.26 Hz, 1 H) 6.78 (d, J=2.26 Hz, 1 H) 7.43 (s, l H) 7.56 (br. s., l H) 7.73 (d, J=8.67 Hz, 1 H) 10.71 (br. s., l H). MS (ESI+) m/z 453 [M+H]+.
Example 81 Methyl 4-({[6—chlor0(2-flu0r0meth0xyphenyl)pyridinyl]sulfonyl}amin0)—2- hydroxybenzoate W0 2013/093095 120 \ \\ O o CI N OH 0\ A mixture of methyl 4- {[(5-bromochloropyridinyl)sulfonyl]amino}hydroxybenzoate (Intermediate 8) (21.1 mg, 0.050 mmol), 2-fluoromethoxyphenylboronic acid (9.7 mg, 0.055 mmol), DIPEA (35 uL, 0.200 mmol) and Pd(dppf)Clg‘CH2Clz (2 mg, 0.002 mmol) in aqueous dioxane (1 mL, 9:1 dioxane/water) was heated at 80 0C under nitrogen atmosphere for 1 day. The reaction mixture was acidified by addition ofTFA (50 uL). After being al- lowed to settle overnight the reaction mixture was filtered, diluted with MeOH and purified by preparative HPLC (acidic system). The product was filrther d by preparative HPLC (Basic system 2) to give the title compound in 7% yield (1.6 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.93 (s, 3 H) 3.94 (s, 3 H) 6.65 (dd, J=8.68, 2.25 Hz, 1 H) 6.72 (d, J=2.25 Hz, 1 H) 6.82 (ddd, J=7.76, 6.08, 1.57 Hz, 1 H) 6.93 (br. s., 1 H) 7.09 (td, J=8.12, 1.57 Hz, 1 H) 7.18 (ddd, J=8.12, 7.76, 1.45 Hz, 1 H) 7.76 (d, J=8.68 Hz, 1 H) 8.08 (d, J=2.44 Hz, 1 H) 8.84 (d, J=2.44 Hz, 1 H) 10.89 (s, 1 H). MS (ESI+) m/Z 467 [M+H]+.
Example 82, General Procedure 9 Methyl 2-hydr0xy{[(2'-hydr0xybiphenylyl)sulf0nyl] amin0}benz0ate OH O\ A mixture of methyl 4- {[(3-bromophenyl)sulfonyl]amino}hydroxybenzoate (Intermediate 4) (19 mg, 0.050 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (12.1 mg, 0.055 mmol), DIPEA (26 mg, 0.200 mmol) and Pd(dppf)Clg‘CH2Clz (2 mg, 0.002 mmol) in aqueous dioxane (0.8 mL, 9:1 dioxane/water) was heated at 80 0C under nitrogen atmosphere for 1 day. The reaction mixture was acidified by on ofTFA (50 uL). The reaction mix- ture was d, diluted with MeOH/MeCN/water and d by preparative HPLC c system). The title compound was obtained in 82% yield (16.2 mg). 1H NMR (500 MHz, CDClg) 8 ppm 3.90 (s, 3 H) 5.22 (br. s., 1 H) 6.64 (dd, J=8.67, 2.20 Hz, 1 H) 6.73 (d, J=2.20 W0 2013/093095 121 Hz, 1 H) 6.93 (d, J=8.09 Hz, 1 H) 7.01 (ddd, J=7.69, 7.50, 0.55 Hz, 1 H) 7.06 (s, 1 H) 7.23 (dd, J=7.69, 1.59 Hz, 1 H) 7.27 (ddd, J=8.09, 7.50, 1.59 Hz, 1 H) 7.56 (dd, J=7.98, 7.74 Hz, 1 H) 7.70 (d, J=8.67 Hz, 1 H) 7.73 (ddd, J=7.74, 1.40, 1.19 Hz, 1 H) 7.85 (ddd, J=7.98, 1.89, 1.19 Hz, 1 H) 8.11 (dd, J=1.89, 1.40 Hz, 1 H) 10.86 (s, 1 H). MS (ESI+) m/Z 400 [M+H]+.
Example 83 Methyl 4-({[6—chlor0(3-flu0r0phenyl)pyridinyl]sulfonyl}amino)—2-hydr0xybenz0ate 013mH \ \\ O o CI N OH O\ The product was prepared from methyl 4- romochloropyridiny1)su1fony1]amino}- 2-hydroxybenzoate (Intermediate 8) (21.1 mg, 0.050 mmol) and 3-fluorobenzeneboronic acid (7.7 mg, 0.055 mmol) according to the General Procedure 9, described in Example 82. The title compound was obtained in 29% yield (6.4 mg). 1H NMR (600 MHZ, CDC13) 5 ppm 3.93 (s, 3 H) 6.67 (dd, , 2.20 Hz, 1 H) 6.71 (d, J=2.20 Hz, 1 H) 6.97 (br. s., 1 H) 7.09 (ddd, J=9.28, 2.55, 1.68 Hz, 1 H) 7.16 (ddd, , 1.68, 0.98 Hz, 1 H) 7.17 (tdd, J=8.45, 2.55, 0.98 Hz, 1 H) 7.45 (ddd, , 7.68, 5.80 Hz, 1 H) 7.77 (d, J=8.66 Hz, 1 H) 8.04 (d, J=2.44 Hz, 1 H) 8.82 (d, J=2.44 Hz, 1 H) 10.91 (s, 1 H). MS (ESI+) m/z 437 [M+H]+.
Example 84 Methyl 4-({[5-(3-amin0phenyl)chlor0pyridinyl]sulfonyl}amino)—2-hydr0xybenzoate 018,NH H2N \ \\ O O CI N OH O\ The product was prepared from methyl 4- {[(5-bromochloropyridiny1)su1fony1]amino} - 2-hydroxybenzoate (Intermediate 8) (21.1 mg, 0.050 mmol) and 3-(4,4,5,5-tetramethy1—1,3,2- dioxaborolany1)ani1ine (12 mg, 0.055 mmol) according to the General Procedure 9, de- scribed in Example 82. The title compound was obtained in 43% yield (9.4 mg). 1H NMR W0 2013/093095 122 2012/076836 (600 MHz, CD30D) 5 ppm 3.91 (s, 3 H) 6.72 (dd, J=8.70, 2.29 Hz, 1 H) 6.76 (d, J=2.29 Hz, 1 H) 7.14 — 7.17 (m, 1 H) 7.17 — 7.18 (m, 1 H) 7.21 (ddd,.]=8.12, 2.21, 0.75 Hz, 1 H) 7.48 (dd, J=8.12, 7.70 Hz, 1 H) 7.76 (d, J=8.70 Hz, 1 H) 8.13 (d, J=2.44 Hz, 1 H) 8.80 (d, J=2.44 Hz, 1 H). MS (ESI+) m/Z 434 [M+H]+.
Example 85 Methyl 4-({[6-chloro-S-(4-flu0r0methylphenyl)pyridinyl]sulfonyl}amin0)—2- hydroxybenzoate 068”H \ \\ CI N OH /O The product was prepared from methyl 4- {[(5-bromochloropyridiny1)su1fony1]amino}- 2-hydroxybenzoate (Intermediate 8) (21.1 mg, 0.050 mmol) and 4-fluoro methylphenylboronic acid (8.5 mg, 0.055 mmol) according to the General ure 9, de- scribed in Example 82. The title compound was ed in 38% yield (8.5 mg). 1H NMR (600 MHz, CDC13) 5 ppm 2.33 (d, J=1.91 Hz, 3 H) 3.93 (s, 3 H) 6.67 (dd, J=8.65, 2.26 Hz, 1 H) 6.71 (d, J=2.26 Hz, 1 H) 7.03 (br. s., 1 H) 7.10 (dd, J=9.20, 8.30 Hz, 1 H) 7.16 - 7.19 (m, 1 H) 7.20 (dddd, J=8.30, 4.76, 2.44, 0.59 Hz, 1 H) 7.77 (d, J=8.65 Hz, 1 H) 8.02 (d, J=2.48 Hz, 1 H) 8.79 (d, J=2.48 Hz, 1 H) 10.92 (s, 1 H). MS (ESI+) m/z 451 [M+H]+.
Example 86 Methyl '-chlorobiphenylyl)sulf0nyl] amin0}hydr0xybenzoate OH O\ The product was prepared from methyl 4- {[(3-bromopheny1)su1fony1]amino} hydroxybenzoate (Intermediate 4) (19 mg, 0.050 mmol) and (3-chloropheny1)boronic acid (8.6 mg, 0.055 mmol) according to the General Procedure 9, described in Example 82. The title compound was obtained in 70% yield (15 mg). 1H NMR (500 MHz, CDC13) 8 ppm 3.90 W0 2013/093095 123 (s, 3 H) 6.66 (dd, J=8.61, 2.20 Hz, 1 H) 6.70 (d, J=2.20 Hz, 1 H) 6.98 (br. s., 1 H) 7.36 — 7.43 (m, 3 H) 7.47 — 7.49 (m, 1 H) 7.56 (td, J=7.82, 0.47 Hz, 1 H) 7.72 (d, J=8.61 Hz, 1 H) 7.74 (ddd, J=7.82, 1.86, 1.07 Hz, 1 H) 7.86 (ddd, J=7.82, 1.91, 1.04 Hz, 1 H) 8.03 (ddd, J=1.91, 1.86, 0.47 Hz, 1 H) 10.85 (s, 1 H). MS (ESI+)m/z418 [M+H]+.
Example 87 Methyl 4-[(biphenylylsulf0nyl)amin0]hydr0xybenzoate OH O\ The product was prepared from methyl 4- {[(3-bromopheny1)su1fony1]amino} ybenzoate (Intermediate 4) (19 mg, 0.050 mmol) and phenylboronic acid (6.7 mg, 0.055 mmol) according to the General Procedure 9, described in Example 82. The title com- pound was ed in 70% yield (13 mg). 1H NMR (500 MHz, CDC13) 8 ppm 3.89 (s, 3 H) 6.65 (dd, J=8.67, 2.20 Hz, 1 H) 6.70 (d, J=2.20 Hz, 1 H) 6.94 (s, 1 H) 7.37 - 7.43 (m, 1 H) 7.44 - 7.48 (m, 2 H) 7.52 - 7.55 (m, 2 H) 7.55 (ddd, J=7.87, 7.78, 0.46 Hz, 1 H) 7.71 (d, J=8.67 Hz, 1 H) 7.78 (ddd, , 1.74, 1.10 Hz, 1 H) 7.83 (ddd, J=7.87, 1.89, 1.10 Hz, 1 H) 8.09 (ddd, J=1.89, 1.74, 0.46 Hz, 1 H) 10.84 (s, 1 H). MS (ESI+) m/z 384 [M+H]+.
Example 88 Methyl 2-hydr0xy{[(3-pyridinylphenyl)sulf0nyl]amin0}benzoate trifluoroacetate N O / \ \\S/NH o \ O The product was prepared from methyl 4- {[(3-bromopheny1)su1fony1]amino} hydroxybenzoate (Intermediate 4) (19 mg, 0.050 mmol) and pyridiny1boronic acid (6.8 mg, 0.055 mmol) according to the General Procedure 9, described in Example 82. The title com- pound was obtained in 69% yield (17 mg). 1H NMR (500 MHz, CDC13) 8 ppm 3.90 (s, 3 H) 6.68 (dd, , 2.20 Hz, 1 H) 6.71 (d, J=2.20 Hz, 1 H) 7.30 (br. s., 1 H) 7.43 (ddd, J=7.95, W0 2013/093095 124 2012/076836 4.87, 0.80 Hz, 1 H) 7.61 (dd, J=7.90, 7.80 Hz, 1 H) 7.72 (d, J=8.67 Hz, 1 H) 7.78 (ddd, J=7.80, 1.83, 1.07 Hz, 1 H) 7.86 (ddd, J=7.95, 2.40, 1.60 Hz, 1 H) 7.91 (ddd,.]=7.90, 1.90, 1.07 Hz, 1 H) 8.07 (dd, J=1.90, 1.83 Hz, 1 H) 8.67 (dd, J=4.87, 1.60 Hz, 1 H) 8.81 (dd, J=2.40, 0.80 Hz, 1 H) 10.85 (s, 1 H). MS (ESI+) m/Z 385 .
Example 89 Methyl 2-hydr0xy{[(3-pyridinylphenyl)sulf0nyl]amin0}benz0ate trifluoroacetate The product was prepared from methyl 4- {[(3-bromopheny1)su1fony1]amino} hydroxybenzoate (Intermediate 4) (19 mg, 0.050 mmol) and pyridiny1boronic acid (6.8 mg, 0.055 mmol) according to the General Procedure 9, described in Example 82. The title com- pound was obtained in 73% yield (18 mg). 1H NMR (500 MHz, CDC13) 8 ppm 3.80 (s, 3 H) 6.73 (dd, J=2.20, 0.53 Hz, 1 H) 6.74 (dd, , 2.20 Hz, 1 H) 7.65 (dd, J=8.49, 0.53 Hz, 1 H) 7.70 - 7.73 (m, 2 H) 7.75 (dd, J=7.91, 7.81 Hz, 1 H) 7.92 (ddd, J=7.91, 1.85, 1.04 Hz, 1 H) 8.08 (ddd, J=7.81, 1.85, 1.04 Hz, 1 H) 8.19 (t, J=1.85 Hz, 1 H) 8.68 - 8.73 (m, 2 H) 10.55 (s, 1 H) 10.94 (s, 1 H). MS (ESI+) m/Z 385 [M+H]+.
Example 90 Methyl 4-({[3-(1-benzofuranyl)phenyl]sulfonyl}amino)—2-hydr0xybenz0ate COO OHO\ The product was prepared from methyl 4- {[(3-bromopheny1)su1fony1]amino} hydroxybenzoate (Intermediate 4) (19 mg, 0.050 mmol) and 1-benzofuran—2-y1boronic acid (8.9 mg, 0.055 mmol) according to the General Procedure 9, described in Example 82. The title compound was ed in 72% yield (15 mg). 1H NMR (500 MHZ, CDC13) 5 ppm 3.88 (s, 3 H) 6.67 (dd, J=8.67, 2.20 Hz, 1 H) 6.72 (d, J=2.20 Hz, 1 H) 7.06 (br. s., 1 H) 7.11 (d, J=0.92 Hz, 1 H) 7.26 (ddd, J=7.72, 7.26, 0.98 Hz, 1 H) 7.33 (ddd, J=8.21, 7.26, 1.35 Hz, 1 H) 7.53 (dddd, J=8.21, 0.98, 0.92, 0.77 Hz, 1 H) 7.55 (t, J=7.85 Hz, 1 H) 7.61 (ddd, J=7.72, 1.35, 0.77 Hz, 1 H) 7.71 (d, J=8.67 Hz, 1 H) 7.81 (ddd, J=7.85, 1.88, 1.05 Hz, 1 H) 8.02 (ddd, J=7.85, 1.66, 1.05 Hz, 1 H) 8.36 (dd, , 1.66 Hz, 1 H) 10.84 (s, 1 H). MS (ESI+) m/Z 424 [M+H]+.
Example 91 Methyl 2-hydr0xy{[(3-quinolinylphenyl)sulfonyl]amin0}benz0ate trifluoroacetate N NH / o .
O O HOJKIEFF The product was prepared from methyl 4- {[(3-bromopheny1)su1fony1]amino} hydroxybenzoate (Intermediate 4) (19 mg, 0.050 mmol) and 6-(4,4,5,5-tetramethy1—1,3,2- orolan—2-yl)quinoline (14 mg, 0.055 mmol) according to the General Procedure 9, de- scribed in Example 82. The title nd was obtained in 58% yield (16 mg). 1H NMR (500 MHz, CDC13:DMSO-d6 6:1) 5 ppm 3.57 (s, 3 H) 6.46 (dd, J=8.75, 2.14 Hz, 1 H) 6.55 (d, J=2.14 Hz, 1 H) 7.20 (dd, J=8.26, 4.20 Hz, 1 H) 7.32 (t, J=7.82 Hz, 1 H) 7.36 (d, J=8.75 Hz, 1 H) 7.59 (ddd, J=7.82, 1.86, 1.04 Hz, 1 H) 7.61 (ddd,.]=7.82, 1.86, 1.04 Hz, 1 H) 7.64 (dd, J=8.76, 2.14 Hz, 1 H) 7.73 (d, J=2.14 Hz, 1 H) 7.87 (d, J=8.76 Hz, 1 H) 7.94 (t, J=1.86 Hz, 1 H) 7.96 — 8.00 (m, 1 H) 8.64 (dd, J=4.20, 1.73 Hz, 1 H) 10.23 (s, 1 H) 10.48 (s, 1 H). MS (ESI+) m/Z 435 [M+H]+.
Example 92 Methyl 4-{[(3'-amin0biphenylyl)sulf0nyl]amin0}hydr0xybenzoate trifluoroacetate W0 2013/093095 126 2012/076836 The product was ed from methyl 4- {[(3-bromophenyl)sulfonyl]amino} hydroxybenzoate (Intermediate 4) (19 mg, 0.050 mmol) and (3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolanyl)aniline (11 mg, 0.050 mmol) according to the General Procedure 9, de- scribed in Example 82. The title compound was obtained in 80% yield (21 mg). 1H NMR (600 MHz, CDClg) 5 ppm 3.78 (br. s., 2 H) 3.90 (s, 3 H) 6.63 (dd, J=8.65, 2.23 Hz, 1 H) 6.70 (d, J=2.23 Hz, 1 H) 6.72 (ddd, J=7.96, 2.29, 0.92 Hz, 1 H) 6.80 (br. s., l H) 6.82 (dd, , 1.72 Hz, 1 H) 6.91 (ddd, J=7.65, 1.72, 0.92 Hz, 1 H) 7.23 (dd, J=7.96, 7.65 Hz, 1 H) 7.52 (t, J=7.86 Hz, 1 H) 7.71 (d, J=8.65 Hz, 1 H) 7.74 (ddd,.]=7.86, 1.86, 1.07 Hz, 1 H) 7.81 (ddd, J=7.86, 1.86, 1.07 Hz, 1 H) 8.04 (t, J=l.86 Hz, 1 H) 10.85 (s, l H). MS (ESI+) m/Z 399 [M+H]+.
Example 93 Methyl 4-{[(3'-acetamid0biphenylyl)sulf0nyl] amin0}hydr0xybenzoate O O\\ /H OH O\ The product was prepared from methyl 4- {[(3-bromophenyl)sulfonyl]amino} hydroxybenzoate (Intermediate 4) (19 mg, 0.050 mmol) and 3-acetamidobenzeneboronic acid (9 mg, 0.050 mmol) according to the General Procedure 9, described in Example 82. The title compound was ed in 79% yield (17 mg). 1H NMR (600 MHz, CDClg) 5 ppm 2.22 (s, 3 H) 3.89 (s, 3 H) 6.63 (dd, J=8.70, 2.14 Hz, 1 H) 6.75 (d, J=2.14 Hz, 1 H) 6.96 (br. s., 1 H) 7.26 - 7.30 (m, l H) 7.40 (t, J=7.94 Hz, 1 H) 7.53 (t, J=7.78 Hz, 1 H) 7.52 - 7.55 (m, l H) 7.68 - 7.71 (m, l H) 7.71 (d, J=8.70 Hz, 1 H) 7.77 (ddd, J=7.78, 1.78, 0.99 Hz, 1 H) 7.83 (d, J=7.78 Hz, 1 H) 8.07 (t, J=l.78 Hz, 1 H) 10.88 (s, l H). MS (ESI+) m/z 441 [M+H]+.
Example 94 Methyl 2-hydr0xy{[(2'-nitr0biphenylyl)sulf0nyl] amin0}benz0ate The product was prepared from methyl 4- {[(3-bromophenyl)sulfonyl]amino} ybenzoate (Intermediate 4) (19 mg, 0.050 mmol) and obenzeneboronic acid (8 mg, 0.050 mmol) according to the General Procedure 9, described in Example 82. The title compound was obtained in 64% yield (14 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.91 (s, 3 H) 6.62 (dd, J=8.70, 2.29 Hz, 1 H) 6.72 (d, J=2.29 Hz, 1 H) 6.81 (br. s., 1 H) 7.36 (dd, J=7.55, 1.40 Hz, 1 H) 7.49 (ddd, J=7.78, 1.82, 1.27 Hz, 1 H) 7.53 (t, J=7.78 Hz, 1 H) 7.56 (ddd, J=8.13, 7.55, 1.40 Hz, 1 H) 7.66 (td, J=7.55, 1.36 Hz, 1 H) 7.73 (d, J=8.70 Hz, 1 H) 7.83 (t, J=1.82 Hz, 1 H) 7.87 (ddd,J=7.78, 1.82, 1.27 Hz, 1 H) 7.97 (dd, J=8.13, 1.36 Hz, 1 H) 10.86 (s, 1 H). MS (ESI+) m/z 429 [M+H]+.
Example 95 Methyl 4-({[3-(5-acetyl—Z-thienyl)phenyl] sulfonyl}amino)—2-hydr0xybenz0ate The product was prepared from methyl 4- {[(3-bromophenyl)sulfonyl]amino} ybenzoate (Intermediate 4) (19 mg, 0.050 mmol) and 5-acetylthiopheneboronic acid (8 mg, 0.050 mmol) according to the General ure 9, described in Example 82. The title compound was obtained in 66% yield (14 mg). 1H NMR (600 MHz, CDClg) 8 ppm 2.58 (s, 3 H) 3.90 (s, 3 H) 6.66 (dd, J=8.62, 2.21 Hz, 1 H) 6.69 (d, J=2.21 Hz, 1 H) 6.90 (br. s., 1 H) 7.36 (d, J=3.97 Hz, 1 H) 7.54 (t, J=7.88 Hz, 1 H) 7.67 (d, J=3.97 Hz, 1 H) 7.73 (d, J=8.62 Hz, 1 H) 7.81 (ddd, J=7.88, 1.79, 0.99 Hz, 1 H) 7.83 (ddd,.]=7.88, 1.68, 0.99 Hz, 1 H) 8.12 (dd, J=1.79, 1.68 Hz, 1 H) 10.85 (s, 1 H). MS (ESI+) m/z 432 [M+H]+.
Example 96 Methyl 2-hydr0xy({[2'-(hydroxymethyl)biphenyl—3-yl] sulfonyl}amin0)benz0ate W0 2013/093095 128 The product was prepared from methyl 4- {[(3-bromophenyl)sulfonyl]amino} ybenzoate (Intermediate 4) (19 mg, 0.050 mmol) and 2-hydroxymethylphenylboronic acid (8 mg, 0.050 mmol) according to the General Procedure 9, described in Example 82. The title compound was obtained in 83% yield (17 mg). 1H NMR (600 MHz, CDClg) 8 ppm 2.00 (br. s., 1 H) 3.91 (s, 3 H) 4.45 (br. s., 2 H) 6.62 (dd, , 2.24 Hz, 1 H) 6.77 (d, J=2.24 Hz, 1 H) 7.03 (br. s., 1 H) 7.23 (dd, J=7.49, 1.35 Hz, 1 H) 7.38 (td, J=7.49, 1.35 Hz, 1 H) 7.43 (td, J=7.49, 1.35 Hz, 1 H) 7.55 (dd, J=7.86, 7.64 Hz, 1 H) 7.56 (dd, J=7.49, 1.35 Hz, 1 H) 7.60 (ddd, , 1.66, 1.20 Hz, 1 H) 7.71 (d, J=8.70 Hz, 1 H) 7.88 (ddd,.]=7.86, 1.85, 1.20 Hz, 1 H) 8.05 (dd, J=1.85, 1.66 Hz, 1 H) 10.93 (s, 1 H). MS (ESI+) m/z 396 +.
Example 97 Methyl 4-{[(3'-cyanobiphenylyl)sulf0nyl] amin0}hydr0xybenzoate O\‘ n O / O O OH O\ The product was prepared from methyl 4- {[(3-bromophenyl)sulfonyl]amino} hydroxybenzoate (Intermediate 4) (19 mg, 0.050 mmol) and 3-cyanophenylboronic acid (7 mg, 0.050 mmol) according to the General Procedure 9, described in Example 82. The title compound was obtained in 59% yield (12 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.91 (s, 3 H) 6.67 (dd, J=8.62, 2.21 Hz, 1 H) 6.69 (d, J=2.21 Hz, 1 H) 6.90 (br. s., 1 H) 7.59 (td, J=7.70, 0.61 Hz, 1 H) 7.61 (t, J=7.81 Hz, 1 H) 7.70 (ddd,.]=7.72, 1.50, 1.20 Hz, 1 H) 7.74 (d, J=8.62 Hz, 1 H) 7.74 - 7.79 (m, 3 H) 7.91 (ddd, J=7.86, 1.83, 1.11Hz, 1 H) 8.04 (t, J=1.83 Hz, 1 H) 10.87 (s, 1 H). MS (ESI+) m/Z 409 [M+H]+.
Example 98 Methyl 2-hydr0xy({[4'-(methylsulfanyl)biphenylyl] sulfonyl}amin0)benz0ate W0 2013/093095 129 The product was prepared from methyl 4- {[(3-bromophenyl)sulfonyl]amino} ybenzoate (Intermediate 4) (19 mg, 0.050 mmol) and (4-methylthio)phenylboronic acid (8 mg, 0.050 mmol) according to the General Procedure 9, described in Example 82. The title compound was obtained in 62% yield (13 mg). 1H NMR (600 MHz, CDClg) 5 ppm 2.53 (s, 3 H) 3.90 (s, 3 H) 6.65 (dd, J=8.70, 2.20 Hz, 1 H) 6.69 (d, J=2.20 Hz, 1 H) 6.82 (br. s., 1 H) 7.31 - 7.35 (m, 2 H) 7.44 - 7.48 (m, 2 H) 7.53 (dd, J=7.92, 7.82 Hz, 1 H) 7.71 (d, J=8.70 Hz, 1 H) 7.75 (ddd, J=7.82, 1.85, 1.06 Hz, 1 H) 7.81 ]=7.92, 1.85, 1.06 Hz, 1 H) 8.05 (t, J=1.85 Hz, 1 H) 10.84 (s, 1 H). MS (ESI+) m/z 430 [M+H]+. e 99 Methyl 2-hydr0xy({[4'-(trifluoromethoxy)biphenyl—3-yl] sulfonyl}amin0)benz0ate o O“ ,N o O O OH O\ The product was prepared from methyl 4- {[(3-bromophenyl)sulfonyl]amino} hydroxybenzoate (Intermediate 4) (19 mg, 0.050 mmol) and 4- (trifluoromethoxy)benzeneboronic acid (10 mg, 0.050 mmol) according to the General Proce- dure 9, described in Example 82. The title compound was obtained in 73% yield (17 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.90 (s, 3 H) 6.65 (dd, J=8.70, 2.20 Hz, 1 H) 6.69 (d, J=2.20 Hz, 1 H) 6.83 (br. s., 1 H) 7.29 - 7.34 (m, 2 H) 7.53 - 7.57 (m, 2 H) 7.57 (dd, J=7.89, 7.79 Hz, 1 H) 7.72 (d, J=8.70 Hz, 1 H) 7.75 (ddd,J=7.79, 1.83, 1.10 Hz, 1 H) 7.86 (ddd,J=7.89, 1.83, 1.10 Hz, 1 H) 8.05 (t, J=1.83 Hz, 1 H) 10.85 (s, 1 H). MS (ESI+) m/z 468 [M+H]+.
Example 100 Methyl 2-hydr0xy({[4'-(triflu0r0methyl)biphenyl—3-yl] sulfonyl}amin0)benz0ate F H F O \ O O\O OH O\ W0 2013/093095 130 The product was prepared from methyl 4- {[(3-bromophenyl)sulfonyl]amino} hydroxybenzoate (Intermediate 4) (19 mg, 0.050 mmol) and 4- oromethyl)benzeneboronic acid (9 mg, 0.050 mmol) according to the l ure 9, described in e 82. The title compound was obtained in 77% yield (17 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.90 (s, 3 H) 6.66 (dd, J=8.70, 2.25 Hz, 1 H) 6.70 (d, J=2.25 Hz, 1 H) 6.86 (br. s., 1 H) 7.59 (dd, J=7.89, 7.78 Hz, 1 H) 7.62 - 7.66 (m, 2 H) 7.70 - 7.74 (m, 2 H) 7.72 (d, J=8.70 Hz, 1 H) 7.79 (ddd,J=7.78, 1.85, 1.10 Hz, 1 H) 7.89 (ddd,J=7.89, 1.85, 1.10 Hz, 1 H) 8.09 (t, J=1.85 Hz, 1 H) 10.86 (s, 1 H). MS (ESI+) m/z 452 [M+H]+.
Example 101 Methyl 4-({[4'-(dimethylcarbamoyl)biphenylyl]sulfonyl}amino)—2-hydr0xybenz0ate The product was prepared from methyl 4- {[(3-bromophenyl)sulfonyl]amino} hydroxybenzoate (Intermediate 4) (19 mg, 0.050 mmol) and [4-(N,N— dimethylaminocarbonyl)phenyl]boronic acid (10 mg, 0.050 mmol) according to the General Procedure 9, described in Example 82. The title compound was obtained in 77% yield (17 mg). 1H NMR (600 MHz,CDC13)8 ppm 3.03 (br. s., 3 H) 3.15 (br. s., 3 H) 3.90 (s, 3 H) 6.67 (dd, J=8.70, 2.25 Hz, 1 H) 6.71 (d, J=2.25 Hz, 1 H) 7.14 (br. s., 1 H) 7.49 - 7.53 (m, 2 H) 7.53 - 7.57 (m, 2 H) 7.56 (dd, J=7.90, 7.78 Hz, 1 H) 7.71 (d, J=8.70 Hz, 1 H) 7.77 (ddd, J=7.78, 1.85, 1.10 Hz, 1 H) 7.86 (ddd, J=7.90, 1.85, 1.10 Hz, 1 H) 8.07 (t, J=1.85 Hz, 1 H) 10.85 (s, 1 H). MS (ESI+) m/Z 455 [M+H]+.
Example 102 Methyl 4-{[(4'-carbamoylbiphenylyl)sulf0nyl]amin0}hydr0xybenzoate O\\ /N H2N So 0 W0 2013/093095 131 The product was prepared from methyl 4- romophenyl)sulfonyl]amino} hydroxybenzoate (Intermediate 4) (19 mg, 0.050 mmol) and (4-aminocarbonylphenyl)boronic acid (8 mg, 0.050 mmol) according to the General Procedure 9, bed in Example 82. The title compound was obtained in 72% yield (15 mg). 1H NMR (600 MHz, CDClg) 5 ppm 3.90 (s, 3 H) 5.70 (br. s., l H) 6.12 (br. s., l H) 6.69 (dd, J=8.70, 2.21 Hz, 1 H) 6.73 (d, J=2.21 Hz, 1 H) 7.32 (br. s., l H) 7.58 (dd, J=7.89, 7.78 Hz, 1 H) 7.59 - 7.63 (m, 2 H) 7.72 (d, J=8.70 Hz, 1 H) 7.79 (ddd, J=7.78, 1.83, 1.07 Hz, 1 H) 7.89 (ddd,.]=7.89, 1.83, 1.07 Hz, 1 H) 7.88 - 7.91 (m, 2 H) 8.10 (t, J=l.83 Hz, 1 H) 10.85 (s, 1 H). MS (ESI+) m/Z 427 [M+H]+.
Example 103 Methyl 4-({[5-chlor0(4-meth0xy-3,5-dimethylphenyl)thi0phen-2—yl]sulfonyl}amin0)—2- hydroxybenzoate CI s \é/NH l/\\ The product was prepared from methyl 4- {[(4-bromochlorothienyl)sulfonyl]amino} hydroxybenzoate (Intermediate 3) (21 mg, 0.050 mmol) and 4-methoxy-3,5- dimethylbenzeneboronic acid (9 mg, 0.050 mmol) according to the General Procedure 9, de- scribed in Example 82. The title compound was obtained in 44% yield (10.6 mg). 1H NMR (600 MHz,CDC13)5 ppm 2.31 (s, 6 H) 3.75 (s, 3 H) 3.92 (s, 3 H) 6.70 (dd, , 2.21 Hz, 1 H) 6.75 (d, J=2.21 Hz, 1 H) 6.90 (br. s., 1 H) 7.11 (s, 2 H) 7.54 (s, 1 H) 7.78 (d, J=8.62 Hz, 1 H) 10.90 (s, 1 H). MS (ESI+) m/Z 482 [M+H]+.
Example 104 Methyl —(3-acetylphenyl)chlor0thienyl] sulfonyl}amino)—2-hydr0xybenzoate W0 2013/093095 132 The product was prepared from methyl 4- {[(4-bromochlorothienyl)sulfonyl]amino} hydroxybenzoate (Intermediate 3) (21 mg, 0.050 mmol) and 3-acetylphenylboronic acid (8 mg, 0.050 mmol) according to the General Procedure 9, bed in Example 82. The title compound was obtained in 21% yield (4.9 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 2.63 (s, 3 H) 3.91 (s, 3 H) 6.77 (dd, J=8.70, 2.20 Hz, 1 H) 6.82 (d, J=2.20 Hz, 1 H) 7.60 (t, J=7.78 Hz, 1 H) 7.70 (s, 1 H) 7.75 (ddd, J=7.63, 1.83, 1.22 Hz, 1 H) 7.78 (d, J=8.70 Hz, 1 H) 8.03 (ddd, J=7.93, 1.83, 1.22 Hz, 1 H) 8.08 (td, , 0.61 Hz, 1 H). MS (ESI+) m/z 466 [M+H]+.
Example 105 Methyl 4-[({5-chlor0[2-(hydroxymethyl)phenyl]thiophen-Z-yl}sulfonyl)amin0] hydroxybenzoate o R \‘S/ O S ‘0 CI \ I O\ The product was prepared from methyl 4- {[(4-bromochlorothienyl)sulfonyl]amino} hydroxybenzoate (Intermediate 3) (21 mg, 0.050 mmol) and 2-hydroxymethylphenylboronic acid (8 mg, 0.050 mmol) according to the General Procedure 9, described in e 82. The title nd was obtained in 52% yield (11.9 mg). 1H NMR (600 MHz, CDClg) 5 ppm 1.98 (t, J=4.27 Hz, 1 H) 3.94 (s, 3 H) 4.38 (d, J=4.27 Hz, 2 H) 6.66 (dd, J=8.62, 2.21 Hz, 1 H) 6.82 (d, J=2.21 Hz, 1 H) 7.05 (br. s., 1 H) 7.24 (dd, J=7.55, 1.37 Hz, 1 H) 7.37 (td, J=7.55, 1.37 Hz, 1 H) 7.44 (td, J=7.55, 1.37 Hz, 1 H) 7.54 - 7.57 (m, 1 H) 7.67 (s, 1 H) 7.79 (d, J=8.62 Hz, 1 H) 11.02 (s, 1 H). MS (ESI+) m/z 436 [M-OH]+.
Example 106 Methyl 4-({[5—chlor0(6-meth0xypyridinyl)thienyl]sulfonyl}amin0)—2- hydroxybenzoate W0 2013/093095 133 The product was prepared from methyl 4- {[(4-bromochlorothienyl)sulfonyl]amino} hydroxybenzoate (Intermediate 3) (21 mg, 0.050 mmol) and 6-methoxypyridineboronic acid (8 mg, 0.050 mmol) according to the General Procedure 9, described in Example 82. The product was fiarther d by ative TLC a, 20% EtOAc in hexane).The title compound was obtained in 28% yield (6.4 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 3.91 (s, 3 H) 3.94 (s, 3 H) 6.75 (dd, J=8.70, 2.20 Hz, 1 H) 6.80 (d, J=2.20 Hz, 1 H) 6.88 (dd, J=8.62, 0.72 Hz, 1 H) 7.66 (s, l H) 7.77 (d, J=8.70 Hz, 1 H) 7.83 (dd, J=8.62, 2.52 Hz, 1 H) 8.28 (dd, , 0.72 Hz, 1 H). MS (ESI+) m/z 455 [M+H]+.
Example 107 Methyl 4-({[4-(3-amin0phenyl)chlorothiophen-Z-yl]sulfonyl}amin0)—2- hydroxybenzoate trifluoroacetate \8 IS00m \ The product was prepared from methyl 4- {[(4-bromochlorothienyl)sulfonyl]amino} hydroxybenzoate (Intermediate 3) (21 mg, 0.050 mmol) and 3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolanyl)aniline (11 mg, 0.050 mmol) according to the General Procedure 9, de- scribed in Example 82. The title compound was obtained in 25% yield (6.8 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 3.90 (s, 3 H) 6.73 (dd, J=8.70, 2.20 Hz, 1 H) 6.73 (ddd, J=8.08, 2.29, 0.95 Hz, 1 H) 6.76 (ddd, J=7.64, 1.71, 0.95 Hz, 1 H) 6.79 (d, J=2.20 Hz, 1 H) 6.83 W0 2013/093095 134 (ddd, J=2.29, 1.71, 0.45 Hz, 1 H) 7.15 (ddd, J=8.08, 7.64, 0.45 Hz, 1 H) 7.54 (s, 1 H) 7.75 (d, J=8.70 Hz, 1 H). MS (1351+) m/Z 439 [M+H]+.
Example 108 Methyl 4-{[(5-chlor0{4-[(methylsulfonyl)amin0]phenyl}thi0phen f0nyl]amin0}hydr0xybenzoate CI 0 I g H / 1 —|s’ HO 0'11 O O \ The product was prepared from methyl 4- {[(4-bromochlorothieny1)su1fony1]amino} hydroxybenzoate (Intermediate 3) (21 mg, 0.050 mmol) and 4- methanesulfonylaminophenylboronic acid pinacol ester (15 mg, 0.050 mmo 1) according to the General Procedure 9, described in Example 82. The title compound was obtained in 6% yield (1.6 mg). 1H NMR (600 MHz, CDgOD) 5 ppm 3.00 (s, 3 H) 3.91 (s, 3 H) 6.74 (dd, J=8.70, 2.20 Hz, 1 H) 6.80 (d, J=2.20 Hz, 1 H) 7.30 - 7.35 (m, 2 H) 7.48 - 7.51 (m, 2 H) 7.62 (s, 1 H) 7.76 (d, J=8.70 Hz, 1 H). MS (ESI+) m/Z 517 [M+H]+.
Example 109 Methyl 4-({[4-(4-carbamoylphenyl)chlor0thi0phenyl]sulfonyl}amin0)—2- hydroxybenzoate CI s (\D\ H \ / TFN O HO The t was prepared from methyl 4- {[(4-bromochlorothieny1)su1fony1]amino} hydroxybenzoate (Intermediate 3) (21 mg, 0.050 mmol) and (4-aminocarbonylpheny1)boronic acid (8 mg, 0.050 mmol) according to the General Procedure 9, described in Example 82. The W0 2013/093095 135 title compound was obtained in 36% yield (8.4 mg). 1H NMR (600 MHz, CDgOD) 5 ppm 3.91 (s, 3 H) 6.75 (dd, J=8.70, 2.20 Hz, 1 H) 6.81 (d, J=2.20 Hz, 1 H) 7.60 - 7.65 (m, 2 H) 7.68 (s, l H) 7.77 (d, J=8.70 Hz, 1 H) 7.94 - 7.97 (m, 2 H). MS (ESI+) m/z 467 [M+H]+. e 110 Methyl 4-({[5-chlor0(3-flu0r0methoxyphenyl)thi0phenyl]sulfonyl}amin0)—2- hydroxybenzoate CI 3 (a H \ / TN \ O F \ The product was ed from methyl 4- {[(4-bromochlorothienyl)sulfonyl]amino} hydroxybenzoate mediate 3) (21 mg, 0.050 mmol) and 3-fluoro yphenylboronic acid (8 mg, 0.050 mrnol) according to the General Procedure 9, de- scribed in Example 82. The title compound was obtained in 38% yield (9 mg). 1H (600 MHz, CDgOD) 5 ppm 3.91 (s, 3 H) 3.91 (s, 3 H) 6.74 (dd, J=8.70, 2.20 Hz, 1 H) 6.80 (d, J=2.20 Hz, 1 H) 7.17 (t, J=8.47 Hz, 1 H) 7.25 - 7.31 (m, 2 H) 7.60 (s, l H) 7.77 (d, J=8.70 Hz, 1 H).
MS (ESI+) m/Z 472 [M+H]+.
Example 1 1 1 Methyl 4-{[(5—chlor0pyridinylthi0phenyl)sulf0nyl] amin0}hydr0xybenz0ate O H CI 8 “/N The product was prepared from methyl 4- {[(4-bromochlorothienyl)sulfonyl]amino} hydroxybenzoate (Intermediate 3) (21 mg, 0.050 mmol) and pyridinylboronic acid (6 mg, 0.049 mmol) according to the General Procedure 9, described in Example 82. The title com- pound was obtained in 16% yield (3.4 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.93 (s, 3 H) W0 2013/093095 136 6.73 (dd, J=8.60, 2.24 Hz, 1 H) 6.76 (d, J=2.24 Hz, 1 H) 7.00 (br. s., 1 H) 7.39 (ddd, J=7.90, 4.88, 0.87 Hz, 1 H) 7.59 (s, 1 H) 7.80 (d, J=8.60 Hz, 1 H) 7.81 (ddd, J=7.90, 2.28, 1.68 Hz, 1 H) 8.64 (dd, J=4.88, 1.68 Hz, 1 H) 8.72 (dd, , 0.87 Hz, 1 H) 10.93 (s, 1 H). MS (ESI+) m/Z 425 .
Example 112 Methyl 2-hydr0xy({[3'-(methylsulfonyl)biphenylyl] sulfonyl}amin0)benz0ate 0.. ,H S“ O o“ o / O \O OH\ The product was prepared from methyl 4- {[(3-bromopheny1)su1fony1]amino} ybenzoate (Intermediate 4) (21 mg, 0.050 mmol) and (3- methy1su1phony1)pheny1boronic acid (10 mg, 0.050 mmol) according to the General Proce- dure 9, described in Example 82. The title compound was ed in 75% yield (17.2 mg). 1H NMR (600 MHz, CD3OD) 8 ppm 3.18 (s, 3 H) 3.88 (s, 3 H) 6.71 (dd, J=8.70, 2.20 Hz, 1 H) 6.76 (d, J=2.20 Hz, 1 H) 7.68 (td, J=7.85, 0.45 Hz, 1 H) 7.71 (d, J=8.70 Hz, 1 H) 7.76 (td, J=7.85, 0.45 Hz, 1 H) 7.92 (ddd, J=7.85, 1.82, 1.05 Hz, 1 H) 7.94 (ddd,J=7.85, 1.87, 1.05 Hz, 1 H) 7.96 (ddd,J=7.85, 1.87, 1.05 Hz, 1 H) 8.01 (ddd,J=7.85, 1.82, 1.05 Hz, 1 H) 8.11 (td, J=1.82, 0.45 Hz, 1 H) 8.11 (td, J=1.85, 0.45 Hz, 1 H). MS (ESI+) m/z 462 [M+H]+.
