(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/034971 Al 10 March 2016 (10.03.2016) P O P C T

(51) International Patent Classification: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, C07C 311/21 (2006.01) A61P 19/06 (2006.01) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, A61K 31/18 (2006.01) A61K 31/44 (2006.01) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, C07D 213/76 (2006.01) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (21) International Application Number: SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, PCT/IB2015/056321 TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (22) International Filing Date: (84) Designated States (unless otherwise indicated, for every 20 August 2015 (20.08.2015) kind of regional protection available): ARIPO (BW, GH, (25) Filing Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (26) Publication Language: English TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (30) Priority Data: DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 62/045,771 4 September 2014 (04.09.2014) US LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 62/155,507 1 May 2015 (01.05.2015) US SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (71) Applicant: PFIZER LIMITED [GB/GB]; 748 Ramsgate Road, Sandwich Kent CT13 9NJ (GB). Declarations under Rule 4.17 : — as to the identity of the inventor (Rule 4.1 7(Ϊ)) (72) Inventors: OWEN, Robert McKenzie; c/o Neusentis, Portway Building, Granta Park, Great Abington Cambridge — as to applicant's entitlement to apply for and be granted a CB21 6GS (GB). STORER, Robert Ian; c/o Neusentis, patent (Rule 4.1 7(H)) Portway Building, Granta Park, Great Abington Cambridge — as to the applicant's entitlement to claim the priority of the CB21 6GS (GB). earlier application (Rule 4.1 7(in)) (74) Agents: LANE, Graham, M. et al; Pfizer Limited, 748 Published: Ramsgate Road, Sandwich Kent CT13 9NJ (GB). — with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, — with sequence listing part of description (Rule 5.2(a)) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,

(54) Title: SULFONAMIDES DERIVATIVES AS URATl INHIBITORS

(I)

© v (57) Abstract: The invention relates to sulfonamide derivatives, to their use in medicine, to compositions containing them, to pro - o cesses for their preparation and to intermediates used in such processes. More particularly the invention relates to a sulfonamide UR - ATI inhibitor of formula (I), or a pharmaceutically acceptable salt thereof for use as a medicament, wherein R 1, X 1 and m as defined o in the description, and to certain new sulfonamide URATl inhibitors. URATl inhibitors are potentially useful in the treatment of a wide range of disorders, particularly . SULFONAMIDES DERIVATIVES AS URAT1 INHIBITORS

The invention relates to sulfonamide derivatives, to their use in medicine, to compositions containing them , to processes for their preparation and to intermediates used in such processes.

Uric acid is the final product of purine metabolism in humans. In humans, unlike many other animals, uric acid is not further broken down, but is predominantly (70%) excreted into the urine with the remaining 30% excreted in faeces. Hyperuricemia is defined as an excessive production or decreased excretion of uric acid and can occur as an overproduction or under excretion of serum uric acid (sUA) , or a combination of the both. Renal under excretion of uric acid is the primary cause of hyperuricemia in about 90% of cases, while overproduction is the cause in less than 10%. Increased sUA concentration above 6.8mg/dl_ results in crystallisation of uric acid in the form of salts, such as monosodium urate, and to precipitation of these crystals in joints, on tendons and in the surrounding tissues. These crystals (known as tophi) trigger a local immune- mediated inflammatory reaction, leading to gout. The risk of gout increases with increased sUA levels.

Gout is a painful condition that can present in a number of ways, although the most usual is a recurrent attack of acute inflammatory arthritis (a red, tender, hot, swollen joint) often occurring in big toes, heels, knees, wrists and fingers.

Gout is treated by agents to both decrease the cause and effects of uric acid crystal inflammation and pain.

The pain associated with gout is commonly treated with pain and anti-inflammatory drugs such as nonsteroidal anti-inflammatory drugs (NSAI Ds), and steroids. Agents that decrease sUA levels may be used to treat the cause of gout. These include agents that: inhibit the enzymes that result in uric acid production, such as xanthine oxidase inhibitors (e.g. , or ), or purine nucleoside phosphorylase (PN P) inhibitors (e.g. ulodesine) ; metabolise uric acid, such as urate oxidases - also known as uricases (e.g. ) ; or increase the excretion of uric acid in the urine (), Uricosurics include agents that inhibit the transporters responsible for renal reabsorption of uric acid back into the blood, such as benziodarone, isobromindione, and sulphinpyrazone, and URAT1 inhibitors (e.g. ) .

URAT1 is also known as solute carrier family 22 (organic anion/cation transporter), member 12 , and is encoded by the gene SLC22A1 2 . Human genetic analysis has demonstrated that polymorphisms in the SLC22A1 2 gene are directly associated with changes in serum uric acid. Inhibitors of uric acid transport, such as URAT1, are therefore effective in the treatment of gout.

There is a continuing need to provide new treatments for gout that are more effective and/or are better tolerated.

Certain URAT1 inhibitors for the treatment of gout are known. WO201 1/1 59840 discloses phenylthioacetate URAT1 inhibitors. Additionally, WO2008/1 18758, WO2009/01 2242, WO201 0/079443, WO201 2/004706, WO201 2/00471 4 and WO201 2/004743 disclose sulphonamides. WO201 3/057722 discloses the use of a certain sulphonamide derivative for the treatment of gout.

There is, however, an ongoing need to provide new URAT1 inhibitors that are good drug candidates.

Furthermore, preferred compounds should have one or more of the following properties: be well absorbed from the gastrointestinal tract; be metabolically stable; have a good metabolic profile, in particular with respect to the toxicity or allergenicity of any metabolites formed; or possess favourable pharmacokinetic properties whilst still retaining their activity profile as URAT1 inhibitors. They should be non-toxic and demonstrate few side-effects. Ideal drug candidates should exist in a physical form that is stable, non-hygroscopic and easily formulated.

We have now found new sulphonamide URAT1 inhibitors. According to a first aspect of the invention there is provided a compound of formula (la)

or a pharmaceutically acceptable salt thereof, wherein each -CF 3 may be attached at any available carbon atom of the respective phenyl or pyridinyl ring.

Described below are a number of embodiments (E1) of this first aspect of the invention, where for convenience E 1. 1 is identical thereto.

E 1.1 A compound of formula (la) as defined above or a pharmaceutically acceptable salt thereof.

E 1.2 A compound according to E1.1 of formula (lb)

or a pharmaceutically acceptable salt thereof wherein the pyridinyl -CF 3 substituent is attached at either the 5- or 6- position pyridinyl carbon.

E 1.3 The compound according to either E1.1 or E 1.2 that is 2-(trifluoromethyl)-N-(6- (trifluoromethyl)pyridin-3-yl)benzenesulfonamide or a pharmaceutically acceptable salt thereof.

E 1.4 The compound according to either E1.1 or E 1.2 that is 2-(trifluoromethyl)-N-(5- (trifluoromethyl)pyridin-3-yl)benzenesulfonamide or a pharmaceutically acceptable salt thereof. According to a second aspect of the invention there is provided a compound of formula (I)

or a pharmaceutically acceptable salt thereof for use as a medicament, wherein:

1 each R is independently: halogen; OH; CN; (Ci-C 4)alkyl optionally substituted by one, two or three F ; or (Ci-C 4)alkyloxy optionally substituted by one, two or three F ;

X1 is phenyl or pyridinyl, wherein said phenyl or pyridinyl is substituted on a ring carbon atom by one, two or three R2;

2 each R is independently: halogen; OH; CN; (Ci-C 4)alkyl optionally substituted by one, two or three F ; (Ci-C 4)alkyl substituted by OH; (Ci-C 4)alkyloxy optionally substituted by 3 4 5 one, two or three F ; -0(CH 2)n(C3-C4)cycloalkyl; -CONR R ; or -S0 2R ;

3 4 each R and R is independently H or (Ci-C 4)alkyl or, together with the nitrogen atom to which they are attached, form a saturated 4- to 6-membered nitrogen containing monocycle;

5 each R is independently (Ci-C 4)alkyl optionally substituted by one, two or three F ; m is 1 , 2 or 3 ; and n is 1 or 2 .

Described below are a number of embodiments (E2) of this second aspect of the invention, where for convenience E2.1 is identical thereto.

E2.1 A compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof. A compound according to E2.1 of formula (lc)

or a pharmaceutically acceptable salt thereof for use as a medicament, wherein:

is

each R is independently: halogen; (Ci-C4)alkyl optionally substituted by one, two or three F ; (C C4)alkyloxy optionally substituted by one, two or three F ;

-OCH2(C3-C4)cycloalkyl or-0(CH 2)2(C3-C4)cycloalkyl.

A compound according to either E2.1 or E2.2 of formula (lc)

or a pharmaceutically acceptable salt thereof for use as a medicament, wherein:

X is

each R is independently: halogen; (Ci-C4)alkyl optionally substituted by one,

two or three F ; or (Ci-C4)alkyloxy optionally substituted by one, two or three F. E2.4 A compound according to E2.1 or a pharmaceutically acceptable salt thereof for use as a medicament wherein X1 is phenyl substituted on a ring carbon atom by one, two or three R2.

E2.5 A compound according to E2.4 or a pharmaceutically acceptable salt thereof for use as a medicament wherein X1 is phenyl substituted on a ring carbon atom by two or three R2.

E2.6 A compound according to either E2.1 or E2.4 of formula (Ic)

or a pharmaceutically acceptable salt thereof for use as a medicament, wherein X1 is phenyl substituted on a ring carbon atom by one, two or three R2.

E2.7 A compound according to E2.6 or a pharmaceutically acceptable salt thereof for use as a medicament, wherein X1 is phenyl substituted on a ring carbon atom two or three R2.

E2.8 A compound according to any one of E2.4, E2.5, E2.6 or E2.7 or a pharmaceutically acceptable salt thereof for use as a medicament, wherein:

2 each R is independently: halogen; CN; (Ci-C 4)alkyl optionally substituted by

one, two or three F ; (Ci-C 4)alkyloxy optionally substituted by one, two or three 3 4 5 F ; -CONR R ; or -S0 2R ;

3 4 each R and R is independently H or (Ci-C 4)alkyl; and

5 each R is independently (Ci-C 4)alkyl optionally substituted by one, two or three F. E2.9 A compound according to E2.8 or a pharmaceutically acceptable salt thereof for

2 use as a medicament, wherein each R is independently: F ; CI; CN; (Ci-C 4)alkyl optionally substituted by one, two or three F ; (Ci-C 4)alkyloxy optionally

substituted by one, two or three F ; -CONH 2;-CONHCH 3; or -CON(CH 3)2

E2.10 A compound according to any one of E2.1 to E2.9 or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder for which a URAT1 inhibitor is indicated.

AlkyI and alkoxy groups, containing the requisite number of carbon atoms, can be unbranched or branched. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy.

Examples of cycloalkyl include cyclopropyl and cyclobutyl.

Halo means fluoro, chloro, bromo or iodo.

Hereinafter, all references to compounds of the invention include compounds of formula (I) or pharmaceutically acceptable salts, solvates, or multi-component complexes thereof, or pharmaceutically acceptable solvates or multi-component complexes of pharmaceutically acceptable salts of compounds of formula (I), as discussed in more detail below.

Preferred compounds of the invention are compounds of formula (I) or pharmaceutically acceptable salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

The skilled person will appreciate that the aforementioned salts include ones wherein the counterion is optically active, for example d-lactate or l-lysine, or racemic, for example dl-tartrate or dl-arginine.

For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH , Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods: (i) by reacting the compound of formula (I) with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) using the desired acid or base; or (iii) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.

The compounds of formula (I) or pharmaceutically acceptable salts thereof may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D20 , de- acetone and d6-DMSO.

A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in

Pharmaceutical Solids by K . R . Morris (Ed. H. G . Brittain, Marcel Dekker, 1995), incorporated herein by reference. Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.

The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').

Also included within the scope of the invention are multi-component complexes (other than salts and solvates) of compounds of formula (I) or pharmaceutically acceptable salts thereof wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, 17 , 1889-1896, by O. Almarsson and M . J. Zaworotko (2004), incorporated herein by reference. For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975), incorporated herein by reference.

The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules + + _ + which possess an ionic (such as -COO Na , -COO K , or -S0 3 Na ) or non-ionic (such + as -N N (CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N . H . Hartshorne and A . Stuart, 4th Edition (Edward Arnold, 1970), incorporated herein by reference.

The compounds of the invention may be administered as prodrugs. Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).

Prodrugs can, for example, be produced by replacing appropriate functionalities present in a compound of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).

Examples of prodrugs include phosphate prodrugs, such as dihydrogen or dialkyl (e.g. di-tert- butyl) phosphate prodrugs. Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

Also included within the scope of the invention are metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include, where the compound of formula (I) contains a phenyl (Ph) moiety, a phenol derivative thereof (-Ph > -PhOH) ;

Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Included within the scope of the invention are all stereoisomers of the compounds of the invention and mixtures of one or more thereof.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1- phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0 .1% diethylamine. Concentration of the eluate affords the enriched mixture.

Mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art; see, for example, "Stereochem istry of Organic Com pounds" by

E . L . Eliel and S . H. Wilen (Wiley, New York, 1994.

The scope of the invention includes all crystal forms of the compounds of the invention, including racemates and racemic mixtures (conglomerates) thereof. Stereoisomeric conglomerates may also be separated by the conventional techniques described herein just above.

The scope of the invention includes all pharmaceutically acceptable isotopically-labelled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18 F, iodine, such as 123l and 125 l, nitrogen, such as 13N and 15 N, oxygen, such as 150 , 170 and 18 0 , phosphorus, such as 32P, and sulphur, such as 35S .

Certain isotopically-labelled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-1 4 , i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as

I I i 8 I 5Q anc | 13|^| can e use fu | jn pos on Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

Also within the scope of the invention are intermediate compounds as hereinafter defined, all salts, solvates and complexes thereof and all solvates and complexes of salts thereof as defined hereinbefore for compounds of formula (I). The invention includes all polymorphs of the aforementioned species and crystal habits thereof.

When preparing a compound of formula (I) in accordance with the invention, a person skilled in the art may routinely select the form of intermediate which provides the best combination of features for this purpose. Such features include the melting point, solubility, processability and yield of the intermediate form and the resulting ease with which the product may be purified on isolation.

The compounds of the invention may be prepared by any method known in the art for the preparation of compounds of analogous structure. In particular, the compounds of the invention can be prepared by the procedures described by reference to the Schemes that follow, or by the specific methods described in the Examples, or by similar processes to either.

The skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions employed for the preparation of compounds of formula (I). It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.

In addition, the skilled person will appreciate that it may be necessary or desirable at any stage in the synthesis of compounds of the invention to protect one or more sensitive groups, so as to prevent undesirable side reactions. In particular, it may be necessary or desirable to protect amino or carboxylic acid groups. The protecting groups used in the preparation of the compounds of the invention may be used in conventional manner. See, for example, those described in 'Greene's Protective Groups in Organic Synthesis' by Theodora W Greene and Peter G M Wuts, fourth edition, (John Wiley and Sons, 2006), in particular chapter 7 ("Protection for the Amino Group"), incorporated herein by reference, which also describes methods for the removal of such groups.

In the following general processes R1, X1 and m are as previously defined for a compound of formula (I) unless otherwise stated.

According to a first process, compounds of formula (I) may be prepared from compounds of formula (II) and (III) as illustrated by Scheme 1.

(ill) (ID

Scheme 1

Compounds of formula (I) may be prepared by coupling compounds of formula (II) and (III) according to process step (i). The sulphonamide formation reaction may be carried out under basic reaction conditions either with or without DMAP. Preferred conditions comprise DMAP in anhydrous pyridine at from 30-60 °C; NMM or triethylamine in a combination of organic solvents such as DCM, THF, DME and DCE; stirring in a single solvent such as anhydrous pyridine or acetonitrile; or lithium hexamethyldisilazide in THF at from 4 °C to room temperature.

According to a second process, compounds of formula (I) wherein R1 is para-F may be interconverted into the corresponding compounds of formula (I) wherein R1 is 6 (Ci-C 4)alkyloxy or OH as illustrated by Scheme 2, wherein R is (Ci-C 4)alkyl, H or a hydroxyl protecting group, such as 2-(methylsulfonyl)ethyl. (I) (IV) (I) Scheme 2

The interconversion may be effected according to process step (ii), an aromatic nucleophilic substitution reaction followed by, if necessary, process step (iii), a deprotection reaction.

Preferred process step (ii) conditions comprise potassium phosphate in DMSO at 80 °C. When the sulphonamide -NH- is protected, preferred process step (ii) conditions comprise sodium hydride in NMP at room temperature, followed by deprotection according to process step (iii) by stirring in HCI in dioxane.

When R6 is a hydroxyl protecting group, such as 2-(methylsulfonyl)ethyl, this may be removed under the acid deprotection conditions of process step (iii) to afford R1 as OH.

The skilled person will appreciate that it may be desirable to protect the sulphonamide -NH-, e.g. with dimethoxybenzyl or tertbutoxycarbonyl; removal of this protecting group may also be effected under the conditions described in Scheme 2 , process step (iii).

According to a third process, compounds of formula (I) wherein R2 is nitrile may be interconverted to the corresponding compounds of formula (I) wherein R2 is primary carboxamide by an oxidative hydrolysis reaction. Preferred conditions comprise potassium carbonate and hydrogen peroxide in DMSO at room temperature.

Compounds of formulae (II), (III) and (IV) are commercially available, known from the literature, easily prepared by methods well known to those skilled in the art, or can be made according to preparations described herein.

All new processes for preparing compounds of formula (I), and corresponding new intermediates employed in such processes, form further aspects of the present invention. Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products or may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

In another aspect the invention provides a pharmaceutical composition comprising a compound of the invention together with one or more pharmaceutically acceptable excipients.

Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).

Suitable modes of administration include oral, parenteral, topical, inhaled/intranasal, rectal/intravaginal, and ocular/aural administration.

Formulations suitable for the aforementioned modes of administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled) , chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays, liquid formulations and buccal/mucoadhesive patches. .

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol , propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, V _ (6),

981 -986, by Liang and Chen (2001 ) .

For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form . In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight % , preferably from 5 weight % to 20 weight % of the dosage form.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesi um stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight % , preferably from 0.5 weight % to 3 weight % of the tablet. Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt- granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in "Pharmaceutical Dosage

Forms: Tablets", Vol. 1, by H. Lieberman and L . Lachman (Marcel Dekker, New York, 1980).

Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6 ,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in "Pharmaceutical

Technology On-line", 25(2), 1- 14 , by Verma et al (2001 ) . The use of chewing gum to achieve controlled release is described in WO 00/35298. The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethra I, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug- coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres.

The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol . Penetration enhancers may be incorporated - see, for example, J

Pharm Sci , 88 ( 10), 955-958, by Finnin and Morgan (October 1999).

Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™ , Bioject™ , etc.) injection.

The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3- heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1µ Ι to 0ΟµΙ . A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol , or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to adm inister a metered dose or "puff" containing from to 100mg of the compound of formula (I) . The overall daily dose will typically be in the range 1µ to 200mg which may be administered in a single dose or, more usually, as divided doses throughout the day.

The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, microbicide, vaginal ring or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH- adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non- biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum , may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.

Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/1 1172, WO 94/0251 8 and WO 98/551 48.

For administration to human patients, the total daily dose of the compounds of the invention is typically in the range 1mg to 10g, such as 10mg to 1g , for example 25mg to 500mg depending, of course, on the mode of administration and efficacy. For example, oral administration may require a total daily dose of from 50mg to 100mg. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.

As noted above, the compounds of the invention are useful because they exhibit pharmacological activity in animals, i.e. , URAT1 inhibition. More particularly, the compounds of the invention are of use in the treatment of disorders for which a URAT1 inhibitor is indicated. Preferably the animal is a mammal , more preferably a human.

In a further aspect of the invention there is provided a compound of the invention for use as a medicament. In a further aspect of the invention there is provided a compound of the invention for the treatment of a disorder for which a URAT1 inhibitor is indicated.

In a further aspect of the invention there is provided use of a compound of the invention for the preparation of a medicament for the treatment of a disorder for which a URAT1 inhibitor is indicated.

In a further aspect of the invention there is provided a method of treating a disorder in an animal (preferably a mammal, more preferably a human) for which a URAT1 inhibitor is indicated, comprising administering to said animal a therapeutically effective amount of a compound of the invention.

Disorders for which a URAT1 inhibitor is indicated include diseases associated with high levels of uric acid in humans and other mammals including (but not limited to) hyperuricemia, asymptomatic hyperuricemia, gout (including juvenile forms), gouty arthritis, inflammatory arthritis, joint inflammation, deposition of urate crystals in the joint, tophaceous gout, chronic kidney disease, nephrolithiasis (kidney stones), Lesch- Nyhan syndrome and Kelley-Seegmiller syndrome.

Hyperuricemia may be defined by blood uric acid levels over 6.8 mg/dL. Guidelines for the management of hyperuricemia recommend that therapies aimed at lowering blood uric acid levels should be maintained until such blood uric acid levels are lowered to below 6.0 mg/dL, such as below 5.0 mg/dL.

The skilled person will appreciate that while by definition without symptoms, asymptomatic hyperuricemia may nevertheless lead to the onset of diseases associated with high levels of uric acid.

The skilled person will also appreciate that the compounds of formula (I) may be used in the treatment of hyperuricemia where this is present together with one or more other diseases, such as kidney failure, type 2 diabetes, cardiovascular disease (e.g. hypertension, myocardial infarction, heart failure, coronary artery disease, cerebrovascular disease, atherosclerosis, angina, aneurism, hyperlipidemia and stroke) , obesity, metabolic syndrome, myeloproliferative disorders, lymphoproliferative disorders and disorders associated with certain medications, such as a diuretic (e.g. a thiazide), an immunosuppressant (e.g. a cyclosporine therapy) , a chemotherapeutic agent (e. g . cisplatin) or .

The skilled person will also appreciate that the compounds of formula (I) may be used in the treatment of hyperuricemia where this is present following organ transplant.

A URAT1 inhibitor may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of a disease associated with elevated blood uric acid levels. Such combinations offer the possibility of significant advantages, including patient compliance, ease of dosing and synergistic activity.

In the combinations that follow the compound of the invention may be administered simultaneously, sequentially or separately in combination with the other therapeutic agent or agents.

The compounds of formula (I) may be administered in combination with one or more additional therapeutic agents. Agents of interest include those that also lower blood uric acid levels. Other agents of interest include those that reduce inflammation or pain. The one or more additional therapeutic agents may be selected from any of the agents or types of agent that follow: • a xanthine oxidase inhibitor (e.g. allopurinol, febuxostat or tisopurine);

· a purine nucleoside phosphorylase (PN P) inhibitor (e.g. ulodesine) ; • a uricase (e.g. pegloticase or ) ; • a , such as an agent that inhibits one or more transporters responsible for reabsorption of uric acid back into the blood at renal or intestinal sites, for example another URAT1 inhibitor (e.g. benzbromarone, PN21 07 or RDEA31 70) ; a glucose transporter (GLUT) inhibitor, such as a GLUT9 inhibitor; an organic anion transporter (OAT) inhibitor, such as an OAT4 inhibitor or an OAT10 inhibitor; or an agent which inhibits one or more of the above transporters, such as benziodarone; isobromindione, probenecid, sulphinpyrazone, arhalofenate,

tranilast, or KUX-1 15 1; an agent that otherwise exerts blood uric acid lowering effects, such as , , or indomethacin; an anti-inflammatory drug such as an NSAI D (e.g. celecoxib), colchicine, a steroid, an interleukin 1 inhibitor (e.g. rilonacept) or an agent that modulates inflammosome signaling cascades (e.g. an IRAK4 inhibitor); or an agent that reduces pain, such as an ion channel modulator (e.g. an inhibitor of Nav1 .7, TRPV1 or TRPM2).