Example 113 Methyl 4-{[(3'-carbamoylbiphenylyl)sulf0nyl]amin0}hydr0xybenzoate o H 08: O H2N OH\ The product was prepared from methyl 4- {[(3-bromopheny1)su1fony1]amino} hydroxybenzoate (Intermediate 4) (21 mg, 0.050 mmol) and (3-carbamoy1pheny1boronic acid (8 mg, 0.050 mmol) according to the General Procedure 9, described in Example 82. The title compound was obtained in 43% yield (9.1 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 3.88 (s, W0 2013/093095 137 3 H) 6.70 (dd, J=8.70, 2.20 Hz, 1 H) 6.75 (d, J=2.20 Hz, 1 H) 7.59 (td, J=7.78, 0.45 Hz, 1 H) 7.64 (ddd, J=7.87, 7.78, 0.45 Hz, 1 H) 7.70 (d, J=8.70 Hz, 1 H) 7.79 (ddd, J=7.78, 1.91, 1.06 Hz, 1 H) 7.88 (ddd, J=7.87, 1.87, 1.06 Hz, 1 H) 7.91 (ddd,.]=7.78, 1.72, 1.06 Hz, 1 H) 7.92 (ddd, J=7.78, 1.87, 1.07 Hz, 1 H) 8.12 (td, J=1.84, 0.45 Hz, 1 H) 8.15 (td, J=1.89, 0.45 Hz, 1 H). MS (ESI+) m/Z 427 [M+H]+.
Example 114 Methyl 2-hydr0xy({[5-(triflu0r0methyl)biphenyl—3-yl] sulfonyl}amin0)benz0ate O /N O F ‘S\\ . o . .1 The product was synthesized from methyl 4-({[3-bromo-5 (trifluorome- thy1)pheny1]su1fony1}amino)hydroxybenzoate (Intermediate 5) (23 mg, 0.050 mmol) and boronic acid (7 mg, 0.06 mmol) according to the l Procedure 9, bed in Example 82, but without purification. The ester intermediate was treated with 1 M NaOH (300 uL) at 60 oC overnight. The crude product was purified by ative HPLC (acidic system) and 2-hydroxy({[5-(trifluoromethy1)bipheny1y1]su1fony1}amino)benzoic acid was obtained in 73% yield over two steps (15.9 mg). 1H NMR (500 MHz, CDgOD) 8 ppm 6.69 (dd, J=8.64, 2.20 Hz, 1 H) 6.74 (d, J=2.20 Hz, 1 H) 7.43 - 7.48 (m, 1 H) 7.48 - 7.53 (m, 2 H) 7.58 — 7.63 (m, 2 H) 7.74 (d, J=8.64 Hz, 1 H) 8.06 (dq, J=1.73, 0.75 Hz, 1 H) 8.11 (dq, J=1.73, 0.75 Hz, 1 H) 8.24 (t, J=1.73 Hz, 1 H). MS (ESI+) m/Z 437 [M+H]+.
The title compound was prepared from 2-hydroxy—4-({[5-(trifluoromethy1)bipheny1 y1]su1fony1}amino)benzoic acid (14.2 mg, 0.032 mmol), 1,1'-carbony1diimidazole (16 mg, 0.100 mmol), MeOH (20 uL, 0.5 mmol) and pyridine (8 mg, 0.100 mmol) in MeCN, accord- ing to the General Procedure 7, described in Example 59. The title compound was obtained in 56% yield (8.2 mg) 1H NMR (600 MHz, CDC13) 8 ppm 3.91 (s, 3 H) 6.68 (dd, J=8.66, 2.20 Hz, 1 H) 6.70 (d, J=2.20 Hz, 1 H) 7.05 (br. s., 1 H) 7.44 - 7.47 (m, 1 H) 7.47 - 7.52 (m, 2 H) 7.52 - 7.55 (m, 2 H) 7.74 (d, J=8.66 Hz, 1 H) 7.99 - 8.01 (m, 1 H) 8.06 - 8.09 (m, 1 H) 8.23 (t, J=1.59 Hz, 1 H) 10.88 (s, 1 H). MS (ESI+) m/z 452 [M+H]+.
W0 2013/093095 138 Example 115 Methyl 4-({[2',5'-diflu0r0(trifluor0methyl)biphenylyl]sulfonyl}amin0)—2- hydroxybenzoate The product was synthesized from methyl 4-({[3-bromo (trifluoromethy1)pheny1]sulfonyl}amino)hydroxybenzoate (Intermediate 5) (23 mg, 0.050 mmol) and 2,5-difluoropheny1boronic acid (9 mg, 0.06 mmol) according to the General Pro- cedure 9, described in Example 82, but without purification. The ester ediate was treat- ed with l M NaOH (300 uL) at 60 oC overnight. The crude product was purified by prepara- tive HPLC (acidic system) and 4-({[2',5'-difluoro(trifluoromethyl)bipheny1—3- y1]su1fony1} amino)hydroxybenzoic acid was obtained in 81% yield over two steps (19.2 mg). 1H NMR (500 MHz, CDgOD) 8 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., l H) 8.13 (br. s., l H) 8.21 - 8.23 (m, 1 H). MS (ESI+) m/z 474 [M+H]+.
The title compound was prepared from 4-({[2',5'-difluoro(trifluoromethyl)bipheny1—3- y1]su1fony1} amino)hydroxybenzoic acid (17.8 mg, 0.038 mmol), arbony1diimidazole (16 mg, 0.100 mmol), MeOH (20 uL, 0.5 mmol) and pyridine (8 mg, 0.100 mmol) in MeCN, according to the General Procedure 7 described in Example 59. The title nd was ob- tained in 62% yield (11.3 mg). 1H NMR (600 MHz, CDC13) 8 ppm 3.91 (s, 3 H) 6.67 - 6.71 (m, 2 H) 7.06 (ddd, J=8.4l, 5.95, 3.12 Hz, 1 H) 7.11 (dddd, , 7.30, 3.80, 3.12 Hz, 1 H) 7.13 (br. s., l H) 7.17 (ddd, J=9.50, 9.11, 4.46 Hz, 1 H) 7.73 - 7.78 (m, l H) 7.95 - 7.97 (m, l H) 8.12 - 8.14 (m, 1 H) 8.17 - 8.19 (m, l H) 10.88 (s, l H). MS (ESI+) m/z 488 [M+H]+.
Example 116 Methyl 4-({[3-(2,3-dihydr0benz0furanyl)—5- (trifluoromethyl)phenyl] sulfonyl}amino)—2-hydr0xybenz0ate W0 2013/093095 139 The t was synthesized from methyl 4-({[3-bromo (trifluoromethyl)phenyl]sulfonyl}amino)hydroxybenzoate mediate 5) (23 mg, 0.050 mmol) and 2,3-dihydrobenzofuranboronic acid (10 mg, 0.06 mmol) according to the Gen- eral Procedure 9, described in Example 82, but without purification. The ester intermediate was treated with 1 M NaOH (300 uL) at 60 oC overnight. The crude product was purified by preparative HPLC (acidic system) and 4-({[3-(2,3-dihydrobenzofuran—5-yl) (trifluoromethyl)phenyl]sulfonyl}amino)hydroxybenzoic acid was ed in 83% yield (19.8 mg) over two steps. 1H NMR (500 MHz, CDgOD) 8 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+) m/Z 480 [M+H]+.
The title compound was prepared from 4-({[3-(2,3-dihydrobenzofi1ran—5-yl) (trifluoromethyl)phenyl]sulfonyl}amino)hydroxybenzoic acid (18.5 mg, 0.039 mmol), 1,1'-carbonyldiimidazole (16 mg, 0.100 mmol), MeOH (20 uL, 0.5 mmol) and ne (8 mg, 0.100 mmol) in MeCN, according to the General Procedure 7, described in Example 59.
The title compound was obtained in 40% yield (7.6 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.28 (t, J=8.79 Hz, 2 H) 3.90 (s, 3 H) 4.65 (t, J=8.79 Hz, 2 H) 6.67 (dd, J=8.66, 2.20 Hz, 1 H) 6.71 (d, J=2.20 Hz, 1 H) 6.87 (d, J=8.30 Hz, 1 H) 7.10 (br. s., 1 H) 7.28 - 7.31 (ddt, , 2.11, 0.70 Hz, 1 H) 7.36 (dq, J=2.11, 0.45 Hz, 1 H) 7.73 (d, J=8.66 Hz, 1 H) 7.91 - 7.94 (m, 1 H) 7.99 - 8.01 (m, 1 H) 8.15 (t, J=1.78 Hz, 1 H) 10.87 (s, 1 H). MS (ESI+) m/z 494 [M+H]+.
Example 117 Methyl 2-hydr0xy({[2'-hydroxy-S-(triflu0r0methyl)biphenyl—3- yl] sulfonyl}amin0)benz0ate W0 93095 140 F F F “S/N The t was synthesized from methyl 4-({[3-bromo (trifluoromethyl)phenyl]sulfonyl}amino)hydroxybenzoate (Intermediate 5) (23 mg, 0.050 mmol) and 2-hydroxyphenylboronic acid pinacol ester (13 mg, 0.06 mmol) according to the General Procedure 9, described in Example 82, but without purification. The ester intermedi- ate was treated with 1 M NaOH (300 uL) at 60 oC overnight. The crude t was purified by ative HPLC (acidic system) and 2-hydroxy({[2'-hydroxy (trifluoromethyl)biphenylyl]sulfonyl} amino)benzoic acid was obtained in 72% yield over two steps (16.3 mg). 1H NMR (500 MHz, CDgOD) 8 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, , 0.78 Hz, 1 H) 8.29 (t, J=1.67 Hz, 1 H). MS (ESI+) m/Z 454 [M+H]+.
The title compound was prepared from 2-hydroxy({[2'-hydroxy (trifluoromethyl)biphenylyl]sulfonyl}amino)benzoic acid (15.8 mg, 0.035 mmol), 1,1'- carbonyldiimidazole (16 mg, 0.100 mmol), MeOH (20 uL, 0.5 mmol) and pyridine (8 mg, 0.100 mmol) in MeCN, according to the General Procedure 7, described in Example 59. The title compound was obtained in 45% yield (7.4 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.91 (s, 3 H) 5.51 (br. s., l H) 6.64 (dd, J=8.66, 2.26 Hz, 1 H) 6.76 (d, J=2.26 Hz, 1 H) 6.91 (dd, J=8.06, 1.12 Hz, 1 H) 7.04 (ddd, J=7.66, 7.38, 1.12 Hz, 1 H) 7.12 (br. s., l H) 7.28 (dd, J=7.66, 1.67 Hz, 1 H) 7.30 (ddd, J=8.06, 7.38, 1.67 Hz, 1 H) 7.73 (d, J=8.66 Hz, 1 H) 7.99 - 8.01 (m, l H) 8.06 - 8.07 (m, l H) 8.36 (t, J=l.70 Hz, 1 H) 10.92 (s, l H). MS (ESI+) m/z 468 [M+H]+.
Example 118 Methyl 4-({[5—(2,5—diflu0r0phenyl)thi0phenyl]sulfonyl}amino)—2-hydr0xybenzoate W0 2013/093095 141 The product was synthesized from 4- {[(5-bromothiophenyl)sulfonyl]amino} hydroxybenzoic acid (Intermediate 9) (19 mg, 0.050 mmol) and 2,5-difluorophenylboronic acid (9 mg, 0.06 mmol) according to the General Procedure 9, described in e 82. The crude product was purified by preparative HPLC (acidic system) and 4-({[5-(2,5- difluorophenyl)thiophenyl]sulfonyl} amino)hydroxybenzoic acid was obtained in 74% yield (15.3 mg). 1H NMR (500 MHz, CDgOD) 8 ppm 6.72 (dd, J=8.63, 2.17 Hz, 1 H) 6.78 (d, J=2.17 Hz, 1 H) 7.15 (dddd, , 7.53, 3.86, 3.16 Hz, 1 H) 7.27 (ddd, 4, 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+) m/z 412 [M+H]+.
The title compound was prepared from 4-({[5-(2,5-difluorophenyl)thiophen yl]sulfonyl} amino)hydroxybenzoic acid (13.9 mg, 0.034 mmol), 1,1'-carbonyldiimidazole (16 mg, 0.100 mmol), MeOH (20 uL, 0.5 mmol) and pyridine (8 mg, 0.100 mmol) in MeCN, according to the General Procedure 7, bed in Example 59. The title nd was ob- tained in 57% yield (8.2 mg). 1H NMR (600 MHZ, CDClg) 8 ppm 3.91 (s, 3 H) 6.71 (dd, J=8.66, 2.26 Hz, 1 H) 6.75 (d, J=2.26 Hz, 1 H) 6.96 (br. s., 1 H) 7.03 (dddd, J=9.13, 7.32, 3.84, 3.09 Hz, 1 H) 7.14 (ddd, J=10.14, 9.13, 4.55 Hz, 1 H) 7.26 (ddd, J=8.80, 5.74, 3.09 Hz, 1 H) 7.35 (dd, J=4.04, 0.74 Hz, 1 H) 7.63 (dd, J=4.04, 1.07 Hz, 1 H) 7.76 (d, J=8.66 Hz, 1 H) 10.88 (s, 1 H). MS (ESI+) m/z 426 [M+H]+.
Example 119 Methyl 4-({[5—(2,3-dihydr0benz0furanyl)thi0phenyl]sulfonyl}amin0)—2- hydroxybenzoate o\\ ,N o s 0 \ 0\ \ OH W0 2013/093095 142 2012/076836 The product was sized from 4- {[(5-bromothiophenyl)sulfonyl]amino} hydroxybenzoic acid (Intermediate 9) (19 mg, 0.050 mmol) and 2,3-dihydrobenzofiJran boronic acid (10 mg, 0.06 mmol) according to the General Procedure 9, described in Example 82. The crude product was purified by preparative HPLC c system) and 4-({[5-(2,3- dihydrobenzofuranyl)thiophenyl] sulfonyl}amino)hydroxybenzoic acid was ob- tained in 73% yield (15.2 mg). 1H NMR (500 MHz, CDgOD) 8 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+) m/z 418 [M+H]+.
The title compound was prepared from 4-({[5-(2,3-dihydrobenzofuran—5-yl)thiophen—2- yl]sulfonyl} amino)hydroxybenzoic acid (14.4 mg, 0.034 mmol), 1,1'-carbonyldiimidazole (16 mg, 0.100 mmol), MeOH (20 uL, 0.5 mmol) and pyridine (8 mg, 0.100 mmol) in MeCN, according to the General Procedure 7, described in Example 59. The title compound was ob- tained in 52% yield (7.8 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.24 (t, J=8.73 Hz, 2 H) 3.91 (s, 3 H) 4.62 (t, J=8.73 Hz, 2 H) 6.69 (dd, J=8.66, 2.20 Hz, 1 H) 6.75 (d, J=2.20 Hz, 1 H) 6.79 (d, J=8.30 Hz, 1 H) 6.91 (br. s., 1 H) 7.04 (d, J=4.03 Hz, 1 H) 7.29 - 7.32 (ddt, J=8.30, 2.08, 0.74 Hz, 1 H) 7.37 (dq, J=2.08, 0.51 Hz, 1 H) 7.57 (d, J=4.03 Hz, 1 H) 7.74 (d, J=8.66 Hz, 1 H) 10.87 (s, 1 H). MS (ESI+) m/z 432 [M+H]+.
Example 120 Methyl 2-hydr0xy({[3-(1-hydr0xyethyl)phenyl]sulfonyl}amin0)benzoate 0“ H l I \\ o Qf OH O HO \ The intermediate 4- cetylphenyl)sulfonyl]amino}hydroxybenzoic acid was synthe- sized in 21% yield (71 mg) from 3-acetylbenzenesulfonyl chloride (220 mg, 1.0 mmol) and 4- aminosalicylic acid (150 mg, 1.0 mmol) according to the General ure 4, described in Example 7. 1H NMR (500 MHz, CDgOD) 8 ppm 2.61 (s, 3 H) 6.66 (dd, J=8.55, 2.20 Hz, 1 H) 6.69 (d, J=2.20 Hz, 1 H) 7.68 (td, J=7.84, 0.54 Hz, 1 H) 7.69 (d, J=8.55 Hz, 1 H) 8.07 (ddd, W0 2013/093095 143 J=7.87, 1.96, 1.10 Hz, 1 H) 8.20 (ddd, J=7.81, 1.69, 1.10 Hz, 1 H) 8.42 (ddd,.]=1.96, 1.69, 0.54 Hz, 1 H). MS (ESI+) m/Z 336 [M+H]+.
A mixture of 4- {[(3-acetylphenyl)sulfonyl]amino} hydroxybenzoic acid (12 mg, 0.036 mmol) and NaBH4 (5 mg, 0.132 mmol) in MeOH (1 mL) was stirred at room temperature for l h. The on was quenched with l M HCl (2 mL) and the product was extracted with EtOAc. The organic phase was concentrated and the crude product was purified by prepara- tive HPLC (acidic ) and 2-hydroxy({[3-(l- hydroxyethyl)phenyl]sulfonyl}amino)benzoic acid was obtained in 70% yield (8.5 mg). 1H NMR (500 MHz, CDgOD) 8 ppm 1.39 (d, J=6.47 Hz, 3 H) 4.83 - 4.89 (m, l H) 6.63 (dd, J=8.64, 2.18 Hz, 1 H) 6.66 (dd, J=2.l8, 0.36 Hz, 1 H) 7.49 (ddd, J=7.8l, 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=7.8l, 1.93, 1.16 Hz, 1 H) 7.89 (dddd, J=l.93, 1.72, 0.57, 0.57 Hz, 1 H). MS (ESI+) m/Z 338 [M+H]+.
The title compound was ed from 2-hydroxy({[3-(l- hydroxyethyl)phenyl]sulfonyl}amino)benzoic acid (7.7 mg, 0.023 mmol), l,l'- carbonyldiimidazole (16 mg, 0.100 mmol), MeOH (20 uL, 0.5 mmol) and pyridine (8 mg, 0.100 mmol) in MeCN, according to the General Procedure 7, described in Example 59. The title compound was ed in 34% yield (2.7 mg). 1H NMR (600 MHz, CDClg) 8 ppm 1.47 (d, J=6.47 Hz, 3 H) 3.90 (s, 3 H) 4.94 (q, J=6.47 Hz, 1 H) 6.63 (dd, J=8.5l, 2.27 Hz, 1 H) 6.64 (dd, J=2.27, 0.55 Hz, 1 H) 6.82 (br. s., l H) 7.46 (ddd, J=7.87, 7.71, 0.48 Hz, 1 H) 7.58 (dddd, J=7.7l, 1.72, 1.11, 0.61 Hz, 1 H) 7.70 (dd, J=8.5l, 0.55 Hz, 1 H) 7.77 (ddd, J=7.87, 1.98, 1.11 Hz, 1 H) 7.89 (dddd, J=l.98, 1.72, 0.57, 0.48 Hz, 1 H) 10.83 (s, l H). MS (ESI+) m/z 334 [M-OH]+.
Example 121 Methyl 0xy{[(3-meth0xyphenyl)sulf0nyl] amin0}benzoate W0 93095 144 The intermediate 2-hydroxy {[(3-methoxyphenyl)sulfonyl]amino}benzoic acid was synthe- sized in 25% yield (81 mg) from 3-methoxybenzenesulfonyl de (210 mg, 1.0 mmol) and 4-aminosalicylic acid (150 mg, 1.0 mmol) according to the General Procedure 4, described in Example 7. 1H NMR (500 MHz, CDgOD) 8 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+) m/Z 324 [M+H]+.
The title compound was prepared from 2-hydroxy {[(3- yphenyl)sulfonyl]amino}benzoic acid (12.0 mg, 0.037 mmol), 1,1'- carbonyldiimidazole (16 mg, 0.100 mmol), MeOH (20 uL, 0.5 mmol) and pyridine (8 mg, 0.100 mmol) in MeCN, according to the General Procedure 7, described in Example 59. The title compound was obtained in 77% yield (9.6 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.81 (s, 3 H) 3.90 (s, 3 H) 6.63 (dd, J=8.66, 2.25 Hz, 1 H) 6.66 (d, J=2.25 Hz, 1 H) 6.77 (br. s., 1 H) 7.08 (ddd, J=8.28, 2.59, 1.00 Hz, 1 H) 7.36 (ddd, J=2.59, 1.70, 0.36 Hz, 1 H) 7.38 (ddd, J=8.28, 7.77, 0.36 Hz, 1 H) 7.44 (ddd, J=7.77, 1.70, 1.00 Hz, 1 H) 7.71 (d, J=8.66 Hz, 1 H) 10.84 (s, 1 H). MS (ESI+) m/Z 338 [M+H]+.
Example 122 Methyl 4-({[3-(2,3-dihydr0benz0furanyl)benzyl] sulfonyl}amino)—2- hydroxybenzoate 4-{[(3-Bromobenzyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 10) (12 mg, 0.030 mmol), 2,3-dihydrobenzofuranboronic acid (6 mg, 0.036 mmol), DIPEA (15 mg, 0.12 mmol) and Pd(dppf)C12‘CH2C12 (1 mg, 0.0012 mmol) were d to react according to the General Procedure 9, described in Example 82. The crude product was d by preparative HPLC (acidic system) and 4-({[3-(2,3-dihydrobenzofuranyl)benzyl]sulfonyl} amino) hydroxybenzoic acid was obtained in 72% yield (9.2 mg). 1H NMR (500 MHz, CDgOD) 8 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, .1=1.47 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). (ESI+) m/Z 426 [M+H]+.
The title compound was ed from 4-({[3-(2,3-dihydrobenzofuran—5- yl)benzyl]sulfonyl}amino)hydroxybenzoic acid (6.1 mg, 0.014 mmol), 1,1'- carbonyldiimidazole (16 mg, 0.100 mmol), MeOH (20 uL, 0.5 mmol) and pyridine (8 mg, 0.100 mmol) in MeCN, ing to the General Procedure 7, described in Example 59. The title compound was obtained in 24% yield (1.5 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.26 (t, J=8.73 Hz, 2 H) 3.95 (s, 3 H) 4.47 (s, 2 H) 4.62 (t, J=8.73 Hz, 2 H) 6.53 (br. s., 1 H) 6.64 (dd, J=8.66, 2.26 Hz, 1 H) 6.73 (d, J=2.26 Hz, 1 H) 6.82 (d, J=8.30 Hz, 1 H) 7.13 - 7.17 (m, 1 H) 7.23 - 7.26 (m, 1 H) 7.30 - 7.32 (m, 1 H) 7.33 (t, J=1.85 Hz, 1 H) 7.38 (t, J=7.77 Hz, 1 H) 7.53 (ddd, J=7.77, 1.85, 1.10 Hz, 1 H) 7.78 (d, J=8.66 Hz, 1 H) 10.95 (s, 1 H). MS (ESI+) m/Z 440 [M+H]+.
Example 123 Methyl 4-({[(2',5'-diflu0r0biphenyl—4-yl)methyl] sulfonyl}amino)—2-hydr0xybenzoate O\\ N O 4-{[(4-Bromobenzyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 11) (12 mg, 0.030 mmol), 2,5-difluorophenylboronic acid (6 mg, 0.036 mmol), DIPEA (15 mg, 0.12 mmol) and f)Clg‘CH2Clz (1 mg, 0.0012 mmol) were allowed to react according to the General Procedure 9, described in e 82. The crude product was purified by preparative HPLC (acidic system) and 4-({[(2',5'-difluorobiphenylyl)methyl]sulfonyl}amino) hydroxybenzoic acid was obtained in 95% yield (11.9 mg). 1H NMR (500 MHz, CDgOD) 8 ppm 4.56 (s, 2 H) 6.66 (dd, J=8.50, 2.00 Hz, 1 H) 6.73 (br. s., 1 H) 7.07-7.13 (m, 1 H).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+) m/Z 420 [M+H]+.
The title compound was prepared from 2',5'-difluorobiphenyl yl)methyl]sulfonyl}amino)hydroxybenzoic acid (9.5 mg, 0.023 mmol), 1,1'- carbonyldiimidazole (16 mg, 0.100 mmol), MeOH (20 uL, 0.5 mmol) and pyridine (8 mg, W0 2013/093095 146 0.100 mmol) in MeCN, according to the General Procedure 7, described in Example 59. The title nd was obtained in 52% yield (5.1 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.95 (s, 3 H) 4.47 (s, 2 H) 6.53 (br. s., l H) 6.61 (dd, J=8.66, 2.26 Hz, 1 H) 6.75 (d, J=2.26 Hz, 1 H) 7.00 - 7.05 (m, l H) 7.08 - 7.12 (m, l H) 7.12 (td, J=9.33, 4.52 Hz, 1 H) 7.30 - 7.34 (m, 2 H) 7.49 - 7.53 (m, 2 H) 7.79 (d, J=8.66 Hz, 1 H) 10.95 (s, l H). MS (ESI+) m/z 434 .
Example 124 Methyl 4-({[4-(2,3-dihydr0benz0furanyl)benzyl] sulfonyl}amino)—2- hydroxybenzoate ~74“I O \ -Bromobenzyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate ll) (12 mg, 0.030 mmol), 2,3-dihydrobenzofuranboronic acid (6 mg, 0.036 mmol), DIPEA (15 mg, 0.12 mmol) and Pd(dppf)Clz‘CH2Clz (1 mg, 0.0012 mmol) were allowed to react according to the General Procedure 9, described in Example 82. The crude product was purified by preparative HPLC (acidic system) and 4-({[4-(2,3-dihydro-l-benzofuranyl)benzyl]sulfonyl} amino) hydroxybenzoic acid was obtained in 96% yield (12.2 mg). 1H NMR (500 MHz, CDgOD) 8 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.l8, 1.83 Hz, 1 H) 7.42 (d, J=l.83 Hz, 1 H) 7.45 - 7.50 (m, 2 H) 7.74 (d, J=8.67 Hz, 1 H).
MS (ESI+) m/Z 426 .
The title compound was prepared from 4-({[4-(2,3-dihydro-l-benzofuran—5- yl)benzyl]sulfonyl}amino)hydroxybenzoic acid (10.4 mg, 0.024 mmol), l,l'- yldiimidazole (16 mg, 0.100 mmol), MeOH (20 uL, 0.5 mmol) and pyridine (8 mg, 0.100 mmol) in MeCN, according to the General Procedure 7, described in Example 59. The title compound was obtained in 27% yield (2.9 mg). 1H NMR (600 MHZ, CDClg) 8 ppm 3.27 (t, J=8.66 Hz, 2 H) 3.95 (s, 3 H) 4.45 (s, 2 H) 4.63 (t, J=8.66 Hz, 2 H) 6.47 (br. s., l H) 6.63 (dd, J=8.66, 2.26 Hz, 1 H) 6.75 (d, J=2.26 Hz, 1 H) 6.85 (d, J=8.25 Hz, 1 H) 7.24 - 7.27 (m, 2 H) 7.29 — 7.33 (ddt, , 2.07, 0.71 Hz, 1 H) 7.39 — 7.41 (m, 1 H) 7.48 _ 7.52 (m, 2 H) 7.79 (d, J=8.66 Hz, 1 H) 10.95 (s, 1 H). MS (ESI+) m/Z 440 [M+H]+.
Example 125 Methyl 4-{[(biphenylylmethyl)sulfonyl]amin0}hydr0xybenz0ate o\\ ,N o 4-{[(4-Bromobenzy1)su1fony1]amino}hydroxybenzoic acid (Intermediate 11) (12 mg, 0.030 mmol), phenylboronic acid (4 mg, 0.036 mmol), DIPEA (15 mg, 0.12 mmol) and Pd(dppf)C12‘CH2C12 (1 mg, 0.0012 mmo 1) were allowed to react according to the General Procedure 9, described in Example 82. The crude product was purified by preparative HPLC c system) and 4- {[(bipheny1y1methy1)su1fony1]amino}hydroxybenzoic acid was obtained in 90% yield (10.3 mg). 1H NMR (500 MHz, CDgOD) 5 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+) m/Z 384 [M+H]+.
The title compound was prepared from 4- {[(bipheny1y1methy1)su1fony1]amino} hydroxybenzoic acid (8.4 mg, 0.022 mmol), arbony1diimidazole (16 mg, 0.100 mmol), MeOH (20 uL, 0.5 mmol) and pyridine (8 mg, 0.100 mmol) in MeCN, according to the Gen- eral Procedure 7, described in Example 59. The title nd was obtained in 49% yield (4.3 mg). 1H NMR (600 MHz, CDC13) 8 ppm 3.95 (s, 3 H) 4.47 (s, 2 H) 6.47 (br. s., 1 H) 6.62 (dd, J=8.66, 2.26 Hz, 1 H) 6.76 (d, J=2.26 Hz, 1 H) 7.28 - 7.33 (m, 2 H) 7.36 - 7.40 (m, 1 H) 7.43 - 7.47 (m, 2 H) 7.54 - 7.59 (m, 4 H) 7.79 (d, J=8.66 Hz, 1 H) 10.95 (s, 1 H). MS (ESI+) m/Z 398 [M+H]+.
Example 126 Methyl 2-hydr0xy({[(2'-hydr0xybiphenyl—4-yl)methyl] sulfonyl}amin0)benz0ate W0 2013/093095 148 4-{[(4-Bromobenzyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 11) (12 mg, 0.030 mmol), 2-hydroxyphenylboronic acid pinacol ester (8 mg, 0.036 mmol), DIPEA (15 mg, 0.12 mmol) and Pd(dpp1)C12‘CH2C12 (1 mg, 0.0012 mmol) were allowed to react according to the General Procedure 9, described in Example 82. The crude product was purified by preparative HPLC (acidic system) giVing 2-hydroxy({[(2'-hydroxybiphenyl—4- hyl]sulfonyl}amino)benzoic acid (12.8 mg). 1H NMR (500 MHz, CDgOD) 8 ppm 4.52 (s, 2 H) 6.69 (dd, , 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, l H) 7.18 - 7.21 (m, l 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+) m/Z 400 .
The title compound was prepared from 2-hydroxy({[(2'-hydroxybiphenyl—4- yl)methyl]sulfonyl}amino)benzoic acid (11.7 mg, 0.029 mmol), l,1'-carbonyldiimidazole (16 mg, 0.100 mmol), MeOH (20 uL, 0.5 mmol) and pyridine (8 mg, 0.100 mmol) in MeCN, ac- cording to the General ure 7, described in Example 59. The title compound was ob- tained in 45% yield (5.5 mg). 1H NMR (600 MHz, CDC13) 8 ppm 3.94 (s, 3 H) 4.48 (s, 2 H) .22 (s, 1 H) 6.60 (dd, J=8.66, 2.26 Hz, 1 H) 6.68 (br. s., 1 H) 6.68 (d, J=2.26 Hz, 1 H) 6.97 (dd, J=8.11, 1.20 Hz, 1 H) 7.00 (ddd,.]=7.58, 7.37, 1.20 Hz, 1 H) 7.21 (dd, J=7.58, 1.71 Hz, 1 H) 7.27 (ddd, J=8.11, 7.37, 1.71 Hz, 1 H) 7.33 - 7.37 (m, 2 H) 7.45 - 7.50 (m, 2 H) 7.78 (d, J=8.66 Hz, 1 H) 10.94 (s, l H). MS (ESI+) m/z 414 [M+H]+.
Example 127 Methyl 4-{[(3'-ethoxybiphenylyl)sulf0nyl] amin0}hydr0xybenz0ate O\\ IN 0 O QS“0 O\ W0 2013/093095 149 A mixture of 4- {[(3-bromophenyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 12) (18.7 mg, 0.05 mmol), 3-ethoxyphenylboronic acid (11.6 mg, 0.07 mmol), K2C03 (20.7 mg, 0.15 mmol) and Pd(dppf)C12:CH2C12 (4 mg, 0.005 mmol) in dioxane (3.2 mL) and water (800 uL) was heated at 145 CC for 900 s in a microwave reactor. The reaction mixture was concen- trated and the crude product was purified by preparative HPLC (neutral method) to give 4- {[(3'-ethoxybiphenylyl)sulfonyl]amino}hydroxybenzoic acid in 80% yield (16.6 mg).
MS (ESI+) calcd mass for C21H19NO6S 413.093308, found 4308.
The title compound was prepared from 4- {[(3'-ethoxybiphenylyl)sulfonyl]amino} hydroxybenzoic acid (9.9 mg, 0.024 mmol), l,l'-carbonyldiimidazole (16 mg, 0.100 mmol), MeOH (20 uL, 0.5 mmol) and pyridine (8 mg, 0.100 mmol) in MeCN, according to the Gen- eral Procedure 7, described in Example 59. The title compound was ed in 41% yield (4.2 mg). 1H NMR (600 MHz, CDC13) 8 ppm 1.45 (t, J=7.03 Hz, 3 H) 3.89 (s, 3 H) 4.09 (q, J=7.03 Hz, 2 H) 6.65 (dd, J=8.66, 2.26 Hz, 1 H) 6.69 (d, J=2.26 Hz, 1 H) 6.84 (br. s., l H) 6.93 (ddd, J=8.26, 2.54, 0.93 Hz, 1 H) 7.04 (dd, , 1.78 Hz, 1 H) 7.10 (ddd, , 1.78, 0.93 Hz, 1 H) 7.36 (dd, J=8.26, 7.64 Hz, 1 H) 7.53 (td, J=7.8l, 0.50 Hz, 1 H) 7.71 (d, J=8.66 Hz, 1 H) 7.76 (ddd, J=7.8l, 1.83, 1.08 Hz, 1 H) 7.83 (ddd,.]=7.8l, 1.92, 1.08 Hz, 1 H) 8.07 (ddd, J=l.92, 1.83, 0.50 Hz, 1 H) 10.84 (s, l H). MS (ESI+) m/z 428 .
Example 128 l-Methylethyl 3'-{[3-hydr0xy(methoxycarbonyl)phenyl] sulfamoyl}biphenyl—3- carboxylate A mixture of 4- {[(3-bromophenyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 12) (18.7 mg, 0.05 mmol), 3-isopropoxycarbonylphenylboronic acid (14.5 mg, 0.07 mmol), K2C03 (20.7 mg, 0.15 mmol) and Pd(dppf)C12:CH2C12 (4 mg, 0.005 mmol) in dioxane (3.2 mL) and water (800 uL) was heated at 145°C for 900 s in a microwave reactor. The reaction mixture was concentrated and the crude product was d by preparative HPLC (neutral method) to give 2-hydroxy [( {3 '- [( l -methylethoxy)carbonyl]biphenyl-3 - W0 2013/093095 150 yl} sulfonyl)amino]benzoic acid in 35% yield (8 mg). MS (ESI+) calcd for C23H21NO7S 455.103873, found 455.104263.
The title compound was ed from 2-hydroxy[({3'-[(1- methylethoxy)carbonyl]biphenylyl} sulfonyl)amino]benzoic acid (3.9 mg, 0.009 mmol), 1,1'-carbonyldiimidazole (16 mg, 0.100 mmol), MeOH (20 uL, 0.5 mmol) and pyridine (8 mg, 0.100 mmol) in MeCN, according to the General ure 7, described in Example 59.
The title compound was obtained in 40% yield (1.6 mg). 1H NMR (600 MHz, CDClg) 8 ppm 1.40 (d, J=6.22 Hz, 6 H) 3.89 (s, 3 H) 5.29 (spt, J=6.22 Hz, 1 H) 6.66 (dd, J=8.66, 2.25 Hz, 1 H) 6.69 (d, J=2.25 Hz, 1 H) 6.91 (br. s., 1 H) 7.53 (td, J=7.73, 0.50 Hz, 1 H) 7.58 (ddd, J=7.81, 7.75, 0.45 Hz, 1 H) 7.71 (ddd, J=7.73, 1.96, 1.15 Hz, 1 H) 7.72 (d, J=8.66 Hz, 1 H) 7.81 (ddd, J=7.75, 1.85, 1.05 Hz, 1 H) 7.87 (ddd,J=7.87, 1.85, 1.05 Hz, 1 H) 8.07 (ddd, J=7.73, 1.67, 1.15 Hz, 1 H) 8.10 (td, J=1.85, 0.45 Hz, 1 H) 8.19 (ddd, J=1.96, 1.67, 0.50 Hz, 1 H) 10.84 (s, 1 H). MS (ESI+) m/Z 470 [M+H]+.
Example 129 Methyl 4-{[(3-acetylphenyl)sulf0nyl] amino}hydr0xybenzoate A mixture of 3-acetylbenzenesulfonyl chloride (109 mg, 0.5 mmol), 4-aminosalicylic acid (153 mg, 1 mmol) and pyridine (0.4 mL, 5 mmol) in CHzClz (10 mL) was stirred at 60 0C for 2 h. The reaction mixture was diluted with EtOAc and the organic phase was washed with 1 M HCl, dried and concentrated. The e was purified by preparative HPLC (acidic sys- tem) giving 155 mg ofthe intermediate 4-{[(3-acetylphenyl)sulfonyl]amino} ybenzoic acid. MS (ESI+) calcd for C15H13NO6S 335.046358, found 335.045738.
H2S04 (170 uL) was added to a solution of 4- {[(3-acetylphenyl)sulfonyl]amino} hydroxybenzoic acid (22 mg, 0.065 mmol) in dry MeOH (2.1 mL). The e was heated at 60 0C for 3 days .The reaction mixture was diluted with EtOAc and the organic phase was washed with water, dried and concentrated. The crude product was purified by preparative HPLC (acidic ). The fractions were neutralized with aqueous NH4OAc (sat) before evaporation. The e was dissolved in EtOAc. The organic solution was washed with di- W0 2013/093095 151 luted HCl to remove the salts, dried and concentrated to give the title compound in 31% yield (7.1 mg). MS (ESI+) calcd for C16H15NO6S 349.062008, found 349.062218.
Example 130 Methyl -(2-flu0r0meth0xyphenyl)pyridinyl]sulfonyl}amin0)—2- hydroxybenzoate \ \\ O o OH O A mixture of methyl 4- {[(5-bromochloropyridinyl)sulfonyl]amino} hydroxybenzoate (Intermediate 8) (42 mg, 0.100 mmol), 2-fluoromethoxyphenylboronic acid (19.4 mg, 0.110 mmol), DIPEA (70 uL, 0.400 mmol) and Pd(dppf)Clg‘CH2C12 (4 mg, 0.005 mmol) in aqueous e (2 mL, 9:1 dioxane/water) was heated at 80 0C under nitrogen atmosphere for 1 day. After additional 2 days stirring at room temperature, the solvent was removed by evaporation giving the intermediate methyl 4-({[6-chloro(2-fluoro methoxyphenyl)pyridinyl]sulfonyl} amino)hydroxybenzoate.
The methyl 4-( { [6-chloro(2-fluoromethoxyphenyl)pyridin-3 -yl]sulfonyl} amino) hydroxybenzoate together with a a of Pd/C (10%) were slurried in MeOH. The tube was sealed and a en atmosphere was d with a balloon. The reaction mixture was stirred at room temperature overnight. More Pd/C (10%) was added and the reaction was stirred under hydrogen atmosphere for onal 3 days. The reaction mixture was filtered and the crude product was purified by preparative HPLC (acidic system). The title compound was obtained in 6% yield (2.6 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.91 (s, 3 H) 3.94 (s, 3 H) 6.68 (dd, J=8.66, 2.20 Hz, 1 H) 6.72 (d, J=2.20 Hz, 1 H) 6.95 (ddd, J=8.02, 6.46, 1.46 Hz, 1 H) 7.06 (td, J=8.02, 1.46 Hz, 1 H) 7.20 (td,J=8.02, 1.46 Hz, 1 H) 7.21 (br. s., 1 H) 7.74 (d, J=8.66 Hz, 1 H) 8.30 - 8.35 (m, 1 H) 8.95 (s, 1 H) 9.04 (s, 1 H) 10.86 (s, 1 H). MS (ESI+) m/Z 433 [M+H]+.
Example 131 W0 2013/093095 152 Methyl 2-hydr0xy({[3-methyl(1-methylethyl)-l-benzofuran-Z- yl] sulfonyl}amin0)benz0ate The intermediate 5-isopropy1methy1benzofuransu1fony1 chloride was prepared accord- ing to the following multistep procedure. A solution of 4-isopropy1phenol (500 mg, 3.67 mmol), N—iodosuccinimide (838 mg, 3.72 mmol) and p-TsOH (70 mg, 0.37 mmol) in CH2C12 (25 mL) was stirred at room temperature overnight. The reaction mixture was diluted with CH2C12 and washed with water. The organic phase was dried and evaporated to give 820 mg of 2-iodoisopropy1phenol (85%). 1H NMR (400 MHZ, CDC13) 8 ppm 1.22 (d, J=7.03 Hz, 6 H) 2.82 (spt, J=7.03 Hz, 1 H) 6.92 (d, J=8.53 Hz, 1 H) 7.11 (dd, J=8.28, 2.01 Hz, 1 H) 7.50 (d, J=2.01 Hz, 1 H).
A mixture of 2-iodoisopropy1phenol (820 mg, 3.13 mmol), a11y1bromide (800 uL, 9.46 mmol) and K2C03 (530 mg, 3.83 mmol) in THF (40 mL) was refluxed for 24 h and then d at room temperature for 48 h. The reaction mixture was diluted with CH2C12. The or- ganic phase was washed with water followed by aqueous NaHC03 (sat) and then dried. Evap- n of the solvent gave a11y1iodoisopropy1pheny1 ether (892 mg) which was used without fiarther purification. MS (ESI+) m/Z 303 [M+H] +.
According to the method described by Xie et al. (Xie et a1., (2004) Tetrahedron Lett. 45, 6235-6237) a mixture of a11y1iodoisopropy1pheny1 ether (300 mg, 0.99 mmol), NBu3 (350 uL, 1.49 mmol), ammonium formate (65 mg, 1.03 mmol) and PdC12 (10 mg, 0.06 mmol) in 1-buty1mety1imidazolium tetrafluoroborate (1.5 mL) was heated at 60 °C for 2 days. A second n of PdClz (24 mg) was added and the mixture was heated at 60 OC additional 5 h. The reaction mixture was extracted with EtzO. Evaporation of the solvent afforded 220 mg of crude product, which was purified on silica using e as eluent giving the 5-isopropy1- 3-methy1benzofuran in 30% yield (55 mg). 1H NMR (400 MHz, CDC13) 8 ppm 1.31 (d, J=6.90 Hz, 6 H) 2.24 (d, J=1.25 Hz, 3 H) 3.03 (spt, J=6.90 Hz, 1 H) 7.17 (dd, , 1.94 Hz, 1 H) 7.34 - 7.39 (m, 3 H). The synthesis was repeated on a larger scale before the su1— fonylation step was carried out.