There is also included within the scope the present invention combinations of a compound of the invention together with one or more additional therapeutic agents which slow down the rate of metabolism of the compound of the invention, thereby leading to increased exposure in patients. Increasing the exposure in such a manner is known as boosting. This has the benefit of increasing the efficacy of the compound of the invention or reducing the dose required to achieve the same efficacy as an unboosted dose. The metabolism of the compounds of the invention includes oxidative processes carried out by P450 (CYP450) enzymes, particularly CYP 3A4 and conjugation by UDP glucuronosyl transferase and sulphating enzymes. Thus, among the agents that may be used to increase the exposure of a patient to a compound of the present invention are those that can act as inhibitors of at least one isoform of the cytochrome P450 (CYP450) enzymes. The isoforms of CYP450 that may be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C1 9 and CYP3A4. Suitable agents that may be used to inhibit CYP 3A4 include ritonavir, saquinavir, ketoconazole, N-(3,4-difluorobenzyl)-N-methyl-2-{[(4- methoxypyridin-3-yl)amino]sulfonyl}benzamide and N-(1 -(2-(5-(4-fluorobenzyl)-3- (pyridin-4-yl)- 1H-pyrazol- 1-yl)acetyl)piperidin-4-yl)methanesulfonamide.

It is within the scope of the invention that two or more pharmaceutical compositions, at least one of which contains a compound of the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.

In another aspect the invention provides a pharmaceutical product (such as in the form of a kit) comprising a compound of the invention together with one or more additional therapeutically active agents as a combined preparation for simultaneous, separate or sequential use in the treatment of a disorder for which a URAT1 inhibitor is indicated.

It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment.

In the non-limiting Examples and Preparations that are set out later in the description, and in the aforementioned Schemes, the following the abbreviations, definitions and analytical procedures may be referred to:

AcOH is acetic acid; aq is aqueous; br is broad; °C is degrees celcius;

CDCI3 is deutero-chloroform; δ is chemical shift; d is doublet; DCE is dichloroethane; DCM is dichloromethane; methylene chloride; DEA is diethylamine; DMAP is dimethylaminopyridine; DME is dimethoxyethane; DMSO is dimethyl sulphoxide; EtOAc is ethyl acetate; g is gram; HCI is hydrochloric acid; HPLC is high pressure liquid chromatography; L is litre; LCMS is liquid chromatography mass spectrometry (Rt = retention time); m is multiplet; M is molar; MeCN is acetonitrile; MeOH is methanol; mg is milligram; MHz is mega Hertz; min is minutes; ml_ is millilitre; mmol is millimole; mol is mole; MS m/z is mass spectrum peak; NaHCC is sodium hydrogencarbonate; NaOH is sodium hydroxide;

NH3 or NH4OH is ammonia or ammonium hydroxide; NMM N-methylmorpholine; NMR is nuclear magnetic resonance; pH is power of hydrogen; ppm is parts per million; py is pyridine; q is quartet; Rt is retention time; s is singlet; t is triplet; TBM E is tert-butyl dimethyl ether; TEA is triethylamine; TFA is trifluoroacetic acid; THF is tetrahydrofuran; µ Ι_ is microlitre; and µηηοΙ is micromol

1H and F Nuclear magnetic resonance (NM R) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (δ ) are given in parts-per-million downfield from tetramethylsilane (for 1H-NM R) and upfield from trichloro-fluoro-methane (for 19 F NM R) using conventional abbreviations for designation of major peaks: e.g. s , singlet; d , doublet; t , triplet; q , quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDCI 3, deuterochloroform; d6-

DMSO, deuterodimethylsulphoxide; and CD3OD, deuteromethanol.

Mass spectra, MS (m/z), were recorded using either electrospray ionisation (ESI) or atmospheric pressure chemical ionisation (APCI).

Where relevant and unless otherwise stated the m/z data provided are for isotopes 19F,

Library Protocol 1

wherein R and X are as described in formula (I) above.

1 µηιοΙ To a solution of the appropriate amine (X NH2, 100 ) in anhydrous pyridine (300 µ Ι_) was added a 0.33M solution of the appropriate sulfonyl chloride in anhydrous pyridine (300 µ Ι_, 100 µηιοΙ) followed by DMAP ( 10 µηιοΙ) . The reaction mixture was shaken at 30 °C for 16 hours before concentrating in vacuo and purifying by one of the three preparative HPLC methods described below. The organic gradient used for each compound is described in the following table. Preparative HPLC Method A : Phenomenex Gemini C 18 250 x 21.2 mm, 8 µηι ; mobile phase A : MeCN , mobile phase B : 0.225% formic acid in water. Gradient time 10 mins; flow rate 30 mL/min. Preparative HPLC Method B : YMC-Actus Triart C 18 150 x 30 mm, 5 µηι ; mobile phase A : MeCN , mobile phase B : 0.225% formic acid in water. Gradient time 10 mins; flow rate 30 mL/min.

Preparative HPLC Method C : D IKMA Diamonsil (2) C 18 ; mobile phase A : MeCN , mobile phase B : 0.225% formic acid in water. Gradient time 8 mins; flow rate 35 mL/min. The retention times quoted in the table below were obtained using one of the following three LCMS methods: LCMS Method A : XBRI DGE 50 x 2 .1 mm, 5 µηι ; mobile phase A : 0.0375% TFA in water; mobile phase B : 0.01 875% TFA in MeCN ; gradient from 1% B to 5% B at 0.60 mins, further to 100% B at 4.00 mins and finally returning to 1% B at 4.30-4.70 mins; flow rate 0.8 mL/min . LCMS Method B : XBRI DGE 50 x 2 .1 mm, 5 µηι ; mobile phase A : 0.0375% TFA in water; mobile phase B : 0.01 875% TFA in MeCN ; gradient from 10% B to 100% B at 4.00 mins and finally returning to 1% B at 4.30-4.70 mins; flow rate 0.8 mL/min. µηι LCMS Method C : XBRI DGE 50 x 2 .1 mm, 5 ; mobile phase A : 0.05% NH4OH in water; mobile phase B : 100% MeCN ; gradient from 5% B to 100% B at 3.40 mins, hold at 100% B to 4.20 mins and finally returning to 5% B at 4.2 1-4.70 mins; flow rate 0.8 mL/min.

The compounds of Examples 1-66 were prepared according to the method described for Library Protocol 1 using either 2-(trifluoromethyl)benzenesulfonyl chloride, 2-chlorobenzenesulfonyl chloride or 2-cyanobenzenesulfonyl chloride and the appropriate amine. Where stated the title compounds were isolated as formate salts.

Ex Name Data/SM

1 N-(5-methylpyridin-3-yl)-2- MS m/z 3 17 [M+H]+ (trifluoromethyl)benzenesul Rt = 2.444 minutes. LCMS Method A , Prep HPLC fonamide formate salt Method A with 11-51 % organic gradient. 5-methyl-3-aminopyridine. 2 N-(4-cyano-2- MS m/z 341 [M+H]+ methylphenyl)-2- Rt = 3.2 10 minutes. LCMS Method A , Prep HPLC (trifluoromethyl)benzene Method C with 40-70% organic gradient. sulfonamide 4-amino-3-methylbenzonitrile. 3 N-(2-cyano-6- MS m/z 372 [M+H]+ ethoxypyridin-3-yl)-2- Rt = 3.31 2 minutes. LCMS Method A , Prep HPLC (trifluoromethyl) Method B with 5 1-81 % organic gradient. benzenesulfonamide 3-amino-6-ethoxypicolinonitrile. formate salt 4 2-(trifluoromethyl)-N- MS m/z 356 [M+H]+ (2,4,5- Rt = 3 .162 minutes. LCMS Method B, Prep HPLC trifluorophenyl)benzene Method B with 5 1-81 % organic gradient. sulfonamide 2,4,5-trifluoroaniline. Name Data/SM N-(3-cyano-4- MS m/z 345 [M+H]+ fluorophenyl)-2- Rt = 3.196 minutes. LCMS Method A , Prep HPLC (trifluoromethyl)benzene Method B with 48-78% organic gradient. sulfonamide 5-amino-2-fluorobenzonitrile. N-(3-fluoropyridin-4-yl)-2- MS m/z 321 [M+H]+ (trifluoromethyl)benzene Rt = 2.329 minutes. LCMS Method A , Prep HPLC sulfonamide formate salt Method A with 6-46% organic gradient. 3-fluoropyridin-4-amine. N-(2,6-dimethylpyridin-3- MS m/z 331 [M+H]+ yl)-2-(trifluoromethyl) Rt = 2.344 minutes. LCMS Method A , Prep HPLC benzenesulfonamide Method A with 19-49% organic gradient. formate salt 2,6-dimethylpyridine-3-amine. N-(6-ethoxypyridin-3-yl)-2- MS m/z 347 [M+H]+ (trifluoromethyl)benzene Rt = 3.003 minutes. LCMS Method B, Prep HPLC sulfonamide formate salt Method B with 47-77% organic gradient. 6-ethoxypyridin-3-amine. N-(2-methoxypyridin-3-yl)- MS m/z 333 [M+H]+ 2-(trifluoromethyl) Rt = 3.098 minutes. LCMS Method A , Prep HPLC benzenesulfonamide Method A with 40-70% organic gradient. formate salt 2-methoxypyridin-3-amine. N-(5-fluoropyridin-3-yl)-2- MS m/z 321 [M+H]+ (trifluoromethyl)benzenesul Rt = 2.907 minutes. LCMS Method A , Prep HPLC fonamide formate salt Method C with 28-58% organic gradient. 5-fluoropyridin-3-amine. N-(5-cyano-2,4- MS m/z 363 [M+H]+ difluorophenyl)-2- Rt = 3.192 minutes. LCMS Method A , Prep HPLC (trifluoromethyl)benzene Method B with 48-78% organic gradient. sulfonamide 5-amino-2,4-difluorobenzonitrile. N-(2-fluorophenyl)-2- MS m/z 320 [M+H]+ (trifluoromethyl)benzene Rt = 3.205 minutes. LCMS Method A , Prep HPLC sulfonamide Method C with 38-68% organic gradient. 2-fluoroaniline. N-(5,6-dimethylpyridin-3- MS m/z 331 [M+H]+ yl)-2-(trifluoromethyl) Rt = 2.396 minutes. LCMS Method A , Prep HPLC benzenesulfonamide Method B with 24-54% organic gradient. formate salt 5,6-dimethylpyridin-3-amine. N-(3-methylpyridin-4-yl)-2- MS m/z 317 [M+H]+ (trifluoromethyl)benzene Rt = 2.409 minutes. LCMS Method A , Prep HPLC sulfonamide Method A with 21-51% organic gradient. formate salt 3-methylpyridin-4-amine. Name Data/SM N-(5-methoxypyridin-3-yl)- MS m/z 333 [M+H]+ 2-(trifluoromethyl) Rt = 2.645 minutes. LCMS Method A , Prep HPLC benzenesulfonamide Method C with 25-55% organic gradient. formate salt 5-methoxypyridin-3-amine. 4-fluorophenyl)-2- MS m/z 320 [M+H]+ (trifluoromethyl)benzene Rt = 3.054 minutes. LCMS Method B, Prep HPLC sulfonamide Method B with 49-79% organic gradient. 4-fluoroaniline. N-(2-cyano-3- MS m/z 345 [M+H]+ fluorophenyl)-2- Rt = 3.126 minutes. LCMS Method A , Prep HPLC (trifluoromethyl)benzene Method B with 51-81% organic gradient. sulfonamide 2-amino-6-fluorobenzonitrile. N-(6-methylpyridin-3-yl)-2- MS m/z 317 [M+H]+ (trifluoromethyl)benzene Rt = 2.351 minutes. LCMS Method A , Prep HPLC sulfonamide formate salt Method C with 18-48% organic gradient. 6-methylpyridin-3-amine N-[2- MS m/z 373 [M+H]+ (cyclopropylmethoxy)pyridi Rt = 2.851 minutes. LCMS Method B, Prep HPLC n-4-yl]-2- Method C with 38-68% organic gradient. (trifluoromethyl)benzene 2-(cyclopropylmethoxy)-pyridin-4-amine. sulfonamide formate salt N-(2,5-difluorophenyl)-2- MS m/z 338 [M+H]+ (trifluoromethyl)benzene Rt = 3.273 minutes. LCMS Method A , Prep HPLC sulfonamide Method B with 50-80% organic gradient. 2,5-difluoroaniline. N-(6-methoxypyridin-3-yl)- MS m/z 333 [M+H]+ 2-(trifluoromethyl) Rt = 3.013 minutes. LCMS Method A , Prep HPLC benzenesulfonamide Method A with 37-67% organic gradient. formate salt 6-methoxypyridin-3-amine. N-(5-fluoro-2- MS m/z 334 [M+H]+ methylphenyl)-2- Rt = 3.186 minutes. LCMS Method B, Prep HPLC (trifluoromethyl)benzene Method B with 52-82% organic gradient. sulfonamide 5-fluoro-2-methylaniline. 2-(trifluoromethyl)-N- MS m/z 356 [M+H]+ (3,4,5- Rt = 3.274 minutes. LCMS Method B, Prep HPLC trifluorophenyl)benzene Method B with 54-84% organic gradient. sulfonamide 3,4,5-trifluoroaniline. N-(2-cyanophenyl)-2- MS m/z 327 [M+H]+ (trifluoromethyl)benzene Rt = 3.045 minutes. LCMS Method A , Prep HPLC sulfonamide Method B with 42-72% organic gradient. 2-cyanoaniline. Name Data/SM N-(3-cyano-5- MS m/z 357 [M+H]+ methoxyphenyl)-2- Rt = 3.210 minutes. LCMS Method A , Prep HPLC (trifluoromethyl)benzene Method B with 48-78% organic gradient. sulfonamide 3-cyano-5-methoxyaniline. N-(4-methoxypyridin-3-yl)- MS m/z 333 [M+H]+ 2-(trifluoromethyl) Rt = 2.266 minutes. LCMS Method A , Prep HPLC benzenesulfonamide Method A with 17-47% organic gradient. formate salt 4-methoxypyridin-3-amine. N-(5-cyano-2- MS m/z 341 [M+H]+ methylphenyl)-2- Rt = 3.179 minutes. LCMS Method A , Prep HPLC (trifluoromethyl)benzene Method B with 48-78% organic gradient. sulfonamide 5-cyano-2-methylaniline. N-(2-cyano-3- MS m/z 341 [M+H]+ methylphenyl)-2- Rt = 2.980 minutes. LCMS Method B, Prep HPLC (trifluoromethyl)benzene Method C with 40-70% organic gradient. sulfonamide 2-cyano-3-methylaniline. N-(2-cyano-4- MS m/z 345 [M+H]+ fluorophenyl)-2- Rt = 3.1 19 minutes. LCMS Method A , Prep HPLC (trifluoromethyl)benzene Method B with 46-76% organic gradient. sulfonamide 2-cyano-4-fluoroaniline. N-(3-chloro-2- MS m/z 361 [M+H]+ cyanophenyl)-2- Rt = 3.041 minutes. LCMS Method B, Prep HPLC (trifluoromethyl)benzene Method B with 48-78% organic gradient. sulfonamide 3-chloro-2-cyanoaniline. N-[2-fluoro-4- MS m/z 398 [M+H]+ (methylsulfonyl)phenyl]-2- Rt = 2.937 minutes. LCMS Method B, Prep HPLC (trifluoromethyl)benzene Method B with 33-63% organic gradient. sulfonamide 2-fluoro-4-(methylsulfonyl)aniline. N-(4-chloro-2- MS m/z 361 [M+H]+ cyanophenyl)-2- Rt = 3.103 minutes. LCMS Method A , Prep HPLC (trifl uoromethyl) benzene Method C with 50-80% organic gradient. sulfonamide 4-chloro-2-cyanoaniline. N-[4-(difluoromethoxy)-3- MS m/z 384 [M-H] fluorophenyl]-2- Rt = 2.266 minutes. LCMS Method C , Prep HPLC (trifluoromethyl)benzene Method B with 52-82% organic gradient. sulfonamide 4-(difluoromethoxy)-3-fluoroaniline. N-(6-methoxy-4- MS m/z 347 [M+H]+ methylpyridin-3-yl)-2- Rt = 3.073 minutes. LCMS Method A , Prep HPLC (trifluoromethyl) Method C with 38-68% organic gradient. benzenesulfonamide 6-methoxy-4-methylpyridin-3-amine. formate salt Name Data/SM N-(4-cyano-3- MS m/z 345 [M+H]+ fluorophenyl)-2- Rt = 3.207 minutes. LCMS Method A , Prep HPLC (trifluoromethyl)benzene Method B with 48-78% organic gradient. sulfonamide 4-cyano-3-fluoroaniline. N-[2-cyano-3- MS m/z 395 [M+H]+ (trifluoromethyl)phenyl]-2- Rt = 3.149 minutes. LCMS Method B, Prep HPLC (trifluoromethyl)benzene Method B with 51-81% organic gradient. sulfonamide 2-cyano-3-(trifluoromethyl)aniline. N-(3,4-difluorophenyl)-2- MS m/z 338 [M+H]+ (trifluoromethyl)benzene Rt = 3.148 minutes. LCMS Method B, Prep HPLC sulfonamide Method B with 51-81% organic gradient. 3,4-difluoroaniline. N-(4-methylpyridin-3-yl)-2- MS m/z 317 [M+H]+ (trifluoromethyl)benzene Rt = 2.334 minutes. LCMS Method A , Prep HPLC sulfonamide formate salt Method A with 19-49% organic gradient. 4-methylpyridin-3-amine. N-(3-cyanophenyl)-2- MS m/z 327 [M+H]+ (trifluoromethyl)benzene Rt = 3.1 13 minutes. LCMS Method A , Prep HPLC sulfonamide Method B with 45-75% organic gradient. 3-cyanoaniline. N-(3-bromopyridin-4-yl)-2- MS m/z 381 [M+H]+ (trifluoromethyl) Rt = 2.576 minutes. LCMS Method A , Prep HPLC benzenesulfonamide Method A with 26-56% organic gradient. formate salt 3-bromopyridin-4-amine. 2-chloro-N-(5- MS m/z 283 [M+H]+ methylpyridin-3- Rt = 3.147 minutes. LCMS Method A , Prep HPLC yl)benzenesulfonamide Method C with 10-40% organic gradient. formate salt 5-methylpyridin-3-amine. 2-chloro-N-[6- MS m/z 337 [M+H]+ (trifluoromethyl)pyridin-3- Rt = 2.645 minutes. LCMS Method A , Prep HPLC yl]benzenesulfonamide Method C with 40-70% organic gradient. formate salt 6-(trifluoromethyl)pyridine-3-amine. 2-chloro-N-(3-fluoropyridin- MS m/z 287 [M+H]+ 4-yl)benzenesulfonamide Rt = 2.127 minutes. LCMS Method A , Prep HPLC formate salt Method A with 3-43% organic gradient. 4-fluoropyridin-3-amine. 2-chloro-N-(2,6- MS m/z 297 [M+H]+ dimethylpyridin-3- Rt = 2.178 minutes. LCMS Method A , Prep HPLC yl)benzenesulfonamide Method A with 14-44% organic gradient. formate salt 2,6-dimethylpyridin-3-amine. Name Data/SM 2-chloro-N-(6- MS m/z 313 [M+H]+ ethoxypyridin-3- Rt = 2.858 minutes. LCMS Method B, Prep HPLC yl)benzenesulfonamide Method B with 43-73% organic gradient. formate salt 6-ethoxypyridin-3-amine. 2-chloro-N-(2- MS m/z 299 [M+H]+ methoxypyridin-3- Rt = 2.963 minutes. LCMS Method A , Prep HPLC yl)benzenesulfonamide Method A with 36-66% organic gradient. formate salt 2-methoxypyridin-3-amine. 2-chloro-N-(5-fluoropyridin- MS m/z 287 [M+H]+ 3-yl)benzenesulfonamide Rt = 2.747 minutes. LCMS Method A , Prep HPLC formate salt Method B with 34-64% organic gradient. 5-fluoropyridin-3-amine. 2-chloro-N-(2- MS m/z 286 [M+H]+ fluorophenyl)benzene Rt = 3.089 minutes. LCMS Method A , Prep HPLC sulfonamide Method C with 33-63% organic gradient. 2-fluoroaniline. 2-chloro-N-(5,6- MS m/z 297 [M+H]+ dimethylpyridin-3- Rt = 2.219 minutes. LCMS Method A , Prep HPLC yl)benzenesulfonamide Method B with 19-49% organic gradient. formate salt 5,6-dimethylpyridin-3-amine. 2-chloro-N-(3- MS m/z 283 [M+H]+ methylpyridin-4- Rt = 2.196 minutes. LCMS Method A , Prep HPLC yl)benzenesulfonamide Method A with 15-45% organic gradient. formate salt 3-methylpyridin-4-amine. 2-chloro-N-(5- MS m/z 299 [M+H]+ methoxypyridin-3- Rt = 2.458 minutes. LCMS Method A , Prep HPLC yl)benzenesulfonamide Method B with 25-55% organic gradient. formate salt 5-methoxypyridin-3-amine. 2-chloro-N-(6- MS m/z 283 [M+H]+ methylpyridin-3- Rt = 2.166 minutes. LCMS Method A , Prep HPLC yl)benzenesulfonamide Method C with 13-43% organic gradient. formate salt 6-methylpyridin-3-amine. 2-chloro-N-[2- MS m/z 339 [M+H]+ (cyclopropylmethoxy) Rt = 2.695 minutes. LCMS Method B, Prep HPLC pyridin-4- Method C with 33-63% organic gradient. yl]benzenesulfonamide 2-(cyclopropylmethoxy)pyridin-4-amine. formate salt 2-chloro-N-(6- MS m/z 299 [M+H]+ methoxypyridin-3- Rt = 2.860 minutes. LCMS Method A , Prep HPLC yl)benzenesulfonamide Method A with 33-63% organic gradient. formate salt 6-methoxypyridin-3-amine Name Data/SM 2-chloro-N-(2- MS m/z 293 [M+H]+ cyanophenyl)benzene Rt = 2.916 minutes. LCMS Method A , Prep HPLC sulfonamide Method C with 33-63% organic gradient. 2-aminobenzonitrile. 2-chloro-N-(4- MS m/z 299 [M+H]+ methoxypyridin-3- Rt = 2.088 minutes. LCMS Method A , Prep HPLC yl)benzenesulfonamide Method A with 11-41% organic gradient. 4-methoxypyridin-3-amine 2-chloro-N-(6-methoxy-4- MS m/z 313 [M+H]+ methylpyridin-3- Rt = 2.936 minutes. LCMS Method A , Prep HPLC yl)benzenesulfonamide Method C with 33-63% organic gradient. formate salt 6-methoxy-4-methylpyridin-3-amine. 2-chloro-N-(3,4- MS m/z 304 [M+H]+ difluorophenyl)benzene Rt = 3.035 minutes. LCMS Method B, Prep HPLC sulfonamide Method C with 40-70% organic gradient. 3,4-difluoroaniline. 2-chloro-N-(4- MS m/z 283 [M+H]+ methylpyridin-3- Rt = 2.149 minutes. LCMS Method A , Prep HPLC yl)benzenesulfonamide Method A with 13-43% organic gradient. formate salt 4-methylpyridin-3-amine. 2-cyano-N-[6- MS m/z 328 [M+H]+ (trifluoromethyl)pyridin-3- Rt = 2.969 minutes. LCMS Method A , Prep HPLC yl]benzene sulphonamide Method C with 30-60% organic gradient. formate salt 6-(trifluoromethyl)pyridin-3-amine. N-(5-chloro-2- MS m/z 318 [M+H]+ cyanophenyl)-2- Rt = 2.916 minutes. LCMS Method A , Prep HPLC cyanobenzenesulfonamide Method C with 28-58% organic gradient. 2-amino-4-chlorobenzonitrile. 2-cyano-N-[2- MS m/z 330 [M+H]+ (cyclopropylmethoxy) Rt = 2.689 minutes. LCMS Method A , Prep HPLC pyridin-4- Method C with 23-53% organic gradient. yl]benzenesulfonamide 2-(cyclopropylmethoxy)pyridin-4-amine. formate salt 2-cyano-N-(2- MS m/z 284 [M+H]+ cyanophenyl)benzene Rt = 2.644 minutes. LCMS Method A , Prep HPLC sulfonamide Method C with 20-50% organic gradient. 2-aminobenzonitrile. 2-cyano-N-(3- MS m/z 284 [M+H]+ cyanophenyl)benzene Rt = 2.783 minutes. LCMS Method A , Prep HPLC sulfonamide Method C with 25-55% organic gradient. 3-aminobenzonitrile. Ex Name Data/SM 65 N-[4-cyano-3- MS m/z 395 [M+H]+ (trifluoromethyl)phenyl]-2- Rt = 3.217 minutes. LCMS Method B, Prep HPLC (trifluoromethyl)benzene Method B with 53-83% organic gradient. sulfonamide 2-trifluoromethyl-4-aminobenzonitrile. 66 2-chloro-N-(3- MS m/z 293 [M+H]+ cyanophenyl)benzene Rt = 2.985 minutes. LCMS Method A , Prep HPLC sulfonamide Method C with 35-65% organic gradient. 3-aminobenzonitrile.