W0 2013/093095 153 The 5-isopropylmethylbenzofuran (8.7 g, 50 mmol) was ved in EtOAc (100 mL) and AczO (14 mL, 148 mmol) was added. Conc. H2SO4 (3 mL, 53 mmol) was added se.
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-isopropylmethylbenzofiaran—2-sulfonate (39%). 1H NMR (400 MHz, DMSO-d6) 8 ppm 1.25 (d, J=7.03 Hz, 6 H) 2.33 (s, 3 H) 3.00 (spt, J=7.03 Hz, 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-isopropylmethylbenzofuran—2-sulfonic acid (100 mg, 0.34 mmol) was mixed with POC13 (5 mL) and the reaction mixture was heated at 60 CC overnight. The POC13 was evaporated and the crude product was dissolved in CHzClz and passed through a short plug of silica to give the ropylmethylbenzo furansulfonyl chloride (30 mg, 33%).
The title nd was prepared from methyl 4-aminosalicylate (22 mg, 0.132 mmol) and 5- isopropylmethylbenzofuransulfonyl chloride (50 mg, 0.183 mmol) according to the General Procedure 4, described in Example 7. The title nd was obtained in 13% yield (5.2 mg). 1H NMR (500 MHz, CDgOD) 8 ppm 1.28 (d, J=6.96 Hz, 6 H) 2.54 (s, 3 H) 3.02 (spt, J=6.96 Hz, 1 H) 3.87 (s, 3 H) 6.69 (dd, J=8.67, 2.20 Hz, 1 H) 6.77 (d, J=2.20 Hz, 1 H) 7.37 (dd, J=8.68, 1.65 Hz, 1 H) 7.38 (dd, J=8.68, 0.82 Hz, 1 H) 7.50 (dt, J=l.65, 0.82 Hz, 1 H) 7.69 (d, J=8.67 Hz, 1 H). MS (ESI+) m/z 404 [M+H]+.
Example 132 Methyl 2-(acetyloxy)—4-{[(4,5-dichlorothiophen-Z-yl)sulfonyl] amin0}benz0ate A mixture of methyl 4-[(tert-butoxycarbonyl)amino]hydroxybenzoate (Intermediate 14) (150 mg, 0.56 mmol), pyridine (49 mg, 0.62 mmol) and acetic anhydride (65 mg, 0.64 mmol) was stirred in MeCN (5 mL) at 70 0C for 2 weeks. The solvent was removed under vacuum.
W0 2013/093095 154 The residue was dissolved in EtOAc, washed with l M HCl, water and brine. The solution was dried (MgSO4) and concentrated under vacuum. The crude, methyl 2-(acetyloxy)[(tert— butoxycarbonyl)amino]benzoate, was obtained as an oil (191 mg) and was used without fur- ther purification in the next step. 1H NMR (600 MHZ, CDClg) 8 ppm 1.51 (s, 9 H) 2.33 (s, 3 H) 3.84 (s, 3 H) 6.71 (s, l H) 7.11 (dd, J=8.66, 2.20 Hz, 1 H) 7.37 (br. s., l H) 7.94 (d, J=8.66 Hz, 1 H). MS (ESI+) m/z 327 [M+NH4]+. The postion of the acetyl group was confirmed by DPFGSE-NOE experiments.
A solution ofmethyl 2-(acetyloxy)[(tert—butoxycarbonyl)amino]benzoate (87 mg, 0.28 mmol) and TFA (230 mg, 2.0 mmol) in CHzClz (1.3 mL) was stirred overnight at room tem- perature. The solution was diluted with more CH2C12, washed with saturated NaHC03 and brine, dried over MgSO4, filtered and concentrated. The product, methyl tyloxy) aminobenzoate, was obtained in 69% yield (41 mg). MS (ESI+) m/Z 210 [M+H]+.
A mixture of methyl 2-(acetyloxy)aminobenzoate (15 mg, 0.072 mmol), 2,3- dichlorothiophenesulfonyl de (29 mg, 0.115 mmol) and pyridine (29 mg, 0.37 mmol) in MeCN (0.7 mL) was shaken at room temperature for 1 day. The solvent was removed un- der vacuum and the residue dissolved in DMSO. The sample was purified by ative HPLC c ). The title compound was obtained in 47% yield (20.1 mg). 1H NMR (600 MHz,CDC13)8 ppm 2.36 (s, 3 H) 3.85 (s, 3 H) 6.97 (d, J=2.14 Hz, 1 H) 7.01 (dd, J=8.54, 2.14 Hz, 1 H) 7.02 (br.s., l H) 7.38 (s, l H) 7.98 (d, J=8.54 Hz, 1 H). MS (ESI+) m/z 441 [M+NH4]+.
Example 133 2-Meth0xyethyl 4-({[5-chlor0(2-hydr0xyphenyl)thienyl] sulfonyl}amino)—2- hydroxybenzoate OH O\\ /N S\\ o OH O\/\O A mixture of 4- {[(4-bromochlorothiophenyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 1) (150 mg, 0.36 mmol), 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)phenol (87 mg, 0.40 mmol), DIPEA (140 mg, 1.1 mmol) and Pd(dppf)C12‘CH2C12 (15 mg, 0.018 mmol) in s dioxane (5 mL dioxane, 1 mL water) was heated at 80 0C under N2 at- mosphere overnight. CHzClz (50 mL) followed by 1 M N32C03 (10 mL) were added to the reaction mixture. The aqueous phase was washed with CH2C12 (2 x 50 mL) and then acidified with conc. H3PO4. EtOAc (100 mL) was added. The c phase was washed with 1 M HCl (2 x 50 mL) and brine, dried over MgSO4, filtered and concentrated. The crude product was dissolved in water/MeOH and purified by preparative HPLC (acidic system) to give 4-({[5- chloro(2-hydroxyphenyl)thiophenyl]sulfonyl}amino)hydroxybenzoic acid as a white solid (37 mg, 24%). 1H NMR (500 MHz, CDgOD) 8 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+) m/Z 426 [M+H]+.
A reaction mixture containing 4-({[5-chloro(2-hydroxyphenyl)thiophen yl]sulfonyl} amino)hydroxybenzoic acid (5 mg, 0.011 mmol), 1,1'-carbonyldiimidazole (16 mg, 0.100 mmol) and pyridine (8 mg, 0.100 mmol) in MeCN (0.5 mL) was stirred at room ature for 30 min, and then 2-methoxyethanol (7.6 mg, 0.100 mmol) was added. The reaction e was stirred at room temperature ght, then acidified with TFA and di- luted with MeOH. The crude product was purified by preparative HPLC (acidic system). The title compound was obtained in 39% yield (2.1 mg). 1H NMR (500 MHz, CDClg) 8 ppm 3.44 (s, 3 H) 3.72 - 3.79 (m, 2 H) 4.45 - 4.54 (m, 2 H) 5.25 (br. s., 1 H) 6.70 (dd, J=8.67, 2.32 Hz, 1 H) 6.77 (d, J=2.20 Hz, 1 H) 6.90 (d, J=8.06 Hz, 1 H) 6.95 (br. s., 1 H) 6.96 - 7.01 (m, 1 H) 7.25 (dd, J=7.69, 1.59 Hz, 1 H) 7.28 - 7.32 (m, 1 H) 7.59 (s, 1 H) 7.83 (d, J=8.55 Hz, 1 H) .83 (s, 1 H). MS (ESI+) m/Z 484 [M+H]+.
Example 134 Methyl 4-{[(5'-flu0r0-2'-hydroxybiphenylyl)sulf0nyl] amin0}hydr0xybenz0ate 0 s: .
O O O\ OH OH A reaction mixture containing 4- fiuoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoic acid (Intermediate 16) (15 mg, 0.037 mmol), 1,1'-carbonyldiimidazole (16 mg, 0.100 mmol), pyridine (8 mg, 0.100 mmol) and MeOH (20 uL, 0.5 mmol) in MeCN (1 mL) was heated at 60 0C overnight. The mixture was acidified with TFA (30 uL) and diluted W0 2013/093095 156 2012/076836 with MeOH/water. The crude product was purified by preparative HPLC (acidic ).
The title compound was obtained in 27% yield (4.3 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 3.88 (s, 3 H) 6.70 (dd, J=8.70, 2.20 Hz, 1 H) 6.74 (d, J=2.20 Hz, 1 H) 6.88 (ddd, J=8.54, 4.73, 0.82 Hz, 1 H) 6.91 - 6.97 (m, 2 H) 7.55 (td, J=7.85, 0.45 Hz, 1 H) 7.69 (d, J=8.70 Hz, 1 H) 7.78 - 7.82 (m, 2 H) 8.10 (td, J=1.82, 0.45 Hz, 1 H). MS (ESI+) m/z 418 [M+H]+.
Example 135 hlor0{[3-hydr0xy(methoxycarbonyl)phenyl] sulfamoyl}thiophenyl)benzoic acid 0 H CI 8 “S/N \ / \\ O O The compound was prepared from methyl 4- {[(4-bromochlorothienyl)sulfonyl]amino}- 2-hydroxybenzoate (Intermediate 3) (128 mg, 0.30 mmol) and 3-carboxyphenylboronic acid (50 mg, 0.30 mmol) as descrided for Intermediate 13. An analytical sample of the crude prod- uct (14 mg) was purified by preparative HPLC (acidic system) to give the title compound in 100% purity (5.3 mg, 38%). 1H NMR (600 MHz, CDgOD) 8 ppm 3.91 (s, 3 H) 6.76 (dd, J=8.70, 2.20 Hz, 1 H) 6.82 (dd, J=2.20, 0.30 Hz, 1 H) 7.57 (td, J=7.78, 0.50 Hz, 1 H) 7.68 (s, 1 H) 7.73 (ddd, J=7.78, 1.88, 1.18 Hz, 1 H) 7.79 (dd, J=8.70, 0.30 Hz, 1 H) 8.06 (ddd, J=7.78, 1.65, 1.18 Hz, 1 H) 8.14 (ddd, J=1.88, 1.65, 0.50 Hz, 1 H). MS (ESI+) m/Z 468 [M+H]+.
Example 136 Methyl 4-({[3-(ethoxycarbonyl)phenyl] sulfonyl}amino)—2-hydr0xybenz0ate A solution of 3-({[3-hydroxy(methoxycarbonyl)phenyl]amino}sulfonyl)benzoic acid (In- termediate 15) (18 mg, 0.050 mmol), pyridine (8 mg, 0.10 mmol) and 1,1’- carbonyldiimidazole (16 mg, 0.10 mmol) in MeCN (700 uL) was prepared. After 30 minutes EtOH (100 uL, excess) was added. The reaction mixture was shaken at 60 0C for 3 days. The reaction was acidified by addition ofTFA (30 uL), d with water/MeOH and purified by preparative HPLC (acidic system). The title compound was obtained in 57% yield (11 mg). 1H NMR (600 MHz, DMSO-d6) 8 ppm 1.32 (t, J=7.17 Hz, 3 H) 3.81 (s, 3 H) 4.34 (q, J=7.17 Hz, 2 H) 6.67 (br. s., 2 H) 7.63 (d, J=8.09 Hz, 1 H) 7.74 (t, J=7.85 Hz, 1 H) 8.07 (d, J=7.85 Hz, 1 H) 8.17 (d, J=7.85 Hz, 1 H) 8.35 (t, J=1.60 Hz, 1 H) 10.56 (s, 1 H) 11.02 (br. s., 1 H).
MS (ESI+) m/Z 380 [M+H]+.
Example 137 Methyl 2-hydr0xy[({3-[(1-methyleth0xy)carb0nyl]phenyl}sulf0nyl)amin0]benzoate O n “3’ O )\ \\O 0 OH A on of 3-({[3-hydroxy(methoxycarbonyl)phenyl]amino}sulfonyl)benzoic acid (In- termediate 15) (18 mg, 0.050 mmol), pyridine (8 mg, 0.10 mmol) and 1,1’- yldiimidazole (16 mg, 0.10 mmol) in MeCN (700 uL) was prepared. After 30 s isopropanol (100 uL, excess) was added. The reaction mixture was shaken at 60 0C for 3 days. The reaction was acidified by addition ofTFA (30 uL), diluted with water/MeOH and purified by preparative HPLC (acidic system). The title compound was obtained in 61% yield (12 mg). 1H NMR (600 MHz, CDClg) 8 ppm 1.37 (d, J=6.26 Hz, 6 H) 3.90 (s, 3 H) 5.26 (spt, J=6.26 Hz, 1 H) 6.64 (dd, J=8.65, 2.25 Hz, 1 H) 6.67 (d, J=2.25 Hz, 1 H) 6.86 (br. s., 1 H) 7.56 (t, J=7.85 Hz, 1 H) 7.71 (d, J=8.65 Hz, 1 H) 8.03 (ddd,.]=7.85, 1.91, 1.22 Hz, 1 H) 8.23 (ddd, J=7.85, 1.51, 1.20 Hz, 1 H) 8.50 (dd, J=1.91, 1.51 Hz, 1 H) 10.84 (s, 1 H). MS (ESI+) m/Z 394 [M+H]+. e 138 Methyl 2-hydr0xy({[3-(methylcarbamoyl)phenyl] sulfonyl}amin0)benzoate W0 2013/093095 158 A on of 3-({[3-hydroxy(methoxycarbonyl)phenyl]amino}sulfonyl)benzoic acid (In- iate 15) (18 mg, 0.050 mmol), DIPEA (10 mg, 0.075 mmol) and propanephosphonic acid cyclic ide (50% in EtOAc, 45 uL, 0.075 mmol) in MeCN (700 uL) was prepared.
After 30 minutes was methylamine, 33% in EtOH (100 uL, excess) added. The reaction was shaken at room temperature for 3 days. The reaction mixture was diluted with water/MeOH and purified by preparative HPLC (acidic system). The title compound was obtained in 49% yield (9 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 2.92 (s, 3 H) 3.88 (s, 3 H) 6.67 (dd, J=8.70, 2.20 Hz, 1 H) 6.70 (d, J=2.20 Hz, 1 H) 7.62 (td, J=7.93, 0.53 Hz, 1 H) 7.68 (d, J=8.70 Hz, 1 H) 7.98 - 8.02 (m, 2 H) 8.33 (td, J=1.83, 0.53 Hz, 1 H). MS (ESI+) m/Z 365 [M+H]+.
Example 139 Methyl 2-hydr0xy({[3-(piperidinylcarb0nyl)phenyl] sulfonyl}amin0)benzoate A solution of 3-({[3-hydroxy(methoxycarbonyl)phenyl]amino}sulfonyl)benzoic acid (In- termediate 15) (18 mg, 0.050 mmol), diisopropylethylamine (10 mg, 0.075 mmol) and pro- panephosphonic acid cyclic ide (50% in EtOAc, 45 uL, 0.075 mmol) in MeCN (700 uL) was prepared. After 30 minutes was piperidine (100 uL, excess) added. The reaction mix- ture was shaken at room temperature for 3 days. The reaction was diluted with water/MeOH and purified by preparative HPLC (acidic system). The title compound was obtained in 53% yield (11.1 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 1.38 - 1.49 (m, 2 H) 1.61 - 1.69 (m, 2 H) 1.66 - 1.72 (m, 2 H) 3.13 - 3.21 (m, 2 H) 3.65 - 3.73 (m, 2 H) 3.89 (s, 3 H) 6.67 (dd, J=8.70, 2.20 Hz, 1 H) 6.70 (d, J=2.20 Hz, 1 H) 7.61 (ddd, J=7.63, 1.60, 1.50 Hz, 1 H) 7.64 (ddd, J=7.63, 7.50, 0.59 Hz, 1 H) 7.69 (d, J=8.70 Hz, 1 H) 7.81 (ddd, , 1.50, 0.59 Hz, 1 H) 7.96 (ddd, J=7.50, 1.96, 1.60 Hz, 1 H). MS (ESI+) m/z 419 [M+H]+.
W0 2013/093095 159 Example 140 Benzyl 2-acet0xy[(1-naphthylsulf0nyl)amin0]benzoate A mixture of methyl 4-[(tert-butoxycarbonyl)amino]hydroxybenzoate (Intermediate 14) (200 mg, 0.75 mmol) in 1 M NaOH (4 mL) and e (2 mL) was stirred at 40 0C over- night. The reaction mixture was first washed with Eth and then acidified with conc. H3PO4 to pH ~3. EtOAc was added. The c phase was washed with brine, dried over MgSO4, filtered and concentrated. The 4-[(tert-butoxycarbonyl)amino]hydroxybenzoic acid was obtained in 99% yield (187 mg). MS (ESI+) m/Z 254 [M+H]+.
A solution of 4-[(tert-butoxycarbonyl)amino]hydroxybenzoic acid (187 mg, 0.74 mmol), 1,1 ’-carbonyldiimidazole (162 mg, 1.0 mmol) and pyridine (79 mg, 1.0 mmol) in MeCN (5 mL) was prepared. After 30 minutes benzyl alcohol (108 mg, 1.0 mmol) was added. The reac- tion mixture was stirred at 50 0C overnight. EtOAc (20 mL) and water (20 mL) was added.
The organic phase was washed with 1 M H3PO4 and brine, dried over MgSO4, filtered and concentrated. The e was d by flash chromatography (silica, 20% EtOAc in hex- ane). The benzyl 4-[(tert-butoxycarbonyl)amino]hydroxybenzoate was obtained in 31% yield (72 mg). ). MS (ESI+) m/Z 288 [M-tBu]+.
A mixture of benzyl 4-[(tert-butoxycarbonyl)amino]hydroxybenzoate (72 mg, 0.23 mmol), DIPEA (89 mg, 0.69 mmol) and acetyl chloride (54 mg, 0.69 mmol) in MeCN (4 mL) was stirred overnight. To the reaction mixture was added water and EtOAc. The organic phase was washed with 1 M H3PO4, water, sat. NaHC03 and brine, dried over MgSO4, filtered and concentrated. The benzyl 2-acetoxy[(tert-butoxycarbonyl)amino]benzoate was obtained in 78% yield (70 mg). MS (ESI+) m/Z 403 ]+.
A mixture of benzyl 2-acetoxy[(tert-butoxycarbonyl)amino]benzoate (70 mg, 0.18 mmol) and TFA (500 uL) in 2 mL of dichloromethane was stirred for 1 h. Water (2 mL) was added.
The organic phase was washed with sat. NaHC03 and brine, dried over MgSO4, filtered and W0 2013/093095 160 concentrated. The benzyl 2-acetoxyaminobenzoate was obtained in 89% yield (46 mg). MS (ESI+) m/Z 286 [M+H]+.
A mixture of benzyl 2-acetoxyaminobenzoate (46 mg, 0.16 mmol), pyridine (25 mg, 0.32 mmol) and 1-naphthalenesulfonyl chloride (54 mg, 0.24 mmol) in MeCN (2 mL) was shaken at 60 0C for 2 h. The reaction mixture was acidified with TFA (100 uL) and d by pre- parative HPLC (acidic system). The title compound was obtained in 39% yield (30 mg). 1H NMR (600 MHz,CDC13)5 ppm 2.05 (s, 3 H) 5.20 (s, 2 H) 6.81 - 6.84 (m, 2 H) 7.30 - 7.38 (m, 5 H) 7.50 (dd, J=8.21, 7.40 Hz, 1 H) 7.60 (ddd, J=8.17, 6.88, 1.07 Hz, 1 H) 7.69 (ddd, J=8.68, 6.88, 1.32 Hz, 1 H) 7.81 - 7.84 (m, 1 H) 7.91 - 7.95 (m, 1 H) 8.05 (d, J=8.21 Hz, 1 H) 8.26 (dd, , 1.07 Hz, 1 H) 8.63 (dq, J=8.68, 1.07 Hz, 1 H). MS (ESI+) m/Z 476 [M+H]+.
Example 141 2-Acet0xy[(1-naphthylsulf0nyl)amin0]benzoic acid A e of benzyl 2-acetoxy[(1-naphthylsulfonyl)amino]benzoate (Example 140) (20 mg, 0.042 mmol) and palladium on charcoal (10%, 5 mg) in EtOAc (3 mL) was stirred in an atmosphere of hydrogen for 2 hours. The reaction mixture was d and purified by pre- parative HPLC (acidic system). The title compound was obtained in 48% yield (7.7 mg). 1H NMR (600 MHz, CDgOD) 5 ppm 2.21 (s, 3 H) 6.84 (dd, J=2.25, 0.31 Hz, 1 H) 6.95 (dd, J=8.70, 2.25 Hz, 1 H) 7.57 (dd, J=8.25, 7.37 Hz, 1 H) 7.62 (ddd, J=8.23, 6.93, 1.00 Hz, 1 H) 7.71 (ddd, J=8.69, 6.93, 1.38 Hz, 1 H) 7.77 (dd, J=8.70, 0.31 Hz, 1 H) 7.98 - 8.01 (m, 1 H) 8.12 - 8.16 (m, 1 H) 8.31 (dd, J=7.37, 1.22 Hz, 1 H) 8.72 (dq, J=8.69, 1.00 Hz, 1 H). MS (ESI+) m/Z 386 . A 15N—gHMBC experiment support the postion of the acetyl group.
Example 142 Methyl 2-hydr0xy({[3-(piperidinyl)phenyl]sulfonyl}amin0)benzoate W0 2013/093095 161 A mixture of methyl 4- {[(3-bromophenyl)sulfonyl]amino}hydroxybenzoate (Intermediate 4) (40 mg, 0.10 mmol), piperidine (14 uL, 0.14 mmol), a)3 (8 mg, 0.009 mmol) and 2'- (dicyclohexylphosphino)-N,N—dimethyl[1,1'-biphenyl]amine (8 mg, 0.02 mmol) was weighed out in a tube, flushed with N2 and capped. Dry THF (2 mL) was added, ed by lithium bis(trimethylsilyl)amide (0.5 mL, 1 M in THF). The vial was heated for 30 minutes in a microwave reactor at 100 CC. The on was quenched with saturated NH4Cl (1 mL) and the organic phase was separated. The solvent was evaporated and the residue was dissolved in MeOH together with 2 drops of TFA. The crude product was purified by preparative HPLC (basic system) and the title compound was obtained in 40% yield (7.6 mg). 1H NMR (600 MHz,CDC13)5 ppm 1.56 - 1.62 (m, 2 H) 1.63 - 1.70 (m, 4 H) 3.15 - 3.21 (m, 4 H) 3.90 (s, 3 H) 6.62 (dd, , 2.26 Hz, 1 H) 6.66 (d, J=2.26 Hz, 1 H) 6.68 (br. s., 1 H) 7.04 (ddd, J=8.39, 2.50, 0.91 Hz, 1 H) 7.21 (ddd, J=7.72, 1.74, 0.91 Hz, 1 H) 7.29 (dd, J=8.39, 7.72 Hz, 1 H) 7.32 (dd, J=2.50, 1.74 Hz, 1 H) 7.69 (d, J=8.66 Hz, 1 H) 10.82 (s, 1 H). MS (ESI+) m/z 391 [M+H]+.
Example 143 Methyl 4-[({5-chlor0[3-(dimethylcarbamoyl)phenyl]thiophen-Z-yl}sulfonyl)amin0] hydroxybenzoate CI 8 “8/“ \ / \\ O O \ HO A solution of 3-(2-chloro {[3-hydroxy(methoxycarbonyl)phenyl]sulfamoyl}thiophen—3- yl)benzoic acid (Intermediate 13) (14 mg, 0.030 mmol), pyridine (8 mg, 0.10 mmol) and 1,1’- carbonyldiimidazole (16 mg, 0.10 mmol) in MeCN (700 uL) was prepared. After 30 minutes dimethylamine (40% in water, 100 uL, excess) was added. The reaction mixture was shaken W0 2013/093095 162 at 60 0C overnight. The reaction was acidified with TFA (30 uL), diluted with water/MeOH and purified by preparative HPLC (acidic system). The title nd was obtained in 14% yield (2.1 mg). 1H NMR (600 MHz,CDC13)8 ppm 3.01 (br. s., 3 H) 3.13 (br. s., 3 H) 3.92 (s, 3 H) 6.72 (dd, , 2.25 Hz, 1 H) 6.76 (d, J=2.25 Hz, 1 H) 7.14 (br. s., 1 H) 7.44 (ddd, J=6.90, 2.10, 1.75 Hz, 1 H) 7.46 - 7.50 (m, 2 H) 7.51 (td, J=1.70, 0.72 Hz, 1 H) 7.55 (s, 1 H) 7.78 (d, J=8.62 Hz, 1 H) 10.91 (s, 1 H). MS (ESI+) m/z 495 .
Example 144 (5-Methyl—2-0x0-1,3-di0xolyl)methyl 4-{[(4,5-dichlor0thienyl)sulf0nyl] amin0} hydroxybenzoate 0 fl A mixture of 4,5-dimethyl-1,3-dioxolone (1.0 g, 8.8 mmol), benzoylperoxide (60 mg, 0.25 mmol) and N—bromosuccinimide (1.6 g, 9.0 mmol) in carbon tetrachloride (10 mL) was heat- ed at reflux for 2 h. The solid was removed from the on mixture by filtration. The moth- er liquid was washed with sat. NaHC03 and brine, dried over MgSO4 and concentrated. The crude product, 4-(bromomethyl)—5-methyl-1,3-dioxol—2-one, was obtained as a yellow oil (1.7 g) and was used without fiarther purification in the next step.
A mixture of 4-(bromomethyl)methyl-1,3-dioxolone (10 mg, 0.052 mmol), 4-{[(4,5- dichlorothienyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 7, 14 mg, 0.037 mmol) and NaHC03 (2.8 mg, 0.033 mmol) in DMF (0.4 mL) was shaken at room temperature overnight. The reaction e was acidified by addition of TFA (50 uL), diluted with wa- ter/MeCN and purified by preparative HPLC (acidic ). The title compound was ob- tained in 38% yield (6.8 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 2.23 (s, 3 H) 5.19 (s, 2 H) 6.74 (dd, J=8.70, 2.20 Hz, 1 H) 6.79 (d, J=2.20 Hz, 1 H) 7.54 (s, 1 H) 7.79 (d, J=8.70 Hz, 1 H). MS (ESI+) m/z 497 [M+NH4]+. 13C-gHSQC and 13C-gHMBC experiments support the structure.
W0 93095 163 Example 145 3-({[3-Hydr0xy(methoxycarbonyl)phenyl] amin0}sulf0nyl)benzoic acid The product was prepared from 3-(chlorosulfonyl)benzoic acid (0.50 g, 2.3 mmol) and methyl 4-aminosalicylate (0.38 g, 2.3 mmol) as described for Intermediate 15. The title compound was obtained in 22% yield (180 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 3.88 (s, 3 H) 6.68 (dd, J=8.70, 2.23 Hz, 1 H) 6.71 (dd, J=2.23, 0.31 Hz, 1 H) 7.64 (td, J=7.86, 0.55 Hz, 1 H) 7.69 (dd, J=8.70, 0.31 Hz, 1 H) 8.05 (ddd,.]=7.86, 1.96, 1.15 Hz, 1 H) 8.21 (ddd,.]=7.86, 1.67, 1.15 Hz, 1 H) 8.48 (ddd, J=1.96, 1.67, 0.55 Hz, 1 H). MS (ESI+) m/z 352 [M+H]+. e 146 2-Amin00x0ethyl 4-{[(4,5—dichlorothiophen-2—yl)sulf0nyl] amin0}hydr0xybenzoate A mixture of 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoic acid - mediate 7) (25 mg, 0.068 mmol), chloroacetamide (5.8 mg, 0.062 mmol), NaHC03 (5.5 mg, 0.065 mmol) and NaI (0.5 mg, 0.003 mrnol) in DMF (500 uL) was shaken at 50 OC overnight.
The crude product was purified by preparative HPLC (basic system) and the title product was obtained in 29% yield (8.4 mg). 1H NMR (600 MHz, DMSO-dg) 5 ppm 4.66 (s, 2 H) 6.72 - 6.76 (m, 1 H) 6.76 (d, J=8.64 Hz, 1 H) 7.35 (br. s., 1 H) 7.56 (br. s., 1 H) 7.77 - 7.82 (m, 1 H) 7.81 (d, J=8.64 Hz, 1 H) 10.49 (s, 1 H) 11.31 (br. s., 1 H). MS (ESI+) m/z 425 [M+H]+.
Example 147 2-[Bis(2—hydroxyethyl)amin0]ethyl 4-{[(2,5-dichlor0thienyl)sulf0nyl] hydroxybenzoate trifluoroacetate W0 2013/093095 164 OH 0 8 / CI \\\ F OH F A mixture of 4- {[(2,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoic acid (Inter- e 6) (18 mg, 0.050 mmol), pyridine (8 mg, 0.10 mmol), carbonyldiimidazole (16 mg, 0.10 mmol) and triethanolamine (15 mg, 0.10 mmol) in 500 uL ofMeCN was shaken over- night. The reaction mixture was acidified by addition of TFA, diluted with water/MeOH and purified by preparative HPLC (acidic system). The title compound was obtained in 58% yield (17.9 mg). 1H NMR (500 MHz,CDC13)8 ppm 3.41 - 3.52 (m, 4 H) 3.71 - 3.81 (m, 2 H) 3.88 - 3.94 (m, 4 H) 4.68 - 4.74 (m, 2 H) 6.72-6.76 (m, 2 H) 7.27 (s, 1 H) 7.86 (m, 1 H). MS (ESI+) m/Z 499 [M+H]+.
Example 148 2-(2-Hydr0xyeth0xy)ethyl 4-{[(2,5-dichlor0thienyl)sulf0nyl] hydroxybenzoate A mixture of 4- -dichlorothiophenyl)sulfonyl]amino}hydroxybenzoic acid (Inter- mediate 6) (18 mg, 0.050 mmol), pyridine (8 mg, 0.10 mmol), arbonyldiimidazole (16 mg, 0.10 mmol) and diethylene glycol (11 mg, 0.10 mmol) in MeCN (500 uL) was shaken overnight. The reaction mixture was acidified by addition of TFA, diluted with water/MeOH and purified by preparative HPLC (acidic system). The title compound was obtained in 25% yield (5.6 mg). 1H NMR (500 MHz, DMSO-d6:CD30D 6:2) 8 ppm 3.46 - 3.52 (m, 4 H) 3.71 - 3.74 (m, 2 H) 4.36 - 4.40 (m, 2 H) 6.69 (d, J=2.20 Hz, 1 H) 6.72 (dd, J=8.67, 2.20 Hz, 1 H) 7.37 (s, 1 H) 7.72 (d, J=8.67 Hz, 1 H). MS (ESI+) m/Z 456 [M+H]+.
Example 149 W0 2013/093095 165 Pentyl 4-{[(4,5—dichlor0thienyl)sulfonyl]amin0}hydr0xybenzoate The product was prepared from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18 mg, 0.50 mmol) (Intermediate 7) and anol (50 uL, excess) according to the General Procedure 8, described in Example 60. The title compound was ob- tained in 71% yield (15.5 mg). 1H NMR (500 MHZ, CDClg) 8 ppm 0.93 (t, J=7.08 Hz, 3 H) 1.35 - 1.46 (m, 4 H) 1.73 - 1.81 (m, 2 H) 4.33 (t, J=6.71 Hz, 2 H) 6.68 (dd, J=8.67, 2.26 Hz, 1 H) 6.73 (d, J=2.26 Hz, 1 H) 6.88 (br. s., 1 H) 7.42 (s, 1 H) 7.80 (d, J=8.67 Hz, 1 H) 11.02 (s, 1 H). MS (ESI+) m/Z 438 [M+H]+.
Example 150 Propyl 4-{[(4,5-dichlor0thienyl)sulfonyl]amin0}hydr0xybenzoate The product was prepared from 4- -dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18 mg, 0.50 mmol) (Intermediate 7) and 1-propanol (50 uL, excess) according to the General Procedure 8, described in Example 60. The title nd was ob- tained in 61% yield (12.6 mg). 1H NMR (500 MHz, CDClg) 8 ppm 1.03 (t, J=7.45 Hz, 3 H) 1.75 - 1.84 (m, 2 H) 4.29 (t, J=6.65 Hz, 2 H) 6.68 (dd, J=8.67, 2.26 Hz, 1 H) 6.73 (d, J=2.26 Hz, 1 H) 6.92 (br. s., 1 H) 7.41 (s, 1 H) 7.81 (d, J=8.67 Hz, 1 H) 11.01 (s, 1 H). MS (ESI+) m/Z 410 [M+H]+.
Example 151 4-(Dimethylamin0)butyl 2-hydr0xy({[3-(2-methyl—1,3-thiazol—4- W0 2013/093095 166 yl)phenyl] sulfonyl}amin0)benzoate roacetate S O\\ INQWO /<\ \ s HOJKK N O F O\ / OH N A e of 3-(2-methyl-1,3-thiazolyl)benzenesulfonyl chloride (137 mg, 0.5 mmol), 4- aminosalicylic acid (153 mg, 1 mmol) and pyridine (396 mg, 5 mmol) in CH2C12 (20 mL) was stirred at room temperature overnight and at 50 0C for 2 h. The reaction was diluted with EtOAc, washed with 1 M HCl, dried and concentrated. The residue was purified by flash chromatography (silica, CHC13+0.5% formic acid). The intermediate, 2-hydroxy({[3-(2- -1,3-thiazolyl)phenyl]sulfonyl}amino)benzoic acid, was obtained in 41% yield (80 mg). MS (ESI+) m/Z 391 [M+H]+.
A mixture of oxy({[3-(2-methyl-1,3-thiazolyl)phenyl]sulfonyl}amino)benzoic acid (26 mg, 67 umol), 4-(dimethylamino)butanol (78 mg, 0.67 mmol), 4-dimethylamino- pyridine (2.4 mg, 20 umol) and N,N'-dicyclohexylcarbodiimide (41 mg, 0.20 mmol) was stirred in THF (1 ml) overnight at room temperature and further at 60 0C for 3 h. The solvent was evaporated and the residue dissolved on MeOH. The compound was purified by prepara- tive HPLC (acidic system). The title compound was obtained in 6% yield (2.5 mg). MS (ESI+) calcd for C23H27N30582: 489.139212, found 489.140522.
Example 152 Methyl 4-({[5'-flu0r0-2'-hydr0xy(trifluor0methyl)biphenyl—3-yl]sulfonyl}amin0)—2- ybenzoate OH O“ ,N O o S\\ F The product was prepared from methyl 4-({[3-bromo (trifluoromethyl)phenyl]sulfonyl}amino)hydroxybenzoate (Intermediate 5) (0.023 g, 0.050 W0 2013/093095 167 mmol) and (5-fluorohydroxyphenyl)boronic acid (0.008 g, 0.050 mmol) according to the General Procedure 9, described in e 82. The title compound was obtained in 79% yield (19.1 mg). 1H NMR (600 MHz,CDC13)8 ppm 3.91 (s, 3 H) 5.51 (br. s., 1 H) 6.65 (dd, J=8.70, 2.22 Hz, 1 H) 6.76 (d, J=2.22 Hz, 1 H) 6.87 (dd, J=8.85, 4.51 Hz, 1 H) 6.96 (dd, J=8.77, 3.05 Hz, 1 H) 7.00 (ddd, , 7.74, 3.05 Hz, 1 H) 7.09 (br. s., 1 H) 7.74 (d, J=8.70 Hz, 1 H) 7.97 - 8.00 (m, 1 H) 8.07 - 8.11 (m, 1 H) 8.32 (t, J=1.69 Hz, 1 H) 10.92 (s, 1 H). MS (ESI+) m/Z 486 .
Example 153 Methyl 4-{[(2',5'-difluor0biphenyl—3-yl)sulf0nyl] amin0}hydr0xybenzoate F O\\,N o O QS“0 0\ F The product was prepared from methyl 4- {[(3-bromophenyl)sulfonyl]amino} hydroxybenzoate (Intermediate 4) (0.019 g, 0.050 mmol) and 2,5-difluorophenylboronic acid (0.008 g, 0.050 mmol) according to the General Procedure 9, described in Example 82. The title compound was obtained in 72% yield (15.2 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.90 (s, 3 H) 6.66 (dd, , 2.25 Hz, 1 H) 6.69 (d, J=2.25 Hz, 1 H) 6.84 (br. s., 1 H) 7.03 - 7.09 (m, 2 H) 7.10 - 7.17 (m, 1 H) 7.57 (dd, J=7.94, 7.81 Hz, 1 H) 7.73 (d, J=8.60 Hz, 1 H) 7.72 - 7.75 (ddt,J=7.81, 1.66, 1.12 Hz, 1 H) 7.89 (ddd,J=7.94, 1.95, 1.10 Hz, 1 H) 8.01 - 8.04 (m, 1 H) 10.86 (s, 1 H). MS (ESI+) m/z 420 [M+H]+.
Example 154 Methyl 4-({[3-(2,3-dihydr0benzofuranyl)phenyl]sulfonyl}amin0)—2- hydroxybenzoate 0, N so 0 O O OH O\ The product was prepared from methyl 4- {[(3-bromophenyl)sulfonyl]amino} hydroxybenzoate (Intermediate 4) (0.019 g, 0.050 mmol) and 2,3-dihydrobenzofuran—5- W0 2013/093095 168 boronic acid (0.008 g, 0.050 mmol) according to the General ure 9, described in Ex- ample 82. The title compound was obtained in 82% yield (17.4 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.27 (t, J=8.70 Hz, 2 H) 3.89 (s, 3 H) 4.63 (t, J=8.70 Hz, 2 H) 6.64 (dd, J=8.70, 2.20 Hz, 1 H) 6.69 (d, J=2.20 Hz, 1 H) 6.83 (br. s., 1 H) 6.85 (d, J=8.24 Hz, 1 H) 7.26 - 7.31 (m, 1 H) 7.34 - 7.38 (m, 1 H) 7.49 (t, J=7.83 Hz, 1 H) 7.70 (d, J=8.70 Hz, 1 H) 7.70 (ddd, J=7.83, 1.87, 1.06 Hz, 1 H) 7.76 (ddd,J=7.83, 1.87, 1.06 Hz, 1 H) 8.00 (t, J=1.87 Hz, 1 H) 10.84 (s, 1 H). MS (ESI+) m/Z 426 [M+H]+.
Example 155 Methyl 4-({[6-chloro-S-(2,3-dihydr0benzofuranyl)pyridinyl]sulfonyl}amin0)—2- hydroxybenzoate The product was prepared from methyl 4- {[(5-bromochloropyridinyl)sulfonyl]amino}- 2-hydroxybenzoate (Intermediate 8) (0.021 g, 0.050 mmol) and 2,3-dihydrobenzofiJran boronic acid (0.008 g, 0.050 mmol) according to the General Procedure 9, described in Ex- ample 82. The title compound was obtained in 39% yield (9.0 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.28 (t, J=8.77 Hz, 2 H) 3.93 (s, 3 H) 4.66 (t, J=8.77 Hz, 2 H) 6.67 (dd, J=8.70, 2.25 Hz, 1 H) 6.72 (d, J=2.25 Hz, 1 H) 6.86 (d, J=8.24 Hz, 1 H) 7.09 (br. s., 1 H) 7.12 - 7.15 (ddt, J=8.24, 2.07, 0.77 Hz, 1 H) 7.21 - 7.23 (m, 1 H) 7.76 (d, J=8.70 Hz, 1 H) 8.03 (d, J=2.50 Hz, 1 H) 8.75 (d, J=2.50 Hz, 1 H) 10.90 (s, 1 H). MS (ESI+) m/z 461 [M+H]+.
Example 156, l ure 10 Methyl 4-({[5-ch10r0(2-hydroxyphenyl)thienyl] sulfonyl}amino)—2-hydr0xybenz0ate W0 2013/093095 169 A mixture of methyl 4- {[(4-bromochlorothienyl)sulfonyl]amino}hydroxybenzoate (Intermediate 3) (0.21 g, 0.50 mmol), ,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenol (0.11 g, 0.50 mmol), DIPEA (0.26 g, 2.0 mmol) and Pd(dppf)C12'CH2C12 (8 mg, 0.010 mmol) in aqueous dioxane (5 mL dioxane, 0.7 mL water) was heated at 80 0C under N2 atmosphere for 3 days. EtOAc and water were added to the reaction mixture. The organic phase was washed with 1 M H3PO4, water and brine, dried with MgSO4, filtered and concentrated. The crude t was purified by flash chromatography (silica, 20-40% EtOAc in hexane). The title compound was obtained as an off-white solid (0.12 g, 56%). 1H NMR (600 MHZ, CDClg) 8 ppm 2.64 (s, 1 H) 3.94 (s, 3 H) 5.00 (br. s., 1 H) 6.71 (dd, J=8.70, 2.29 Hz, 1 H) 6.78 (d, J=2.44 Hz, 1 H) 6.92 (dd, , 0.76 Hz, 1 H) 6.97 - 7.02 (m, 1 H) 7.26 (dd, J=7.63, 1.53 Hz, 1 H) 7.28 - 7.32 (m, 1 H) 7.65 (s, 1 H) 7.79 (d, J=8.54 Hz, 1 H) 10.93 (s, 1 H). MS (ESI+) m/Z 440 . e 157 Methyl 4-({[5—chlor0(5-flu0r0hydr0xyphenyl)thienyl]sulfonyl}amin0)—2- hydroxybenzoate S OoS/N ‘ O \ l ODY OH O\ The product was prepared from methyl 4- {[(4-bromochlorothienyl)sulfonyl]amino} hydroxybenzoate (Intermediate 3) (0.21 g, 0.50 mmol) and (5-fluoro hydroxyphenyl)boronic acid (0.078 g, 0.50 mmol) according to the General Procedure 10, described in Example 156, with a modified reaction time (1 day). The crude product was puri- fied by preparative HPLC (acidic system). The title compound was obtained in 44% yield (0.10 g). 1H NMR (600 MHz, CDClg) 8 ppm 3.93 (s, 3 H) 5.07 (br. s., 1 H) 6.70 (dd, J=8.67, 2.21 Hz, 1 H) 6.77 (d, J=2.21 Hz, 1 H) 6.84 - 6.90 (m, 1 H) 6.96 - 7.02 (m, 2 H) 7.06 (br. s., 1 H) 7.64 (s, 1 H) 7.78 (d, J=8.67 Hz, 1 H) 10.92 (s, 1 H). MS (ESI+) m/z 458 [M+H]+.