Library Protoco

wherein R1, X1 and m are as described in formula (I) above.

1 µ To a 0.25M solution of the appropriate amine (X NH2) in anhydrous pyridine (300 , 75 µηιοΙ) was added a 0.275M solution of the appropriate sulfonyl chloride in anhydrous pyridine (300 µ , 82.5 µηιοΙ) followed by DMAP ( 1 .8 mg, 15 µηιοΙ) . The reaction mixture was shaken at 60 °C for 16 hours before concentrating in vacuo and purifying by one of the five preparative HPLC methods described below. The organic gradient used for each compound is described in the following table. Preparative HPLC Method A : Phenomenex Gemini C18 250 x 2 1.2 mm, 8 µηι ; mobile phase A : MeCN, mobile phase B : 0.225% formic acid in water. Gradient time 8 mins; flow rate 30 mL/min. Preparative HPLC Method Ai: Phenomenex Gemini C18 250 x 2 1.2 mm, 8 µηι ; mobile phase A : MeCN, mobile phase B : ammonium hydroxide (pH=10). Gradient time 12 mins; flow rate 25 mL/min. Preparative HPLC Method B : Waters Sunfire C8 150 x 30 mm, 5 µηι ; mobile phase A :

MeCN, mobile phase B : 0.225% formic acid in water. Gradient time 8 mins; flow rate 40 mL/min. Preparative HPLC Method C : DIKMA Diamonsil C18 200 x 25 mm, 5 µηι ; mobile phase A : MeCN, mobile phase B : 0.225% formic acid in water. Gradient time 10 mins; flow rate 25 mL/min. Preparative HPLC Method D: Agela DuraShell C 18 150 x 2 1.2 mm, 5 µηι ; mobile phase A : MeCN , mobile phase B : 0.225% formic acid in water. Gradient time 12 mins; flow rate 25 mL/min.

The retention times quoted in the table below were obtained using one of the following two LCMS methods: µηι LCMS Method A : XBRI DGE 50 x 2 .1 mm, 5 ; mobile phase A : 0.05% NH4OH in water; mobile phase B : 100% MeCN ; gradient from 5% B to 100% B at 3.40 mins, hold at 100% B to 4.20 mins and finally returning to 5% B at 4.2 1-4.70 mins; flow rate 0.8 mL/min. µηι LCMS Method B: XBRI DGE 50 x 2 .1 mm, 5 ; mobile phase A : 0.05% NH4OH in water; mobile phase B : 100% MeCN ; gradient from 1% B to 100% B at 3.40 mins, hold at 100% B to 4.20 mins and finally returning to 1% B at 4.2 1-4.70 mins; flow rate 0.8 mL/min.

The compounds of Examples 67-1 29 were prepared according to the method described for Library Protocol 2 using one of the following five amines and the appropriate sulfonyl chloride as described in the table below. Amines: 2-aminobenzonitrile, 3-aminobenzonitrile, 2-amino-6-chlorobenzonitrile, 5-amino-2-chlorobenzonitrile and 4-amino-2-chlorobenzonitrile.

Ex Name Data/SM 67 N-(3-chloro-2-cyanophenyl)- MS m/z 327 [M-H] ; 2,6- Rt = 1.529 minutes. LCMS Method A , Prep difluorobenzenesulfonamide HPLC Method A with 35-65% organic gradient. 2,6-difluorobenzenesulfonyl chloride. 68 2-cyanophenyl)-2,6- MS m/z 293 [M-H] ; difluorobenzenesulfonamide Rt = 2 .156 minutes. LCMS Method B, Prep HPLC Method B with 23-53% organic gradient. 2,6-difluorobenzenesulfonyl chloride. 69 N-(3-chloro-4-cyanophenyl)- MS m/z 327 [M-H] ; 2,6- Rt = 1.556 minutes. LCMS Method A , Prep difluorobenzenesulfonamide HPLC Method B with 33-63% organic gradient. 2,6-difluorobenzenesulfonyl chloride. Name Data/SM N-(4-chloro-3-cyanophenyl)- MS m/z 327 [M-H] ; 2,6- Rt = 1.597 minutes. LCMS Method A , Prep difluorobenzenesulfonamide HPLC Method B with 43-73% organic gradient. 2,6-difluorobenzenesulfonyl chloride. N-(3-chloro-2-cyanophenyl)- MS m/z 375 [M-H] ; 2-(trifluoromethoxy)benzene Rt = 2.210 minutes. LCMS Method A , Prep sulfonamide HPLC Method A with 43-73% organic gradient. 2-trifluoromethoxybenzenesulfonyl chloride. N-(2-cyanophenyl)-2- MS m/z 341 [M-H] ; (trifluoromethoxy)benzene Rt = 2.057 minutes. LCMS Method A , Prep sulfonamide HPLC Method D with 44-74% organic gradient. 2-trifluoromethoxybenzenesulfonyl chloride. N-(3-chloro-4-cyanophenyl)- MS m/z 375 [M-H] ; 2-(trifluoromethoxy)benzene Rt = 2.149 minutes. LCMS Method A , Prep sulfonamide HPLC Method A with 40-70% organic gradient. 2-trifluoromethoxybenzenesulfonyl chloride. N-(3-cyanophenyl)-2- MS m/z 341 [M-H] ; (trifluoromethoxy)benzene Rt = 2.046 minutes. LCMS Method A , Prep sulfonamide HPLC Method C with 20-50% organic gradient. 2-trifluoromethoxybenzenesulfonyl chloride. N-(4-chloro-3-cyanophenyl)- MS m/z 375 [M-H] ; 2-(trifluoromethoxy)benzene Rt = 2.191 minutes. LCMS Method A , Prep sulfonamide HPLC Method A with 45-75% organic gradient. 2-trifluoromethoxybenzenesulfonyl chloride. N-(3-chloro-2-cyanophenyl)- MS m/z 323 [M-H] ; 2-fluoro-5- Rt = 2.125 minutes. LCMS Method A , Prep methylbenzenesulfonamide HPLC Method A with 40-70% organic gradient. 2-fluoro-5-methylbenzenesulfonyl chloride. N-(2-cyanophenyl)-2-fluoro- MS m/z 289 [M-H] ; 5- Rt = 1.959 minutes. LCMS Method A , Prep methylbenzenesulfonamide HPLC Method D with 32-62% organic gradient. 2-fluoro-5-methylbenzenesulfonyl chloride. N-(3-chloro-4-cyanophenyl)- MS m/z 323 [M-H] ; 2-fluoro-5- Rt = 2.057 minutes. LCMS Method A , Prep methylbenzenesulfonamide HPLC Method A with 41-71% organic gradient. 2-fluoro-5-methylbenzenesulfonyl chloride. N-(3-cyanophenyl)-2-fluoro- MS m/z 289 [M-H] ; 5- Rt = 1.930 minutes. LCMS Method A , Prep methylbenzenesulfonamide HPLC Method D with 39-69% organic gradient. 2-fluoro-5-methylbenzenesulfonyl chloride. Name Data/SM N-(4-chloro-3-cyanophenyl)- MS m/z 323 [M-H] ; 2-fluoro-5- Rt = 2.105 minutes. LCMS Method A , Prep methylbenzenesulfonamide HPLC Method A with 42-72% organic gradient. 2-fluoro-5-methylbenzenesulfonyl chloride. N-(3-chloro-4-cyanophenyl)- MS m/z 305 [M-H] ; 2- Rt = 2.052 minutes. LCMS Method A , Prep methylbenzenesulfonamide HPLC Method A with 40-70% organic gradient. 2-methylbenzenesulfonyl chloride. N-(4-chloro-3-cyanophenyl)- MS m/z 305 [M-H] ; 2- Rt = 2.102 minutes. LCMS Method A , Prep methylbenzenesulfonamide HPLC Method A with 41-71% organic gradient. 2-methylbenzenesulfonyl chloride. N-(3-chloro-4-cyanophenyl)- MS m/z 316 [M-H] ; 2- Rt = 1.960 minutes. LCMS Method A , Prep cyanobenzenesulfonamide HPLC Method A with 34-64% organic gradient. 2-cyanobenzenesulfonyl chloride. N-(4-chloro-3-cyanophenyl)- MS m/z 316 [M-H] ; 2- Rt = 2.000 minutes. LCMS Method A , Prep cyanobenzenesulfonamide HPLC Method A with 35-65% organic gradient. 2-cyanobenzenesulfonyl chloride. 2,4-dichloro-N-(3-chloro-2- MS m/z 359 [M-H] ; cyanophenyl)benzene Rt = 2.259 minutes. LCMS Method A , Prep sulfonamide HPLC Method B with 40-70% organic gradient. 2,4-dichlorobenzenesulfonyl chloride. 2,4-dichloro-N-(2- MS m/z 325 [M-H] ; cyanophenyl)benzene Rt = 2.104 minutes. LCMS Method A , Prep sulfonamide HPLC Method A with 39-69% organic gradient. 2,4-dichlorobenzenesulfonyl chloride. 2,4-dichloro-N-(3-chloro-4- MS m/z 359 [M-H] ; cyanophenyl)benzene Rt = 2.209 minutes. LCMS Method A , Prep sulfonamide HPLC Method A with 46-76% organic gradient. 2,4-dichlorobenzenesulfonyl chloride. 2,4-dichloro-N-(3- MS m/z 325 [M-H] ; cyanophenyl)benzene Rt = 2.094 minutes. LCMS Method A , Prep sulfonamide HPLC Method D with 22-52% organic gradient. 2,4-dichlorobenzenesulfonyl chloride. 2,4-dichloro-N-(4-chloro-3- MS m/z 359 [M-H] ; cyanophenyl)benzene Rt = 2.228 minutes. LCMS Method A , Prep sulfonamide HPLC Method Ai with 23-53% organic gradient. 2,4-dichlorobenzenesulfonyl chloride. Name Data/SM N-(3-chloro-2-cyanophenyl)- MS m/z 335 [M-H] ; 2- Rt = 1.734 minutes. LCMS Method A , Prep ethoxybenzenesulfonamide HPLC Method B with 46-76% organic gradient. 2-ethoxybenzenesulfonyl chloride. N-(2-cyanophenyl)-2- MS m/z 301 M-H] ; ethoxybenzenesulfonamide Rt = 1.942 minutes. LCMS Method A , Prep HPLC Method A with 36-66% organic gradient. 2-ethoxybenzenesulfonyl chloride. N-(3-chloro-4-cyanophenyl)- MS m/z 335 [M-H] ; 2- Rt = 2.050 minutes. LCMS Method A , Prep ethoxybenzenesulfonamide HPLC Method A with 41-71% organic gradient. 2-ethoxybenzenesulfonyl chloride. N-(4-chloro-3-cyanophenyl)- MS m/z 335 [M-H] ; 2- Rt = 2.177 minutes. LCMS Method A , Prep ethoxybenzenesulfonamide HPLC Method A with 42-72% organic gradient. 2-ethoxybenzenesulfonyl chloride. 2,3-dichloro-N-(3-chloro-2- MS m/z 359 [M-H] ; cyanophenyl)benzene Rt = 2.224 minutes. LCMS Method A , Prep sulfonamide HPLC Method A with 43-73% organic gradient. 2,3-dichlorobenzenesulfonyl chloride. 2,3-dichloro-N-(2- MS m/z 325 [M-H] ; cyanophenyl)benzene Rt = 2.066 minutes. LCMS Method A , Prep sulfonamide HPLC Method D with 40-70% organic gradient. 2,3-dichlorobenzenesulfonyl chloride. 2,3-dichloro-N-(3-chloro-4- MS m/z 359 [M-H] ; cyanophenyl)benzene Rt = 2.168 minutes. LCMS Method A , Prep sulfonamide HPLC Method A with 45-75% organic gradient. 2,3-dichlorobenzenesulfonyl chloride. 2,3-dichloro-N-(3- MS m/z 325 [M-H] ; cyanophenyl)benzene Rt = 2.032 minutes. LCMS Method A , Prep sulfonamide HPLC Method C with 22-52% organic gradient. 2,3-dichlorobenzenesulfonyl chloride. 2,3-dichloro-N-(4-chloro-3- MS m/z 359 [M-H] ; cyanophenyl)benzene Rt = 2.199 minutes. LCMS Method A , Prep sulfonamide HPLC Method A with 45-75% organic gradient. 2,3-dichlorobenzenesulfonyl chloride. 2,6-dichloro-N-(4-chloro-3- MS m/z 359 [M-H] ; cyanophenyl)benzene Rt = 2.131 minutes. LCMS Method A , Prep sulfonamide HPLC Method A with 43-73% organic gradient. 2,6-dichlorobenzenesulfonyl chloride. Name Data/SM N-(3-chloro-2-cyanophenyl)- MS m/z 327 [M-H] ; 2,5- Rt = 2.096 minutes. LCMS Method A , Prep difluorobenzenesulfonamide HPLC Method A with 37-67% organic gradient. 2,5-difluorobenzenesulfonyl chloride. N-(2-cyanophenyl)-2,5- MS m/z 293 [M-H] ; difluorobenzenesulfonamide Rt = 1.905 minutes. LCMS Method A , Prep HPLC Method D with 38-68% organic gradient. 2,5-difluorobenzenesulfonyl chloride. N-(3-chloro-4-cyanophenyl)- MS m/z 327 [M-H] ; 2,5- Rt = 2.029 minutes. LCMS Method A , Prep difluorobenzenesulfonamide HPLC Method A with 39-69% organic gradient. 2,5-difluorobenzenesulfonyl chloride. N-(4-chloro-3-cyanophenyl)- MS m/z 327 [M-H] ; 2,5- Rt = 1.615 minutes. LCMS Method A , Prep difluorobenzenesulfonamide HPLC Method B with 44-74% organic gradient. 2,5-difluorobenzenesulfonyl chloride. 2-chloro-N-(3-chloro-2- MS m/z 325 [M-H] ; cyanophenyl)benzene Rt = 2.085 minutes. LCMS Method A , Prep sulfonamide HPLC Method A with 38-68% organic gradient. 2-chlorobenzenesulfonyl chloride. 2-chloro-N-(3-chloro-4- MS m/z 325 [M-H] ; cyanophenyl)benzene Rt = 2.015 minutes. LCMS Method A , Prep sulfonamide HPLC Method A with 39-69% organic gradient. 2-chlorobenzenesulfonyl chloride. 2-chloro-N-(4-chloro-3- MS m/z 325 [M-H] ; cyanophenyl)benzene Rt = 2.055 minutes. LCMS Method A , Prep sulfonamide HPLC Method A with 40-70% organic gradient. 2-chlorobenzenesulfonyl chloride. N-(3-chloro-2-cyanophenyl)- MS m/z 334 [M-H] ; 2-cyano-3- Rt = 2.071 minutes. LCMS Method A , Prep fluorobenzenesulfonamide HPLC Method A with 40-70% organic gradient. 2-cyano-3-fluorobenzenesulfonyl chloride. 2-cyano-N-(2-cyanophenyl)- MS m/z 300 [M-H] ; 3-fluorobenzenesulfonamide Rt = 1.885 minutes. LCMS Method A , Prep HPLC Method A with 27-57% organic gradient. 2-cyano-3-fluorobenzenesulfonyl chloride. N-(3-chloro-4-cyanophenyl)- MS m/z 334 [M-H] ; 2-cyano-3- Rt = 2.032 minutes. LCMS Method A , Prep fluorobenzenesulfonamide HPLC Method A with 40-70% organic gradient. 2-cyano-3-fluorobenzenesulfonyl chloride. Name Data/SM

2-cyano-N-(3-cyanophenyl)- MS m/z 300 [M-H]-; 3-fluorobenzenesulfonamide Rt = 1.884 minutes. LCMS Method A , Prep HPLC Method A with 31-61% organic gradient. 2-cyano-3-fluorobenzenesulfonyl chloride. N-(4-chloro-3-cyanophenyl)- MS m/z 334 [M-H] ; 2-cyano-3- Rt = 2.077 minutes. LCMS Method A , Prep fluorobenzenesulfonamide HPLC Method A with 37-67% organic gradient. 2-cyano-3-fluorobenzenesulfonyl chloride. 2,5-dichloro-N-(3-chloro-2- MS m/z 359 [M-H] ; cyanophenyl)benzene Rt = 2.242 minutes. LCMS Method A , Prep sulfonamide HPLC Method A with 44-74% organic gradient. 2,5-dichlorobenzenesulfonyl chloride. 2,5-dichloro-N-(2- MS m/z 325 [M-H] ; cyanophenyl)benzene Rt = 2.081 minutes. LCMS Method A , Prep sulfonamide HPLC Method D with 50-80% organic gradient. 2,5-dichlorobenzenesulfonyl chloride. 2,5-dichloro-N-(3-chloro-4- MS m/z 359 [M-H] ; cyanophenyl)benzene Rt = 2.178 minutes. LCMS Method A , Prep sulfonamide HPLC Method A with 46-76% organic gradient. 2,5-dichlorobenzenesulfonyl chloride. 2,5-dichloro-N-(3- MS m/z 325 [M-H] ; cyanophenyl)benzene Rt = 2.047 minutes. LCMS Method A , Prep sulfonamide HPLC Method C with 21-51% organic gradient. 2,5-dichlorobenzenesulfonyl chloride. 2,5-dichloro-N-(4-chloro-3- MS m/z 359 [M-H] ; cyanophenyl)benzene Rt = 2.202 minutes. LCMS Method A , Prep sulfonamide HPLC Method A with 47-77% organic gradient. 2,5-dichlorobenzenesulfonyl chloride. N-(3-chloro-2-cyanophenyl)- MS m/z 321 [M-H] ; 2-methoxybenzene Rt = 1.544 minutes. LCMS Method A , Prep sulfonamide HPLC Method B with 37-67% organic gradient. 2-methoxybenzenesulfonyl chloride. N-(3-chloro-4-cyanophenyl)- MS m/z 321 [M-H] ; 2-methoxybenzene Rt = 1.949 minutes. LCMS Method A , Prep sulfonamide HPLC Method B with 37-67% organic gradient. 2-methoxybenzenesulfonyl chloride. N-(2-cyanophenyl)-2- MS m/z 287 [M-H] ; methoxybenzene Rt = 1.849 minutes. LCMS Method A , Prep sulfonamide HPLC Method B with 27-57% organic gradient. 2-methoxybenzenesulfonyl chloride. Name Data/SM N-(3-cyanophenyl)-2- MS m/z 287 [M-H] ; methoxybenzene Rt = 1.943 minutes. LCMS Method A , Prep sulfonamide HPLC Method B with 32-62% organic gradient. 2-methoxybenzenesulfonyl chloride. N-(4-chloro-3-cyanophenyl)- MS m/z 321 [M-H] ; 2-methoxybenzene Rt = 2.056 minutes. LCMS Method A , Prep sulfonamide HPLC Method B with 39-69% organic gradient. 2-methoxybenzenesulfonyl chloride. 3,5-dichloro-N-(2- MS m/z 341 [M-H] ; cyanophenyl)-2- Rt = 2.027 minutes. LCMS Method A , Prep hydroxybenzene HPLC Method A with 38-68% organic gradient. sulfonamide 3,5-dichloro-2-hydroxybenzenesulfonyl chloride. 3,5-dichloro-N-(3-chloro-4- MS m/z 375 [M-H] ; cyanophenyl)-2- Rt = 2.133 minutes. LCMS Method A , Prep hydroxybenzene HPLC Method B with 36-66% organic gradient. sulfonamide 3,5-dichloro-2-hydroxybenzenesulfonyl chloride. 3,5-dichloro-N-(3- MS m/z 341 [M-H] ; cyanophenyl)-2- Rt = 2.125 minutes. LCMS Method A , Prep hydroxybenzene HPLC Method A with 39-69% organic gradient. sulfonamide 3,5-dichloro-2-hydroxybenzenesulfonyl chloride. N-(2-cyanophenyl)-2- MS m/z 271 [M-H] ; methylbenzenesulfonamide Rt = 1.958 minutes. LCMS Method A , Prep HPLC Method A with 33-63% organic gradient. 2-methylbenzenesulfonyl chloride. N-(3-cyanophenyl)-2,5- MS m/z 293 [M-H] ; difluorobenzenesulfonamide Rt = 1.846 minutes. LCMS Method A , Prep HPLC Method A with 40-70% organic gradient. 2,5-difluorobenzenesulfonyl chloride. N-(3-cyanophenyl)-2- MS m/z 271 [M-H] ; methylbenzenesulfonamide Rt = 1.942 minutes. LCMS Method A , Prep HPLC Method A with 40-70% organic gradient. 2-methylbenzenesulfonyl chloride. N-(3-cyanophenyl)-2,6- MS m/z 293 [M-H] ; difluorobenzenesulfonamide Rt = 2.030 minutes. LCMS Method B, Prep HPLC Method B with 32-62% organic gradient. 2,6-difluorobenzenesulfonyl chloride. 2,6-dichloro-N-(3- MS m/z 325 [M-H] ; cyanophenyl)benzene Rt = 1.846 minutes. LCMS Method A , Prep sulfonamide HPLC Method A with 37-67% organic gradient. 2,6-dichlorobenzenesulfonyl chloride. Library Protocol 3

wherei R1 an X 1 are as described in formula (I) above.