Example 158 W0 2013/093095 170 Methyl 4-({[4-(1,3-benzodioxol—5-yl)chlor0thienyl] sulfonyl}amino)—2- ybenzoate S OoS/N ‘ O C' l ODY \ OH O\ The product was prepared from methyl 4- {[(4-bromochlorothieny1)su1fony1]amino} hydroxybenzoate (Intermediate 3) (0.21 g, 0.50 mmol) and 3,4- methylenedioxybenzeneboronic acid (0.083 g, 0.50 mmol) according to the General Proce- dure 10, described in Example 156, with a modified reaction time (1 day). The crude product was purified by preparative HPLC c system). The title compound was obtained in 36% yield (0.085 g). 1H NMR (600 MHz, CDC13) 8 ppm 3.92 (s, 3 H) 6.01 (s, 2 H) 6.71 (dd, J=8.70, 2.25 Hz, 1 H) 6.75 (d, J=2.25 Hz, 1 H) 6.86 (d, J=8.05 Hz, 1 H) 6.92 (dd, J=8.05, 1.80 Hz, 1 H) 6.94 (br. s., 1 H) 6.94 (d, J=1.80 Hz, 1 H) 7.53 (s, 1 H) 7.78 (d, J=8.70 Hz, 1 H) .90 (s, 1 H). MS (ESI+) m/Z 468 [M+H]+.
Example 159 3-M0rpholinylpr0pyl 2-hydr0xy{[(2'-hydr0xybiphenyl—3- yl)sulf0nyl]amin0}benz0ate trifluoroacetate S“ O O OH 0\/\/ A mixture of methyl 2-hydroxy {[(2'-hydroxybipheny1—3-y1)su1fony1]amino}benzoate (Ex- ample 82) (0.14 g, 0.35 mmol) in 1 M NaOH (2 ml) was d at 60 0C for 6 h. The aqueous solution was washed with EtZO, acidified with conc. H3PO4 and extracted with EtOAc. The organic phase was washed with water and brine, dried over MgSO4, d and concentrated.
The residue was recrystallized from water/MeOH yielding 2-hydroxy {[(2'- W0 93095 171 hydroxybiphenylyl)sulfonyl]amino}benzoic acid (83 mg, 63%). 1H NMR (600 MHz, CDgOD) 5 ppm 6.68 (dd, J=8.70, 2.29 Hz, 1 H) 6.72 (d, J=2.14 Hz, 1 H) 6.87 - 6.93 (m, 2 H) 7.16 - 7.23 (m, 2 H) 7.54 (t, J=7.63 Hz, 1 H) 7.70 (d, J=8.54 Hz, 1 H) 7.75 - 7.79 (m, 1 H) 7.79 - 7.83 (m, 1 H) 8.10 (t, J=1.68 Hz, 1 H). MS (ESI+) m/z 386 [M+H]+.
The product was prepared from 2-hydroxy {[(2'-hydroxybiphenyl—3- yl)sulfonyl]amino}benzoic acid (0.019 g, 0.050 mmol) and 4-(3-hydroxypropyl)-morpholine (15 mg, 0.10 mmol) ing to the General Procedure 7, described in Example 59. The title compound was obtained in 32% yield (9.8 mg). MS (ESI+) m/z 513 [M+H]+.
Example 160 holinylpr0pyl 4-{[(5'-flu0r0-2'-hydroxybiphenyl—3-yl)sulf0nyl] amin0} hydroxybenzoate trifluoroacetate OH H HonfiF O 0°,N F 0 f0 OH O\/\/ The product was prepared from 4- {[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoic acid (Intermediate 16) (0.020 g, 0.050 mmol) and 4-(3-hydroxypropyl)— morpholine (15 mg, 0.10 mmol) according to the General Procedure 7, described in Example 59. The title compound was obtained in 26% yield (8.1 mg). MS (ESI+) m/z 531 .
Example 161 2-Meth0xyethyl 4-({[4-(1,3-benzodioxol—5-yl)chlor0thienyl] sulfonyl}amino)—2- hydroxybenzoate S Qé/N \ O / \ I oDY 0 OH O\) O W0 2013/093095 172 The product was prepared from 4-({[4-(1,3-benzodioxolyl)chloro thienyl]sulfonyl}amino)hydroxybenzoic acid (Intermediate 17) (0.023 g, 0.050 mmol) and methoxyethanol (8 mg, 0.10 mmol) according to the l Procedure 7, described in Example 59. The title compound was ed in 39% yield (9.9 mg). 1H NMR (600 MHz, CDC13)8 ppm 3.42 (s, 3 H) 3.70 - 3.74 (m, 2 H) 4.46 - 4.50 (m, 2 H) 6.02 (s, 2 H) 6.71 (dd, J=8.70, 2.29 Hz, 1 H) 6.76 (d, J=2.14 Hz, 1 H) 6.88 (d, J=7.93 Hz, 1 H) 6.93 (dd, J=8.24, 1.83 Hz, 1 H) 6.96 (d, J=1.53 Hz, 1 H) 7.54 (s, 1 H) 7.84 (d, J=8.54 Hz, 1 H) 10.86 (s, 1 H).
MS (ESI+) m/Z 512 [M+H]+.
Example 162 holinylpr0pyl 4-({[4-(1,3-benzodioxol-S-yl)—5-chlor0 thienyl] sulfonyl}amino)—2-hydr0xybenzoate roacetate The product was prepared from 4-({[4-(1,3-benzodioxolyl)chloro thienyl]sulfonyl}amino)hydroxybenzoic acid (Intermediate 17) (0.023 g, 0.050 mmol) and 4-(3-hydroxypropyl)-morpholine (15 mg, 0.10 mmol) according to the General Procedure 7, described in Example 59. The title compound was obtained in 28% yield (9.9 mg). 1H NMR (600 MHz, CDClg) 8 ppm 2.24 (br. s., 2 H) 2.83 (br. s., 2H) 3.07 (br. s., 2H) 3.53 (br. s., 2H) 3.95 (br. s., 4 H) 4.41 (t, J=6.10 Hz, 2 H) 6.02 (s, 2 H) 6.71 (dd, J=8.70, 2.29 Hz, 1 H) 6.80 (d, J=2.14 Hz, 1 H) 6.88 (d, J=7.93 Hz, 1 H) 6.94 (dd, J=7.43, 1.83 Hz, 1 H) 6.96 (d, J=1.53 Hz, 1 H) 7.55 (s, 1 H) 7.75 (d, J=8.85 Hz, 1 H) 10.75 (br. s., 1 H). MS (ESI+) m/z 581 [M+H]+.
Example 163 3-M0rpholinylpr0pyl 4-({[5-chlor0(2,3-dihydr0benzofuranyl)—2- thienyl] sulfonyl}amino)—2-hydr0xybenzoate trifluoroacetate W0 2013/093095 173 The product was prepared from 4-({[5-chloro(2,3-dihydrobenzofuranyl)thiophen yl]sulfonyl} amino)hydroxybenzoic acid (Intermediate 2) (0.023 g, 0.050 mmol) and 4-(3- hydroxypropyl)-morpholine (15 mg, 0.10 mmol) according to the General Procedure 7, de- scribed in Example 59. The title compound was obtained in 29% yield (10 mg). 1H NMR (600 MHz,CDC13)8 ppm 2.24 (br. s., 2 H) 2.83 (br. s., 2 H) 3.08 (br. s., 2 H) 3.26 (t, J=8.70 Hz, 2 H) 3.52 (br. s., 2H) 3.96 (br. s., 4 H) 4.40 (t, J=6.10 Hz, 2 H) 4.63 (t, J=8.70 Hz, 2 H) 6.71 (dd, J=8.70, 2.29 Hz, 1 H) 6.80 (d, J=2.14 Hz, 1 H) 6.84 (d, J=8.24 Hz, 1 H) 7.23 (dd, J=8.24, 1.83 Hz, 1 H) .33 (m, 1 H) 7.57 (s, 1 H) 7.75 (d, J=8.85 Hz, 1 H) 10.75 (br. s., 1 H).
MS (ESI+) m/Z 579 [M+H]+.
Example 164 3-M0rpholinylpr0pyl 2-hydr0xy{[(2,4,5-trichlor0 thienyl)sulf0nyl] amin0}benzoate CI q\ H ors’ po owaw OH o The product was prepared from 2-hydroxy ,5-trichloro thienyl)sulfonyl]amino}benzoic acid (Intermediate 18) (0.019 g, 0.048 mmol) and 4-(3- hydroxypropyl)-morpholine (41 mg, 0.28 mmol) according to the General Procedure 7, de- scribed in Example 59. After purification the compound was dissolved in EtOAc and washed with N32C03 (aq. sat.). tration of the organic phase gave the title compound in 35% yield (10 mg). 1H NMR (600 MHz, 8 ppm 1.87 - 2.07 (m, 2 H) 2.19 - 2.75 (m, 6 H) 3.55 - 3.90 (m, 4 H) 4.39 (t, J=6.33 Hz, 2 H) 6.67 (dd, J=8.70, 2.21 Hz, 1 H) 6.71 (d, J=2.21 Hz, 1 H) 7.75 (d, J=8.70 Hz, 1 H) 10.89 (br. s., 1 H). MS (ESI+) m/Z 529 [M+H]+.
W0 2013/093095 174 Example 165 2-Meth0xyethyl 2-hydr0xy{[(2,4,5-trichlor0thienyl)sulf0nyl] amin0}benz0ate o H 3 CI 1 The product was prepared from 2-hydroxy {[(2,4,5-trichloro thienyl)sulfonyl]amino}benzoic acid (Intermediate 18) (0.019 g, 0.048 mmol) and methoxy- ethanol (22 mg, 0.28 mmol) according to the General Procedure 7, described in Example 59.
The title compound was obtained in 38% yield (8.4 mg). 1H NMR (600 MHz, CDC13) 8 ppm 3.41 (s, 3 H) 3.68 - 3.73 (m, 2 H) 4.45 - 4.48 (m, 2 H) 6.67 (dd, J=8.70, 2.29 Hz, 1 H) 6.70 (d, J=2.29 Hz, 1 H) 7.82 (d, J=8.70 Hz, 1 H) 10.83 (s, 1 H). MS (ESI+) m/z 460 [M+H]+.
Example 166 rt-butoxycarbonyl)amin0]propyl 2-hydr0xy{[(2,4,5-trichlor0 thienyl)sulf0nyl]amin0}benz0ate 0%] Q‘s’NH \\ H o O\/\/N o s Y OH o >(o The t was prepared from 2-hydroxy {[(2,4,5-trichloro thienyl)sulfonyl]amino}benzoic acid (Intermediate 18) (0.019 g, 0.048 mmol) and tert—butyl (3 -hydroxypropyl)carbamate (59 mg, 0.34 mrno 1) according to the General ure 7, de- scribed in Example 59. The title compound was obtained in 40% yield (11 mg). 1H NMR (600 MHz, CDC13) 8 ppm 1.44 (s, 9 H) 1.96 (quin, J=6.33 Hz, 2 H) 3.28 (q, J=6.10 Hz, 2 H) 4.40 (t, J=6.10 Hz, 2 H) 4.69 (br. s., 1 H) 6.67 (dd, J=8.54, 2.14 Hz, 1 H) 6.72 (d, J=2.14 Hz, 1 H) 7.19 (s, 1 H) 7.77 (d, J=8.85 Hz, 1 H) 10.90 (s, 1 H). MS (ESI+) m/Z 581 +.
Example 167 1-Methylpiperidinyl 2-hydr0xy{[(2,4,5-trichlor0thienyl)sulf0nyl] amin0}benz0ate CI Qé,NH OH 0 U\ The product was prepared from 2-hydroxy {[(2,4,5-trichloro thienyl)sulfonyl]amino}benzoic acid (Intermediate 18) (0.019 g, 0.048 mmol) and 1- piperidinol (32 mg, 0.28 mmol) ing to the General Procedure 7, described in Example 59. After purification the compound was dissolved in EtOAc and washed with Na2C03 (aq. sat.). Concentration of the organic phase gave the title compound in 15% yield (3.6 mg). 1H NMR (600 MHz, CDC13)8 ppm 1.81 - 1.93 (m, 2 H) 1.96 - 2.07 (m, 2 H) 2.26 - 2.42 (m, 5 H) 2.63 - 2.73 (m, 2 H) 5.00 - 5.13 (m, 1 H) 6.68 (dd, J=8.70, 1.98 Hz, 1 H) 6.72 (d, J=1.83 Hz, 1 H) 7.78 (d, J=8.54 Hz, 1 H) 10.99 (br. s., 1 H). MS (ESI+) m/Z 499 [M+H]+.
Example 168 4-M0rpholinylbutyl 2-hydr0xy{[(2,4,5—trichlor0thienyl)sulf0nyl] amin0}benz0ate trifluoroacetate CIV18“S, 0 ONNfi OH 0 o K/o MYFF The product was prepared from 2-hydroxy {[(2,4,5-trichloro thienyl)sulfonyl]amino}benzoic acid mediate 18) (0.020 g, 0.050 mmol) and 4- linylbutanol (48 mg, 0.30 mmol) according to the General Procedure 7, de- scribed in Example 59. The title compound was obtained in 65% yield (18 mg). 1H NMR (600 MHz,CDC13)8 ppm 1.79 - 1.86 (m, 2 H) 1.92 (br. s., 2 H) 2.77 (br. s., 2 H) 3.00 (br. s., 2 H) 3.46 (br. s., 2 H) 3.97 (br. s., 4 H) 4.29 - 4.38 (m, 2 H) 6.64 (dd, J=8.70, 2.29 Hz, 1 H) 6.73 (d, J=2.14 Hz, 1 H) 7.18 (br. s., 1 H) 7.71 (d, J=8.54 Hz, 1 H) 10.82 (s, 1 H). MS (ESI+) m/z 543 [M+H]+.
W0 2013/093095 176 Example 169 l-Methylpyrrolidinyl 0xy{[(2,4,5-trichlor0 thienyl)sulf0nyl] amin0}benz0ate trifluoroacetate CI Q‘s/NH O S I) F N F The product was ed from 2-hydroxy {[(2,4,5-trichloro thienyl)sulfonyl]amino}benzoic acid (Intermediate 18) (0.020 g, 0.050 mmol) and l- methylpyrrolidin—3-ol (30 mg, 0.30 mmol) according to the General Procedure 7, described in Example 59. The title compound was obtained in 49% yield (12 mg). 1H NMR (600 MHz, CDgOD) 8 ppm 2.27 - 2.39 (m, l H) 2.50 - 2.68 (m, l H) 2.95 (br. s., 3 H) 3.44 - 3.86 (m, 4 H) 5.61 - 5.66 (m, l H) 6.71 - 6.75 (m, 2 H) 7.80 - 7.85 (m, l H). MS (ESI+) m/Z 485 [M+H]+.
Example 170, General Procedure 11 4-M0rpholinylbutyl 4-{[(5'-flu0r0-2'-hydroxybiphenyl—3-yl)sulf0nyl] amin0} hydroxybenzoate trifluoroacetate OH H O 00 /N HOJKKF 8‘6 O F A mixture of 4- {[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 16) (20 mg, 0.050 mmol) and thionyl chloride (18 mg, 0. 15 mmol) in MeCN (2 mL) was stirred at room temperature for 20 minutes. The reaction mixture was concentrated to half the volume with a stream of nitrogen and a solution of 4-morpholinylbutan—l-ol (40 mg, 0.25 mmol) in MeCN (1 mL) was added. The on mixture was stirred at room tem- re for 3 days, and purified by preparative HPLC c system). The title compound was obtained in 31% yield (10.2 mg). MS (ESI+) m/Z 545 [M+H]+. 177 2012/076836 Example 171 3-M0rpholinylpr0pyl 4-{[(2',5'-diflu0r0biphenyl—3-yl)sulf0nyl]amin0} ybenzoate trifluoroacetate O H “s; o 0 OH O\/\/ HO&F The product was prepared from 4- {[(2',5'-difluorobiphenylyl)sulfonyl]amino} hydroxybenzoic acid (Intermediate 19) (20 mg, 0.050 mmol) and ydroxypropyl)- morpholine (36 mg, 0.25 mmol) according to the General Procedure 11, described in Example 170. The title compound was obtained in 73% yield (24 mg). 1H NMR (600 MHz, DMSO-d6) 8 ppm 2.04 (br. s., 2 H) 2.93 - 3.26 (m, 4 H) 3.40 - 3.69 (m, 4 H) 3.97 (br. s., 2 H) 4.30 (t, J=5.95 Hz, 2 H) 6.71 - 6.77 (m, 2 H) 7.30 - 7.38 (m, l H) 7.40 - 7.50 (m, 2 H) 7.69 (d, J=8.24 Hz, 1 H) 7.73 (t, J=7.93 Hz, 1 H) 7.84-7.92 (m, 2 H) 8.00-8.06 (m, l H) 9.51 (br. s., l H) .56 (br. s., 1 H) 10.98 (br. s., 1 H). MS (ESI+) m/Z 533 [M+H]+.
Example 172 2-Meth0xyethyl 4-{[(2',5'-difluor0biphenyl—3-yl)sulf0nyl] amin0}hydr0xybenzoate 00,“ O 8‘. o F O / The product was prepared from 4- {[(2',5'-difluorobiphenylyl)sulfonyl]amino} hydroxybenzoic acid (Intermediate 19) (20 mg, 0.050 mmol) and methoxyethanol (19 mg, 0.25 mmol) according to the General Procedure 11, described in Example 170. The title com- pound was obtained in 76% yield (18 mg). 1H NMR (600 MHz, DMSO-dg) 8 ppm 3.27 (s, 3 H) 3.58 - 3.64 (m, 2 H) 4.32 - 4.39 (m, 2 H) 6.71 (d, J=1.83 Hz, 1 H) 6.74 (dd, , 1.98 Hz, 1 H) 7.29 - 7.38 (m, 1 H) 7.40 - 7.49 (m, 2 H) 7.65 (d, J=8.54 Hz, 1 H) 7.72 (t, J=7.78 Hz, 1 H) 7.87 (d, J=7.63 Hz, 1 H) 7.89 (d, J=7.93 Hz, 1 H) 8.00-8.05 (m, 1 H) 10.55 (s, 1 H) .96 (br. s., 1 H). MS (ESI+) m/Z 464 [M+H]+.
W0 2013/093095 178 e 173 4-M0rpholinylbutyl 4-{[(2',5'-diflu0robiphenyl—3-yl)sulf0nyl] amin0} hydroxybenzoate trifluoroacetate o“ H HOJKK 0 8‘13mo F F O OH O\/\/\N/\\ \\/o The product was prepared from 4- {[(2',5'-difluorobiphenylyl)sulfonyl]amino} hydroxybenzoic acid (Intermediate 19) (20 mg, 0.050 mmol) and 4-morpholinylbutan—l-ol (40 mg, 0.25 mmol) according to the l ure 11, described in Example 170. The title compound was obtained in 60% yield (20 mg). MS (ESI+) m/z 547 [M+H]+.
Example 174 3-M0rpholinylpr0pyl 4-({[3-(2,3-dihydr0benz0furanyl)phenyl]sulfonyl}amin0)— 2-hydr0xybenz0ate trifluoroacetate The product was ed from 4-({[3-(2,3-dihydrobenzofuran—5- yl)phenyl]sulfonyl}amino)hydroxybenzoic acid (Intermediate 20) (21 mg, 0.050 mmol) and 4-(3-hydroxypropyl)-morpholine (36 mg, 0.25 mmol) according to the General Procedure 11, described in Example 170. The title compound was obtained in 69% yield (22 mg). 1H NMR (600 MHz, DMSO-dg) 8 ppm 3.25 (t, J=8.85 Hz, 2 H) 4.29 (t, J=5.95 Hz, 2 H) 4.59 (t, J=8.70 Hz, 2 H) 6.71 - 6.77 (m, 2 H) 6.88 (d, J=8.24 Hz, 1 H) 7.39 (dd, J=8.24, 2.14 Hz, 1H) 7.53 (s, l H) 7.62 (t, J=7.78 Hz, 1 H) 7.69 (d, J=9.15 Hz, 1 H) 7.73 (d, J=8.54 Hz, 1 H) 7.87 (d, J=7.93 Hz, 1 H) 8.00 (s, l H) 9.50 (br. s., l H) 10.56 (br. s., l H) 10.89 (br. s., l H). MS (ESI+) m/Z 539 [M+H]+.
Example 175 W0 2013/093095 179 2-Meth0xyethyl 4-({[3-(2,3-dihydr0benz0furanyl)phenyl]sulfonyl}amin0)—2- hydroxybenzoate 0. N so 0 O O / OH O\/\O The product was prepared from 4-({[3-(2,3-dihydrobenzofuran—5- nyl]sulfonyl}amino)hydroxybenzoic acid (Intermediate 20) (21 mg, 0.050 mmol) and methoxyethanol (19 mg, 0.25 mmol) according to the General Procedure 11, bed in Example 170. The title compound was obtained in 41% yield (9.7 mg). 1H NMR (600 MHz, DMSO-dg) 5 ppm 3.24 (t, J=8.85 Hz, 2 H) 3.26 (s, 3 H) 3.57 - 3.64 (m, 2 H) 4.32 - 4.39 (m, 2 H) 4.59 (t, J=8.70 Hz, 2 H) .73 (m, l H) 6.74 (d, J=8.85 Hz, 1 H) 6.88 (d, J=8.24 Hz, 1 H) 7.38 (dd, J=8.24, 2.14 Hz, 1 H) 7.49-7.53 (m, l H) 7.62 (t, J=7.78 Hz, 1 H) 7.65 (d, J=8.85 Hz, 1 H) 7.73 (d, J=7.93 Hz, 1 H) 7.86 (d, J=7.93 Hz, 1 H) 7.98 (t, J=l.68 Hz, 1 H) .54 (s, l H) 10.86 (br. s., l H). MS (ESI+) m/z 470 [M+H]+.
Example 176 4-M0rpholinylbutyl -(2,3-dihydr0benz0furanyl)phenyl]sulfonyl}amin0)—2- hydroxybenzoate trifluoroacetate H F O. N 0 o HO& woo F.
O OH ONNOO The product was prepared from 4-({[3-(2,3-dihydrobenzofuran—5- yl)phenyl]sulfonyl}amino)hydroxybenzoic acid (Intermediate 20) (21 mg, 0.050 mmol) and 4-morpholinylbutan-l-ol (40 mg, 0.25 mmol) according to the General Procedure ll, described in Example 170. The title compound was obtained in 69% yield (23 mg). MS (ESI+) m/Z 553 [M+H]+.
Example 177 Methyl 4-{[(3-br0m0methoxyphenyl)sulf0nyl] amin0}hydr0xybenzoate W0 2013/093095 180 A on of oanisole (5.00 g, 26.7 mmol) in CHzClz (100 mL) was cooled on ice.
Chlorosulfonic acid (9.3 g, 80 mrnol) in CHzClz (100 mL) was added dropwise at 0 0C. The reaction mixture was allowed to reach room temperature overnight and was then added slowly to a d solution of brine. The organic phase was separated and washed with brine, dried over MgSO4, filtered and concentrated. The ediate 3-bromomethoxybenzenesulfonyl chloride was obtained in 97% yield (7.33 g). 1H NMR (600 MHz, CDClg) 8 ppm 4.03 (s, 3 H) 7.04 (d, J=8.85 Hz, 1 H) 7.99 (dd, J=8.85, 2.44 Hz, 1 H) 8.22 (d, J=2.44 Hz, 1 H). MS (ESI+) m/Z 249 [M-Cl]+.
A mixture of 3-bromomethoxybenzenesulfonyl chloride (2.86 g, 10 mmol), methyl 4- amino-salicylate (1.84 g, 11 mmol) and pyridine (0.87 g, 11 mmol) in MeCN (100 mL) was stirred at 80 0C for 1 day. Water and EtOAc were added. The organic phase was washed with l M HCl, water and brine, dried over MgSO4, filtered and concentrated. The residue was re- crystallized from toluene/heptane. The title compound was obtained in 78% yield (3.26 g). 1H NMR (600 MHz, DMSO-dg) 8 ppm 3.82 (s, 3 H) 3.91 (s, 3 H) 6.66 - 6.73 (m, 2 H) 7.28 (d, J=8.85 Hz, 1 H) 7.66 (d, J=8.85 Hz, 1 H) 7.81 (dd, J=8.70, 2.29 Hz, 1 H) 7.96 (d, J=2.14 Hz, 1 H) 10.58 (s, l H) 10.81 (s, l H). MS (ESI+) m/z4l6 [M+H]+. e 178, General Procedure 12 2-Meth0xymethylethyl 4-{[(5'-flu0r0-2'-hydroxybiphenylyl)sulf0nyl] amin0} hydroxybenzoate OH 0?0 A mixture of 4- {[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 16) (0.020 g, 0.050 mmol), l-methoxypropanol (400 uL) and conc. sulfiaric W0 2013/093095 181 acid (40 uL) was stirred at 80 0C for 1 week. The reaction mixture was diluted with MeCN and purified by preparative HPLC (acidic ). The title compound was obtained in 33% yield (7.8 mg). 1H NMR (600 MHz, DMSO-dg) 8 ppm 1.23 (d, J=6.41 Hz, 3 H) 3.25 (s, 3 H) 3.42 - 3.52 (m, 2 H) 5.16 - 5.21 (m, 1 H) 6.70 (d, J=2.14 Hz, 1 H) 6.74 (dd, J=8.85, 2.14 Hz, 1 H) 6.96 (dd, J=9.00, 5.03 Hz, 1 H) 7.04 - 7.09 (m, 1 H) 7.11 (dd, J=9.61, 3.20 Hz, 1 H) 7.60 - 7.65 (m, 2 H) 7.78 (d, J=8.85 Hz, 1 H) 7.83 (d, J=7.93 Hz, 1 H) 8.10 (t, J=1.83 Hz, 1 H) 9.82 (s, 1 H) 10.62 (s, 1 H) 10.91 (s, 1 H). MS (ESI+) m/z 476 [M+H]+.
Example 179 Tetrahydrofuranyl 4-{[(5'-flu0r0-2'-hydroxybiphenyl—3-yl)sulf0nyl] amin0} hydroxybenzoate O 0, ,H 8., o OH one The product was prepared from 4- {[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} ybenzoic acid (Intermediate 16) (0.020 g, 0.050 mmol) and 3-hydroxytetrahydrofiaran (400 uL) according to the General ure 12, described in Example 178. The title com- pound was obtained in 30% yield (7.2 mg). 1H NMR (600 MHz, DMSO-dg) 8 ppm 1.98 - 2.05 (m, 1 H) 2.15 - 2.23 (m, 1 H) 3.71 - 3.76 (m, 1 H) 3.78 - 3.86 (m, 3 H) 5.40 - 5.44 (m, 1 H) 6.70 (d, J=1.83 Hz, 1 H) 6.73 (dd, J=8.54, 2.14 Hz, 1 H) 6.96 (dd, J=8.85, 4.88 Hz, 1 H) 7.04 - 7.09 (m, 1 H) 7.11 (dd, J=9.46, 3.05 Hz, 1 H) 7.59 - 7.66 (m, 2 H) 7.75 - 7.80 (m, 1 H) 7.81 - 7.86 (m, 1 H) 8.10 (t, J=1.83 Hz, 1 H) 9.82 (s, 1 H) 10.56 (s, 1 H) 10.91 (s, 1 H). MS (ESI+) m/Z 474 [M+H]+.
Example 180 1-(Meth0xymethyl)pr0pyl 4-{[(5'-flu0r0-2'-hydroxybiphenyl—3-yl)sulf0nyl] amin0} hydroxybenzoate W0 2013/093095 182 The product was prepared from 4- {[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} ybenzoic acid (Intermediate 16) (0.020 g, 0.050 mmol) and 1-methoxybutanol (400 uL) according to the General ure 12, described in Example 178. The title nd was obtained in 18% yield (4.3 mg). 1H NMR (600 MHZ, DMSO-dg) 8 ppm 0.86 (t, J=7.48 Hz, 3 H) 1.56 - 1.70 (m, 2 H) 3.24 (s, 3 H) 3.45 - 3.49 (m, 1 H) 3.49 - 3.55 (m, 1 H) 5.06 - .12 (m, 1 H) 6.71 (d, J=2.14 Hz, 1 H) 6.74 (dd, J=8.85, 2.14 Hz, 1 H) 6.96 (dd, J=8.85, 4.88 Hz, 1 H) 7.03 - 7.09 (m, 1 H) 7.11 (dd, J=9.46, 3.36 Hz, 1 H) 7.58 - 7.68 (m, 2 H) 7.75 - 7.80 (m, 1 H) 7.82 - 7.86 (m, 1 H) 8.11 (t, J=1.83 Hz, 1 H) 9.82 (s, 1 H) 10.63 (s, 1 H) 10.92 (s, 1 H). MS (ESI+) m/Z 490 [M+H]+.
Example 181 2-Eth0xy(eth0xymethyl)ethyl 4-{[(5'-flu0r0-2'-hydroxybiphenyl—3-yl)sulf0nyl] amino}- 2-hydroxybenzoate OH 00/“ O 8.. o F O O /\ OH ofo The product was prepared from 4- fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoic acid (Intermediate 16) (0.020 g, 0.050 mmol) and 1,3-diethoxypropanol (400 uL) according to the General Procedure 12, described in Example 178. The title compound was obtained in 17% yield (4.6 mg). 1H NMR (600 MHz, DMSO-dg) 8 ppm 1.05 (t, J=7.02 Hz, 6 H) 3.37 - 3.50 (m, 4 H) 3.53 - 3.61 (m, 4 H) 5.18 - 5.27 (m, 1 H) 6.71 (d, J=2.14 Hz, 1 H) 6.74 (dd, J=8.54, 2.14 Hz, 1 H) 6.96 (dd, J=8.85, 4.88 Hz, 1 H) 7.02 - 7.10 (m, 1 H) 7.11 (dd, J=9.46, 3.05 Hz, 1 H) 7.59 - 7.68 (m, 2 H) 7.78 (d, J=8.85 Hz, 1 H) 7.84 (d, J=7.63 Hz, 1 H) 8.11 (t, J=1.83 Hz, 1 H) 9.82 (s, 1 H) 10.53 (s, 1 H) 10.93 (s, 1 H). MS (ESI+) m/z 534 [M+H]+.
W0 2013/093095 183 Example 182 2-Meth0xybutyl 4-{[(5'-flu0r0-2'-hydroxybiphenylyl)sulf0nyl] amin0} hydroxybenzoate o O ,H F O / OH \10 The product was prepared from 4- fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoic acid (Intermediate 16) (0.020 g, 0.050 mmol) and 2-methoxybutanol (400 uL) according to the General Procedure 12, described in Example 178. The title compound was obtained in 57% yield (14 mg). 1H NMR (600 MHZ, DMSO-dg) 8 ppm 0.88 (t, J=7.48 Hz, 3 H) 1.46 - 1.55 (m, 2 H) 3.30 (s, 3 H) 3.36 - 3.42 (m, 1 H) 4.18 (dd, J=11.75, 5.65 Hz,1 H) 4.34 (dd, J=11.75, 3.81 Hz, 1 H) 6.71 (d, J=2.14 Hz, 1 H) 6.74 (dd, J=8.85, 2.14 Hz, 1 H) 6.96 (dd, J=8.85, 4.88 Hz, 1 H) 7.04 - 7.09 (m, 1 H) 7.11 (dd, J=9.46, 3.36 Hz, 1 H) 7.59 - 7.69 (m, 2 H) 7.79 (d, J=8.54 Hz, 1 H) 7.84 (d, J=7.93 Hz, 1 H) 8.11 (t, J=1.68 Hz, 1 H) 9.82 (s, 1 H) 10.56 (s, 1 H) 10.92 (s, 1 H). MS (ESI+) m/Z 490 [M+H]+.
Example 183 2-Hydr0xyethyl 4-{[(5'-flu0r0-2'-hydroxybiphenylyl)sulf0nyl] amin0} hydroxybenzoate O O“ ,H S“ o F O OH O\/\OH The product was prepared from 4- {[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} ybenzoic acid (Intermediate 16) (0.020 g, 0.050 mrnol) and ethylene glycol (400 uL) according to the l Procedure 12, described in e 178 with a modified reaction time of 1 day. The title compound was obtained in 100% yield (22 mg). 1H NMR (600 MHz, g) 5 ppm 3.60 - 3.70 (m, 2 H) 4.23 - 4.29 (m, 2 H) 4.90 (t, J=5.65 Hz, 1 H) 6.70 (d, J=2.14 Hz, 1 H) 6.73 (dd, J=8.70, 1.98 Hz, 1 H) 6.96 (dd, J=9.15, 4.88 Hz, 1 H) 7.03 - 7.09 (m, 1 H) 7.12 (dd, J=9.46, 3.05 Hz, 1 H) 7.63 (t, J=7.93 Hz, 1 H) 7.71 (d, J=8.54 Hz, 1 H) W0 2013/093095 184 7.78 (d, J=8.85 Hz, 1 H) 7.83 (d, J=7.63 Hz, 1 H) 8.11 (t, J=1.68 Hz, 1 H) 9.82 (s, 1 H) 10.60 (s, 1 H) 10.91 (s, 1 H). MS (ESI+) m/Z 448 [M+H]+. e 183 was also prepared on an 6-g scale ing to a similar protocol with some minor changes, such as a lower temperature (50 0C for 1 week) and extractive workup (EtOAc).
Example 184 3-Hydr0xypr0pyl 4-{[(5'-flu0r0-2'-hydroxybiphenyl—3-yl)sulf0nyl] hydroxybenzoate O O“ N 8“ mo . O OH OH O\/\/ The product was prepared from 4- {[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoic acid (Intermediate 16) (0.020 g, 0.050 mrnol) and 1,3-propandiol (400 uL) according to the General Procedure 12, described in Example 178 with a modified reaction time of 1 day. The title compound was obtained in 70% yield (16 mg). 1H NMR (600 MHZ, DMSO-dg) 5 ppm 1.77 - 1.86 (m, 2 H) 3.46 - 3.55 (m, 2 H) 4.30 (t, J=6.41 Hz, 2 H) 4.57 (t, J=5.03 Hz, 1 H) 6.70 (d, J=2.14 Hz, 1 H) 6.73 (dd, J=8.85, 2.14 Hz, 1 H) 6.96 (dd, J=8.85, 4.88 Hz, 1 H) 7.04 - 7.09 (m, 1 H) 7.11 (dd, J=9.46, 3.36 Hz, 1 H) 7.63 (t, J=7.78 Hz, 1 H) 7.65 (d, J=8.54 Hz, 1 H) 7.75 - 7.80 (m, 1 H) 7.82 - 7.86 (m, 1 H) 8.10 (t, J=1.68 Hz, 1 H) 9.82 (s, 1 H) 10.62 (s, 1 H) 10.90 (s, 1 H). MS (ESI+) m/z 462 [M+H]+.
Example 185 2-Meth0xyethyl 4-{[(5'-flu0r0-2'-hydroxybiphenyl—3-yl)sulf0nyl] hydroxybenzoate O O\‘ H 8,. o O O F / OH O\/\O W0 2013/093095 185 The product was prepared from 4- {[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoic acid (Intermediate 16) (0.040 g, 0.10 mmol) and methoxyethanol (0.038 g, 0.5 mmol) ing to the General Procedure 11, described in Example 170, with a d reaction time (1 h). The title compound was obtained in 74% yield (34 mg). 1H NMR (600 MHz,CDC13)8 ppm 3.42 (s, 3 H) 3.69 - 3.75 (m, 2 H) 4.42 - 4.52 (m, 2 H) 4.99 (br. s., l H) 6.62 (d, J=8.54 Hz, 1 H) 6.71-6.75 (m, l H) 6.82 (s, l H) 6.86 (dd, J=8.85, 4.58 Hz, 1 H) 6.93 (dd, J=8.70, 2.90 Hz, 1 H) 6.95 - 7.01 (m, l H) 7.58 (t, J=7.93 Hz, 1 H) 7.71 (d, J=6.71 Hz, 1 H) 7.77 (d, J=8.54 Hz, 1 H) 7.88 (d, J=7.93 Hz, 1 H) 8.06 (s, l H) 10.82 (s, 1 H). MS (ESI+) m/Z 462 [M+H]+.
Example 186 2-Meth0xyethyl 4-{[(3,5—dichlor0phenyl)sulf0nyl] amin0}hydr0xybenz0ate 0, ,H 8‘ O / The product was prepared from 4- {[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 21) (0.018 g, 0.050 mmol) and 2-methoxyethanol (15 mg, 0.20 mmol) ac- cording to the General ure 8, described in Example 60. The title compound was ob- tained in 58% yield (12 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.41 (s, 3 H) 3.69 - 3.72 (m, 2 H) 4.45 - 4.49 (m, 2 H) 6.63 (dd, J=8.54, 2.44 Hz, 1 H) 6.65 (d, J=2.14 Hz, 1 H) 6.74 (br. s., l H) 7.54 (t, J=l.83 Hz, 1 H) 7.73 (d, J=l.83 Hz, 2 H) 7.81 (d, J=8.54 Hz, 1 H) 10.83 (s, l H). MS (ESI+) m/Z 420 .
Example 187 3-M0rpholinylpr0pyl 4-{[(3,5—dichlor0phenyl)sulf0nyl] amin0}hydr0xybenz0ate trifluoroacetate o“ H S. N o O 0 W0 2013/093095 186 The product was prepared from 4- {[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 21) (0.018 g, 0.050 mmol) and 4-(3-hydroxypropyl)morpholine (29 mg, 0.20 mmol) according to the General Procedure 8, bed in Example 60. The title com- pound was obtained in 65% yield (19 mg). 1H NMR (600 MHz, CDClg) 8 ppm 2.21 - 2.35 (m, 2 H) 2.74 - 2.99 (m, 2 H) 3.11 - 3.22 (m, 2 H) 3.45 - 3.67 (m, 2 H) 3.90 - 4.09 (m, 4 H) 4.39 (t, J=5.95 Hz, 2 H) 6.62 (dd, J=8.70, 2.29 Hz, 1 H) 6.70 (d, J=2.14 Hz, 1 H) 7.17 (br. s., 1 H) 7.54 (t, J=1.83 Hz, 1 H) 7.70 (d, J=8.54 Hz, 1 H) 7.74 (d, J=1.83 Hz, 2 H) 10.68 (br. s., 1 H).
MS (ESI+) m/Z 489 [M+H]+.
Example 188 Tetrahydrofuranyl 4-{[(3,5-dichlor0phenyl)sulf0nyl] amin0}hydr0xybenz0ate 0, ,H 8‘ 0 OH 0\0 CI o The product was prepared from 4- -dichlorophenyl)sulfonyl]amino} hydroxybenzoic acid (Intermediate 21) (0.018 g, 0.050 mmol) and 3-hydroxytetrahydrofi1ran (18 mg, 0.20 mmol) according to the General Procedure 8, described in Example 60. The title compound was obtained in 67% yield (14 mg). 1H NMR (600 MHz, CDClg) 8 ppm 2.11 - 2.18 (m, 1 H) 2.25 - 2.32 (m, 1 H) 3.90 (td, J=8.47, 4.42 Hz, 1 H) 3.93 - 4.01 (m, 3 H) 5.53 (dddd, , 4.31, 1.98, 1.68 Hz, 1 H) 6.63 (dd, J=8.70, 2.29 Hz, 1 H) 6.66 (d, J=2.14 Hz, 1 H) 6.75 (br. s., 1 H) 7.55 (t, J=1.83 Hz, 1 H) 7.73 (d, J=1.83 Hz, 2 H) 7.75 (d, J=8.85 Hz, 1 H) 10.83 (s, 1 H). MS (ESI+) m/Z 432 [M+H]+.
Example 189 1-(Meth0xymethyl)pr0pyl 4-{[(3,5-dichlor0phenyl)sulf0nyl]amin0}hydr0xybenz0ate 0,. ,H S, 0 “U 019%OH 0 W0 93095 187 The product was prepared from 4- {[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 21) (0.018 g, 0.050 mmol) and l-methoxybutanol (21 mg, 0.20 mmol) according to the General Procedure 8, described in Example 60. The title nd was ob- tained in 60% yield (13 mg). 1H NMR (600 MHz, CDClg) 8 ppm 0.96 (t, J=7.48 Hz, 3 H) 1.73 (quin, J=7.25 Hz, 2 H) 3.36 (s, 3 H) 3.53 (dd, J=10.68, 3.66 Hz, 1 H) 3.57 (dd, 8, 6.10 Hz, 1 H) 5.18 - 5.23 (m, 1 H) 6.63 (dd, , 2.44 Hz, 1 H) 6.65 (d, J=1.83 Hz, 1 H) 6.73 (br. s., 1 H) 7.55 (t, J=1.83 Hz, 1 H) 7.73 (d, J=1.83 Hz, 2 H) 7.79 (d, J=8.85 Hz, 1 H) .96 (s, 1 H). MS (ESI+) m/z 448 [M+H]+.
Example 190 2-Meth0xybutyl 4-{[(3,5-dichlor0phenyl)sulf0nyl]amin0}hydr0xybenz0ate 0, ,H S. 0 OH 0 The product was prepared from 4- {[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 21) (0.018 g, 0.050 mmol) and 2-methoxy-l-butanol (21 mg, 0.20 mmol) according to the General Procedure 8, described in Example 60. The title compound was ob- tained in 70% yield (16 mg). 1H NMR (600 MHz, CDClg) 8 ppm 0.98 (t, J=7.48 Hz, 3 H) 1.62 (qd, J=7.07, 2.59 Hz, 2 H) 3.39 - 3.43 (m, 1 H) 3.43 (s, 3 H) 4.27 (dd, J=11.60, 5.80 Hz, 1 H) 4.41 (dd, J=11.75, 3.81 Hz, 1 H) 6.63 (dd, J=8.54, 2.44 Hz, 1 H) 6.66 (d, J=2.14 Hz, 1 H) 6.73 (br. s., 1 H) 7.55 (t, J=1.83 Hz, 1 H) 7.73 (d, J=1.83 Hz, 2 H) 7.78 (d, J=8.85 Hz, 1 H) 10.86 (s, 1 H). MS (ESI+) m/z 448 [M+H]+.
Example 191 2-Meth0xy(meth0xymethyl)ethyl 4-{[(3,5—dichlor0phenyl)sulf0nyl] amin0} hydroxybenzoate W0 2013/093095 188 The product was prepared from 4- {[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 21) (0.018 g, 0.050 mmol) and 1,3-dimethoxypropanol (24 mg, 0.20 mmol) according to the l Procedure 8, described in Example 60. The title compound was obtained in 71% yield (16 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.37 (s, 6 H) 3.64 (dd, 8, 4.30 Hz, 2 H) 3.66 (dd, J=10.68, 5.80 Hz, 2 H) 5.35 - 5.41 (m, 1 H) 6.63 (dd, J=8.54, 2.14 Hz, 1 H) 6.65 (d, J=2.14 Hz, 1 H) 6.71 (s, 1 H) 7.55 (t, J=1.83 Hz, 1 H) 7.73 (d, J=1.83 Hz, 2 H) 7.81 (d, J=8.85 Hz, 1 H) 10.83 (s, 1 H). MS (ESI+) m/z 464 [M+H]+.