1 µι ιο Ι To a solution of the appropriate amine (X NH2, 100 ) in anhydrous pyridine (600 µ Ι_) was added a 1.2M solution of the appropriate sulfonyl chloride in anhydrous pyridine ( 100 µ Ι_, 120 µ ι ιο Ι) followed by DMAP (2 mg, 20 µι ιο Ι) . The reaction mixture was shaken at 30°C for 2 hours followed by 60°C for 16 hours before concentrating in vacuo and purifying by one of the four preparative HPLC methods described below. The organic gradient used for each compound is described in the following table. Preparative HPLC Method A : Phenomenex Gemini C 18 250 x 21.2 mm, 8 µηι ; mobile phase A : MeCN , mobile phase B : 0.225% formic acid in water. Gradient time 8 mins; flow rate 30 mL/min. Preparative HPLC Method B: Waters Sunfire C8 150 x 30 mm, 5 µηι ; mobile phase A :

MeCN , mobile phase B : 0.225% formic acid in water. Gradient time 8 mins; flow rate 40 mL/min. Preparative HPLC Method C : YMC-Actus Triart C 18 150 x 30 mm, 5 µηι ; mobile phase A : MeCN , mobile phase B : 0.225% formic acid in water. Gradient time 9 mins; flow rate 30 mL/min. Preparative HPLC Method D: Agela DuraShell C 18 150 x 2 1.2 mm, 5 µηι ; mobile phase A : MeCN , mobile phase B : 0.225% formic acid in water. Gradient time 10 mins; flow rate 30 mL/min.

The retention times quoted in the table below were obtained using one of the following three LCMS methods: LCMS Method A : XBRI DGE 50 x 2 .1 mm, 5 µηι ; mobile phase A : 0.0375%TFA in water; mobile phase B : 0.01 875% TFA in MeCN ; gradient from 1% B to 5% B at 0.60 mins, further to 100% B at 4.00 mins and finally returning to 1% B at 4.30-4.70 mins; flow rate 0.8 mL/min. LCMS Method B : XBRI DGE 50 x 2 .1 mm, 5 µηι ; mobile phase A : 0.0375%TFA in water; mobile phase B : 0.01 875% TFA in MeCN ; gradient from 10% B to 100% B at 4.00 mins and finally returning to 1% B at 4.30-4.70 mins; flow rate 0.8 mL/min. µηι LCMS Method C : XBRIDGE 50 x 2.1 mm, 5 ; mobile phase A : 0.05%NH 4OH in water; mobile phase B : 100% MeCN; gradient from 5% B to 100% B at 3.40 mins, hold at 100% B to 4.20 mins and finally returning to 5% B at 4.21-4.70 mins; flow rate 0.8 mL/min.

The compounds of Examples 130-175 were prepared according to the method described for Library Protocol 3 using either 2-cyanobenzensulfonyl chloride or 2-(trifluoromethyl)benzenesulfonyl chloride and the appropriate amine as described below. Where stated the title compounds were isolated as formate salts.

Ex Name Data/SM 130 N-(2-cyano-4- MS m/z 355 [M-H] ; methoxyphenyl)-2- Rt = 2.103 minutes. LCMS Method C, Prep (trifluoromethyl)benzene HPLC Method C with 47-77% organic gradient. sulfonamide 2-amino-5-methoxybenzonitrile. 131 N-(4,5-dichloro-2- MS m/z 386 [M+H]+; hydroxyphenyl)-2- Rt = 3.503 minutes. LCMS Method B, Prep (trifluoromethyl)benzene HPLC Method D with 50-80% organic gradient. sulfonamide 2-amino-4,5-dichlorophenol. 132 N-(3-chloro-2-fluorophenyl)- MS m/z 352 [M-H] ; 2-(trifluoromethyl)benzene Rt = 2.204 minutes. LCMS Method C, Prep sulfonamide HPLC Method D with 49-79% organic gradient. 2-fluoro-3-chloroaniline. 133 N-[4-cyano-2- MS m/z 409 [M-H] ; (trifluoromethoxy)phenyl]-2- Rt = 2.292 minutes. LCMS Method C, Prep (trifluoromethyl)benzene HPLC Method C with 56-86% organic gradient. sulfonamide 4-amino-3-(trifluoromethoxy)benzonitrile. 134 N-[3-cyano-5- MS m/z 393 [M-H] ; (trifluoromethyl)phenyl]-2- Rt = 2.343 minutes. LCMS Method C, Prep (trifluoromethyl)benzene HPLC Method A with 49-79% organic gradient. sulfonamide 3-amino-5-(trifluoromethyl)benzonitrile. 135 N-[2,3-difluoro-4- MS m/z 404 [M-H] ; (trifluoromethyl)phenyl]-2- Rt = 2.410 minutes. LCMS Method C, Prep (trifluoromethyl)benzene HPLC Method C with 61-91% organic gradient. sulfonamide 2,3-difluoro-4-trifluoromethylaniline. 136 N-(3,5-dichloro-4- MS m/z 393 [M-H] ; cyanophenyl)-2- Rt = 2.348 minutes. LCMS Method C, Prep (trifluoromethyl)benzene HPLC Method C with 58-88% organic gradient. sulfonamide 4-amino-2,6-dichlorobenzonitrile 137 N-(2-chloro-5-cyano-4- MS m/z 373 [M-H] ; methylphenyl)-2- Rt = 2.221 minutes. LCMS Method C, Prep (trifluoromethyl)benzene HPLC Method C with 53-83% organic gradient. sulfonamide 5-amino-4-chloro-2-methylbenzonitrile

Name Data/SM N-[2-chloro-4- MS m/z 402 [M-H] ; (trifluoromethyl)phenyl]-2- Rt = 2.405 minutes. LCMS Method C, Prep (trifluoromethyl)benzenesulf HPLC Method C with 63-93% organic gradient. onamide 2-chloro-4-trifluoromethylaniline. N-(2-fluoro-6- MS m/z 348 [M-H] ; methoxyphenyl)-2- Rt = 2.299 minutes. LCMS Method C, Prep (trifluoromethyl)benzene HPLC Method C with 48-78% organic gradient. sulfonamide 2-fluoro-6-methoxyaniline. N-(6-methoxypyridin-2-yl)-2- MS m/z 331 [M-H] ; (trifluoromethyl)benzene Rt = 1.977 minutes. LCMS Method C, Prep sulfonamide formate salt HPLC Method C with 47-77% organic gradient. 6-methoxypyridin-2-amine. N-[2- MS m/z 366 [M-H] ; (difluoromethoxy)phenyl]-2- Rt = 2.301 minutes. LCMS Method C, Prep (trifluoromethyl)benzene HPLC Method C with 53-83% organic gradient. sulfonamide 2-(difluoromethoxy)aniline. N-(2-chloro-5-cyanophenyl)- MS m/z 359 [M-H] ; 2-(trifluoromethyl)benzene Rt = 2.159 minutes. LCMS Method C, Prep sulfonamide HPLC Method D with 46-76% organic gradient. 3-amino-4-chlorobenzonitrile. N-(2-cyano-5- MS m/z 339 [M-H] ; methylphenyl)-2- Rt = 2.180 minutes. LCMS Method C, Prep (trifluoromethyl)benzene HPLC Method C with 48-78% organic gradient. sulfonamide 2-amino-4-methylbenzonitrile. N-[2-cyano-3-(propan-2- MS m/z 383 [M-H] ; yloxy)phenyl]-2- Rt = 2.281 minutes. LCMS Method C, Prep (trifluoromethyl)benzene HPLC Method D with 48-78% organic gradient. sulfonamide 2-amino-6-isopropoxybenzonitrile. N-(4-cyano-2-ethylphenyl)- MS m/z 353 [M-H] ; 2-(trifluoromethyl)benzene Rt = 2.218 minutes. LCMS Method C, Prep sulfonamide HPLC Method D with 48-78% organic gradient. 3-ethyl-4-aminobenzonitrile. N-(2,3-dichlorophenyl)-2- MS m/z 368 [M-H] ; (trifluoromethyl)benzene Rt = 2.280 minutes. LCMS Method C, Prep sulfonamide HPLC Method C with 59-89% organic gradient. 2,3-dichloroaniline. N-[4-fluoro-3- MS m/z 386 [M-H] ; (trifluoromethyl)phenyl]-2- Rt = 2.350 minutes. LCMS Method C, Prep (trifluoromethyl)benzene HPLC Method C with 59-89% organic gradient. sulfonamide 3-trifluoromethyl-4-fluoroaniline. N-(5-chloro-2-cyano-4- MS m/z 377 [M-H] ; fluorophenyl)-2- Rt = 2.334 minutes. LCMS Method C, Prep (trifluoromethyl)benzene HPLC Method C with 54-84% organic gradient. sulfonamide 2-amino-4-chloro-5-fluorobenzonitrile. 2-cyano-N-[4- MS m/z 325 [M-H] ; (trifluoromethyl)phenyl] Rt = 2.176 minutes. LCMS Method C, Prep benzenesulfonamide HPLC Method A with 44-74% organic gradient. 4-trifluoromethylaniline. Name Data/SM N-[3-chloro-4- MS m/z 377 [M+H]+; (trifluoromethoxy)phenyl]-2- Rt = 4.430 minutes. LCMS Method A , Prep cyanobenzenesulfonamide HPLC Method C with 57-77% organic gradient. 3-chloro-4-trifluoromethoxyaniline. N-(3-chloro-2,4- MS m/z 327 [M-H] ; difluorophenyl)-2- Rt = 2.083 minutes. LCMS Method C, Prep cyanobenzenesulfonamide HPLC Method C with 46-76% organic gradient. 2,4-difluoro-3-chloroaniline. 2-cyano-N-(3,5-dichloro-4- MS m/z 350 [M-H] ; cyanophenyl)benzene Rt = 2.198 minutes. LCMS Method C, Prep sulfonamide HPLC Method B with 40-70% organic gradient. 4-amino-2,6-dichlorobenzonitrile. 2-cyano-N-[4-fluoro-2- MS m/z 343 [M-H] ; (trifluoromethyl)phenyl] Rt = 2.173 minutes. LCMS Method C, Prep benzenesulfonamide HPLC Method C with 47-77% organic gradient. 2-trifluoromethyl-4-fluoroaniline. N-[3-chloro-4-(2,2,2- MS m/z 389 [M-H] ; trifluoroethoxy)phenyl]-2- Rt = 2.252 minutes. LCMS Method C, Prep cyanobenzenesulfonamide HPLC Method C with 52-82% organic gradient. 3-chloro-4-(2,2,2-trifluoroethoxy)aniline. N-(5-chloro-2- MS m/z 307 [M-H] ; hydroxyphenyl)-2- Rt = 2.063 minutes. LCMS Method C, Prep cyanobenzenesulfonamide HPLC Method C with 43-63% organic gradient. 2-amino-4-chlorophenol. N-[4-chloro-2- MS m/z 359 [M-H] ; (trifluoromethyl)phenyl]-2- Rt = 2.298 minutes. LCMS Method C, Prep cyanobenzenesulfonamide HPLC Method C with 51-81% organic gradient. 2-trifluoromethyl-4-chloroaniline. 2-cyano-N-[3,5-difluoro-4- MS m/z 361 [M-H] ; (trifluoromethyl)phenyl] Rt = 2.322 minutes. LCMS Method C, Prep benzenesulfonamide HPLC Method D with 50-80% organic gradient. 3,5-difluoro-4-(trifluoromethyl)aniline. N-[4-chloro-2- MS m/z 375 [M-H] ; (trifluoromethoxy)phenyl]-2- Rt = 2.288 minutes. LCMS Method C, Prep cyanobenzenesulfonamide HPLC Method C with 55-85% organic gradient. 2-trifluoromethoxy-4-chloroaniline. 2-cyano-N-[2-fluoro-3- MS m/z 343 [M-H] ; (trifluoromethyl)phenyl] Rt = 2.167 minutes. LCMS Method C, Prep benzenesulfonamide HPLC Method C with 48-78% organic gradient. 2-fluoro-3-trifluoromethylaniline. N-(2-chloro-4,5- MS m/z 327 [M-H] ; difluorophenyl)-2- Rt = 2.130 minutes. LCMS Method C, Prep cyanobenzenesulfonamide HPLC Method C with 52-72% organic gradient. 2-chloro-4,5-difluoroaniline. 2-cyano-N-[4-cyano-3- MS m/z 350 [M-H]-; (trifluoromethyl)phenyl] Rt = 2.151 minutes. LCMS Method C, Prep benzenesulfonamide HPLC Method C with 47-77% organic gradient. 2-trifluoromethyl-4-aminobenzonitrile. Ex Name Data/SM 173 N-[2-cyano-4- MS m/z 393 [M-H]-; (trifluoromethyl)phenyl]-2- Rt = 2.415 minutes. LCMS Method C, Prep (trifluoromethyl)benzene HPLC Method D with 51-81% organic gradient. sulfonamide 2-amino-5-trifluoromethylbenzonitrile. 174 N-[2-chloro-5- MS m/z 359 [M-H]-; (trifluoromethyl)phenyl]-2- Rt = 2.248 minutes. LCMS Method C, Prep cyanobenzenesulfonamide HPLC Method C with 50-80% organic gradient. 2-chloro-5-trifluoromethylaniline. 175 N-[4-chloro-3- MS m/z 359 [M-H]-; (trifluoromethyl)phenyl]-2- Rt = 2.263 minutes. LCMS Method C, Prep cyanobenzenesulfonamide HPLC Method C with 55-85% organic gradient. 3-trifluoromethyl-4-chloroaniline.