Example 192 2-Meth0xymethylethyl 4-{[(3,5-dichlor0phenyl)sulf0nyl]amin0}hydr0xybenz0ate 0,. ,H St 0 CI O\©\~\// OH of The product was prepared from 4- {[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoic acid (Intermediate 21) (0.018 g, 0.050 mmol) and l-methoxypropanol (18 mg, 0.20 mmol) according to the General Procedure 8, bed in Example 60. The title compound was ob- tained in 82% yield (18 mg). 1H NMR (600 MHz, CDClg) 8 ppm 1.34 (d, J=6.41 Hz, 3 H) 3.38 (s, 3 H) 3.50 (dd, J=10.68, 3.66 Hz, 1 H) 3.56 (dd, J=10.68, 6.41 Hz, 1 H) 5.29 - 5.38 (m, 1 H) 6.63 (d, J=8.54, 2.14 Hz, 1 H) 6.64 (d, J=2.14 Hz, 1 H) 6.71 (br. s., 1 H) 7.54 (t, J=1.98 Hz, 1 H) 7.73 (d, J=1.83 Hz, 2 H) 7.78 (d, J=8.54 Hz, 1 H) 10.94 (s, 1 H). MS (ESI+) m/Z 434 [M+H]+.
Example 193 W0 2013/093095 189 2012/076836 1-Methyl—3-m0rpholinylpr0pyl 4-{[(4,5-dichlorothiophenyl)sulf0nyl] amin0} hydroxybenzoate) roacetate 0, ,H S S“ O \ I CI OH 0 CI F {N} F The product was prepared from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (Intermediate 7) (0.018 g, 0.050 mmol) and 4-(morpholinyl)butan 01 (16 mg, 0.10 mmol) according to the General Procedure 8, described in Example 60. The title nd was obtained in 56% yield (17 mg). 1H NMR (600 MHz, CDClg) 8 ppm 1.41 (d, J=6.10 Hz, 3 H) 2.07 - 2.29 (m, 2 H) 2.73 - 2.92 (m, 2 H) 2.99 - 3.17 (m, 2 H) 3.47 - 3.62 (m, 2 H) 3.92 - 4.04 (m, 4 H) 5.16 - 5.22 (m, l H) 6.65 (dd, J=8.54, 2.14 Hz, 1 H) 6.77 (d, J=2.14 Hz, 1 H) 6.94 (br. s., l H) 7.43 (s, l H) 7.76 (d, J=8.54 Hz, 1 H) 10.80 (br. s., l H).
MS (ESI+) m/Z 509 [M+H]+.
Example 194 2-Meth0xymethylethyl 4-{[(4,5-dichlorothiophen-Z-yl)sulfonyl]amin0} hydroxybenzoate The product was prepared from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} ybenzoic acid (Intermediate 7) (0.018 g, 0.050 mmol) and 1-methoxypropanol (18 mg, 0.20 mmol) according to the General Procedure 8, described in Example 60. The title compound was obtained in 77% yield (17 mg). 1H NMR (600 MHz, CDClg) 8 ppm 1.36 (d, J=6.41 Hz, 3 H) 3.39 (s, 3 H) 3.51 (dd, J=10.68, 3.97 Hz, 1 H) 3.57 (dd, J=10.68, 6.41 Hz, 1 W0 2013/093095 190 2012/076836 H) 5.30 — 5.37 (m, 1 H) 6.66 (dd, J=8.70, 2.29 Hz, 1 H) 6.71 (d, J=2.14 Hz, 1 H) 6.74 (br. s., 1 H) 7.41 (s, 1 H) 7.81 (d, J=8.54 Hz, 1 H) 10.97 (s, 1 H). MS (ESI+) m/Z 440 [M+H]+.
Example 195 1-(Meth0xymethyl)pr0pyl 4-{[(4,5-dichlorothiophenyl)sulf0nyl]amin0} hydroxybenzoate The product was prepared from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18.4 mg, 0.050 mmol) mediate 7) and 1-methoxybutanol (23 uL, 0.20 mmol) according to the General Procedure 8, described in Example 60. The title nd was obtained in 39% yield (8.8 mg). 1H NMR (600 MHz, DMSO-d6:CD3OD 6:1) 8 ppm 0.88 (t, J=7.48 Hz, 3 H) 1.59 — 1.69 (m, 1 H) 1.65 — 1.73 (m, 1 H) 3.26 (s, 3 H) 3.49 (dd, 1:10.99, 3.67 Hz, 1 H) 3.53 (dd, 1:10.99, 6.54 Hz, 1 H) 5.13 (dddd, J=7.50, 6.54, 5.44, 3.67 Hz, 1 H) 6.74 (d, J=2.14 Hz, 1 H) 6.79 (dd, J=8.70, 2.14 Hz, 1 H) 7.74 (d, J=8.70 Hz, 1 H) 7.78 (s, 1 H). MS (ESI+) m/Z 454 [M+H]+.
Example 196 2-Meth0xybutyl 4-{[(4,5-dichlorothiophenyl)sulf0nyl]amin0}hydr0xybenzoate \\ / S S\‘ O CI \I The product was prepared from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18.4 mg, 0.050 mmol) (Intermediate 7) and 2-methoxybutanol (23 uL, 0.20 mrnol) ing to the General Procedure 8, described in Example 60. The title W0 2013/093095 191 compound was obtained in 77% yield (17.4 mg). 1H NMR (600 MHz, DMSO-d6:CD3OD 6: 1) 8 ppm 0.90 (t, J=7.40 Hz, 3 H) 1.48 — 1.59 (m, 2 H) 3.32 (s, 3 H) 3.41 (tdd, J=6.40, 5.72, 3.66 Hz, 1 H) 4.21 (dd, J=11.67, 5.72 Hz, 1 H) 4.38 (dd, J=11.67, 3.66 Hz, 1 H) 6.75 (d, J=2.21 Hz, 1 H) 6.79 (dd, J=8.62, 2.21 Hz, 1 H) 7.74 (d, J=8.70 Hz, 1 H) 7.78 (s, 1 H). MS (ESI+) m/Z 454 [M+H]+.
Example 197 2-Meth0xyethyl 4-{[(4-br0m0-2,5-dichlor0thi0phenyl)sulf0nyl]amin0} ybenzoate s: o 8 Cl OH O\/\o/ The product was prepared from 4- {[(4-bromo-2,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (19.3 mg, 0.043 mmol) (Intermediate 22) and 2-methoxy-ethanol (14 uL, 0.172 mmol) according to the General Procedure 8, described in Example 60. The title compound was obtained in 37% yield (8.1 mg). 1H NMR (600 MHz, DMSO-d6:CD3OD 6:1) 8 ppm 3.28 (s, 3 H) 3.61 - 3.65 (m, 2 H) 4.36 - 4.40 (m, 2 H) 6.67 (d, J=2.14 Hz, 1 H) 6.69 (dd, J=8.70, 2.14 Hz, 1 H) 7.71 (d, J=8.70 Hz, 1 H). MS (ESI+) m/z 504 [M+H]+.
Example 198 Tetrahydrofuranyl -br0m0-2,5-dichlorothiophenyl)sulf0nyl] amin0} hydroxybenzoate Br 0° N The product was prepared from 4- romo-2,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (19.3 mg, 0.043 mmol) (Intermediate 22) and 3-hydroxytetrahydrofuran (14 uL, 0.172 mmol) according to the General ure 8, described in Example 60. The W0 2013/093095 192 2012/076836 title compound was obtained in 45% yield (10.1 mg). 1H NMR (600 MHZ, DMSO-d6iCD3OD 6:1) 8 ppm 2.01 - 2.08 (m, 1 H) 2.17 - 2.25 (m, 1 H) 3.75 (td, J=8.35, 4.50 Hz, 1 H) 3.80 - 3.87 (m, 3 H) 5.43 - 5.47 (m, 1 H) 6.66 (d, J=2.14 Hz, 1 H) 6.68 (dd, J=8.54, 2.14 Hz, 1 H) 7.71 (d, J=8.54 Hz, 1 H). MS (ESI+) m/Z 516 [M+H]+.
Example 199 3-M0rpholinylpr0pyl 4-{[(4-br0m0-2,5-dichlor0thi0phenyl)sulf0nyl] amin0} hydroxybenzoate trifluoroacetate mom08H FQJOLOHO OH OWNQ The product was prepared from 4- {[(4-bromo-2,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (19.3 mg, 0.043 mmol) (Intermediate 22) and 4-(3- hydroxypropyl)morpholine (24 uL, 0.172 mmol) according to the General Procedure 8, de- scribed in Example 60 with a d reaction time (2 days). The title nd was ob- tained in 41% yield (12.0 mg). 1H NMR (600 MHz, CDC13) 8 ppm 2.24 - 2.32 (m, 2 H) 2.81- 2.94 (m, 2 H) 3.14 — 3.22 (m, 2 H) 3.54—3.65 (m, 2 H) 3.90 — 4.08 (m, 4 H) 4.40 (t, J=5.95 Hz, 2 H) 6.67 (dd, J=8.70, 2.29 Hz, 1 H) 6.74 (d, J=2.29 Hz, 1 H) 7.37 (s, 1 H) 7.73 (d, J=8.70 Hz, 1 H) 10.67 (br. s., 1 H) 13.54 (s, 1 H). MS (ESI+) m/Z 573 [M+H]+.
Example 200 Methyl 4-{[(5—br0m0ch10r0thienyl)sulf0nyl] amin0}hydr0xybenz0ate The product was prepared from methyl 4-amino-salicylate (0.46 g, 2.8 mmol) and 5-bromo chlorothiophenesulfonyl chloride (0.68 g, 2.3 mmol) as described for Intermediate 23. The title compound was obtained in 61% yield (0.60 g). 1H NMR (600 MHz, CDClg) 8 ppm 3.95 W0 2013/093095 193 (s, 3 H) 6.69 (dd, J=8.70, 2.29 Hz, 1 H) 6.74 (d, J=2.14 Hz, 1 H) 6.83 (br. s., 1 H) 7.41 (s, 1 H) 7.80 (d, J=8.54 Hz, 1 H) 10.93 (s, 1 H). MS (ESI+) m/z 426 .
Example 201 (l-Methyl-Z-nitro-1H-imidazolyl)methyl -chlor0(2,3-dihydr0-l-benzofuran- -yl)thienyl] sulfonyl}amino)—2-hydr0xybenz0ate The product was prepared from -chloro(2,3-dihydrobenzofuranyl)thiophen yl]sulfonyl} amino)hydroxybenzoic acid (Intermediate 2) (0.023 g, 0.050 mmol) and (3- methylnitro-3H-imidazolyl)-methanol (16 mg, 0.10 mmol) according to the General ure 8, described in Example 60. The title compound was obtained in 31% yield (9.2 mg). 1H NMR (600 MHz, DMSO-dg) 8 ppm 3.21 (t, J=8.70 Hz, 2 H) 3.97 (s, 3 H) 4.57 (t, J=8.70 Hz, 2 H) 5.44 (s, 2 H) 6.76 (dd, J=8.85, 1.83 Hz, 1 H) 6.80 (d, J=1.83 Hz, 1 H) 6.84 (d, J=8.54 Hz, 1 H) 7.28 (dd, J=8.39, 1.68 Hz, 1 H) 7.33 (s, 1 H) 7.42 (s, 1 H) 7.68 - 7.75 (m, 2 H) 10.48 (s, 1 H) 11.20 (br. s., 1 H). MS (ESI+) m/z 591 [M+H]+.
Example 202 (l-Methyl-Z-nitro-1H-imidaz0]—5-yl)methyl 4-{[(4,5-dichlor0thi0phen yl)sulf0nyl] amin0}hydr0xybenz0ate H o O“ ,N N \ Ni (DI/Qs 8b JENf ‘o’ O OH \ The product was prepared from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (Intermediate 7) (0.018 g, 0.050 mmol) and (3-methylnitro-3H- imidazolyl)-methanol (16 mg, 0.10 mmol) according to the General Procedure 8, described W0 2013/093095 194 in Example 60. The title compound was obtained in 56% yield (14 mg). 1H NMR (600 MHZ, g) 8 ppm 3.98 (s, 3 H) 5.45 (s, 2 H) 6.74 (dd, J=8.85, 2.14 Hz, 1 H) 6.77 (d, J=2.14 Hz, 1 H) 7.34 (s, 1 H) 7.73 (d, J=8.85 Hz, 1 H) 7.82 (s, 1 H) 10.50 (s, 1 H) 11.31 (br. s., 1 H).
MS (ESI+) m/Z 507 [M+H]+.
Example 203 2-Phen0xyethyl 4-{[(5'-flu0r0-2'-hydr0xybiphenyl—3-yl)sulf0nyl] amin0} hydroxybenzoate O O“ N 8.. o O O F OH O\/\O The product was prepared from 4- {[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoic acid (Intermediate 16) (0.020 g, 0.050 mmol) and 2-phenoxyethanol (400 uL) ing to the General Procedure 12, described in Example 178 with a modified reac- tion time (1 day). The title compound was obtained in 59% yield (15 mg). 1H NMR (600 MHz, DMSO-d6) 8 ppm 4.25 - 4.33 (m, 2 H) 4.52 - 4.62 (m, 2 H) 6.67 - 6.74 (m, 2 H) 6.89 - 6.99 (m, 4 H) 7.03 - 7.09 (m, 1 H) 7.11 (dd, J=9.61, 3.20 Hz, 1 H) 7.23-7.32 (m, 2 H) 7.56 - 7.66 (m, 2 H) 7.77 (d, J=7.93 Hz, 1 H) 7.83 (d, J=7.63 Hz, 1 H) 8.10 (s, 1 H) 9.81 (s, 1 H) .52 (s, 1 H) 10.91 (s, 1 H). MS (ESI+) m/Z 524 [M+H]+.
Example 204 l-Benzylpyrrolidinyl 2-hydr0xy{[(2,4,5-trichlor0 thienyl)sulf0nyl] amin0}benz0ate The product was ed from 2-hydroxy {[(2,4,5-trichloro thienyl)sulfonyl]amino}benzoic acid (Intermediate 18) (0.019 g, 0.048 mmol) and 1- benzylpyrrolidinol (50 mg, 0.28 mmol) according to the General ure 7, described in W0 2013/093095 195 e 59. After preparative chromatography the compound was dissolved in EtOAc and washed with N32C03 (aq. sat.). Removal ofthe solvents gave the title compound in 17% yield (4.7 mg). 1H NMR (600 MHz, CDC13)8 ppm 1.95 - 2.04 (m, 1 H) 2.32 - 2.41 (m, 1 H) 2.49 - 2.57 (m, 1 H) 2.73 - 2.80 (m, 1 H) 2.80 - 2.87 (m, 1 H) 2.88 - 2.94 (m, 1 H) 3.64 (d, 1 Hz, 1 H) 3.70 (d, J=12.21 Hz, 1 H) 5.36 - 5.45 (m, 1 H) 6.68 (d, J=8.85 Hz, 1 H) 6.70 (s, 1 H) 7.31 - 7.38 (m, 5 H) 7.78 (d, J=7.63 Hz, 1 H) 10.91 (br. s., 1 H). MS (ESI+) m/z 561 [M+H]+.
Example 205 tert-Butyl 3-[(2-hydr0xy{[(2,4,5-trichlor0 thienyl)sulf0nyl] amin0}benz0yl)0xy]pyrrolidine-l-carboxylate CI H 0%Qé,N“O o O OH O 04O The product was prepared from 2-hydroxy {[(2,4,5-trichloro thienyl)sulfonyl]amino}benzoic acid (Intermediate 18) (0.019 g, 0.048 mmol) and utyl 3-hydroxypyrrolidinecarboxylate (53 mg, 0.28 mmol) ing to the General Procedure 7, described in Example 59. The title compound was obtained in 35% yield (10 mg). 1H NMR (600 MHz, CDC13)8 ppm 1.47 (s, 9 H) 2.12 - 2.23 (m, 2 H) 3.41 - 3.60 (m, 2 H) 3.60 - 3.68 (m, 2 H) 5.49 - 5.53 (m, 1 H) 6.67 (dd, J=8.70, 2.29 Hz, 1 H) 6.72 (d, J=2.29 Hz, 1 H) 7.72 (d, J=8.70 Hz, 1 H) 10.81 (s, 1 H). MS (ESI+) m/z 593 [M+Na]+.
Example 206 Methyl 4-({[4-chlor0(2-hydroxyphenyl)thi0phenyl]sulfonyl}amin0)—2- hydroxybenzoate W0 2013/093095 196 The product was prepared from methyl 4- romochlorothienyl)sulfonyl]amino} hydroxybenzoate (Intermediate 23) (21 mg, 0.050 mmol) and 2-hydroxybenzeneboronic acid (10 mg, 0.075 mmol) according to the General Procedure 9, described in Example 82. The title compound was obtained in 50% yield (11 mg). 1H NMR (600 MHz, DMSO-dg) 5 ppm 3.84 (s, 3 H) 6.77 - 6.82 (m, 2 H) 6.89 (td, J=7.55, 1.07 Hz, 1 H) 6.97 (dd, J=8.24, 0.92 Hz, 1 H) 7.27 - 7.32 (m, 1 H) 7.43 (dd, J=7.63, 1.53 Hz, 1 H) 7.71 - 7.75 (m, 2 H) 10.34 (s, 1 H) .63 (s, 1 H) 11.23 (s, 1 H). MS (ESI+) m/z 440 .
Example 207 Methyl 4-({[4—chlor0(2-meth0xyphenyl)thi0phenyl]sulfonyl}amin0)—2- hydroxybenzoate The product was prepared from methyl 4- {[(5-bromochlorothienyl)sulfonyl]amino} hydroxybenzoate mediate 23) (21 mg, 0.050 mmol) and 2-methoxyphenylboronic acid (11 mg, 0.075 mmol) according to the General Procedure 9, described in Example 82. The title compound was obtained in 42% yield (10 mg). 1H NMR (600 MHz, DMSO-dg) 5 ppm 3.79 (s, 3 H) 3.84 (s, 3 H) 6.78 - 6.83 (m, 2 H) 7.05 (td, J=7.55, 1.07 Hz, 1 H) 7.18 (d, J=7.93 Hz, 1 H) 7.45 (dd, J=7.63, 1.83 Hz, 1 H) 7.47 - 7.51 (m, 1 H) 7.69 - 7.75 (m, 1 H) 7.75 (s, 1 H) 10.63 (s, 1 H) 11.25 (s, 1 H). MS (ESI+) m/z 454 [M+H]+.
Example 208 0xyethyl 4-({[5-chlor0(5-fluor0hydroxyphenyl)thienyl]sulfonyl}amin0)—2- hydroxybenzoate W0 93095 197 The product was prepared from 4-({[5-chloro(5-fluorohydroxyphenyl) thienyl]sulfonyl}amino)hydroxybenzoic acid (Intermediate 24) (22 mg, 0.050 mmol) and 2-methoxyethanol (200 uL) according to the General Procedure 12, described in Example 178 with a modified reaction temperature of 60 0C. The title compound was ed in 81% yield (20 mg). 1H NMR (600 MHz, DMSO-dg) 8 ppm 3.28 (s, 3 H) 3.60 - 3.66 (m, 2 H) 4.34 - 4.42 (m, 2 H) 6.77 (d, J=2.14 Hz, 1 H) 6.80 (dd, J=8.54, 2.14 Hz, 1 H) 6.94 (dd, J=9.00, 4.73 Hz, 1H) 7.06 - 7.15 (m, 2 H) 7.68 - 7.75 (m, 2 H) 9.90 (s, 1 H) 10.60 (s, 1 H) 11.25 (s, 1 H). MS (ESI+) m/Z 502 [M+H]+.
Example 209 Tetrahydrofuranyl 4-({[5-chlor0(5-flu0r0hydr0xyphenyl)—2- thienyl] yl}amino)—2-hydr0xybenz0ate The product was prepared from 4-({[5-chloro(5-fluorohydroxyphenyl) thienyl]sulfonyl}amino)hydroxybenzoic acid mediate 24) (22 mg, 0.050 mmol) and 3-hydroxytetrahydrofi4ran (200 uL) according to the General Procedure 12, described in Ex- ample 178 with a modified reaction temperature of 60 0C. The title compound was obtained in 39% yield (9.9 mg). 1H NMR (600 MHz, DMSO-dg) 5 ppm 2.01 - 2.07 (m, 1 H) 2.18 - 2.25 (m, 1 H) 3.72 - 3.78 (m, 1 H) 3.80 - 3.88 (m, 3 H) 5.43 - 5.47 (m, 1 H) 6.74 - 6.77 (m, 1 H) 6.78 - 6.81 (m, 1 H) 6.94 (dd, J=8.85, 4.88 Hz, 1 H) 7.06 - 7.15 (m, 2 H) 7.71 (s, 1 H) 7.72 (d, J=8.54 Hz, 1 H) 9.91 (s, 1 H) 10.61 (s, 1 H) 11.24 (s, 1 H). MS (ESI+) m/z 514 [M+H]+.
Example 210 W0 2013/093095 198 2-Meth0xybutyl 4-({[5-chlor0(S-flu0r0hydr0xyphenyl)thienyl]sulfonyl}amin0)— oxybenzoate The product was prepared from 4-({[5-chloro(5-fluorohydroxyphenyl) thienyl]sulfonyl}amino)hydroxybenzoic acid (Intermediate 24) (22 mg, 0.050 mmol) and 2-methoxybutanol (200 uL) according to the General Procedure 12, described in Example 178 with a modified reaction temperature of 60 0C. The title compound was obtained in 76% yield (20 mg). 1H NMR (600 MHz, g) 5 ppm 0.89 (t, J=7.48 Hz, 3 H) 1.50 - 1.57 (m, 2 H) 3.31 (s, 3 H) 4.21 (m, 1 H) 4.37 (dd, J=11.60, 3.66 Hz, 1 H) 6.78 (d, J=2.14 Hz, 1 H) 6.80 (dd, J=8.85, 2.14 Hz, 1 H) 6.94 (dd, J=8.85, 4.88 Hz, 1 H) 7.07 - 7.14 (m, 2 H) 7.72 (s, 1 H) 7.73 (d, J=8.85 Hz, 1 H) 9.90 (s, 1 H) 10.61 (s, 1 H) 11.25 (s, 1 H). MS (ESI+) m/z 530 UM+HT.
Example 21 1 Ethyl 4-({[5-chlor0(5-fluoro-Z-hydroxyphenyl)thienyl] sulfonyl}amino)—2- hydroxybenzoate s QS’N \ 0 CI \/ o\©\y¢ OH O\/ The product was prepared from 4-({[5-chloro(5-fluorohydroxyphenyl) thienyl]sulfonyl}amino)hydroxybenzoic acid (Intermediate 24) (22 mg, 0.050 mmol) and ethanol (200 uL) according to the General Procedure 12, described in e 178 with a modified reaction temperature of 60 0C. The title compound was obtained in 92% yield (22 mg). 1H NMR (600 MHz, g) 8 ppm 1.30 (t, J=7.02 Hz, 3 H) 4.31 (q, J=7.02 Hz, 2 H) 6.76 (d, J=2.14 Hz, 1 H) 6.79 (dd, J=8.70, 2.29 Hz, 1 H) 6.94 (dd, J=8.85, 4.88 Hz, 1 H) 7.06 W0 93095 199 — 7.15 (m, 2 H) 7.70 (s, 1 H) 7.72 (d, J=8.85 Hz, 1 H) 9.90 (s, 1 H) 10.70 (s, 1 H) 11.23 (s, 1 H). MS (ESI+) m/Z 472 [M+H]+.
Example 212, General Procedure 13 3-(2,6—Dimethylmorpholinyl)propyl 4-{[(5'-fluoro-2'-hydroxybiphenyl—3- yl)sulfonyl] amino}hydroxybenzoate trifluoroacetate O 8‘5mo *0 OH OWNQ\ FSAOH A mixture of 3-br0m0propyl 4-{[(5'-fluoro-2'-hydr0xybiphenylyl)sulf0nyl]amin0} hydroxybenzoate (Intermediate 25) (14 mg, 0.027 mmol) and cis-2,6-dimethylm0rph0line (23 mg, 0.20 mmol) in MeCN (0.4 mL) was heated at 60 0C overnight. The crude product was purified by preparative HPLC (acidic system). The title compound was obtained in 46% yield (8.3 mg). 1H NMR (600 MHz, CDClg) 8 ppm 1.23 (d, J=6.41 Hz, 6 H) 2.23-2.30 (m, 2 H) 2.37 (t, 9 Hz, 2 H) 3.09 - 3.21 (m, 2 H) 3.52 (d, 9 Hz, 2 H) 4.01 - 4.09 (m, 2 H) 4.31 - 4.37 (m, 2 H) 6.46 (d, J=2.14 Hz, 1 H) 6.80 (dd, J=8.85, 4.88 Hz, 1 H) 6.85 - 6.90 (m, l H) 6.91 (s, l H) 6.97 - 7.02 (m, 2 H) 7.54 - 7.58 (m, l H) 7.59 - 7.63 (m, l H) 7.74 (d, J=8.85 Hz, 1 H) 7.81 - 7.88 (m, l H) 8.45 (t, J=l.68 Hz, 1 H). MS (ESI+) m/Z 559 [M+H]+.
Example 213 3-Morpholinylpropyl 4-({[5-chloro(5-fluorohydroxyphenyl)—2- thienyl] sulfonyl}amino)—2-hydroxybenzoate trifluoroacetate W0 2013/093095 200 The product was prepared from 3-bromopropyl -chloro(5-fluorohydroxyphenyl)- 2-thienyl]sulfonyl}amino)hydroxybenzoate (Intermediate 26) (16 mg, 0.029 mmol) and morpholine (23 mg, 0.27 mmol) according to the General Procedure 13, described in e 212. The title compound was obtained in 74% yield (15 mg). 1H NMR (600 MHZ, CDClg) 5 ppm 2.29 (br. s., 2 H) 2.90 (br. s., 2 H) 3.14 - 3.26 (m, 2 H) 3.58 (br. s., 2 H) 3.99 (br. s., 2 H) 4.07 (br. s., 2 H) 4.33 - 4.44 (m, 2 H) 6.58 (d, J=2.14 Hz, 1 H) 6.76 (dd, J=9.16, 4.58 Hz, 1 H) 6.86 - 6.93 (m, 3 H) 7.08 - 7.12 (m, 1 H) 7.74 (d, J=8.85 Hz, 1 H) 7.85 (s, 1 H). MS (ESI+) mkSfllM+HT Example 214 3-(2,6—Dimethylm0rpholinyl)propyl 4-({[5-chlor0(5-flu0r0hydroxyphenyl)—2- thienyl] sulfonyl}amino)—2-hydr0xybenz0ate trifluoroacetate S Qé/N OH O\/\/N F FYLOHF The product was prepared from 3-bromopropyl 4-({[5-chloro(5-fluorohydroxyphenyl)- 2-thienyl]sulfonyl}amino)hydroxybenzoate (Intermediate 26) (16 mg, 0.029 mmol) and cis-2,6-dimethylmorpholine (23 mg, 0.20 mmol) according to the General Procedure 13, de- scribed in Example 212. The title compound was ed in 77% yield (16 mg). 1H NMR (600 MHz, CDClg) 5 ppm 1.25 (d, J=6.41 Hz, 6 H) .33 (m, 2 H) 2.39 (t, J=11.75 Hz, 2 H) 3.11 - 3.21 (m, 2 H) 3.52 (d, J=11.29 Hz, 2 H) 4.05 (br. s., 2 H) 4.36 - 4.43 (m, 2 H) 6.58 W0 2013/093095 201 (d, J=2.14 Hz, 1 H) 6.75 (dd, J=9.16, 4.58 Hz, 1 H) 6.84 — 6.93 (m, 3 H) 7.11 (dd, , 3.05 Hz, 1 H) 7.74 (d, J=8.85 Hz, 1 H) 7.86 (s, 1 H). MS (ESI+) m/Z 599 [M+H]+.
Example 215 1-(Meth0xymethyl)pr0pyl 4-{[(5—chlor0phenyl—2-thienyl)sulfonyl] amin0} hydroxybenzoate CI 3.,oggfi The product was prepared from 4- {[(5-chlorophenylthienyl)sulfonyl]amino} hydroxybenzoic acid mediate 27) (16 mg, 0.040 mmol) and 1-methoxy—2-butanol (21 mg, 0.2 mmol) according to the General Procedure 8, described in Example 60. The title compound was obtained in 59% yield (12 mg). 1H NMR (600 MHz, CDClg) 8 ppm 0.98 (t, J=7.48 Hz, 3 H) 1.72 - 1.79 (m, 2 H) 3.37 (s, 3 H) 3.52 - 3.56 (m, 1 H) 3.57 - 3.61 (m, 1 H) .19 - 5.26 (m, 1 H) 6.71 (dd, J=8.70, 2.29 Hz, 1 H) 6.76 (d, J=2.14 Hz, 1 H) 6.77 (s, 1 H) 7.38 - 7.50 (m, 5 H) 7.61 (s, 1 H) 7.83 (d, J=8.85 Hz, 1 H) 10.99 (s, 1 H). MS (ESI+) m/z 496 Example 216 2-Meth0xymethylethyl 4-{[(5-chlor0phenyl—2-thienyl)sulfonyl] amin0} hydroxybenzoate CI wed? W0 2013/093095 202 The product was ed from 4- {[(5-chlorophenylthienyl)sulfonyl]amino} ybenzoic acid (Intermediate 27) (16 mg, 0.040 mmol) and 1-methoxypropanol (18 mg, 0.2 mmol) according to the General Procedure 8, described in Example 60. The title compound was obtained in 69% yield (13 mg). 1H NMR (600 MHz, CDClg) 8 ppm 1.36 (d, J=6.41 Hz, 3 H) 3.39 (s, 3 H) 3.48 - 3.54 (m, 1 H) 3.55 - 3.61 (m, 1 H) 5.32 - 5.38 (m, 1 H) 6.71 (dd, , 2.14 Hz, 1 H) 6.75 (d, J=2.14 Hz, 1 H) 6.77 (s, 1 H) 7.37 - 7.51 (m, 5 H) 7.60 (s, 1 H) 7.82 (d, J=8.85 Hz, 1 H) 10.96 (s, 1 H). MS (ESI+) m/z 482 .
Example 217 2-Hydr0xyethyl 4-{[(5-chlor0phenylthienyl)sulf0nyl] amin0}hydr0xybenz0ate O/\/OH 08,0 CI N The product was prepared from 4- {[(5-chlorophenylthienyl)sulfonyl]amino} hydroxybenzoic acid (Intermediate 27) (16 mg, 0.040 mmol) and ethylene glycol (110 mg, 1.8 mmol) according to the General Procedure 8, described in Example 60 using preparative HPLC (basic system 2) as purification method. The title compound was obtained in 64% yield (12 mg). 1H NMR (600 MHz,CDC13)8 ppm 1.81 (t, J=6.10 Hz, 1 H) 3.93 - 4.02 (m, 2 H) 4.43 - 4.52 (m, 2 H) 6.73 (dd, J=8.70, 2.29 Hz, 1 H) 6.77 (d, J=2.44 Hz, 1 H) 6.80 (br. s., 1 H) 7.37 - 7.52 (m, 5 H) 7.61 (s, 1 H) 7.84 (d, J=8.54 Hz, 1 H) 10.83 (s, 1 H). MS (ESI+) m/z 454 [M+H]+.
Example 218 1-(Meth0xymethyl)pr0pyl 4-({[5-chlor0(3-flu0r0phenyl)—2-thienyl]sulfonyl}amin0)—2- hydroxybenzoate W0 2013/093095 203 The product was prepared from 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino)- 2-hydroxybenzoic acid (Intermediate 28) (17 mg, 0.040 mmol) and 1-methoxybutanol (21 mg, 0.2 mmol) according to the General Procedure 8, bed in Example 60. The title compound was obtained in 62% yield (13 mg). 1H NMR (600 MHz, CDClg) 8 ppm 0.98 (t, J=7.48 Hz, 3 H) 1.70 - 1.79 (m, 2 H) 3.37 (s, 3 H) 3.51 - 3.56 (m, 1 H) 3.57 - 3.63 (m, 1 H) .18 - 5.26 (m, 1 H) 6.71 (dd, J=8.70, 2.29 Hz, 1 H) 6.76 (d, J=2.44 Hz, 1 H) 6.78 (s, 1 H) 7.07 - 7.13 (m, 1 H) 7.21 (ddd, J=9.61, 1.98, 1.83 Hz, 1 H) 7.24 - 7.26 (m, 1 H) 7.39 - 7.46 (m, 1 H) 7.59 (s, 1 H) 7.84 (d, J=8.54 Hz, 1 H) 10.99 (s, 1 H). MS (ESI+) m/z 514 [M+H]+.
Example 219 2-Hydr0xyethyl 4-({[5-chlor0(3-flu0r0phenyl)—2-thienyl]sulfonyl}amin0)—2- hydroxybenzoate O/\/OH The product was prepared from 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino)- 2-hydroxybenzoic acid (Intermediate 28) (17 mg, 0.040 mmol) and ethylene glycol (110 mg, 1.8 mmol) according to the General Procedure 8, bed in e 60, using preparative HPLC (basic system 2) as purification method. The title compound was obtained in 58% yield (11 mg). 1H NMR (600 MHz, CDC13) 8 ppm 1.81 (t, J: 5.95 Hz, 1 H) 3.94 - 4.01 (m, 2 H) 4.45 - 4.51 (m, 2 H) 6.73 (dd, J=8.70, 2.29 Hz, 1 H) 6.77 (d, J=2.14 Hz, 1 H) 6.80 (br. s., 1 H) W0 2013/093095 204 7.08 — 7.13 (m, 1 H) 7.21 (dt, J=9.69, 2.02 Hz, 1 H) 7.24 — 7.26 (m, 1 H) 7.38 _ 7.46 (m, 1 H) 7.59 (s, 1 H) 7.85 (d, J=8.55 Hz, 1 H) 10.84 (s, 1 H). MS (ESI+) m/Z 472 [M+H]+.
Example 220 2-Meth0xyethyl 4-({[5-chlor0(3-flu0r0phenyl)—2-thienyl]sulfonyl}amin0)—2- hydroxybenzoate O OdONO\ 8 “8'; CI N OH \ I H The product was prepared from 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino)- 2-hydroxybenzoic acid (Intermediate 28) (17 mg, 0.040 mmol) and 2-methoxyethanol (15 mg, 0.2 mmol) according to the General Procedure 8, described in Example 60. The title com- pound was obtained in 69% yield (13 mg). 1H NMR (600 MHz, CDC13) 5 ppm 3.41 (s, 3 H) 3.67 - 3.73 (m, 2 H) 4.45 - 4.51 (m, 2 H) 6.70 (dd, J=8.55, 2.44 Hz, 1 H) 6.75 (d, J=2.44 Hz, 1 H) 6.77 (s, 1 H) 7.06 - 7.12 (m, 1 H) 7.20 (dt, J=9.69, 2.02 Hz, 1 H) 7.22 - 7.25 (m, 1 H) 7.37 - 7.45 (m, 1 H) 7.57 (s, 1 H) 7.84 (d, J=8.55 Hz, 1 H) 10.85 (s, 1 H). MS (ESI+) m/z 486 [M+H]+.
Example 221 3-M0rpholinylpr0pyl -chlor0(3-flu0r0phenyl)—2-thienyl]sulfonyl}amin0)—2- ybenzoate trifluoroacetate /\/\ o\.,,o Nfi s s\ K/o CI OH \I H W0 2013/093095 205 The t was prepared from -chloro(3-fluorophenyl)thienyl]sulfonyl}amino)- 2-hydroxybenzoic acid (Intermediate 28) (17 mg, 0.040 mmol) and 4-(3- hydroxypropyl)morpholine (29 mg, 0.2 mmol) according to the General Procedure 8, de- scribed in Example 60. The title compound was obtained in 65% yield (17 mg). 1H NMR (600 MHz,CDC13)8 ppm 2.30 (br. s., 2 H) 2.88 (br. s., 2 H) 3.14 - 3.21 (m, 2 H) 3.59 (br. s., 2 H) 4.02 (br. s., 4 H) 4.41 (t, J=5.95 Hz, 2 H) 6.70 (dd, J=8.70, 2.29 Hz, 1 H) 6.81 (d, J=2.14 Hz, 1 H) 7.07 - 7.14 (m, 2 H) 7.20 (dt, J=9.54, 2.10 Hz, 1 H) 7.24 - 7.27 (m, 1 H) 7.42 (td, , 6.26 Hz, 1 H) 7.59 (s, 1 H) 7.76 (d, J=8.55 Hz, 1 H). MS (ESI+) m/z 555 [M+H]+.
Example 222 2-Meth0xy(meth0xymethyl)ethyl 4-({[5-chlor0(3-flu0r0phenyl)—2- thienyl] sulfonyl}amino)—2-hydr0xybenzoate The product was prepared from 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino)- 2-hydroxybenzoic acid (Intermediate 28) (17 mg, 0.040 mmol) and 1,3-dimethoxypropanol (24 mg, 0.2 mmol) according to the General Procedure 8, described in Example 60. The title compound was obtained in 48% yield (10 mg). 1H NMR (600 MHz, CDClg) 8 ppm 3.39 (s, 6 H) 3.61 - 3.71 (m, 4 H) 5.36 - 5.44 (m, 1 H) 6.71 (dd, J=8.70, 2.29 Hz, 1 H) 6.76 (d, J=2.14 Hz, 1 H) 6.79 (s, 1 H) 7.07 - 7.13 (m, 1 H) 7.21 (dt, J=9.54, 2.10 Hz, 1 H) 7.24 - 7.26 (m, 1 H) 7.42 (td, , 6.10 Hz, 1 H) 7.59 (s, 1 H) 7.85 (d, J=8.55 Hz, 1 H) 10.86 (s, 1 H). MS (ESI+) m/Z 530 [M+H]+.
Example 223 2-Phen0xyethyl 4-({[5-chlor0(3-flu0r0phenyl)—2-thienyl]sulfonyl}amin0)—2- hydroxybenzoate W0 2013/093095 206 The product was prepared from 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino)- 2-hydroxybenzoic acid (Intermediate 28) (17 mg, 0.040 mmol) and 2-phenoxyethanol (28 mg, 0.2 mmol) according to the General Procedure 8, described in Example 60. The title com- pound was obtained in 67% yield (15 mg). 1H NMR (600 MHz, CDClg) 5 ppm 4.27 - 4.35 (m, 2 H) 4.64 - 4.71 (m, 2 H) 6.69 (dd, , 2.29 Hz, 1 H) 6.78 (d, J=2.44 Hz, 1 H) 6.79 (s, l H) 6.90-6.96 (m, 2 H) .02 (m, l H) 7.06 - 7.13 (m, l H) 7.21 (dt, J=9.69, 2.02 Hz, 1 H) 7.23-7.26 (m, l H) 7.28 - 7.34 (m, 2 H) 7.38 - 7.45 (m, l H) 7.58 (s, l H) 7.82 (d, J=8.55 Hz, 1 H) 10.83 (s, 1 H). MS (ESI+) m/Z 548 [M+H]+.
Example 224 Methyl 4-({[5—chlor0(5-fluoro-Z-methoxyphenyl)thienyl]sulfonyl}amin0)—2- hydroxybenzoate 0. H s S.
‘ O OH O\ The product was prepared from methyl 4- {[(4-bromochlorothienyl)sulfonyl]amino} hydroxybenzoate (Intermediate 3) (21 mg, 0.050 mmol) and 5-fluoromethoxyphenyl bo- ronic acid (8 mg, 0.050 mmol) according to the General ure 9, described in Example 82. The title compound was obtained in 50% yield (12 mg). 1H NMR (600 MHz, CDClg) 5 ppm 3.75 (s, 3 H) 3.92 (s, 3 H) 6.67 (dd, J=8.70, 2.29 Hz, 1 H) 6.77 (d, J=2.l4 Hz, 1 H) 6.80 (s, l H) 6.89 (dd, J=8.85, 4.27 Hz, 1 H) 7.02 - 7.09 (m, 2 H) 7.63 (s, l H) 7.78 (d, J=8.54 Hz, 1 H) 10.91 (s, l H). MS (ESI+) m/z 472 [M+H]+ W0 2013/093095 207 Example 225 2-Phen0xyethyl 4-{[(4,5-dichlorothiophenyl)sulf0nyl]amin0}hydr0xybenz0ate /\/O o. .o 3\ \© The product was prepared from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18 mg, 0.050 mmol) (Intermediate 7) and 1-phenoxyethanol (28 mg, 0.20 mmol) according to the General Procedure 8, described in Example 60. The title com- pound was obtained in 62% yield (15 mg). 1H NMR (600 MHz, CDClg) 5 ppm 4.27 - 4.35 (m, 2 H) 4.63 - 4.72 (m, 2 H) 6.66 (dd, J=8.70, 2.29 Hz, 1 H) 6.75 (d, J=2.14 Hz, 1 H) 6.76 (br. s., 1 H) 6.91 - 6.96 (m, 2 H) 6.97 - 7.03 (m, 1 H) 7.29 - 7.35 (m, 2 H) 7.43 (s, 1 H) 7.82 (d, J=8.55 Hz, 1 H) 10.84 (s, 1 H). MS (ESI+) m/z 488 [M+H]+.
Example 226 2- [(6-Chloropyridinyl)0xy] ethyl 4-{[(4,5-dichlor0thienyl)sulf0nyl] amin0} hydroxybenzoate roacetate The product was ed from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18 mg, 0.050 mmol) (Intermediate 7) and 2-[(6-chloropyridin yl)oxy]ethanol (40 mg, 0.20 mmol) ing to the General Procedure 8, described in Example 60. The title compound was obtained in 65% yield (17 mg). 1H NMR (600 MHz, DMSO- d6) 5 ppm 4.38 - 4.45 (m, 2 H) 4.55 - 4.64 (m, 2 H) 6.68 - 6.77 (m, 2 H) 7.43 (d, J=8.55 Hz, 1 H) 7.55 (dd, J=8.70, 3.20 Hz, 1 H) 7.65 (d, J=9.16 Hz, 1 H) 7.77 (s, 1 H) 8.17 (d, J=3.05 Hz, 1 H) 10.53 (s, 1 H). MS (ESI+) m/Z 523 [M+H]+.
W0 2013/093095 208 Example 227 2-[3-(Meth0xymethyl)phen0xy] ethyl 4-{[(4,5—dichlor0thienyl)sulf0nyl] amin0} hydroxybenzoate The product was prepared from 4- {[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoic acid (18 mg, 0.050 mmol) (Intermediate 7) and 2-[3- xymethyl)phenoxy]ethanol (36 mg, 0.20 mmol) according to the General Procedure 8, described in Example 60. The title compound was obtained in 66% yield (17 mg). 1H NMR (600 MHz, CDC13)5 ppm 3.40 (s, 3 H) 4.29 - 4.35 (m, 2 H) 4.44 (s, 2 H) 4.64 - 4.72 (m, 2 H) 6.66 (dd, J=8.70, 2.29 Hz, 1 H) 6.75 (d, J=2.14 Hz, 1 H) 6.77 (br. s., l H) 6.84 - 6.89 (m, l H) 6.92 - 6.98 (m, 2 H) 7.28 (t, J= 8.24 Hz, 1 H) 7.43 (s, l H) 7.82 (d, J=8.55 Hz, 1 H) 10.84 (s, 1 H). MS (ESI+) m/Z 549 ]+.
Example 228 2-(3-Carbamoylphenoxy)ethyl 4-({[5-chlor0(2-flu0r0meth0xyphenyl)—2- l5 thienyl] sulfonyl}amino)—2-hydr0xybenz0ate The t was ed from 4-({[5-chloro(2-fluoromethoxyphenyl) thienyl]sulfonyl}amino)hydroxybenzoic acid (Intermediate 29) (18 mg, 0.040 mmol) and 3-(2-hydroxyethoxy)benzamide (35 mg, 0.20 mmol) according to the General Procedure 8, described in Example 60. The title compound was obtained in 53% yield (13 mg). 1H NMR W0 2013/093095 209 (600 MHz, CDC13) 5 ppm 3.92 (s, 3 H) 4.34 — 4.42 (m, 2 H) 4.64 — 4.73 (m, 2 H) 6.70 (dd, J=8.70, 2.29 Hz, 1 H) 6.80 (d, J=2.14 Hz, 1 H) 6.93 (ddd, J=7.86, 6.18, 1.53 Hz, 1 H) 7.02 (td, , 1.22 Hz, 1 H) 7.09 — 7.15 (m, 2 H) 7.18 (br. s., 1 H) 7.33 — 7.40 (m, 2 H) 7.45-7.48 (m, 1 H) 7.59 (d, J=1.53 Hz, 1 H) 7.80 (d, J=8.54 Hz, 1 H) 10.79 (s, 1 H). MS (ESI+) m/Z 621 [M+H]+.
Example 229 0xypr0pyl 4-({[5-chlor0(2-flu0r0meth0xyphenyl)—2-thienyl] sulfonyl}amino)- 2-hydroxybenzoate The product was prepared from 4-({[5-chloro(2-fluoromethoxyphenyl) thienyl]sulfonyl}amino)hydroxybenzoic acid (Intermediate 29) (18 mg, 0.040 mmol) and 1,3-propanediol (158 mg, 2.1 mmol) according to the General Procedure 8, described in EX- ample 60 with a modified purification method (basic system 2). The title nd was ob- tained in 42% yield (8.7 mg). 1H NMR (600 MHZ, DMSO-dg) 5 ppm 1.83 (quin, J=6.33 Hz, 2 H) 3.53 (q, J=5.80 Hz, 2 H) 3.87 (s, 3 H) 4.32 (t, J=6.41 Hz, 2 H) 4.60 (t, J=5.19 Hz, 1 H) 6.66-6.79 (m, 2 H) 6.98 (t, J=6.71 Hz, 1 H) 7.19 - 7.30 (m, 2 H) 7.61-7.75 (m, 2 H) 10.65 (s, 1 H). MS (ESI+) m/Z 516 [M+H]+.
Example 230, General Procedure 14 3-(Pyridinylamin0)pr0pyl 4-{[(5'-flu0r0-2'-hydroxybiphenyl—3-yl)sulf0nyl] amin0} hydroxybenzoate trifluoroacetate W0 2013/093095 210 OH O\/\/ \ O N FVLOH A mixture of 3-bromopropyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate (Intermediate 25) (16 mg, 0.031 mmol), potassium iodide (10 mg, 0.060 mmol) and 3-aminopyridine (15 mg, 0.16 mmol) in MeCN (0.4 mL) was heated at 60 0C overnight. The crude product was d by preparative HPLC c system). The title compound was obtained in 55% yield (11 mg). 1H NMR (600 MHz, DMSO-dg) 8 ppm 2.30 (dq, J=6.56, 6.36 Hz, 2 H) 4.29 (t, J=5.80 Hz, 2 H) 4.55 (t, J=7.17 Hz, 2 H) 6.61 (br. s., 2 H) 6.69 - 6.78 (m, 2 H) 6.97 (dd, J=8.85, 4.88 Hz, 1 H) 7.03 - 7.09 (m, 1 H) 7.11 (dd, J=9.46, 3.05 Hz, 1 H) 7.53 (dd, J=8.55, 1.83 Hz, 1 H) 7.59 (d, J=8.55 Hz, 1 H) 7.62 - 7.70 (m, 2 H) 7.79 (d, J=8.54 Hz, 1 H) 7.85 (d, J=7.63 Hz, 1 H) 8.10 (d, J=7.93 Hz, 2 H) 8.14 (d, J=5.80 Hz, 1 H) 9.89 (s, 1 H) 10.55 (s, 1 H) 10.95 (s, 1 H). MS (ESI+) m/z 538 .
Example 231 3-[(l-Methyl-1H-pyraz01—5-yl)amin0]propyl 4-{[(5'-flu0r0-2'-hydr0xybiphenyl—3- yl)sulf0nyl] amin0}hydr0xybenzoate trifluoroacetate F o 0 q,“ F OH O F O : YO H I OH N N CH O\/\/ EN The product was prepared from 3-bromopropyl 4- {[(5'-fluoro-2'-hydroxybiphenyl yl)sulfonyl]amino}hydroxybenzoate (Intermediate 25) (16 mg, 0.031 mmol) and 1-methyl- 1H-pyrazolylamine (15 mg, 0.15 mmol) according to the General Procedure 14, described in Example 230, but heating at 80 0C for 2 days. The title compound was ed in 41% yield (8.0 mg). 1H NMR (600 MHz, DMSO-dg) 5 ppm 2.07 - 2.14 (m, 2 H) 3.68 (s, 3 H) 4.21 W0 2013/093095 211 2012/076836 (t, J=5.95 Hz, 2 H) 4.29 (t, J=6.87 Hz, 2 H) 5.77 (d, J=3.36 Hz, 1 H) 6.71 (d, J=2.14 Hz, 1 H) 6.73 (dd, J=8.85, 2.14 Hz, 1 H) 6.96 (dd, J=8.85, 4.88 Hz, 1 H) 7.04 — 7.13 (m, 2 H) 7.16 (br. s., 2 H) 7.63 (t, J=7.78 Hz, 1 H) 7.67 (d, J=8.85 Hz, 1 H) 7.79 (d, J=8.85 Hz, 1 H) 7.85 (d, J=7.63 Hz, 1 H) 8.03 (d, J=3.36 Hz, 1 H) 8.10 (s, 1 H) 9.85 (s, 1 H) 10.56 (s, 1 H) 10.93 (s, 1 H). MS (ESI+) m/Z 541 .
Example 232 3-[(5-Methylis0xazolyl)amin0]propyl 4-{[(5'-flu0r0-2'-hydr0xybiphenyl—3- yl)sulf0nyl] amin0}hydr0xybenz0ate trifluoroacetate F F F#0“ O o H \S: F O O The product was prepared from 3-bromopropyl 4- {[(5'-fluoro-2'-hydroxybiphenyl yl)sulfonyl]amino}hydroxybenzoate (Intermediate 25) (16 mg, 0.031 mmol) and o- -methyl-isoxazole (23 mg, 0.23 mmol) according to the General Procedure 14, described in Example 230, but heating at 80 0C for 3 days. The title compound was obtained in 44% yield (8.6 mg). 1H NMR (600 MHz, DMSO-dg) 5 ppm 2.17 (quin, J=6.26 Hz, 2 H) 2.28 (s, 3 H) 4.30 (t, J=5.95 Hz, 2 H) 4.35 (t, J=6.56 Hz, 2 H) 6.20 (s, 1 H) 6.69 - 6.72 (m, 1 H) 6.73 (dd, J=8.70, 1.98 Hz, 1 H) 6.96 (dd, J=8.85, 4.88 Hz, 1 H) 7.04 - 7.14 (m, 2 H) 7.57 - 7.68 (m, 2 H) 7.79 (d, J=8.24 Hz, 1 H) 7.85 (d, J=7.93 Hz, 1 H) 8.10 (s, 1 H) 8.56 (br. s., 2 H) 9.85 (s, 1 H) 10.54 (s, 1 H) 10.94 (s, 1 H). MS (ESI+) m/z 542 [M+H]+.
BIOLOGICAL TESTS 6-phosphofructokinase/fructose-2,6-bisphosphatase (PFK—2/BPase-2) is a bi—functional enzyme that catalyses the formation and degradation of fructose-2,6-bisphosphate -P2) (For reviews see e.g. Pilkis et al., (1995) Annu. Rev. Biochem. 64, 799-835; and Okar et al., (2001) Trends Biochem. Sci. 26, 30-5). The relative kinase (formation) and phosphatase (degradation ) activities of the ctional enzymes PFKFB3 and PFKFB4 control the intracellu- lar levels of this regulator (F-2,6-P2), which acts as an allosteric activator of glycolysis. Both W0 93095 212 the relative activities as well as the kinase to phosphatase ratios differ between the isoforms of the bi-filnctional enzymes, referred to as PFKFBl, PFKFB2, PFKFB3 and PFKFB4. Intracel- lular F-2,6-P2 levels are uently controlled by variable tissue expression of these isoforms, including splice variants or ranslational modifications (see e.g. Rider et al. (2007) Biochem J. 381, 561-579).
Method for quantification of F-2,6—P2 in six different cancer cell lines A method for quantification of F-2,6-P2 has been described by Van Schaftingen et al. (1982) Eur. J. Biochem. 129, 191-5. This sensitive assay is based on the potent activation of pyro- phosphate dependent phosphofructokinase-l FK) from potato tubers by F-2,6-P2. The use of a series of coupled s leads to a consumption ofNADH (nicotinamide adenine dinucleotide) that can be followed spectrophotometrically (an updated protocol is available in Van Schaftingen, (1984) Methods of tic Analysis (Bergmeyer, H. U., ed.), 3rd edn., vol. 6, pp. 335-341, Verlag Chemie, Weinheim). A protocol for measurements in 96-well mi- crotiter plate format is also ble (Bruni et al., (1989) Anal. m. 178, 324-6).
The levels of F-2,6-P2 have been determined using the van Shaftingen assay as bed in the protocol below, in six different cancer cell lines endogenously expressing varying levels ofthe different isoforms of PFK—2/BPase-2 (MCF-7, PANC-l, NUGC-3, SW480, SW620 and MIA PaCa-2). All reagents were purchased from commercial sources or prepared in—house.
Cell line A (MCF-7, human breast adenocarcinoma cell line): MCF-7 cells (ATCC-HTB- 22), . 58469417. Growth medium: Eagle's Minimum Essential Medium (EMEM), Sig- ma-Aldrich #M5650, 500 ml; 10% FBS, Invitrogen, 169; 5 mL 200 mM L-glutamine, Invitrogen 25030024; 5 mL 100 mM Sodium Pyruvate, Invitrogen 11360039; 0.5 mL 10 mg/ml Bovine Insulin, Sigma-Aldrich 10516. Cells were seeded at a concentration of 450 000 cells/mL in 100 uL growth medium (~45 000 cells/well).
Cell line B (PANC-l, human pancreatic carcinoma cell line): PANC-1 cells (ATCC-CRL- 1469), lot.no. 58564651. Cells were seeded at a concentration of ~250 000 cells/mL in 100 uL growth medium (~25 000 cells/well).
Cell line C (NUGC-3, human gastric cancer cell line): NUGC-3 cells (JCRBO822), lot no. 04272009. Growth medium: RPM11640, #R8758, Sigma-Aldrich; 10% FBS, Invitrogen, 106 or co's Modified Eagle's Medium, DMEM, VWR, LONZ12-604F;_10% W0 2013/093095 213 FBS, Invitrogen, 106. Cells were seeded at a concentration of ~350 000 cells/mL in 100 uL growth medium (~35 000 cells/well).
Cell line D (SW480, human colorectal adenocarcinoma): SW480 cells (ATCC-CCL-228), lot.no. 58471880. Cells were seeded at a concentration of ~350 000 cells/mL in 100 uL growth medium (~35 000 cells/well).
Cell line E , human colorectal adenocarcinoma): SW620 cells (ATCC-CCL-227), lot.no. 58483168. Cells were seeded at a concentration of ~350 000 cells/mL in 100 uL growth medium (~35 000 cells/well).
Cell line F (MIA PaCa-2, human pancreatic carcinoma): MIA PaCa-2 cells (ATCC-CRL- 1420), lot.no. 59270201. Cells were seeded at a concentration of ~250 000 cells/mL in 100 uL growth medium (~25 000 cells/well).
Growth medium (cell lines B-F): Dulbecco ’s Modified Eagle's Medium, DMEM, VWR, -604F;_10% FBS, Invitrogen, 10270-106.
Starvation medium (cell lines A-F): DMEM/F12 without phenol red and glucose free, SVA, 991373; 0.25% FBS, ogen, 10270-106.
Induction medium (cell lines A-F): 12 without phenol red and glucose free, SVA, 991373; 0.25% FBS, Invitrogen, 10270-106 (same as starvation medium).
Cells were seeded in 96-well Corning Costar tissue culture plates (CLS3595, Sigma-Aldrich) using the concentrations specified above for the different cell lines A-F and incubated over night at 37 0C and 5% C02. Row A in the plate was left empty and the cell lines added to rows B-H. Next day the growth medium was discarded and replaced with 100 uL tion medium. The plates were incubated for 18 h at 37 0C and 5% C02. After 18 h of starvation the cells were induced with 100 uL nd or control solutions. Compounds were either tested in two concentrations (50 uM and 10 uM) or in dose response curves starting from 50 uM.
The final DMSO concentration in assay plates was 0.5%. Also a dose response curve of a reference inhibitor was ed in row H on each plate. All compounds were tested in dupli- cate plates. nds (in 96 well CLS 3365, Sigma-Aldrich plates) were serial diluted in DMSO from 10 mM compound DMSO stock ons with Janus (automated liquid handling workstation from PerkinElmer). Five uL were transferred to a Greiner deep well plate (73 6- 0155, VWR) with 495 uL starvation medium. The final start concentration of compounds in W0 2013/093095 214 the dilution plate was 100 uM, 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 uL to separate dilution plates with 495 uL starvation medium. The final trations of compounds in these dilution plates were 100 or 20 uM, respectively, and final concentration ofDMSO was 1%. The plates were incubated at 37 0C and 5% CO2 for l h, followed by the addition of 10 uL 20 mM D-glucose in starvation medium. ls, with and without 1 mM glucose, were included in row B. The final assay volume was 210 uL per well. After 2 h of incubation at 37 0C and 5% C02, the supematants were discarded and the cells lysed by the addition of 25 uL 250 mM NaOH. The plates were incubated at 37 0C and 5% CO2 for 5 min followed by an addition of 75 uL MilliQ dH20. The supematants were further diluted with 210 uL MilliQ dH20 to a final concentration of 20 mM NaOH. 200 uL were transferred to NUNC l plates (7322661, VWR) and the plates were sealed and stored at -20 0C until analysis.
A few compounds were also tested, in parallel in NUGC-3 (9 000 cells/well) and PANC-l (25 000 cells/well), under hypoxic ions with oxygen 02 levels set to 1%. During the addi- tion of compounds and glucose the 02 levels were ~0.6%. All additions were done manually.
The amount of F-2,6-P2 was quantified based on the coupled enzymatic reaction described by Van ingen. If necessary the samples were further diluted in 20 mM NaOH before quan- tification. Plates stored at -20 0C were thawed and the F-2,6-P2 quantification was initiated by transferring 40 uL from each well of the NUNC plate to the corresponding position in a trans- parent 96-well SpectraPlate-MB (6005649, PerkinElmer). In order to ensure that all F-2,6-P2 measured values were within the linear range of response (between 0-1 nM final tra- tion of F-2,6-P2 as described by Van ingen), the same sample volume (40 uL) of an in- house produced F-2,6-P2 standard was ed on each plate in row A.
The ure bed below involved consecutive additions of three solutions with the following ed components: 0 Assay-mix (40 uL): Tris-acetate at pH 8.0, NADH and Mg(0Ac)2 0 Substrate-mix (80 uL): Pyrophosphate and F6P o Enzyme-mix (40 uL): Tris-acetate at pH 8.0, aldolase, triose phos- phate isomerase, glycerolphosphate dehydrogenase, pyrophosphate-dependent phosphofructokinase fiom potato tubers and bovine serum albumin (BSA) The final concentrations of all reagents in a total assay volume of 200 uL 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 neutralized to remove any contaminating F-2,6-P2; see Van Schaftingen, 1984 in s 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 se; 5 U/mL triose phosphate isomerase; 1.7 U/mL glycerolphosphate dehydrogenase; 0.01 U/mL pyrophosphate- dependent phosphofructokinase from potato tubers; 0.2 mg/mL BSA & Test samples contain- ing variable concentrations of F-2,6-P2 diluted in NaOH.
The coupled enzymatic reaction was allowed to proceed for 45 minutes at room temperature and the absorbance at 340 nm was uously ed every 30 seconds (SpectraMax plate reader, Molecular Devices). The ed absorbance is proportional to the concentra- tion ofNADH, which in turn is proportional to the levels of F-2,6-P2 within the linear range.
This was defined by the 0 to 1.0 nM F-2,6-P2 controls in row A of the aPlate. The IC50 values for test compounds were calculated using a four-parameter model (model 205) in XLfit (Excel) and in XLfit (IDBS ActivityBase).
Examples included herein have IC50 values in the range 100 nM to 25 uM (see Table I for exemplary data) or Z 50% inhibition at 125-50 uM as measured using the above described assay. es 23, 31, 35, 36, 42, 43, 64, 65, 73, 77, 83, 98, 100, 121, 129, 130, 140, 207, 226 and 227 are representative examples with Z 50% inhibition at 125-50 uM in PANC-l cells.
W0 2013/093095 216 2012/076836 TABLE I. IC50 values for representative Examples in different cell lines based on quan- tification of F-2,6-P2 12,3 PANC—l 107 2 8 PANC—l 19,6 PANC—l 7,7 PANC—l 6,7 '0ANC—1 PANC—l 1,9 'U'U'UANC—1 5,4 PANC—l ANC—1 1,7 PANC—l 1, 7 ANC—1 2,0 PANC—l ,4 PANC—l 5,9 PANC—l 2, 3 PANC—l 1,4 PANC—l MN NN ;00do: 13,3 PANC—l 1,5 PANC—l ANC—1 1,2 PANC—l 3, 6 'UANC—1 —\ 11,1 PANC—l 2, 1 'U'U'U'UANC—1 1,5 PANC—l 19, 0 ANC—1 2,4 PANC—l , 8 ANC—1 5,1 NUGC—3 , 7 ANC—1 PANC—l , 8 '0ANC—1 2,8 SW620 3, 1 'U'U'U'U'U'U'U'U'UANC—1 2,0 MIA PaCa—2 01N 5, 7 ANC—1 2,8 NUGC—3 , 6 ANC—1 5,4 SW480 ANC—1 0,7 PANC—l ANC—1 0,2 MIA PaCa—2 ,7 ANC—1 PANC—l 03N 5,2 ANC—1 1,4 NUGC—3 NN —\o 0,2 ANC—1 1,2 NUGC—3 ANC—1 SW620 N03 iCF—7 197 3,5 PANC—l 1.08* NUGC—3 NUGC—3 6,2 LnW48O 1,8 PANC—l 00N 1,6 'UANC—1 PANC—l 6,7 ANC—1 PANC—l 4,5 ANC—1 217 PANC—l 1,7 ANC—1 PANC—l 2,4 'UANC—1 PANC—l ANC—1 PANC—l * The cells were seeded at a concentration of 25 000 cells/well. #The experiment was carried out under hypoxia (0.6-1 % 02) Method for measurement of inhibition of cancer cell proliferation To assess the antiproliferative response ed by the compounds of the present invention in different tumour cell lines, total cellular protein in samples was quantified using the Sulphorhodamine B kit, TOX6, (Sigma-Aldrich). The protocol is based on quantitation of total cellular n after indicated treatments and incubation times using the Sulphorhoda- mine B kit, TOX6, (Sigma-Aldrich).
Briefly, after protein precipitation using TCA ing to the manufacturer's instructions, the sulphorhodamine dye (80 uL/well) was added to the air-dried wells. After 20 min incuba- tion at room temperature, the dye was discarded and the samples were gently rinsed with 1% HOAc until clear. After air drying, bound dye was solubilised in 200 ML 10 mM Tris base, and the absorbance of dye was measured at 565 nm. To quantify growth, s were col- lected also at t=0 h, and the resulting absorbance was set to 100%.
To assess the chemotherapy-p0tentiating, antiproliferative and anti-outgrowth s elicited by Example 27 in combination with the standard chemotherapeutic agent cisplatin, the f0 1- lowing protocol was applied: The c cancer cell line NUGC3 was cultured at 37°C, 5% C02, in DMEM/Fl2 medium with 10 % FBS and penicillin/streptomycin. Cells were plated at a density of 6,000 cells/well and allowed to attach overnight. Cellular n in five or more wells was quantitated using the Sulphorhodamine B kit, in order to create a to value from which to calculate subsequent growth. From all other s, media supernatants were then replaced with either fresh me- dium, or cisplatin or Example 27 diluted in cell culture medium to ted concentrations, and to a maximal DMSO concentration of 0.1%. Combination treatments with cisplatin and Example 27 at the indicated concentrations were also prepared. All treatments were in quad- ruplicate.
After 48 h, the media were removed from all samples. In one complete set of samples, the total cellular protein in each well was quantitated. In another complete set, post-treatment capacity for regrowth was assessed by allowing the cells to recuperate in fresh drug-free me- dium for another 48 h, after which time cellular protein was tated. Results (growth) are expressed as fold increase in cellular n compared to the level at t=0.
W0 2013/093095 218 For experiments studying the effect of the herein described compounds per se, z'.e. without combination treatment with tin, the above protocol was applied with the following mod- ifications. See Table II for details for each specific cell line. Briefly, cells were plated at a y of 6,000 cells/well 96-well Corning Costar tissue culture plates (CLS3596, Sigma- Aldrich) in assay medium and allowed to attach over night at 37°C, 5% C02. Day 2 the compounds were diluted 1/2 in dose response curve mode in 100% DMSO, required volume was transferred to assay medium to a l DMSO concentration of 0.1%. The diluted com- pounds were added to the cells with a ng dose response concentration of 100 uM. All compounds were tested in duplicate plates. After a total of 72 h, the measured effect on cancer cell proliferation was quantified as the ratio between 72 h value and the 0 h value in percent, and this value was subsequently divided with the 72 h 0.1% DMSO control sample in percent demonstrating the growth-inhibitory effect.
After n precipitation using TCA according to the manufacturer's instructions, the sul- forhodamine B dye (50 uL/well) was added to the air-dried wells. After 20 min incubation at room temperature, the dye was discarded and the samples were gently rinsed with 1% HOAc until clear. After air drying, bound dye was solubilised in 100 uL 10 mM Tris base, and the absorbance of dye was measured at 530 nm and a background absorbance (subtract from the measurement at 530nm) at 690nm. To fy growth, samples were collected also at t=0 h.
Table 11. Experimental conditions for different cell lines used for ination of total cellular protein upon treatment with Examples of the present invention.
Cell line Growth medium Assay medium Cell density NUGC3 RPMI 1640 Sigma- 12 SVA991373, 5% 6000 cells/well Aldrich R8758, 10% FBS Invitrogen #10270106, ( 100 ML) FBS Invitrogen #10106- 5 .5mM glucose BDH-AnalaR 169 B17673 MIA PaCa-2, DMEM LONZ12-604F, DMEM/F12 SVA991373, 5% 6000 well PANCl, 10% FBS Invitrogen FBS Invitrogen #10270106, (100 uL) SW620 and #10270106 5.5mM glucose BDH-AnalaR SW480 B17673 W0 2013/093095 219 Examples demonstrating the growth-inhibitory effect on different tumour cell lines are illus- trated in Figures 1 and 2. In brief, e 27 and cisplatin were added at the indicated con- centrations (Figure 1). After a total of 72 h, the measured effect on cancer cell proliferation was quantified as described above. Figure 2 is a chart representing the effect of the com- pounds of Example 27 and Example 82 per se on cell proliferation in NUGC-3 cells.
Examples demonstrating effects on cell viability in different tumour cell lines are shown in Table 111.
TABLE III. IC50 values for representative Examples in different cell lines based on quantitation of total cellular protein after treatment 132 11,8 SW620 192 22,3 SW480 134 13,0 N UGC—3 195 20,4 SW480 156 16,1 PANC—l 199 20,6 PANC—l 163 30,2 PANC—l NUGC—3 Method for measurement of cell toxicity The CellTiter-Blue® Cell Viability Assay provides a homogeneous, fluorometric method for ting the number of viable cells present in multi-well plates. It uses the indicator dye resazurin to measure the metabolic ty of cells. Viable cells retain the ability to reduce resazurin into resorufin, which is highly cent. Nonviable cells rapidly lose metabolic capacity, do not reduce the tor dye, and thus do not generate a fluorescent signal.
Stock solutions (10 or 100 mM in DMSO) of compounds were serially diluted 1:2 in 11 con- centrations. 25 l (100 mM stock) or 50 nL/well (10 mM stock) were acoustically dis- pensed in assay plates with EDC acoustic dispenser. Final starting cone. in assay was 20 uM (0.2% DMSO) or 100 uM (0.1% DMSO) for test nds.
Cells (MIA-PaCa-2; pancreatic carcinoma) were seeded in assay plates (3 84-well black/clear, Greiner #781091) pre-dispensed with compounds, 25 uL/well, and cultured for 72 h. The cell concentration was 750 cells/well. After 72 h culture, Celltiter Blue reagent was added (5 l) and the plates were incubated for 2 h. The plates were read in an Envision fluores- W0 93095 220 cence reader with Ex544 nm/Em590 nm. Results were calculated as % cytotoxicity compared to background (cells d with 0.2% DMSO).
Examples trating effects on cell toxicity in different tumour cell lines are illustrated in Table IV.
TABLE IV. IC50 values for representative Examples based on cell toxicity in Mia PaCa- 2 cells after treatment with nds of the t invention. 3 6 MIA PaCa—Z 182 6,3 MIA PaCa—Z 183 2,6 MIA PaCa—Z 17,7 MIA PaCa-Z In vitro metabolic stability in human liver omes Pooled human liver microsomes (final protein conc 0.5 mg/ml), 0.1 M phosphate buffer (pH 7.4) and NADPH (final conc 1 mM) were pre-incubated at 37 CC. Example 183 (final conc 3 uM) was added to initiate the reaction. A control incubation where 0.1 M phosphate buffer (pH 7.4) was added instead ofNADPH was done as a parallel experiment. After incubation for 0, 5, 10, 30 and 45 min with NADPH (for 45 min in the control incubation), MeCN con- taining internal standard was added to stop the reactions. The samples were centrifuged at 2500 rpm for 20 min at 4 CC before analysis using MS. The in vitro half life of Ex- ample 183 was found 55 min and the intrinsic clearance was 25 uL/min/mg.
In vivo tolerance, plasma exposure and inhibition of tumour growth In vivo tolerance was tested in NMRI mice using Examples 157 and 183 in 2 doses (25 and 45 mg/kg), following intraperitoneal injections daily for seven days. Macro observations dur- ing and after treatment showed no sign of abnormal behavior or health problem during and after treatment. Specific lesions consistent with toxic damage were not ed in histologi- cal examinations of adrenal gland, brain, cerebellum, heart, intestines, kidneys, liver, lungs, mesenteric lymph node, pancreas and spleen.
W0 2013/093095 221 Figure 3 illustrates the effects of treatment with Example 183 on the growth of established xenografts from the human pancreatic carcinoma cell line MIA PaCa-2 in NMRI nude mice.
NMRI nude mice were injected subcutaneously with MIA PaCa-2 cells. At an average tumor size of around 100 mm3 mice were selected and randomized into treated (injected with sub- stance) and control (vehicle treated) groups. Example 183 was administered at two doses, 25 mg/kg and 45 mg/kg, twice a day with 12 hours between administrations. From the day of inoculation the tumors were scored or measured three times a week using a digital r, and the body weights were determined at the same time . The dose of injected substance was adjusted to the actual body weight of each animal. The dosing of the animals was in a period of 3 weeks. Treatment with Example 183 at 45 mg/kg caused a significant tion (p<0.01) of the tumor growth ed to a vehicle treated group.
In a related study using the same dosing schedule in NMRI nude mice, blood samples were drawn 0.5 h after last injection (day 21) to determine exposure of Example 183. Plasma, pre- pared by centrifugation of the blood, was frozen and kept at -20 CC. Thawed plasma samples were precipitated with MeCN, centrifuged and the supematants were analyzed by LC-MSMS.
Standard samples, prepared by g blank plasma with Example 183, were used for quanti- fication. The re of d Example 183 exceeded the in vitro IC50 value (MIA PaCa- 2 cells) in animals dosed with 45 mg/kg (Figure 4).

Claims (56)

1. A compound of formula (I) H O A S R3 n (I) RbOOC R2 wherein n is 0 or 1; A is O, S, -CR4=CR4- or -CR4=N-; R1 is selected from H; n; C1-C6 alkyl, optionally substituted with at least one halogen; and C1-C6 alkoxy, optionally substituted with at least one halogen; R2 and R3 are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; carbamoyl; secondary or tertiary C1-C6 alkylamido; carbocyclylcarbonylamino-C0-C2 alkyl; 5- or ered cyclic arbonyl optionally containing a further heteroatom in the ring; C1-C6 alkylcarbonylamino; C1-C6 alkylsulfonyl; hydroxy-C0-C6 alkyl, C1-C6 alkylcarbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; yclyloxy; heterocyclyloxy; carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; and cyclyl-C2-C3 alkenyl; wherein any alkyl is optionally tuted 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 R5; or R2 and R3 form, together with the carbon atoms to which they are ed, a 5- or 6- membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R5; provided that R1, R2 and R3 are not all hydrogen; each R4 is independently selected from H, halogen, monocyclic C3-C6 carbocyclyl and C1- C6 alkyl, wherein any alkyl is optionally substituted with at least one halogen; each R5 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, optionally containing at least one further heteroatom in the ring; C1-C6 alkylcarbonylamino; carbamoyl; secondary or tertiary C1-C6 alkylamido; 5- or ered cyclic aminocarbonyl; C1-C6 alkoxycarbonylamino; hydroxy-C0-C6 alkyl; C1-C6-alkylthio; carboxy-C0-C6-alkyl; C1-C6 carbonyl; C1-C6 alkylcarbonyl; C1-C6-alkylsulfonyl; and C1-C6 alkylsulfonylamino; wherein any alkyl is optionally substituted with at least one halogen; Ra is selected from H and C1-C6 alkylcarbonyl; Rb is selected from H, C1-C6 alkyl, C1-C6 alkyl substituted with at least one R6; carbocyclyl- C0-C5 alkyl; and heterocyclyl-C0-C5 alkyl; wherein any carbocyclyl and heterocyclyl is 5- or 6- membered and is optionally substituted with at least one R7 and optionally comprises at least one oxo group in the ring; provided that Ra and Rb are not both H; each R6 is ndently selected from hydroxy; C1-C6 alkoxy; y-C1-C6 alkoxy; C1- C6 alkylcarbonyloxy; C1-C6 alkoxycarbonyloxy; 5- or ered carbocyclylcarbonyl or heterocyclylcarbonyl; amino; secondary or tertiary C1-C6 alkylamino; ary or tertiary hydroxy-C1-C6 alkylamino; 5- or 6-membered cyclic amino optionally containing at least one further atom in the ring and wherein the ring is optionally substituted with at least one C1-C6 alkyl; C1-C6 alkylcarbonylamino; C1-C6 alkoxycarbonylamino; (C1-C6 alkoxycarbonyl)(C1-C6 amino; (C1-C6 alkoxycarbonyl)(5- or 6-membered carbocyclyl or heterocyclyl)amino; (C1-C6 arbonyl)(C1-C6 alkyl)amino; carbamoyl; secondary or tertiary C1-C6 alkylamido wherein any alkyl is optionally substituted by OH or CONH2; 5- or 6-membered carbocyclyl- or cyclylcarbamoyl; 5- or 6-membered cyclic aminocarbonyl, optionally containing at least one further heteroatom in the ring, and wherein the ring is optionally substituted with at least one C1-C6 alkyl; 5-ormembered carbocyclylamino or heterocyclylamino; 5-ormembered carbocyclyloxy or heterocyclyloxy; n any alkyl is optionally substituted with at least one halogen and any 5- or 6-membered carbocyclyl or heterocyclyl is optionally substituted with at least one R8; each R7 and R8 is independently selected from C1-C6 alkyl; hydroxy-C0-C3 alkyl; C1-C6 alkoxy-C0-C3 alkyl; C1-C6 alkoxycarbonyl; carbocyclyl-C0-C4 alkyl; heterocyclyl-C0-C4 alkyl; C1-C6 alkylsulfinyl; amino; nitro; C1-C6 secondary or tertiary amino; halogen; carbamoyl; secondary or tertiary C1-C6 alkylamido-C0-C3 alkyl; C1-C6 alkylcarbonylamino; and 5- or 6-membered cyclic amino, optionally containing at least one further atom in the ring and wherein the ring is optionally substituted with at least one C1-C6 alkyl; wherein any alkyl is optionally substituted with at least one halogen; wherein any carbocyclyl and heterocyclyl is 5- or 6- membered; or a ceutically acceptable salt thereof, ed that the compound is not 5-(N-(3-hydroxy(methoxycarbonyl)phenyl)sulfamoyl)methoxybenzoic acid, methyl 2-hydroxy(4-propylphenylsulfonamido)benzoate, methyl 4-(4-ethylphenylsulfonamido)hydroxybenzoate, methyl 4-(4-butylphenylsulfonamido)hydroxybenzoate, methyl 4-(3-bromophenylsulfonamido)hydroxybenzoate, methyl 4-(4-(tert-butyl)phenylsulfonamido)hydroxybenzoate, methyl 4-(3,5-dichlorophenylsulfonamido)hydroxybenzoate, methyl 2-hydroxy(3-methylphenylsulfonamido)benzoate, methyl 4-(3-fluorophenylsulfonamido)hydroxybenzoate, ethyl 4-(4-acetamidophenylsulfonamido)hydroxybenzoate, methyl 4-(4-acetamidophenylsulfonamido)hydroxybenzoate, phenyl oxy(4-methylphenylsulfonamido)benzoate, phenyl 4-(4-chlorophenylsulfonamido)hydroxybenzoate, methyl 2-hydroxy(4-(4-oxo-1,4-dihydropyrazolo[1,5-a][1,3,5]triazin yl)phenylsulfonamido)benzoate, methyl 2-hydroxy(4-methylphenylsulfonamido)benzoate, oxy(4-methylphenylsulfonamido)benzoic acid, methyl 2-hydroxy(3-(methylcarbamoyl)phenylsulfonamido)benzoate, methyl 2-hydroxy(3-(piperidinecarbonyl)phenylsulfonamido)benzoate, methyl 4-(3-bromo(trifluoromethyl)phenylsulfonamido)hydroxybenzoate, 3-(N-(3-hydroxy(methoxycarbonyl)phenyl)sulfamoyl)benzoic acid, methyl 4-((3-bromophenyl)methylsulfonamido)hydroxybenzoate, or methyl 4-(4,5-dichlorothiophenesulfonamido)hydroxybenzoate.
2. A compound according to claim 1, wherein A is O, S, -CR4=CR4- or -CR4=N-; and when A is -CR4=CR4- or -CR4=N-, one of R2 and R3 is selected from carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; cyclyl-C0-C3 alkyl; and 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 ally substituted with at least one R5; or R2 and R3 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 R5; or a pharmaceutically able salt thereof.
3. A compound according to claim 2, wherein A is O, S, -CR4=CR4- or -CR4=N-; and when A is -CR4=CR4- or -CR4=N-, R2 is selected from carbocyclyl-C0-C3 alkyl; carbocyclyl- C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is 5- or ered monocyclyl or 9- or 10-membered bicyclyl; and R3 is ed from H; halogen; and C1-C6 alkyl, optionally substituted with at least one halogen; or R2 and R3 form, er 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 R5; or a pharmaceutically acceptable salt thereof.
4. A compound according to any one of the claims 1 to 3, wherein A is O, S, -CR4=CR4- or -CR4=N-; and when A is O or S, R2 and R3 are each independently selected from H; n; C1-C6 alkyl; C1-C6 alkoxy; carbamoyl; secondary or tertiary C1-C6 alkylamido; carbocyclylcarbonylamino-C0-C2 alkyl; 5- or 6-membered cyclic arbonyl optionally containing a further heteroatom in the ring; C1-C6 alkylcarbonylamino; C1-C6 alkylsulfonyl; hydroxy-C0-C6 alkyl, C1-C6 arbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; wherein any alkyl is optionally substituted with at least one halogen; or a pharmaceutically acceptable salt thereof.
5. A nd according to claim 1, wherein R3 is selected from H; halogen; and C1-C6 alkyl, wherein any alkyl is optionally substituted with at least one halogen; or R2 and R3 form, together with the carbon atoms to which they are attached, a 5- or ered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R5, or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 1, wherein R2 is selected from H; halogen; C1-C6 alkyl; carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; n any alkyl is optionally substituted with at least one halogen; any yclyl or heterocyclyl is 5- or 6- ed monocyclyl or 9- or 10-membered bicyclyl; and any yclyl or heterocyclyl is optionally substituted with at least one R5; or R2 and R3 form, er 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 R5, or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 6, wherein R2 is selected from carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; and cyclyl-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 ally substituted with at least one R5; or R2 and R3 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 R5, or a pharmaceutically acceptable salt thereof.
8. A compound according to any one of the claims 1 to 7, wherein A is -CR4=CR4- or -CR4=N-, or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 8, wherein A is R4-, or a pharmaceutically acceptable salt thereof.
10. A compound according any one of the claims 1 to 7, wherein A is S or O, or a pharmaceutically acceptable salt thereof.
11. A compound according to any one of the claims 1 to 10, wherein n is 0, or a pharmaceutically acceptable salt thereof.
12. A compound according to any one of the claims 1 to 11, wherein Ra is H, or a pharmaceutically acceptable salt thereof.
13. A compound according to claim 1, selected from methyl 4-({[5-chloro(3-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[5-chloro(2,3-dihydrobenzofuranyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl -bromo-2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(4-bromochlorothienyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2-chlorofluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(3-chloromethylphenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-[(1-benzofuranylsulfonyl)amino]hydroxybenzoate, methyl 2-hydroxy({[2-methyl(trifluoromethyl)furanyl]sulfonyl}amino)benzoate, methyl 4-{[(3-chloromethylphenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-bromothienyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chlorothienyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-bromochloropyridinyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy{[(5-isopropylmethylbenzothienyl)sulfonyl]amino}benzoate, methyl 2-hydroxy({[4-(trifluoromethyl)phenyl]sulfonyl}amino)benzoate, methyl 4-{[(3-chlorofluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl -chlorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, methyl -chlorofluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chloro-2,4-difluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(4-bromobenzyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy{[(4-methylnaphthyl)sulfonyl]amino}benzoate, methyl 2-hydroxy[(1-naphthylsulfonyl)amino]benzoate, methyl 4-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-({[3-(difluoromethoxy)phenyl]sulfonyl}amino)hydroxybenzoate, methyl 4-{[(3-chlorofluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(4-fluoronaphthyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2,3-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-[(biphenylylsulfonyl)amino]hydroxybenzoate, methyl 4-[(2,1,3-benzothiadiazolylsulfonyl)amino]hydroxybenzoate, methyl 2-hydroxy{[(4-phenoxyphenyl)sulfonyl]amino}benzoate, methyl 2-hydroxy[(naphthalenylsulfonyl)amino]benzoate, methyl 4-({[5-(dimethylamino)naphthalenyl]sulfonyl}amino)hydroxybenzoate, trifluoroacetate, methyl 2-hydroxy{[(5-{[(phenylcarbonyl)amino]methyl}thiophen fonyl]amino}benzoate, methyl -chlorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2-chloromethylphenyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[3-(trifluoromethoxy)phenyl]sulfonyl}amino)benzoate, methyl 4-({[5-chloro(2,5-difluorophenyl)thienyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy({[3-(trifluoromethyl)phenyl]sulfonyl}amino)benzoate, methyl 4-{[(3-bromochlorothiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chloromethylthienyl)sulfonyl]amino}hydroxybenzoate, methyl -bromo-2,4-difluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(3-cyanophenyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[3-(methylsulfonyl)phenyl]sulfonyl}amino)benzoate, methyl 4-[(1-benzothienylsulfonyl)amino]hydroxybenzoate, methyl 4-{[(2,5-dichloromethylthienyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, methyl 4-{[(3,5-dibromothiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chloromethylthiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(3,4-dibromothiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-bromomethylthiophenyl)sulfonyl]amino}hydroxybenzoate, 2-methoxyethyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, ethyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, 2-(1H-pyrrolyl)ethyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, pyrrolyl)propyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, 3-morpholinylpropyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, 3-(1H-imidazolyl)propyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate oroacetate, ethylpiperazinyl)propyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 2-ethoxyethyl ,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, tetrahydrofuranyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, isopropyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, 2-methoxyethyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, butyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, benzyl ,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, hexyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, phenyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, tetrahydrofuranyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, tetrahydrofuranylmethyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, 2-methoxyethyl 4-({[5-chloro(2,3-dihydrobenzofuranyl)thienyl]sulfonyl}amino)- 2-hydroxybenzoate, methyl 4-[({5-chloro[3-(methoxycarbonyl)phenyl]thiophenyl}sulfonyl)amino] hydroxybenzoate, methyl 4-{[(5-chloro{3-[(1-methylethoxy)carbonyl]phenyl}thiophen yl)sulfonyl]amino}hydroxybenzoate, 3-hydroxypropyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, 3-(dimethylamino)propyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, methyl 4-({[6-chloro(2-fluoromethoxyphenyl)pyridinyl]sulfonyl}amino) hydroxybenzoate, methyl 2-hydroxy{[(2'-hydroxybiphenylyl)sulfonyl]amino}benzoate, methyl 4-({[6-chloro(3-fluorophenyl)pyridinyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[5-(3-aminophenyl)chloropyridinyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[6-chloro(4-fluoromethylphenyl)pyridinyl]sulfonyl}amino) hydroxybenzoate, methyl 4-{[(3'-chlorobiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 4-[(biphenylylsulfonyl)amino]hydroxybenzoate, methyl 2-hydroxy{[(3-pyridinylphenyl)sulfonyl]amino}benzoate, trifluoroacetate, methyl 2-hydroxy{[(3-pyridinylphenyl)sulfonyl]amino}benzoate trifluoroacetate, methyl 4-({[3-(1-benzofuranyl)phenyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy{[(3-quinolinylphenyl)sulfonyl]amino}benzoate trifluoroacetate, methyl 4-{[(3'-aminobiphenylyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, methyl 4-{[(3'-acetamidobiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl oxy{[(2'-nitrobiphenylyl)sulfonyl]amino}benzoate, methyl 4-({[3-(5-acetylthienyl)phenyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy({[2'-(hydroxymethyl)biphenylyl]sulfonyl}amino)benzoate, methyl 4-{[(3'-cyanobiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[4'-(methylsulfanyl)biphenylyl]sulfonyl}amino)benzoate, methyl 2-hydroxy({[4'-(trifluoromethoxy)biphenylyl]sulfonyl}amino)benzoate, methyl 2-hydroxy({[4'-(trifluoromethyl)biphenylyl]sulfonyl}amino)benzoate, methyl '-(dimethylcarbamoyl)biphenylyl]sulfonyl}amino)hydroxybenzoate, methyl 4-{[(4'-carbamoylbiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 4-({[5-chloro(4-methoxy-3,5-dimethylphenyl)thiophenyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[4-(3-acetylphenyl)chlorothienyl]sulfonyl}amino)hydroxybenzoate, methyl -chloro[2-(hydroxymethyl)phenyl]thiophenyl}sulfonyl)amino] hydroxybenzoate, methyl 4-({[5-chloro(6-methoxypyridinyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[4-(3-aminophenyl)chlorothiophenyl]sulfonyl}amino)hydroxybenzoate trifluoroacetate, methyl 4-{[(5-chloro{4-[(methylsulfonyl)amino]phenyl}thiophenyl)sulfonyl]amino} hydroxybenzoate, methyl 4-({[4-(4-carbamoylphenyl)chlorothiophenyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[5-chloro(3-fluoromethoxyphenyl)thiophenyl]sulfonyl}amino) hydroxybenzoate, methyl 4-{[(5-chloropyridinylthiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[3'-(methylsulfonyl)biphenylyl]sulfonyl}amino)benzoate, methyl 4-{[(3'-carbamoylbiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[5-(trifluoromethyl)biphenylyl]sulfonyl}amino)benzoate, methyl 4-({[2',5'-difluoro(trifluoromethyl)biphenylyl]sulfonyl}amino) ybenzoate, methyl 4-({[3-(2,3-dihydrobenzofuranyl)(trifluoromethyl)phenyl]sulfonyl}amino) ybenzoate, methyl 2-hydroxy({[2'-hydroxy(trifluoromethyl)biphenyl yl]sulfonyl}amino)benzoate, methyl 4-({[5-(2,5-difluorophenyl)thiophenyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[5-(2,3-dihydrobenzofuranyl)thiophenyl]sulfonyl}amino) hydroxybenzoate, methyl 2-hydroxy({[3-(1-hydroxyethyl)phenyl]sulfonyl}amino)benzoate, methyl 2-hydroxy{[(3-methoxyphenyl)sulfonyl]amino}benzoate, methyl 4-({[3-(2,3-dihydrobenzofuranyl)benzyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[(2',5'-difluorobiphenylyl)methyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[4-(2,3-dihydrobenzofuranyl)benzyl]sulfonyl}amino)hydroxybenzoate, methyl 4-{[(biphenylylmethyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[(2'-hydroxybiphenylyl)methyl]sulfonyl}amino)benzoate, methyl 4-{[(3'-ethoxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 1-methylethyl 3'-{[3-hydroxy(methoxycarbonyl)phenyl]sulfamoyl}biphenylcarboxylate, methyl 4-{[(3-acetylphenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-({[5-(2-fluoromethoxyphenyl)pyridinyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy({[3-methyl(1-methylethyl)benzofuran yl]sulfonyl}amino)benzoate, methyl tyloxy){[(4,5-dichlorothiophenyl)sulfonyl]amino}benzoate, 2-methoxyethyl 4-({[5-chloro(2-hydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 3-(2-chloro{[3-hydroxy(methoxycarbonyl)phenyl]sulfamoyl}thiophenyl)benzoic acid, methyl 4-({[3-(ethoxycarbonyl)phenyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy[({3-[(1-methylethoxy)carbonyl]phenyl}sulfonyl)amino]benzoate, benzyl 2-acetoxy[(1-naphthylsulfonyl)amino]benzoate, oxy[(1-naphthylsulfonyl)amino]benzoic acid, methyl 2-hydroxy({[3-(piperidinyl)phenyl]sulfonyl}amino)benzoate, methyl 4-[({5-chloro[3-(dimethylcarbamoyl)phenyl]thiophenyl}sulfonyl)amino] ybenzoate, (5-methyloxo-1,3-dioxolyl)methyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, ooxoethyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, 2-[bis(2-hydroxyethyl)amino]ethyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 2-(2-hydroxyethoxy)ethyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, pentyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, propyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, 4-(dimethylamino)butyl 2-hydroxy({[3-(2-methyl-1,3-thiazol yl)phenyl]sulfonyl}amino)benzoate trifluoroacetate, methyl 4-({[5'-fluoro-2'-hydroxy(trifluoromethyl)biphenylyl]sulfonyl}amino) hydroxybenzoate, methyl 4-{[(2',5'-difluorobiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 4-({[3-(2,3-dihydrobenzofuranyl)phenyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[6-chloro(2,3-dihydrobenzofuranyl)pyridinyl]sulfonyl}amino) hydroxybenzoate, methyl -chloro(2-hydroxyphenyl)thienyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[5-chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[4-(1,3-benzodioxolyl)chlorothienyl]sulfonyl}amino) hydroxybenzoate, 3-morpholinylpropyl 2-hydroxy{[(2'-hydroxybiphenylyl)sulfonyl]amino}benzoate trifluoroacetate, 3-morpholinylpropyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 2-methoxyethyl 4-({[4-(1,3-benzodioxolyl)chlorothienyl]sulfonyl}amino) hydroxybenzoate, 3-morpholinylpropyl 4-({[4-(1,3-benzodioxolyl)chlorothienyl]sulfonyl}amino) hydroxybenzoate trifluoroacetate, 3-morpholinylpropyl 4-({[5-chloro(2,3-dihydrobenzofuranyl) thienyl]sulfonyl}amino)hydroxybenzoate trifluoroacetate, 3-morpholinylpropyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, 2-methoxyethyl oxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, 3-[(tert-butoxycarbonyl)amino]propyl 2-hydroxy{[(2,4,5-trichloro l)sulfonyl]amino}benzoate, 1-methylpiperidinyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, 4-morpholinylbutyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate trifluoroacetate, 1-methylpyrrolidinyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate trifluoroacetate, 4-morpholinylbutyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 3-morpholinylpropyl 4-{[(2',5'-difluorobiphenylyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, 2-methoxyethyl ',5'-difluorobiphenylyl)sulfonyl]amino}hydroxybenzoate, 4-morpholinylbutyl 4-{[(2',5'-difluorobiphenylyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, 3-morpholinylpropyl 4-({[3-(2,3-dihydrobenzofuranyl)phenyl]sulfonyl}amino) hydroxybenzoate trifluoroacetate, 2-methoxyethyl 4-({[3-(2,3-dihydrobenzofuranyl)phenyl]sulfonyl}amino) hydroxybenzoate, 4-morpholinylbutyl 4-({[3-(2,3-dihydrobenzofuranyl)phenyl]sulfonyl}amino) hydroxybenzoate trifluoroacetate, methyl 4-{[(3-bromomethoxyphenyl)sulfonyl]amino}hydroxybenzoate, 2-methoxymethylethyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, tetrahydrofuranyl '-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, hoxymethyl)propyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, 2-ethoxy(ethoxymethyl)ethyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, oxybutyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 2-hydroxyethyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 3-hydroxypropyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, 2-methoxyethyl '-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 2-methoxyethyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, 3-morpholinylpropyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate oroacetate, tetrahydrofuranyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, 1-(methoxymethyl)propyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, 2-methoxybutyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, 2-methoxy(methoxymethyl)ethyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino} hydroxybenzoate, 2-methoxymethylethyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, 1-methylmorpholinylpropyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate,) trifluoroacetate, 2-methoxymethylethyl ,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, 1-(methoxymethyl)propyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, 2-methoxybutyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, oxyethyl 4-{[(4-bromo-2,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, tetrahydrofuranyl 4-{[(4-bromo-2,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, 3-morpholinylpropyl 4-{[(4-bromo-2,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, methyl 4-{[(5-bromochlorothienyl)sulfonyl]amino}hydroxybenzoate, (1-methylnitro-1H-imidazolyl)methyl 4-({[5-chloro(2,3-dihydrobenzofuranyl)- 2-thienyl]sulfonyl}amino)hydroxybenzoate, (1-Methylnitro-1H-imidazolyl)methyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}- 2-hydroxybenzoate, oxyethyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 1-benzylpyrrolidinyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, tert-butyl 3-[(2-hydroxy{[(2,4,5-trichloro thienyl)sulfonyl]amino}benzoyl)oxy]pyrrolidinecarboxylate, methyl 4-({[4-chloro(2-hydroxyphenyl)thiophenyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[4-chloro(2-methoxyphenyl)thiophenyl]sulfonyl}amino) hydroxybenzoate, oxyethyl 4-({[5-chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, ydrofuranyl 4-({[5-chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino)- 2-hydroxybenzoate, 2-methoxybutyl 4-({[5-chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, ethyl 4-({[5-chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 3-(2,6-dimethylmorpholinyl)propyl '-fluoro-2'-hydroxybiphenyl yl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, 3-morpholinylpropyl 4-({[5-chloro(5-fluorohydroxyphenyl) thienyl]sulfonyl}amino)hydroxybenzoate trifluoroacetate, 3-(2,6-dimethylmorpholinyl)propyl 4-({[5-chloro(5-fluorohydroxyphenyl) thienyl]sulfonyl}amino)hydroxybenzoate trifluoroacetate, 1-(methoxymethyl)propyl 4-{[(5-chlorophenylthienyl)sulfonyl]amino} hydroxybenzoate, 2-methoxymethylethyl 4-{[(5-chlorophenylthienyl)sulfonyl]amino} hydroxybenzoate, 2-hydroxyethyl 4-{[(5-chlorophenylthienyl)sulfonyl]amino}hydroxybenzoate, 1-(methoxymethyl)propyl 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 2-hydroxyethyl 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 2-methoxyethyl -chloro(3-fluorophenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 3-morpholinylpropyl 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino) hydroxybenzoate trifluoroacetate, 2-methoxy(methoxymethyl)ethyl 4-({[5-chloro(3-fluorophenyl) thienyl]sulfonyl}amino)hydroxybenzoate, 2-phenoxyethyl 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[5-chloro(5-fluoromethoxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 2-phenoxyethyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, 2-[(6-chloropyridinyl)oxy]ethyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 2-[3-(methoxymethyl)phenoxy]ethyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino} hydroxybenzoate, 2-(3-carbamoylphenoxy)ethyl 4-({[5-chloro(2-fluoromethoxyphenyl) thienyl]sulfonyl}amino)hydroxybenzoate, 3-hydroxypropyl 4-({[5-chloro(2-fluoromethoxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 3-(pyridinylamino)propyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, methyl-1H-pyrazolyl)amino]propyl 4-{[(5'-fluoro-2'-hydroxybiphenyl fonyl]amino}hydroxybenzoate trifluoroacetate, 3-[(5-methylisoxazolyl)amino]propyl '-fluoro-2'-hydroxybiphenyl yl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, or a pharmaceutically acceptable salt thereof.
14. Use of a compound of formula (I) H O A S R3 n (I) RbOOC R2 wherein n is 0 or 1; A is O, S, -CR4=CR4- or -CR4=N-; R1 is selected from H; halogen; C1-C6 alkyl, optionally substituted with at least one halogen; and C1-C6 alkoxy, optionally substituted with at least one halogen; R2 and R3 are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; carbamoyl; secondary or tertiary C1-C6 alkylamido; yclylcarbonylamino-C0-C2 alkyl; 5- or 6-membered cyclic aminocarbonyl optionally ning a further heteroatom in the ring; C1-C6 alkylcarbonylamino; C1-C6 alkylsulfonyl; hydroxy-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 l; wherein any alkyl is optionally substituted with at least one halogen; any yclyl 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 R5; or R2 and R3 form, together with the carbon atoms to which they are ed, a 5- or 6- ed carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R5; ed that R1, R2 and R3 are not all hydrogen; each R4 is ndently selected from H, halogen, monocyclic C3-C6 carbocyclyl and C1- C6 alkyl, wherein any alkyl is optionally substituted with at least one halogen; each R5 is independently selected from n; C1-C6 alkyl; C1-C6 alkoxy; phenoxy; amino; cyano; nitro; secondary or tertiary C1-C6 alkylamino; 5- or 6-membered cyclic amino, optionally containing at least one further heteroatom in the ring; C1-C6 alkylcarbonylamino; carbamoyl; secondary or tertiary C1-C6 alkylamido; 5- or 6-membered cyclic aminocarbonyl; C1-C6 alkoxycarbonylamino; hydroxy-C0-C6 alkyl; C1-C6-alkylthio; carboxy-C0-C6-alkyl; C1-C6 alkoxycarbonyl; C1-C6 alkylcarbonyl; C1-C6-alkylsulfonyl; and C1-C6 alkylsulfonylamino; n any alkyl is optionally substituted with at least one halogen; Ra is ed from H and C1-C6 alkylcarbonyl; Rb is selected from H, C1-C6 alkyl, C1-C6 alkyl substituted with at least one R6; carbocyclyl- C0-C5 alkyl; and heterocyclyl-C0-C5 alkyl; wherein any carbocyclyl and heterocyclyl is 5- or 6- membered and is optionally substituted with at least one R7 and optionally comprises at least one oxo group in the ring; ed that Ra and Rb are not both H; each R6 is independently selected from hydroxy; C1-C6 alkoxy; hydroxy-C1-C6 alkoxy; C1- C6 alkylcarbonyloxy; C1-C6 alkoxycarbonyloxy; 5- or 6-membered carbocyclylcarbonyl or heterocyclylcarbonyl; amino; secondary or tertiary C1-C6 alkylamino; secondary or tertiary hydroxy-C1-C6 alkylamino; 5- or 6-membered cyclic amino optionally ning at least one further heteroatom in the ring and wherein the ring is optionally substituted with at least one C1-C6 alkyl; C1-C6 alkylcarbonylamino; C1-C6 alkoxycarbonylamino; (C1-C6 alkoxycarbonyl)(C1-C6 alkyl)amino; (C1-C6 alkoxycarbonyl)(5- or 6-membered carbocyclyl or heterocyclyl)amino; (C1-C6 arbonyl)(C1-C6 alkyl)amino; oyl; secondary or tertiary C1-C6 alkylamido wherein any alkyl is optionally substituted by OH or CONH2; 5- or 6-membered carbocyclyl- or heterocyclylcarbamoyl; 5- or 6-membered cyclic arbonyl, optionally containing at least one further heteroatom in the ring, and wherein the ring is optionally substituted with at least one C1-C6 alkyl; 5-ormembered carbocyclylamino or heterocyclylamino; 5-ormembered carbocyclyloxy or heterocyclyloxy; wherein any alkyl is optionally substituted with at least one n and any 5- or 6-membered yclyl or heterocyclyl is optionally substituted with at least one R8; each R7 and R8 is independently selected from C1-C6 alkyl; hydroxy-C0-C3 alkyl; C1-C6 alkoxy-C0-C3 alkyl; C1-C6 alkoxycarbonyl; carbocyclyl-C0-C4 alkyl; heterocyclyl-C0-C4 alkyl; C1-C6 alkylsulfinyl; amino; nitro; C1-C6 secondary or tertiary amino; halogen; carbamoyl; secondary or tertiary C1-C6 alkylamido-C0-C3 alkyl; C1-C6 alkylcarbonylamino; and 5- or ered cyclic amino, optionally containing at least one further heteroatom in the ring and wherein the ring is optionally substituted with at least one C1-C6 alkyl; wherein any alkyl is optionally substituted with at least one halogen; wherein any carbocyclyl and cyclyl is 5- or 6- membered; or a pharmaceutically acceptable salt thereof, provided that the compound is not ethyl cetamidophenylsulfonamido)hydroxybenzoate, methyl 4-(4-acetamidophenylsulfonamido)hydroxybenzoate, phenyl 2-hydroxy(4-methylphenylsulfonamido)benzoate, or methyl 2-hydroxy(4-(4-oxo-1,4-dihydropyrazolo[1,5-a][1,3,5]triazin yl)phenylsulfonamido)benzoate, in the manufacture of a medicament for use in therapy.
15. A use according to claim 14 wherein A is O, S, -CR4=CR4- or -CR4=N-; and when A is -CR4=CR4- or -CR4=N-, one of R2 and R3 is selected from carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; and 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 R5; or R2 and R3 form, together with the carbon atoms to which they are attached, a 5- or ered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R5; or a pharmaceutically acceptable salt thereof.
16. A use ing to claim 15 wherein A is O, S, -CR4=CR4- or -CR4=N-; and when A is -CR4=CR4- or -CR4=N-, R2 is selected from carbocyclyl-C0-C3 alkyl; yclyl- C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered yl; and R3 is selected from H; halogen; and C1-C6 alkyl, ally substituted with at least one halogen; or R2 and R3 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 R5; or a pharmaceutically acceptable salt thereof.
17. A use according to any one of the claims 14 to 16 wherein A is O, S, -CR4=CR4- or -CR4=N-; and when A is O or S, R2 and R3 are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; oyl; secondary or tertiary C1-C6 alkylamido; carbocyclylcarbonylamino-C0-C2 alkyl; 5- or 6-membered cyclic aminocarbonyl optionally containing a further heteroatom in the ring; C1-C6 alkylcarbonylamino; C1-C6 alkylsulfonyl; hydroxy-C0-C6 alkyl, C1-C6 arbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; wherein any alkyl is optionally substituted with at least one halogen; or a pharmaceutically able salt thereof.
18. A use according to claim 14 wherein R3 is selected from H; halogen; and C1-C6 alkyl, wherein any alkyl is optionally substituted with at least one halogen; or R2 and R3 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 R5, or a pharmaceutically acceptable salt thereof.
19. A use according to claim 14, wherein R2 is selected from H; halogen; C1-C6 alkyl; carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; and cyclyl-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 cyclyl is optionally tuted with at least one R5; or R2 and R3 form, together with the carbon atoms to which they are ed, a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R5, or a pharmaceutically acceptable salt thereof.
20. A use ing to claim 19, wherein R2 is selected from yclyl-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 cyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R5; or R2 and R3 form, together with the carbon atoms to which they are attached, a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally tuted with at least one R5, or a pharmaceutically acceptable salt thereof.
21. A use according to any one of the claims 14 to 20, wherein A is -CR4=CR4- or -CR4=N-, or a pharmaceutically acceptable salt thereof.
22. A use according to claim 21, wherein A is -CR4=CR4-, or a pharmaceutically acceptable salt thereof.
23. A use according any one of the claims 14 to 20, wherein A is S or O, or a pharmaceutically acceptable salt thereof.
24. A use according to any one of the claims 14 to 23, n n is 0, or a pharmaceutically acceptable salt f.
25. A use according to any one of the claims 14 to 24, wherein Ra is H, or a pharmaceutically acceptable salt thereof.
26. A use according to claim 14, wherein the compound of formula I is selected from methyl 4-({[5-chloro(3-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[5-chloro(2,3-dihydrobenzofuranyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl 4-{[(4-bromo-2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(4-bromochlorothienyl)sulfonyl]amino}hydroxybenzoate, methyl -chlorofluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(3-chloromethylphenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-[(1-benzofuranylsulfonyl)amino]hydroxybenzoate, methyl oxy({[2-methyl(trifluoromethyl)furanyl]sulfonyl}amino)benzoate, methyl 4-{[(3-chloromethylphenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-bromothienyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chlorothienyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-bromochloropyridinyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy{[(5-isopropylmethylbenzothienyl)sulfonyl]amino}benzoate, methyl 2-hydroxy({[4-(trifluoromethyl)phenyl]sulfonyl}amino)benzoate, methyl 4-{[(3-chlorofluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(3-chlorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chlorofluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chloro-2,4-difluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(4-bromobenzyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, methyl oxy{[(4-methylnaphthyl)sulfonyl]amino}benzoate, methyl 2-hydroxy[(1-naphthylsulfonyl)amino]benzoate, methyl 4-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-({[3-(difluoromethoxy)phenyl]sulfonyl}amino)hydroxybenzoate, methyl 4-{[(3-chlorofluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(4-fluoronaphthyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2,3-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-[(biphenylylsulfonyl)amino]hydroxybenzoate, methyl 4-[(2,1,3-benzothiadiazolylsulfonyl)amino]hydroxybenzoate, methyl 2-hydroxy{[(4-phenoxyphenyl)sulfonyl]amino}benzoate, methyl 2-hydroxy[(naphthalenylsulfonyl)amino]benzoate, methyl 4-({[5-(dimethylamino)naphthalenyl]sulfonyl}amino)hydroxybenzoate, trifluoroacetate, methyl 2-hydroxy{[(5-{[(phenylcarbonyl)amino]methyl}thiophen yl)sulfonyl]amino}benzoate, methyl 4-{[(4-chlorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2-chloromethylphenyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[3-(trifluoromethoxy)phenyl]sulfonyl}amino)benzoate, methyl 4-({[5-chloro(2,5-difluorophenyl)thienyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy({[3-(trifluoromethyl)phenyl]sulfonyl}amino)benzoate, methyl 4-{[(3-bromochlorothiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chloromethylthienyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-bromo-2,4-difluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(3-cyanophenyl)sulfonyl]amino}hydroxybenzoate, methyl oxy({[3-(methylsulfonyl)phenyl]sulfonyl}amino)benzoate, methyl 4-[(1-benzothienylsulfonyl)amino]hydroxybenzoate, methyl 4-{[(2,5-dichloromethylthienyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, methyl 4-{[(3,5-dibromothiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chloromethylthiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(3,4-dibromothiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-bromomethylthiophenyl)sulfonyl]amino}hydroxybenzoate, 2-methoxyethyl ,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, ethyl ,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, 2-(1H-pyrrolyl)ethyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, 3-(1H-pyrrolyl)propyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, holinylpropyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, 3-(1H-imidazolyl)propyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 3-(4-methylpiperazinyl)propyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 2-ethoxyethyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, tetrahydrofuranyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, isopropyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, 2-methoxyethyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, butyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, benzyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, hexyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, phenyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, tetrahydrofuranyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, tetrahydrofuranylmethyl ,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, 2-methoxyethyl 4-({[5-chloro(2,3-dihydrobenzofuranyl)thienyl]sulfonyl}amino)- 2-hydroxybenzoate, methyl 4-[({5-chloro[3-(methoxycarbonyl)phenyl]thiophenyl}sulfonyl)amino] hydroxybenzoate, methyl 4-{[(5-chloro{3-[(1-methylethoxy)carbonyl]phenyl}thiophen yl)sulfonyl]amino}hydroxybenzoate, oxypropyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, 3-(dimethylamino)propyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, methyl 4-({[6-chloro(2-fluoromethoxyphenyl)pyridinyl]sulfonyl}amino) hydroxybenzoate, methyl 2-hydroxy{[(2'-hydroxybiphenylyl)sulfonyl]amino}benzoate, methyl -chloro(3-fluorophenyl)pyridinyl]sulfonyl}amino)hydroxybenzoate, methyl -(3-aminophenyl)chloropyridinyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[6-chloro(4-fluoromethylphenyl)pyridinyl]sulfonyl}amino) hydroxybenzoate, methyl 4-{[(3'-chlorobiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 4-[(biphenylylsulfonyl)amino]hydroxybenzoate, methyl 2-hydroxy{[(3-pyridinylphenyl)sulfonyl]amino}benzoate, trifluoroacetate, methyl 2-hydroxy{[(3-pyridinylphenyl)sulfonyl]amino}benzoate trifluoroacetate, methyl 4-({[3-(1-benzofuranyl)phenyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy{[(3-quinolinylphenyl)sulfonyl]amino}benzoate trifluoroacetate, methyl 4-{[(3'-aminobiphenylyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, methyl 4-{[(3'-acetamidobiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy{[(2'-nitrobiphenylyl)sulfonyl]amino}benzoate, methyl 4-({[3-(5-acetylthienyl)phenyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy({[2'-(hydroxymethyl)biphenylyl]sulfonyl}amino)benzoate, methyl 4-{[(3'-cyanobiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[4'-(methylsulfanyl)biphenylyl]sulfonyl}amino)benzoate, methyl 2-hydroxy({[4'-(trifluoromethoxy)biphenylyl]sulfonyl}amino)benzoate, methyl 2-hydroxy({[4'-(trifluoromethyl)biphenylyl]sulfonyl}amino)benzoate, methyl 4-({[4'-(dimethylcarbamoyl)biphenylyl]sulfonyl}amino)hydroxybenzoate, methyl 4-{[(4'-carbamoylbiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 4-({[5-chloro(4-methoxy-3,5-dimethylphenyl)thiophenyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[4-(3-acetylphenyl)chlorothienyl]sulfonyl}amino)hydroxybenzoate, methyl 4-[({5-chloro[2-(hydroxymethyl)phenyl]thiophenyl}sulfonyl)amino] ybenzoate, methyl 4-({[5-chloro(6-methoxypyridinyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[4-(3-aminophenyl)chlorothiophenyl]sulfonyl}amino)hydroxybenzoate trifluoroacetate, methyl 4-{[(5-chloro{4-[(methylsulfonyl)amino]phenyl}thiophenyl)sulfonyl]amino} hydroxybenzoate, methyl 4-({[4-(4-carbamoylphenyl)chlorothiophenyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[5-chloro(3-fluoromethoxyphenyl)thiophenyl]sulfonyl}amino) hydroxybenzoate, methyl -chloropyridinylthiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[3'-(methylsulfonyl)biphenylyl]sulfonyl}amino)benzoate, methyl 4-{[(3'-carbamoylbiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[5-(trifluoromethyl)biphenylyl]sulfonyl}amino)benzoate, methyl 4-({[2',5'-difluoro(trifluoromethyl)biphenylyl]sulfonyl}amino) hydroxybenzoate, methyl -(2,3-dihydrobenzofuranyl)(trifluoromethyl)phenyl]sulfonyl}amino) hydroxybenzoate, methyl 2-hydroxy({[2'-hydroxy(trifluoromethyl)biphenyl yl]sulfonyl}amino)benzoate, methyl 4-({[5-(2,5-difluorophenyl)thiophenyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[5-(2,3-dihydrobenzofuranyl)thiophenyl]sulfonyl}amino) hydroxybenzoate, methyl 2-hydroxy({[3-(1-hydroxyethyl)phenyl]sulfonyl}amino)benzoate, methyl 2-hydroxy{[(3-methoxyphenyl)sulfonyl]amino}benzoate, methyl 4-({[3-(2,3-dihydrobenzofuranyl)benzyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[(2',5'-difluorobiphenylyl)methyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[4-(2,3-dihydrobenzofuranyl)benzyl]sulfonyl}amino)hydroxybenzoate, methyl 4-{[(biphenylylmethyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[(2'-hydroxybiphenylyl)methyl]sulfonyl}amino)benzoate, methyl 4-{[(3'-ethoxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 1-methylethyl 3'-{[3-hydroxy(methoxycarbonyl)phenyl]sulfamoyl}biphenylcarboxylate, methyl 4-{[(3-acetylphenyl)sulfonyl]amino}hydroxybenzoate, methyl -(2-fluoromethoxyphenyl)pyridinyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy({[3-methyl(1-methylethyl)benzofuran yl]sulfonyl}amino)benzoate, methyl 2-(acetyloxy){[(4,5-dichlorothiophenyl)sulfonyl]amino}benzoate, 2-methoxyethyl 4-({[5-chloro(2-hydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl '-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 3-(2-chloro{[3-hydroxy(methoxycarbonyl)phenyl]sulfamoyl}thiophenyl)benzoic acid, methyl -(ethoxycarbonyl)phenyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy[({3-[(1-methylethoxy)carbonyl]phenyl}sulfonyl)amino]benzoate, benzyl 2-acetoxy[(1-naphthylsulfonyl)amino]benzoate, 2-acetoxy[(1-naphthylsulfonyl)amino]benzoic acid, methyl 2-hydroxy({[3-(piperidinyl)phenyl]sulfonyl}amino)benzoate, methyl 4-[({5-chloro[3-(dimethylcarbamoyl)phenyl]thiophenyl}sulfonyl)amino] hydroxybenzoate, (5-methyloxo-1,3-dioxolyl)methyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, 2-aminooxoethyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, 2-[bis(2-hydroxyethyl)amino]ethyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 2-(2-hydroxyethoxy)ethyl ,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, pentyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, propyl ,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, 4-(dimethylamino)butyl 2-hydroxy({[3-(2-methyl-1,3-thiazol nyl]sulfonyl}amino)benzoate oroacetate, methyl 4-({[5'-fluoro-2'-hydroxy(trifluoromethyl)biphenylyl]sulfonyl}amino) hydroxybenzoate, methyl 4-{[(2',5'-difluorobiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 4-({[3-(2,3-dihydrobenzofuranyl)phenyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[6-chloro(2,3-dihydrobenzofuranyl)pyridinyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[5-chloro(2-hydroxyphenyl)thienyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[5-chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[4-(1,3-benzodioxolyl)chlorothienyl]sulfonyl}amino) hydroxybenzoate, 3-morpholinylpropyl 2-hydroxy{[(2'-hydroxybiphenylyl)sulfonyl]amino}benzoate trifluoroacetate, 3-morpholinylpropyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 2-methoxyethyl 4-({[4-(1,3-benzodioxolyl)chlorothienyl]sulfonyl}amino) hydroxybenzoate, 3-morpholinylpropyl 4-({[4-(1,3-benzodioxolyl)chlorothienyl]sulfonyl}amino) hydroxybenzoate oroacetate, 3-morpholinylpropyl 4-({[5-chloro(2,3-dihydrobenzofuranyl) thienyl]sulfonyl}amino)hydroxybenzoate trifluoroacetate, 3-morpholinylpropyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, 2-methoxyethyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, 3-[(tert-butoxycarbonyl)amino]propyl 2-hydroxy{[(2,4,5-trichloro thienyl)sulfonyl]amino}benzoate, 1-methylpiperidinyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, 4-morpholinylbutyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate trifluoroacetate, 1-methylpyrrolidinyl oxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate trifluoroacetate, 4-morpholinylbutyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 3-morpholinylpropyl 4-{[(2',5'-difluorobiphenylyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, 2-methoxyethyl 4-{[(2',5'-difluorobiphenylyl)sulfonyl]amino}hydroxybenzoate, 4-morpholinylbutyl 4-{[(2',5'-difluorobiphenylyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, 3-morpholinylpropyl 4-({[3-(2,3-dihydrobenzofuranyl)phenyl]sulfonyl}amino) hydroxybenzoate trifluoroacetate, 2-methoxyethyl 4-({[3-(2,3-dihydrobenzofuranyl)phenyl]sulfonyl}amino) hydroxybenzoate, 4-morpholinylbutyl -(2,3-dihydrobenzofuranyl)phenyl]sulfonyl}amino) hydroxybenzoate trifluoroacetate, methyl 4-{[(3-bromomethoxyphenyl)sulfonyl]amino}hydroxybenzoate, 2-methoxymethylethyl '-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, tetrahydrofuranyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, 1-(methoxymethyl)propyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, 2-ethoxy(ethoxymethyl)ethyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, 2-methoxybutyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 2-hydroxyethyl '-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 3-hydroxypropyl '-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, 2-methoxyethyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 2-methoxyethyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, 3-morpholinylpropyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, tetrahydrofuranyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, hoxymethyl)propyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, 2-methoxybutyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, 2-methoxy(methoxymethyl)ethyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino} hydroxybenzoate, 2-methoxymethylethyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, 1-methylmorpholinylpropyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate,) trifluoroacetate, 2-methoxymethylethyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, 1-(methoxymethyl)propyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, 2-methoxybutyl ,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, 2-methoxyethyl 4-{[(4-bromo-2,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, tetrahydrofuranyl 4-{[(4-bromo-2,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, holinylpropyl 4-{[(4-bromo-2,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, methyl 4-{[(5-bromochlorothienyl)sulfonyl]amino}hydroxybenzoate, (1-methylnitro-1H-imidazolyl)methyl 4-({[5-chloro(2,3-dihydrobenzofuranyl)- 2-thienyl]sulfonyl}amino)hydroxybenzoate, (1-Methylnitro-1H-imidazolyl)methyl ,5-dichlorothiophenyl)sulfonyl]amino}- 2-hydroxybenzoate, 2-phenoxyethyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 1-benzylpyrrolidinyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, tert-butyl 3-[(2-hydroxy{[(2,4,5-trichloro thienyl)sulfonyl]amino}benzoyl)oxy]pyrrolidinecarboxylate, methyl 4-({[4-chloro(2-hydroxyphenyl)thiophenyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[4-chloro(2-methoxyphenyl)thiophenyl]sulfonyl}amino) ybenzoate, 2-methoxyethyl 4-({[5-chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, tetrahydrofuranyl 4-({[5-chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino)- 2-hydroxybenzoate, 2-methoxybutyl -chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, ethyl 4-({[5-chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 3-(2,6-dimethylmorpholinyl)propyl '-fluoro-2'-hydroxybiphenyl yl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, 3-morpholinylpropyl 4-({[5-chloro(5-fluorohydroxyphenyl) thienyl]sulfonyl}amino)hydroxybenzoate trifluoroacetate, 3-(2,6-dimethylmorpholinyl)propyl 4-({[5-chloro(5-fluorohydroxyphenyl) thienyl]sulfonyl}amino)hydroxybenzoate trifluoroacetate, 1-(methoxymethyl)propyl 4-{[(5-chlorophenylthienyl)sulfonyl]amino} hydroxybenzoate, 2-methoxymethylethyl 4-{[(5-chlorophenylthienyl)sulfonyl]amino} hydroxybenzoate, 2-hydroxyethyl 4-{[(5-chlorophenylthienyl)sulfonyl]amino}hydroxybenzoate, 1-(methoxymethyl)propyl 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 2-hydroxyethyl 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 2-methoxyethyl 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 3-morpholinylpropyl 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino) ybenzoate trifluoroacetate, 2-methoxy(methoxymethyl)ethyl 4-({[5-chloro(3-fluorophenyl) thienyl]sulfonyl}amino)hydroxybenzoate, 2-phenoxyethyl 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl -chloro(5-fluoromethoxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, oxyethyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, 2-[(6-chloropyridinyl)oxy]ethyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 2-[3-(methoxymethyl)phenoxy]ethyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino} hydroxybenzoate, 2-(3-carbamoylphenoxy)ethyl 4-({[5-chloro(2-fluoromethoxyphenyl) thienyl]sulfonyl}amino)hydroxybenzoate, 3-hydroxypropyl -chloro(2-fluoromethoxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 3-(pyridinylamino)propyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} ybenzoate trifluoroacetate, 3-[(1-methyl-1H-pyrazolyl)amino]propyl '-fluoro-2'-hydroxybiphenyl yl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, 3-[(5-methylisoxazolyl)amino]propyl 4-{[(5'-fluoro-2'-hydroxybiphenyl fonyl]amino}hydroxybenzoate trifluoroacetate, or a pharmaceutically acceptable salt thereof.
27. A pharmaceutical composition comprising a compound of formula (I) H O A S R3 n (I) RbOOC R2 wherein: n is 0 or 1; A is O, S, -CR4=CR4- or -CR4=N-; R1 is selected from H; halogen; C1-C6 alkyl, ally substituted with at least one halogen; and C1-C6 alkoxy, optionally substituted with at least one halogen; R2 and R3 are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 ; carbamoyl; secondary or tertiary C1-C6 alkylamido; carbocyclylcarbonylamino-C0-C2 alkyl; 5- or 6-membered cyclic aminocarbonyl optionally containing a further heteroatom in the ring; C1-C6 alkylcarbonylamino; C1-C6 alkylsulfonyl; hydroxy-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 yclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10- membered yl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R5; or R2 and R3 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 R5; provided that R1, R2 and R3 are not all hydrogen; each R4 is ndently ed from H, halogen, monocyclic C3-C6 carbocyclyl and C1- C6 alkyl, wherein any alkyl is optionally substituted with at least one halogen; each R5 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, optionally containing at least one r heteroatom in the ring; C1-C6 alkylcarbonylamino; carbamoyl; secondary or ry C1-C6 alkylamido; 5- or 6-membered cyclic aminocarbonyl; C1-C6 alkoxycarbonylamino; hydroxy-C0-C6 alkyl; C1-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; Ra is selected from H and C1-C6 alkylcarbonyl; Rb is selected from H, C1-C6 alkyl, C1-C6 alkyl substituted with at least one R6; carbocyclyl- C0-C5 alkyl; and heterocyclyl-C0-C5 alkyl; wherein any carbocyclyl and heterocyclyl is 5- or 6- membered and is optionally substituted with at least one R7 and optionally comprises at least one oxo group in the ring; provided that Ra and Rb are not both H; each R6 is independently selected from hydroxy; C1-C6 alkoxy; hydroxy-C1-C6 alkoxy; C1- C6 alkylcarbonyloxy; C1-C6 carbonyloxy; 5- or 6-membered carbocyclylcarbonyl or heterocyclylcarbonyl; amino; secondary or ry C1-C6 alkylamino; secondary or ry hydroxy-C1-C6 mino; 5- or 6-membered cyclic amino optionally ning at least one further heteroatom in the ring and wherein the ring is optionally substituted with at least one C1-C6 alkyl; C1-C6 arbonylamino; C1-C6 alkoxycarbonylamino; (C1-C6 alkoxycarbonyl)(C1-C6 alkyl)amino; (C1-C6 carbonyl)(5- or 6-membered carbocyclyl or heterocyclyl)amino; (C1-C6 alkylcarbonyl)(C1-C6 alkyl)amino; carbamoyl; secondary or tertiary C1-C6 alkylamido wherein any alkyl is optionally substituted by OH or CONH2; 5- or 6-membered carbocyclyl- or heterocyclylcarbamoyl; 5- or 6-membered cyclic aminocarbonyl, optionally containing at least one further heteroatom in the ring, and wherein the ring is optionally substituted with at least one C1-C6 alkyl; 5-ormembered carbocyclylamino or heterocyclylamino; and 5-ormembered carbocyclyloxy or heterocyclyloxy; wherein any alkyl is optionally substituted with at least one halogen and any 5- or 6-membered carbocyclyl or heterocyclyl is optionally substituted with at least one R8; each R7 and R8 is independently selected from C1-C6 alkyl; hydroxy-C0-C3 alkyl; C1-C6 alkoxy-C0-C3 alkyl; C1-C6 alkoxycarbonyl; carbocyclyl-C0-C4 alkyl; cyclyl-C0-C4 alkyl; C1-C6 alkylsulfinyl; amino; nitro; C1-C6 secondary or tertiary amino; halogen; oyl; secondary or ry C1-C6 alkylamido-C0-C3 alkyl; C1-C6 alkylcarbonylamino; and 5- or 6-membered cyclic amino, optionally containing at least one further heteroatom in the ring and wherein the ring is optionally substituted with at least one C1-C6 alkyl; n any alkyl is optionally substituted with at least one halogen; wherein any yclyl and heterocyclyl is 5- or 6- membered; or a pharmaceutically acceptable salt thereof, provided that the nd is not ethyl 4-(4-acetamidophenylsulfonamido)hydroxybenzoate, methyl 4-(4-acetamidophenylsulfonamido)hydroxybenzoate, phenyl 2-hydroxy(4-methylphenylsulfonamido)benzoate, or methyl 2-hydroxy(4-(4-oxo-1,4-dihydropyrazolo[1,5-a][1,3,5]triazin yl)phenylsulfonamido)benzoate.
28. A ceutical composition according to claim 27, wherein A is O, S, -CR4=CR4- or -CR4=N-; and when A is -CR4=CR4- or -CR4=N-, one of R2 and R3 is selected from carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10- membered bicyclyl; and any yclyl or heterocyclyl is optionally substituted with at least one R5; or R2 and R3 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 R5; or a pharmaceutically acceptable salt thereof.
29. A pharmaceutical ition according to claim 28, wherein A is O, S, -CR4=CR4- or -CR4=N-; and when A is -CR4=CR4- or -CR4=N-, R2 is selected from carbocyclyl-C0-C3 alkyl; carbocyclyl- C2-C3 l; cyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and R3 is selected from H; halogen; and C1-C6 alkyl, optionally substituted with at least one halogen; or R2 and R3 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 R5; or a pharmaceutically able salt thereof.
30. A pharmaceutical composition according to any one of the claims 27 to 29, wherein A is O, S, -CR4=CR4- or -CR4=N-; and when A is O or S, R2 and R3 are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; carbamoyl; secondary or tertiary C1-C6 alkylamido; carbocyclylcarbonylamino-C0-C2 alkyl; 5- or 6-membered cyclic arbonyl ally containing a further heteroatom in the ring; C1-C6 alkylcarbonylamino; C1-C6 alkylsulfonyl; hydroxy-C0-C6 alkyl, C1-C6 arbonyl; carboxy; C1-C6 alkoxycarbonyl; cyano; wherein any alkyl is optionally substituted with at least one halogen; or a pharmaceutically acceptable salt thereof.
31. A ceutical composition according to claim 27, wherein R3 is selected from H; halogen; and C1-C6 alkyl, wherein any alkyl is optionally substituted with at least one halogen; or R2 and R3 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 R5, or a pharmaceutically acceptable salt thereof.
32. A pharmaceutical composition according to claim 27, wherein R2 is selected from H; n; C1-C6 alkyl; carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; n 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 R5; or R2 and R3 form, er with the carbon atoms to which they are attached, a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally tuted with at least one R5, or a pharmaceutically acceptable salt thereof.
33. A pharmaceutical composition ing to claim 32, wherein R2 is selected from carbocyclyl-C0-C3 alkyl; yclyl-C2-C3 l; heterocyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any alkyl is ally 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 R5; or R2 and R3 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 R5, or a pharmaceutically acceptable salt thereof.
34. A pharmaceutical composition according to any one of the claims 27 to 33, wherein A is -CR4=CR4- or -, or a pharmaceutically acceptable salt thereof.
35. A pharmaceutical composition according to claim 34, wherein A is R4-, or a pharmaceutically acceptable salt thereof.
36. A pharmaceutical composition according any one of the claims 27 to 33, wherein A is S or O, or a pharmaceutically acceptable salt thereof.
37. A pharmaceutical composition according to any one of the claims 27 to 36, wherein n is 0, or a pharmaceutically acceptable salt thereof.
38. A pharmaceutical composition according to any one of the claims 27 to 37, wherein Ra is H, or a ceutically acceptable salt thereof.
39. A pharmaceutical composition according to claim 27, wherein the compound of formula I is selected from methyl -chloro(3-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl -chloro(2,3-dihydrobenzofuranyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl 4-{[(4-bromo-2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(4-bromochlorothienyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2-chlorofluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(3-chloromethylphenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-[(1-benzofuranylsulfonyl)amino]hydroxybenzoate, methyl 2-hydroxy({[2-methyl(trifluoromethyl)furanyl]sulfonyl}amino)benzoate, methyl 4-{[(3-chloromethylphenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-bromothienyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chlorothienyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-bromochloropyridinyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy{[(5-isopropylmethylbenzothienyl)sulfonyl]amino}benzoate, methyl 2-hydroxy({[4-(trifluoromethyl)phenyl]sulfonyl}amino)benzoate, methyl 4-{[(3-chlorofluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(3-chlorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chlorofluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chloro-2,4-difluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(4-bromobenzyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy{[(4-methylnaphthyl)sulfonyl]amino}benzoate, methyl 2-hydroxy[(1-naphthylsulfonyl)amino]benzoate, methyl 4-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-({[3-(difluoromethoxy)phenyl]sulfonyl}amino)hydroxybenzoate, methyl 4-{[(3-chlorofluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(4-fluoronaphthyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2,3-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, methyl phenylylsulfonyl)amino]hydroxybenzoate, methyl 4-[(2,1,3-benzothiadiazolylsulfonyl)amino]hydroxybenzoate, methyl 2-hydroxy{[(4-phenoxyphenyl)sulfonyl]amino}benzoate, methyl 2-hydroxy[(naphthalenylsulfonyl)amino]benzoate, methyl 4-({[5-(dimethylamino)naphthalenyl]sulfonyl}amino)hydroxybenzoate, trifluoroacetate, methyl 2-hydroxy{[(5-{[(phenylcarbonyl)amino]methyl}thiophen yl)sulfonyl]amino}benzoate, methyl 4-{[(4-chlorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2-chloromethylphenyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[3-(trifluoromethoxy)phenyl]sulfonyl}amino)benzoate, methyl 4-({[5-chloro(2,5-difluorophenyl)thienyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy({[3-(trifluoromethyl)phenyl]sulfonyl}amino)benzoate, methyl 4-{[(3-bromochlorothiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chloromethylthienyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-bromo-2,4-difluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(3-cyanophenyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[3-(methylsulfonyl)phenyl]sulfonyl}amino)benzoate, methyl 4-[(1-benzothienylsulfonyl)amino]hydroxybenzoate, methyl 4-{[(2,5-dichloromethylthienyl)sulfonyl]amino}hydroxybenzoate, methyl oxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, methyl 4-{[(3,5-dibromothiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chloromethylthiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(3,4-dibromothiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-bromomethylthiophenyl)sulfonyl]amino}hydroxybenzoate, 2-methoxyethyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, ethyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, 2-(1H-pyrrolyl)ethyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, 3-(1H-pyrrolyl)propyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, 3-morpholinylpropyl ,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, 3-(1H-imidazolyl)propyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 3-(4-methylpiperazinyl)propyl ,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 2-ethoxyethyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, tetrahydrofuranyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, isopropyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, 2-methoxyethyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, butyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, benzyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, hexyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, phenyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, tetrahydrofuranyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, tetrahydrofuranylmethyl ,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, 2-methoxyethyl -chloro(2,3-dihydrobenzofuranyl)thienyl]sulfonyl}amino)- 2-hydroxybenzoate, methyl 4-[({5-chloro[3-(methoxycarbonyl)phenyl]thiophenyl}sulfonyl)amino] hydroxybenzoate, methyl 4-{[(5-chloro{3-[(1-methylethoxy)carbonyl]phenyl}thiophen yl)sulfonyl]amino}hydroxybenzoate, 3-hydroxypropyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, 3-(dimethylamino)propyl ,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, methyl 4-({[6-chloro(2-fluoromethoxyphenyl)pyridinyl]sulfonyl}amino) hydroxybenzoate, methyl 2-hydroxy{[(2'-hydroxybiphenylyl)sulfonyl]amino}benzoate, methyl 4-({[6-chloro(3-fluorophenyl)pyridinyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[5-(3-aminophenyl)chloropyridinyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[6-chloro(4-fluoromethylphenyl)pyridinyl]sulfonyl}amino) hydroxybenzoate, methyl 4-{[(3'-chlorobiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 4-[(biphenylylsulfonyl)amino]hydroxybenzoate, methyl 2-hydroxy{[(3-pyridinylphenyl)sulfonyl]amino}benzoate, trifluoroacetate, methyl 2-hydroxy{[(3-pyridinylphenyl)sulfonyl]amino}benzoate trifluoroacetate, methyl -(1-benzofuranyl)phenyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy{[(3-quinolinylphenyl)sulfonyl]amino}benzoate trifluoroacetate, methyl 4-{[(3'-aminobiphenylyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, methyl 4-{[(3'-acetamidobiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy{[(2'-nitrobiphenylyl)sulfonyl]amino}benzoate, methyl 4-({[3-(5-acetylthienyl)phenyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy({[2'-(hydroxymethyl)biphenylyl]sulfonyl}amino)benzoate, methyl 4-{[(3'-cyanobiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[4'-(methylsulfanyl)biphenylyl]sulfonyl}amino)benzoate, methyl 2-hydroxy({[4'-(trifluoromethoxy)biphenylyl]sulfonyl}amino)benzoate, methyl 2-hydroxy({[4'-(trifluoromethyl)biphenylyl]sulfonyl}amino)benzoate, methyl 4-({[4'-(dimethylcarbamoyl)biphenylyl]sulfonyl}amino)hydroxybenzoate, methyl 4-{[(4'-carbamoylbiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 4-({[5-chloro(4-methoxy-3,5-dimethylphenyl)thiophenyl]sulfonyl}amino) hydroxybenzoate, methyl -(3-acetylphenyl)chlorothienyl]sulfonyl}amino)hydroxybenzoate, methyl 4-[({5-chloro[2-(hydroxymethyl)phenyl]thiophenyl}sulfonyl)amino] hydroxybenzoate, methyl 4-({[5-chloro(6-methoxypyridinyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[4-(3-aminophenyl)chlorothiophenyl]sulfonyl}amino)hydroxybenzoate trifluoroacetate, methyl 4-{[(5-chloro{4-[(methylsulfonyl)amino]phenyl}thiophenyl)sulfonyl]amino} hydroxybenzoate, methyl 4-({[4-(4-carbamoylphenyl)chlorothiophenyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[5-chloro(3-fluoromethoxyphenyl)thiophenyl]sulfonyl}amino) hydroxybenzoate, methyl -chloropyridinylthiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[3'-(methylsulfonyl)biphenylyl]sulfonyl}amino)benzoate, methyl 4-{[(3'-carbamoylbiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[5-(trifluoromethyl)biphenylyl]sulfonyl}amino)benzoate, methyl 4-({[2',5'-difluoro(trifluoromethyl)biphenylyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[3-(2,3-dihydrobenzofuranyl)(trifluoromethyl)phenyl]sulfonyl}amino) hydroxybenzoate, methyl 2-hydroxy({[2'-hydroxy(trifluoromethyl)biphenyl fonyl}amino)benzoate, methyl 4-({[5-(2,5-difluorophenyl)thiophenyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[5-(2,3-dihydrobenzofuranyl)thiophenyl]sulfonyl}amino) hydroxybenzoate, methyl 2-hydroxy({[3-(1-hydroxyethyl)phenyl]sulfonyl}amino)benzoate, methyl 2-hydroxy{[(3-methoxyphenyl)sulfonyl]amino}benzoate, methyl 4-({[3-(2,3-dihydrobenzofuranyl)benzyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[(2',5'-difluorobiphenylyl)methyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[4-(2,3-dihydrobenzofuranyl)benzyl]sulfonyl}amino)hydroxybenzoate, methyl 4-{[(biphenylylmethyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[(2'-hydroxybiphenylyl)methyl]sulfonyl}amino)benzoate, methyl 4-{[(3'-ethoxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 1-methylethyl 3'-{[3-hydroxy(methoxycarbonyl)phenyl]sulfamoyl}biphenylcarboxylate, methyl 4-{[(3-acetylphenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-({[5-(2-fluoromethoxyphenyl)pyridinyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy({[3-methyl(1-methylethyl)benzofuran yl]sulfonyl}amino)benzoate, methyl 2-(acetyloxy){[(4,5-dichlorothiophenyl)sulfonyl]amino}benzoate, 2-methoxyethyl 4-({[5-chloro(2-hydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 3-(2-chloro{[3-hydroxy(methoxycarbonyl)phenyl]sulfamoyl}thiophenyl)benzoic acid, methyl 4-({[3-(ethoxycarbonyl)phenyl]sulfonyl}amino)hydroxybenzoate, methyl oxy[({3-[(1-methylethoxy)carbonyl]phenyl}sulfonyl)amino]benzoate, benzyl 2-acetoxy[(1-naphthylsulfonyl)amino]benzoate, 2-acetoxy[(1-naphthylsulfonyl)amino]benzoic acid, methyl 2-hydroxy({[3-(piperidinyl)phenyl]sulfonyl}amino)benzoate, methyl -chloro[3-(dimethylcarbamoyl)phenyl]thiophenyl}sulfonyl)amino] hydroxybenzoate, (5-methyloxo-1,3-dioxolyl)methyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, 2-aminooxoethyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, 2-[bis(2-hydroxyethyl)amino]ethyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 2-(2-hydroxyethoxy)ethyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, pentyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, propyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, 4-(dimethylamino)butyl 2-hydroxy({[3-(2-methyl-1,3-thiazol nyl]sulfonyl}amino)benzoate trifluoroacetate, methyl 4-({[5'-fluoro-2'-hydroxy(trifluoromethyl)biphenylyl]sulfonyl}amino) hydroxybenzoate, methyl 4-{[(2',5'-difluorobiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 4-({[3-(2,3-dihydrobenzofuranyl)phenyl]sulfonyl}amino)hydroxybenzoate, methyl -chloro(2,3-dihydrobenzofuranyl)pyridinyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[5-chloro(2-hydroxyphenyl)thienyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[5-chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[4-(1,3-benzodioxolyl)chlorothienyl]sulfonyl}amino) hydroxybenzoate, 3-morpholinylpropyl 2-hydroxy{[(2'-hydroxybiphenylyl)sulfonyl]amino}benzoate trifluoroacetate, 3-morpholinylpropyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} ybenzoate trifluoroacetate, oxyethyl 4-({[4-(1,3-benzodioxolyl)chlorothienyl]sulfonyl}amino) hydroxybenzoate, 3-morpholinylpropyl 4-({[4-(1,3-benzodioxolyl)chlorothienyl]sulfonyl}amino) hydroxybenzoate trifluoroacetate, 3-morpholinylpropyl -chloro(2,3-dihydrobenzofuranyl) thienyl]sulfonyl}amino)hydroxybenzoate trifluoroacetate, 3-morpholinylpropyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, 2-methoxyethyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, 3-[(tert-butoxycarbonyl)amino]propyl 2-hydroxy{[(2,4,5-trichloro thienyl)sulfonyl]amino}benzoate, 1-methylpiperidinyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, 4-morpholinylbutyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate trifluoroacetate, 1-methylpyrrolidinyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate trifluoroacetate, 4-morpholinylbutyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 3-morpholinylpropyl 4-{[(2',5'-difluorobiphenylyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, 2-methoxyethyl 4-{[(2',5'-difluorobiphenylyl)sulfonyl]amino}hydroxybenzoate, 4-morpholinylbutyl 4-{[(2',5'-difluorobiphenylyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, 3-morpholinylpropyl 4-({[3-(2,3-dihydrobenzofuranyl)phenyl]sulfonyl}amino) hydroxybenzoate trifluoroacetate, 2-methoxyethyl 4-({[3-(2,3-dihydrobenzofuranyl)phenyl]sulfonyl}amino) hydroxybenzoate, 4-morpholinylbutyl 4-({[3-(2,3-dihydrobenzofuranyl)phenyl]sulfonyl}amino) hydroxybenzoate oroacetate, methyl 4-{[(3-bromomethoxyphenyl)sulfonyl]amino}hydroxybenzoate, 2-methoxymethylethyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, tetrahydrofuranyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} ybenzoate, hoxymethyl)propyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, xy(ethoxymethyl)ethyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, 2-methoxybutyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 2-hydroxyethyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, oxypropyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, 2-methoxyethyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 2-methoxyethyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, 3-morpholinylpropyl ,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, tetrahydrofuranyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, 1-(methoxymethyl)propyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, 2-methoxybutyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, 2-methoxy(methoxymethyl)ethyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino} hydroxybenzoate, 2-methoxymethylethyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, 1-methylmorpholinylpropyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate,) trifluoroacetate, 2-methoxymethylethyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} ybenzoate, 1-(methoxymethyl)propyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, 2-methoxybutyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, oxyethyl 4-{[(4-bromo-2,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, tetrahydrofuranyl 4-{[(4-bromo-2,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, 3-morpholinylpropyl 4-{[(4-bromo-2,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, methyl 4-{[(5-bromochlorothienyl)sulfonyl]amino}hydroxybenzoate, (1-methylnitro-1H-imidazolyl)methyl 4-({[5-chloro(2,3-dihydrobenzofuranyl)- 2-thienyl]sulfonyl}amino)hydroxybenzoate, hylnitro-1H-imidazolyl)methyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}- 2-hydroxybenzoate, 2-phenoxyethyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 1-benzylpyrrolidinyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, tert-butyl 3-[(2-hydroxy{[(2,4,5-trichloro l)sulfonyl]amino}benzoyl)oxy]pyrrolidinecarboxylate, methyl 4-({[4-chloro(2-hydroxyphenyl)thiophenyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[4-chloro(2-methoxyphenyl)thiophenyl]sulfonyl}amino) hydroxybenzoate, 2-methoxyethyl 4-({[5-chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, tetrahydrofuranyl 4-({[5-chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino)- 2-hydroxybenzoate, 2-methoxybutyl 4-({[5-chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, ethyl 4-({[5-chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 3-(2,6-dimethylmorpholinyl)propyl 4-{[(5'-fluoro-2'-hydroxybiphenyl yl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, 3-morpholinylpropyl 4-({[5-chloro(5-fluorohydroxyphenyl) thienyl]sulfonyl}amino)hydroxybenzoate trifluoroacetate, 3-(2,6-dimethylmorpholinyl)propyl 4-({[5-chloro(5-fluorohydroxyphenyl) thienyl]sulfonyl}amino)hydroxybenzoate trifluoroacetate, hoxymethyl)propyl 4-{[(5-chlorophenylthienyl)sulfonyl]amino} ybenzoate, 2-methoxymethylethyl 4-{[(5-chlorophenylthienyl)sulfonyl]amino} hydroxybenzoate, 2-hydroxyethyl 4-{[(5-chlorophenylthienyl)sulfonyl]amino}hydroxybenzoate, 1-(methoxymethyl)propyl 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 2-hydroxyethyl -chloro(3-fluorophenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 2-methoxyethyl 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 3-morpholinylpropyl 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino) hydroxybenzoate trifluoroacetate, oxy(methoxymethyl)ethyl 4-({[5-chloro(3-fluorophenyl) thienyl]sulfonyl}amino)hydroxybenzoate, 2-phenoxyethyl 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino) ybenzoate, methyl 4-({[5-chloro(5-fluoromethoxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 2-phenoxyethyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, 2-[(6-chloropyridinyl)oxy]ethyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 2-[3-(methoxymethyl)phenoxy]ethyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino} hydroxybenzoate, 2-(3-carbamoylphenoxy)ethyl 4-({[5-chloro(2-fluoromethoxyphenyl) l]sulfonyl}amino)hydroxybenzoate, 3-hydroxypropyl 4-({[5-chloro(2-fluoromethoxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 3-(pyridinylamino)propyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 3-[(1-methyl-1H-pyrazolyl)amino]propyl 4-{[(5'-fluoro-2'-hydroxybiphenyl yl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, methylisoxazolyl)amino]propyl 4-{[(5'-fluoro-2'-hydroxybiphenyl yl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, or a pharmaceutically able salt thereof.
40. The use of a compound of formula (I) H O A S R3 n (I) RbOOC R2 wherein: n is 0 or 1; A is O, S, -CR4=CR4- or -; R1 is selected from H; halogen; C1-C6 alkyl, optionally substituted with at least one halogen; and C1-C6 alkoxy, optionally substituted with at least one halogen; R2 and R3 are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; carbamoyl; secondary or tertiary C1-C6 alkylamido; carbocyclylcarbonylamino-C0-C2 alkyl; 5- or 6-membered cyclic aminocarbonyl optionally containing a further heteroatom in the ring; C1-C6 arbonylamino; C1-C6 alkylsulfonyl; hydroxy-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 tuted with at least one R5; or R2 and R3 form, er 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 R5; provided that R1, R2 and R3 are not all hydrogen; each R4 is independently selected from H, halogen, monocyclic C3-C6 carbocyclyl and C1- C6 alkyl, wherein any alkyl is optionally substituted with at least one halogen; each R5 is independently selected from halogen; C1-C6 alkyl; C1-C6 alkoxy; phenoxy; amino; cyano; nitro; secondary or tertiary C1-C6 alkylamino; 5- or ered cyclic amino, optionally ning at least one further heteroatom in the ring; C1-C6 alkylcarbonylamino; carbamoyl; secondary or ry C1-C6 alkylamido; 5- or 6-membered cyclic aminocarbonyl; C1-C6 carbonylamino; hydroxy-C0-C6 alkyl; C1-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; Ra is selected from H and C1-C6 alkylcarbonyl; Rb is selected from H, C1-C6 alkyl, C1-C6 alkyl substituted with at least one R6; carbocyclyl- C0-C5 alkyl; and heterocyclyl-C0-C5 alkyl; wherein any carbocyclyl and heterocyclyl is 5- or 6- membered and is optionally substituted with at least one R7 and ally comprises at least one oxo group in the ring; provided that Ra and Rb are not both H; each R6 is independently selected from hydroxy; C1-C6 alkoxy; hydroxy-C1-C6 alkoxy; C1- C6 alkylcarbonyloxy; C1-C6 carbonyloxy; 5- or 6-membered carbocyclylcarbonyl or heterocyclylcarbonyl; amino; secondary or tertiary C1-C6 alkylamino; secondary or tertiary hydroxy-C1-C6 mino; 5- or ered cyclic amino optionally containing at least one further heteroatom in the ring and wherein the ring is optionally substituted with at least one C1-C6 alkyl; C1-C6 alkylcarbonylamino; C1-C6 alkoxycarbonylamino; (C1-C6 alkoxycarbonyl)(C1-C6 alkyl)amino; (C1-C6 alkoxycarbonyl)(5- or 6-membered carbocyclyl or heterocyclyl)amino; (C1-C6 alkylcarbonyl)(C1-C6 alkyl)amino; carbamoyl; secondary or tertiary C1-C6 alkylamido wherein any alkyl is optionally tuted by OH or CONH2; 5- or ered carbocyclyl- or heterocyclylcarbamoyl; 5- or 6-membered cyclic aminocarbonyl, optionally containing at least one further heteroatom in the ring, and wherein the ring is optionally substituted with at least one C1-C6 alkyl; 5-ormembered carbocyclylamino or heterocyclylamino; and 5-ormembered carbocyclyloxy or heterocyclyloxy; wherein any alkyl is optionally substituted with at least one halogen and any 5- or 6-membered carbocyclyl or heterocyclyl is optionally substituted with at least one R8; each R7 and R8 is independently selected from C1-C6 alkyl; hydroxy-C0-C3 alkyl; C1-C6 alkoxy-C0-C3 alkyl; C1-C6 alkoxycarbonyl; carbocyclyl-C0-C4 alkyl; heterocyclyl-C0-C4 alkyl; C1-C6 alkylsulfinyl; amino; nitro; C1-C6 secondary or tertiary amino; halogen; carbamoyl; secondary or tertiary C1-C6 alkylamido-C0-C3 alkyl; C1-C6 alkylcarbonylamino; and 5- or 6-membered cyclic amino, optionally ning at least one further heteroatom in the ring and wherein the ring is optionally substituted with at least one C1-C6 alkyl; wherein any alkyl is ally substituted with at least one halogen; wherein any carbocyclyl and cyclyl is 5- or 6- membered; or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer, mation or an inflammatory disorder, provided that the nd is not methyl 2-hydroxy(4-(4-oxo-1,4-dihydropyrazolo[1,5-a][1,3,5]triazin yl)phenylsulfonamido)benzoate.
41. A use according to claim 40, wherein A is O, S, -CR4=CR4- or -CR4=N-; and when A is -CR4=CR4- or -CR4=N-, one of R2 and R3 is selected from carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 l; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10- membered bicyclyl; and any carbocyclyl or heterocyclyl is ally substituted with at least one R5; or R2 and R3 form, together with the carbon atoms to which they are attached, a 5- or ered carbocyclic or heterocyclic ring, which ring is optionally substituted with at least one R5; or a pharmaceutically acceptable salt thereof.
42. A use according to claim 41, wherein A is O, S, -CR4=CR4- or -CR4=N-; and when A is -CR4=CR4- or -CR4=N-, R2 is selected from yclyl-C0-C3 alkyl; carbocyclyl- C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any carbocyclyl or heterocyclyl is 5- or 6-membered monocyclyl or 9- or 10-membered bicyclyl; and R3 is ed from H; halogen; and C1-C6 alkyl, ally substituted with at least one halogen; or R2 and R3 form, together with the carbon atoms to which they are attached, a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally tuted with at least one R5; or a pharmaceutically acceptable salt thereof.
43. A use according to any one of the claims 40 to 42, wherein A is O, S, -CR4=CR4- or -CR4=N-; and when A is O or S, R2 and R3 are each independently selected from H; halogen; C1-C6 alkyl; C1-C6 alkoxy; carbamoyl; secondary or tertiary C1-C6 alkylamido; carbocyclylcarbonylamino-C0-C2 alkyl; 5- or 6-membered cyclic aminocarbonyl ally containing a further heteroatom in the ring; C1-C6 alkylcarbonylamino; C1-C6 alkylsulfonyl; hydroxy-C0-C6 alkyl, C1-C6 alkylcarbonyl; y; C1-C6 alkoxycarbonyl; cyano; wherein any alkyl is optionally substituted with at least one halogen; or a pharmaceutically acceptable salt thereof.
44. A use according to claim 40, wherein R3 is selected from H; halogen; and C1-C6 alkyl, wherein any alkyl is optionally substituted with at least one halogen; or R2 and R3 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 R5, or a pharmaceutically acceptable salt thereof.
45. A use according to claim 40, wherein R2 is selected from H; halogen; C1-C6 alkyl; carbocyclyl-C0-C3 alkyl; carbocyclyl-C2-C3 alkenyl; heterocyclyl-C0-C3 alkyl; and heterocyclyl-C2-C3 alkenyl; wherein any alkyl is optionally tuted with at least one halogen; any carbocyclyl or heterocyclyl is 5- or 6- ed monocyclyl or 9- or 10-membered bicyclyl; and any carbocyclyl or heterocyclyl is optionally substituted with at least one R5; or R2 and R3 form, together with the carbon atoms to which they are attached, a 5- or 6-membered carbocyclic or heterocyclic ring, which ring is optionally tuted with at least one R5, or a ceutically acceptable salt f.
46. A use according to claim 45, wherein R2 is selected from 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 n; 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 R5; or R2 and R3 form, er with the carbon atoms to which they are attached, a 5- or 6-membered carbocyclic or cyclic ring, which ring is optionally substituted with at least one R5, or a pharmaceutically acceptable salt thereof.
47. A use according to any one of the claims 40 to 46, wherein A is -CR4=CR4- or -CR4=N-, or a pharmaceutically acceptable salt thereof.
48. A use according to claim 47, wherein A is -CR4=CR4-, or a pharmaceutically acceptable salt thereof.
49. A use according any one of the claims 40 to 46, n A is S or O, or a pharmaceutically acceptable salt f.
50. A use according to any one of the claims 40 to 49, wherein n is 0, or a pharmaceutically acceptable salt thereof.
51. A use according to any one of the claims 40 to 50, wherein Ra is H, or a pharmaceutically acceptable salt thereof.
52. A use ing to claim 40, wherein the compound of formula I is selected from methyl -chloro(3-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl -chloro(2,3-dihydrobenzofuranyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl 4-{[(4-bromo-2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(4-bromochlorothienyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2-chlorofluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(3-chloromethylphenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-[(1-benzofuranylsulfonyl)amino]hydroxybenzoate, methyl 2-hydroxy({[2-methyl(trifluoromethyl)furanyl]sulfonyl}amino)benzoate, methyl 4-{[(3-chloromethylphenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-bromothienyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chlorothienyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-bromochloropyridinyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy{[(5-isopropylmethylbenzothienyl)sulfonyl]amino}benzoate, methyl 2-hydroxy({[4-(trifluoromethyl)phenyl]sulfonyl}amino)benzoate, methyl 4-{[(3-chlorofluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(3-chlorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chlorofluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chloro-2,4-difluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(4-bromobenzyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy{[(4-methylnaphthyl)sulfonyl]amino}benzoate, methyl 2-hydroxy[(1-naphthylsulfonyl)amino]benzoate, methyl 4-{[(4-bromo-2,5-difluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-({[3-(difluoromethoxy)phenyl]sulfonyl}amino)hydroxybenzoate, methyl 4-{[(3-chlorofluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(4-fluoronaphthyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2,3-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-[(biphenylylsulfonyl)amino]hydroxybenzoate, methyl 4-[(2,1,3-benzothiadiazolylsulfonyl)amino]hydroxybenzoate, methyl 2-hydroxy{[(4-phenoxyphenyl)sulfonyl]amino}benzoate, methyl 2-hydroxy[(naphthalenylsulfonyl)amino]benzoate, methyl 4-({[5-(dimethylamino)naphthalenyl]sulfonyl}amino)hydroxybenzoate, trifluoroacetate, methyl 2-hydroxy{[(5-{[(phenylcarbonyl)amino]methyl}thiophen yl)sulfonyl]amino}benzoate, methyl 4-{[(4-chlorophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(2-chloromethylphenyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[3-(trifluoromethoxy)phenyl]sulfonyl}amino)benzoate, methyl 4-({[5-chloro(2,5-difluorophenyl)thienyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy({[3-(trifluoromethyl)phenyl]sulfonyl}amino)benzoate, methyl 4-{[(3-bromochlorothiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chloromethylthienyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-bromo-2,4-difluorophenyl)sulfonyl]amino}hydroxybenzoate, methyl -cyanophenyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[3-(methylsulfonyl)phenyl]sulfonyl}amino)benzoate, methyl 4-[(1-benzothienylsulfonyl)amino]hydroxybenzoate, methyl 4-{[(2,5-dichloromethylthienyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, methyl 4-{[(3,5-dibromothiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-chloromethylthiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(3,4-dibromothiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-{[(5-bromomethylthiophenyl)sulfonyl]amino}hydroxybenzoate, 2-methoxyethyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, ethyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, 2-(1H-pyrrolyl)ethyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, 3-(1H-pyrrolyl)propyl ,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, 3-morpholinylpropyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate oroacetate, 3-(1H-imidazolyl)propyl ,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 3-(4-methylpiperazinyl)propyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 2-ethoxyethyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, tetrahydrofuranyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, isopropyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, 2-methoxyethyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, butyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, benzyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, hexyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, phenyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, tetrahydrofuranyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, tetrahydrofuranylmethyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, 2-methoxyethyl 4-({[5-chloro(2,3-dihydrobenzofuranyl)thienyl]sulfonyl}amino)- 2-hydroxybenzoate, methyl 4-[({5-chloro[3-(methoxycarbonyl)phenyl]thiophenyl}sulfonyl)amino] ybenzoate, methyl 4-{[(5-chloro{3-[(1-methylethoxy)carbonyl]phenyl}thiophen yl)sulfonyl]amino}hydroxybenzoate, 3-hydroxypropyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, 3-(dimethylamino)propyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, methyl 4-({[6-chloro(2-fluoromethoxyphenyl)pyridinyl]sulfonyl}amino) hydroxybenzoate, methyl 2-hydroxy{[(2'-hydroxybiphenylyl)sulfonyl]amino}benzoate, methyl -chloro(3-fluorophenyl)pyridinyl]sulfonyl}amino)hydroxybenzoate, methyl -(3-aminophenyl)chloropyridinyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[6-chloro(4-fluoromethylphenyl)pyridinyl]sulfonyl}amino) hydroxybenzoate, methyl 4-{[(3'-chlorobiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl phenylylsulfonyl)amino]hydroxybenzoate, methyl 2-hydroxy{[(3-pyridinylphenyl)sulfonyl]amino}benzoate, trifluoroacetate, methyl 2-hydroxy{[(3-pyridinylphenyl)sulfonyl]amino}benzoate trifluoroacetate, methyl 4-({[3-(1-benzofuranyl)phenyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy{[(3-quinolinylphenyl)sulfonyl]amino}benzoate trifluoroacetate, methyl 4-{[(3'-aminobiphenylyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, methyl 4-{[(3'-acetamidobiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy{[(2'-nitrobiphenylyl)sulfonyl]amino}benzoate, methyl 4-({[3-(5-acetylthienyl)phenyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy({[2'-(hydroxymethyl)biphenylyl]sulfonyl}amino)benzoate, methyl 4-{[(3'-cyanobiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[4'-(methylsulfanyl)biphenylyl]sulfonyl}amino)benzoate, methyl 2-hydroxy({[4'-(trifluoromethoxy)biphenylyl]sulfonyl}amino)benzoate, methyl 2-hydroxy({[4'-(trifluoromethyl)biphenylyl]sulfonyl}amino)benzoate, methyl 4-({[4'-(dimethylcarbamoyl)biphenylyl]sulfonyl}amino)hydroxybenzoate, methyl 4-{[(4'-carbamoylbiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 4-({[5-chloro(4-methoxy-3,5-dimethylphenyl)thiophenyl]sulfonyl}amino) ybenzoate, methyl 4-({[4-(3-acetylphenyl)chlorothienyl]sulfonyl}amino)hydroxybenzoate, methyl 4-[({5-chloro[2-(hydroxymethyl)phenyl]thiophenyl}sulfonyl)amino] ybenzoate, methyl 4-({[5-chloro(6-methoxypyridinyl)thienyl]sulfonyl}amino) ybenzoate, methyl 4-({[4-(3-aminophenyl)chlorothiophenyl]sulfonyl}amino)hydroxybenzoate trifluoroacetate, methyl 4-{[(5-chloro{4-[(methylsulfonyl)amino]phenyl}thiophenyl)sulfonyl]amino} hydroxybenzoate, methyl 4-({[4-(4-carbamoylphenyl)chlorothiophenyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[5-chloro(3-fluoromethoxyphenyl)thiophenyl]sulfonyl}amino) hydroxybenzoate, methyl 4-{[(5-chloropyridinylthiophenyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[3'-(methylsulfonyl)biphenylyl]sulfonyl}amino)benzoate, methyl 4-{[(3'-carbamoylbiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[5-(trifluoromethyl)biphenylyl]sulfonyl}amino)benzoate, methyl 4-({[2',5'-difluoro(trifluoromethyl)biphenylyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[3-(2,3-dihydrobenzofuranyl)(trifluoromethyl)phenyl]sulfonyl}amino) hydroxybenzoate, methyl 2-hydroxy({[2'-hydroxy(trifluoromethyl)biphenyl yl]sulfonyl}amino)benzoate, methyl 4-({[5-(2,5-difluorophenyl)thiophenyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[5-(2,3-dihydrobenzofuranyl)thiophenyl]sulfonyl}amino) hydroxybenzoate, methyl 2-hydroxy({[3-(1-hydroxyethyl)phenyl]sulfonyl}amino)benzoate, methyl 2-hydroxy{[(3-methoxyphenyl)sulfonyl]amino}benzoate, methyl 4-({[3-(2,3-dihydrobenzofuranyl)benzyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[(2',5'-difluorobiphenylyl)methyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[4-(2,3-dihydrobenzofuranyl)benzyl]sulfonyl}amino)hydroxybenzoate, methyl 4-{[(biphenylylmethyl)sulfonyl]amino}hydroxybenzoate, methyl 2-hydroxy({[(2'-hydroxybiphenylyl)methyl]sulfonyl}amino)benzoate, methyl 4-{[(3'-ethoxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 1-methylethyl 3'-{[3-hydroxy(methoxycarbonyl)phenyl]sulfamoyl}biphenylcarboxylate, methyl 4-{[(3-acetylphenyl)sulfonyl]amino}hydroxybenzoate, methyl 4-({[5-(2-fluoromethoxyphenyl)pyridinyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy({[3-methyl(1-methylethyl)benzofuran yl]sulfonyl}amino)benzoate, methyl 2-(acetyloxy){[(4,5-dichlorothiophenyl)sulfonyl]amino}benzoate, oxyethyl 4-({[5-chloro(2-hydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl '-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 3-(2-chloro{[3-hydroxy(methoxycarbonyl)phenyl]sulfamoyl}thiophenyl)benzoic acid, methyl 4-({[3-(ethoxycarbonyl)phenyl]sulfonyl}amino)hydroxybenzoate, methyl 2-hydroxy[({3-[(1-methylethoxy)carbonyl]phenyl}sulfonyl)amino]benzoate, benzyl 2-acetoxy[(1-naphthylsulfonyl)amino]benzoate, 2-acetoxy[(1-naphthylsulfonyl)amino]benzoic acid, methyl 2-hydroxy({[3-(piperidinyl)phenyl]sulfonyl}amino)benzoate, methyl 4-[({5-chloro[3-(dimethylcarbamoyl)phenyl]thiophenyl}sulfonyl)amino] hydroxybenzoate, (5-methyloxo-1,3-dioxolyl)methyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, ooxoethyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, 2-[bis(2-hydroxyethyl)amino]ethyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 2-(2-hydroxyethoxy)ethyl 4-{[(2,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, pentyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, propyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino}hydroxybenzoate, 4-(dimethylamino)butyl 2-hydroxy({[3-(2-methyl-1,3-thiazol nyl]sulfonyl}amino)benzoate trifluoroacetate, methyl 4-({[5'-fluoro-2'-hydroxy(trifluoromethyl)biphenylyl]sulfonyl}amino) hydroxybenzoate, methyl 4-{[(2',5'-difluorobiphenylyl)sulfonyl]amino}hydroxybenzoate, methyl 4-({[3-(2,3-dihydrobenzofuranyl)phenyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[6-chloro(2,3-dihydrobenzofuranyl)pyridinyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[5-chloro(2-hydroxyphenyl)thienyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[5-chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl 4-({[4-(1,3-benzodioxolyl)chlorothienyl]sulfonyl}amino) ybenzoate, 3-morpholinylpropyl 2-hydroxy{[(2'-hydroxybiphenylyl)sulfonyl]amino}benzoate trifluoroacetate, 3-morpholinylpropyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 2-methoxyethyl 4-({[4-(1,3-benzodioxolyl)chlorothienyl]sulfonyl}amino) hydroxybenzoate, 3-morpholinylpropyl 4-({[4-(1,3-benzodioxolyl)chlorothienyl]sulfonyl}amino) hydroxybenzoate oroacetate, 3-morpholinylpropyl 4-({[5-chloro(2,3-dihydrobenzofuranyl) thienyl]sulfonyl}amino)hydroxybenzoate trifluoroacetate, 3-morpholinylpropyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, 2-methoxyethyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, 3-[(tert-butoxycarbonyl)amino]propyl 2-hydroxy{[(2,4,5-trichloro thienyl)sulfonyl]amino}benzoate, 1-methylpiperidinyl oxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, 4-morpholinylbutyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate trifluoroacetate, 1-methylpyrrolidinyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate trifluoroacetate, 4-morpholinylbutyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate oroacetate, 3-morpholinylpropyl 4-{[(2',5'-difluorobiphenylyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, 2-methoxyethyl 4-{[(2',5'-difluorobiphenylyl)sulfonyl]amino}hydroxybenzoate, 4-morpholinylbutyl 4-{[(2',5'-difluorobiphenylyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, 3-morpholinylpropyl 4-({[3-(2,3-dihydrobenzofuranyl)phenyl]sulfonyl}amino) hydroxybenzoate trifluoroacetate, 2-methoxyethyl 4-({[3-(2,3-dihydrobenzofuranyl)phenyl]sulfonyl}amino) hydroxybenzoate, 4-morpholinylbutyl 4-({[3-(2,3-dihydrobenzofuranyl)phenyl]sulfonyl}amino) ybenzoate trifluoroacetate, methyl 4-{[(3-bromomethoxyphenyl)sulfonyl]amino}hydroxybenzoate, 2-methoxymethylethyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, tetrahydrofuranyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, 1-(methoxymethyl)propyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, 2-ethoxy(ethoxymethyl)ethyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, 2-methoxybutyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 2-hydroxyethyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 3-hydroxypropyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate, 2-methoxyethyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 2-methoxyethyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, holinylpropyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, tetrahydrofuranyl ,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, 1-(methoxymethyl)propyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, 2-methoxybutyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, 2-methoxy(methoxymethyl)ethyl ,5-dichlorophenyl)sulfonyl]amino} hydroxybenzoate, oxymethylethyl 4-{[(3,5-dichlorophenyl)sulfonyl]amino}hydroxybenzoate, 1-methylmorpholinylpropyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate,) trifluoroacetate, 2-methoxymethylethyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, 1-(methoxymethyl)propyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, 2-methoxybutyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, 2-methoxyethyl 4-{[(4-bromo-2,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, tetrahydrofuranyl 4-{[(4-bromo-2,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate, 3-morpholinylpropyl 4-{[(4-bromo-2,5-dichlorothiophenyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, methyl 4-{[(5-bromochlorothienyl)sulfonyl]amino}hydroxybenzoate, (1-methylnitro-1H-imidazolyl)methyl 4-({[5-chloro(2,3-dihydrobenzofuranyl)- 2-thienyl]sulfonyl}amino)hydroxybenzoate, hylnitro-1H-imidazolyl)methyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}- 2-hydroxybenzoate, 2-phenoxyethyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino}hydroxybenzoate, 1-benzylpyrrolidinyl 2-hydroxy{[(2,4,5-trichlorothienyl)sulfonyl]amino}benzoate, tert-butyl 3-[(2-hydroxy{[(2,4,5-trichloro thienyl)sulfonyl]amino}benzoyl)oxy]pyrrolidinecarboxylate, methyl -chloro(2-hydroxyphenyl)thiophenyl]sulfonyl}amino)hydroxybenzoate, methyl 4-({[4-chloro(2-methoxyphenyl)thiophenyl]sulfonyl}amino) hydroxybenzoate, 2-methoxyethyl 4-({[5-chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, tetrahydrofuranyl -chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino)- 2-hydroxybenzoate, 2-methoxybutyl 4-({[5-chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, ethyl -chloro(5-fluorohydroxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 3-(2,6-dimethylmorpholinyl)propyl 4-{[(5'-fluoro-2'-hydroxybiphenyl yl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, 3-morpholinylpropyl 4-({[5-chloro(5-fluorohydroxyphenyl) thienyl]sulfonyl}amino)hydroxybenzoate trifluoroacetate, 3-(2,6-dimethylmorpholinyl)propyl 4-({[5-chloro(5-fluorohydroxyphenyl) thienyl]sulfonyl}amino)hydroxybenzoate trifluoroacetate, 1-(methoxymethyl)propyl 4-{[(5-chlorophenylthienyl)sulfonyl]amino} hydroxybenzoate, 2-methoxymethylethyl 4-{[(5-chlorophenylthienyl)sulfonyl]amino} hydroxybenzoate, 2-hydroxyethyl 4-{[(5-chlorophenylthienyl)sulfonyl]amino}hydroxybenzoate, 1-(methoxymethyl)propyl 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino) ybenzoate, oxyethyl 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 2-methoxyethyl 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 3-morpholinylpropyl -chloro(3-fluorophenyl)thienyl]sulfonyl}amino) hydroxybenzoate trifluoroacetate, 2-methoxy(methoxymethyl)ethyl 4-({[5-chloro(3-fluorophenyl) thienyl]sulfonyl}amino)hydroxybenzoate, 2-phenoxyethyl 4-({[5-chloro(3-fluorophenyl)thienyl]sulfonyl}amino) hydroxybenzoate, methyl -chloro(5-fluoromethoxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 2-phenoxyethyl 4-{[(4,5-dichlorothiophenyl)sulfonyl]amino}hydroxybenzoate, 2-[(6-chloropyridinyl)oxy]ethyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 2-[3-(methoxymethyl)phenoxy]ethyl 4-{[(4,5-dichlorothienyl)sulfonyl]amino} hydroxybenzoate, 2-(3-carbamoylphenoxy)ethyl 4-({[5-chloro(2-fluoromethoxyphenyl) thienyl]sulfonyl}amino)hydroxybenzoate, 3-hydroxypropyl 4-({[5-chloro(2-fluoromethoxyphenyl)thienyl]sulfonyl}amino) hydroxybenzoate, 3-(pyridinylamino)propyl 4-{[(5'-fluoro-2'-hydroxybiphenylyl)sulfonyl]amino} hydroxybenzoate trifluoroacetate, 3-[(1-methyl-1H-pyrazolyl)amino]propyl 4-{[(5'-fluoro-2'-hydroxybiphenyl yl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, 3-[(5-methylisoxazolyl)amino]propyl 4-{[(5'-fluoro-2'-hydroxybiphenyl yl)sulfonyl]amino}hydroxybenzoate trifluoroacetate, or a pharmaceutically acceptable salt thereof.
53. A compound according to claim 1 substantially as herein bed or ified.
54. A use according to claim 14 ntially as herein described or exemplified.
55. A pharmaceutical composition according to claim 27 substantially as herein described or exemplified.
56. A use ing to claim 40 substantially as herein described or exemplified.
NZ626950A 2011-12-22 2012-12-21 Bisarylsulfonamides useful in the treatment of inflammation and cancer NZ626950B2 (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US201161579360P 2011-12-22 2011-12-22
US61/579,360 2011-12-22
EP11195456 2011-12-22
EP11195456.6 2011-12-22
EP11195962.3 2011-12-28
EP11195962 2011-12-28
PCT/EP2012/076836 WO2013093095A1 (en) 2011-12-22 2012-12-21 Bisarylsulfonamides useful in the treatment of inflammation and cancer

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NZ626950B2 true NZ626950B2 (en) 2016-11-29

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