1 Ethyl 4-amino-2-hydroxybenzenesulfonate may be prepared according to the synthesis of 3-amino-2-chloro-6-(ethylsulfonyl)phenol as described in WO 2001017956.

Library Protocol 4

wherein R1, X1 and m are as described in formula (I) above.

To a 0.48M solution of the appropriate sulfonyl chlorides in anhydrous pyridine (250 µ , 120 µηιοΙ) was added a 0.4M solution of the appropriate amine in anhydrous pyridine 1 µ µηιοΙ (X NH2, 250 , 100 ) . The reaction mixture was shaken at 30°C for 2 hours followed by 60°C for 16 hours before concentrating in vacuo and purifying by one of the two preparative HPLC methods described below. The organic gradient used for each compound is described in the following table. Preparative HPLC Method A : Boston Symmetrix ODS-H 150 x 30 mm, 5 µηι ; mobile phase A : Acetonitrile, mobile phase B : 0.1% TFA in water. Gradient time 8 mins; flow rate 30 mL/min. Preparative HPLC Method B : Kromasil Eternity-5 C18 150 x 30 mm, 5 µηι ; mobile phase A : Acetonitrile, mobile phase B : 0.1% TFA in water. Gradient time 10 mins; flow rate 30 mL/min. The retention times quoted in the table below were obtained using one of the following two LCMS methods: LCMS Method A : XBRI DGE 50 x 2 .1 mm, 5 µηι ; mobile phase A : 0.0375% TFA in water; mobile phase B : 0.01 875% TFA in MeCN ; gradient from 1% B to 5% B at 0.60 mins, further to 100% B at 4.00 mins and finally returning to 1% B at 4.30-4.70 mins; flow rate 0.8 mL/min. LCMS Method B : XBRI DGE 50 x 2 .1 mm, 5 µηι ; mobile phase A : 0.0375% TFA in water; mobile phase B : 0.01 875% TFA in MeCN ; gradient from 10% B to 100% B at 4.00 mins and finally returning to 1% B at 4.30-4.70 mins; flow rate 0.8 mL/min.

The compounds of Examples 176-1 84 were prepared according to the method described for Library Protocol 4 using 5-bromopyridin-3-amine and the appropriate sulfonyl chloride as described below. Where stated the title compounds were isolated as trifluoroacetate salts.

Ex Name Data/SM

176 N-(5-bromopyridin-3-yl)-2- MS m/z 327 [M+ H]+; methylbenzenesulfonamide Rt = 3.040 minutes. LCMS Method A , Prep trifluoroacetate salt HPLC Method B with 4 1-71 % organic gradient. 2-methylbenzenesulfonyl chloride. 177 N-(5-bromopyridin-3-yl)-4- MS m/z 345 [M+ H]+; fluoro-2- Rt = 3 .138 minutes. LCMS Method A , Prep methylbenzenesulfonamide HPLC Method B with 44-74% organic gradient. trifluoroacetate salt 2-methyl-4-fluorobenzenesulfonyl chloride. 178 N-(5-bromopyridin-3-yl)-5- MS m/z 345 [M+ H]+; fluoro-2- Rt = 3 .135 minutes. LCMS Method A , Prep methylbenzenesulfonamide HPLC Method B with 44-74% organic gradient. trifluoroacetate salt 2-methyl-5-fluorobenzenesulfonyl chloride. 179 N-(5-bromopyridin-3-yl)-3- MS m/z 347 [M+H]+ chlorobenzenesulfonamide Rt = 3 .154 minutes. LCMS Method A , Prep trifluoroacetate salt HPLC Method A with 48-78% organic gradient. 3-chlorobenzenesulfonyl chloride. 180 3-bromo-N-(5-bromopyridin- MS m/z 393 [M+H]+; 3-yl)benzenesulfonamide Rt = 3.01 2 minutes. LCMS Method B, Prep trifluoroacetate salt HPLC Method B with 46-76% organic gradient. 3-bromobenzenesulfonyl chloride. 18 1 N-(5-bromopyridin-3-yl)-2- MS m/z 365 [M+H]+; chloro-4- Rt = 3.094 minutes. LCMS Method A , Prep fluorobenzenesulfonamide HPLC Method A with 46-76% organic gradient. trifluoroacetate salt 2-chloro-4-fluorobenzenesulfonyl chloride. Ex Name Data/SM 182 N-(5-bromopyridin-3-yl)-2- MS m/z 347 [M+H]+; chlorobenzenesulfonamide Rt = 3.000 minutes. LCMS Method A , Prep trifluoroacetate salt HPLC Method B with 40-70% organic gradient. 2-chlorobenzenesulfonyl chloride. 183 2-bromo-N-(5-bromopyridin- MS m/z 4 11 [M+H]+; 3-yl)-5- Rt = 3 .134 minutes. LCMS Method A , Prep fluorobenzenesulfonamide HPLC Method A with 47-77% organic gradient. trifluoroacetate salt 2-bromo-5-fluorobenzenesulfonyl chloride. 184 N-(5-bromopyridin-3-yl)-2,6- MS m/z 381 [M+H]+; dichlorobenzene Rt = 2.994 minutes. LCMS Method B, Prep sulfonamide trifluoroacetate HPLC Method B with 44-74% organic gradient. salt 2,6-dichlorobenzenesulfonyl chloride.

Example 185 N-(3-hvdroxvDvridin-2-vl)-2-(trifluoromethvl)benzenesulfonamide

To a solution of 2-aminopyridin-3-ol ( 1 mmol) in THF (5 mL) was added NMM ( 1 11 µ , 1 mmol) followed by a 1M solution of 2-trifluoromethylbenzenesulfonyl chloride in DCM

( 100 µ , 1 mmol) . The reaction mixture was stood at room temperature for 18 hours before concentrating in vacuo to afford the title compound .

The compounds of Examples 186-200 were prepared according to the method of Example 185 using the appropriate amines and sulfonyl chlorides as described below.

Ex Name SM 186 N-(3-hydroxypyridin-2-yl)-2- 2-aminopyridin-3-ol and 2- (trifluoromethoxy)benzene trifluoromethoxybenzenesulfonyl chloride. sulfonamide 187 2,4-dichloro-N-(6- 6-aminopyridin-2-ol and 2,4-dichloro-5- hydroxypyridin-2-yl)-5- methylbenzenesulfonyl chloride. methylbenzene sulfonamide

188 N-(6-methoxypyridin-3-yl)-2- 6-methoxypyridin-3-amine and 2- methylbenzene sulfonamide methylbenzenesulfonyl chloride. Name SM 3,5-dichloro-2-hydroxy-N-(6- 6-methoxypyridin-3-amine and 3,5-dichloro-2- methoxypyridin-3- hydroxybenzenesulfonyl chloride. yl)benzenesulfonamide 2,3-dichloro-N-(6- 6-methoxypyridin-3-amine and 2,3- methoxypyridin-3- dichlorobenzenesulfonyl chloride. yl)benzenesulfonamide 2-bromo-N-(6- 6-methoxypyridin-3-amine and 2- methoxypyridin-3- bromobenzenesulfonyl chloride. yl)benzenesulfonamide 2,6-dichloro-N-(6- 6-methoxypyridin-3-amine and 2,6- methoxypyridin-3- dichlorobenzenesulfonyl chloride. yl)benzenesulfonamide N-(6-methoxy pyridin-3-yl)- 6-methoxypyridin-3-amine and 2- 2-(trifluoromethoxy) trifluoromethoxybenzenesulfonyl chloride. benzenesulfonamide 2-chloro-N-(6- 6-methoxypyridin-3-amine and 2-chloro-5- methoxypyridin-3-yl)-5- trifluoromethylbenzenesulfonyl chloride. (trifluoromethyl) benzenesulfonamide 2-cyano-N-(6- 6-methoxypyridin-3-amine and 2- methoxypyridin-3- cyanobenzenesulfonyl chloride. yl)benzenesulfonamide 2-chloro-4-fluoro-N-(6- 6-methoxypyridin-3-amine and 2-chloro-4- methoxypyridin-3- fluorobenzenesulfonyl chloride. yl)benzenesulfonamide N-(5-chloropyridin-2-yl)-2- 5-chloropyridin-2-amine and 2- (trifluoromethoxy)benzene trifluoromethoxybenzenesulfonyl chloride. sulfonamide N-(3,5-dichloropyridin-2-yl)- 3,5-dichloropyridin-2-amine and 3- 3-(trifluoromethyl) trifluoromethylbenzenesulfonyl chloride. benzenesulfonamide 2,4-dichloro-N-(6- 6-methoxypyridin-3-amine and 2,4- methoxypyridin-3- dichlorobenzensulfonyl chloride. yl)benzenesulfonamide 2,5-dichloro-N-(6- 6-methoxypyridin-3-amine and 2,5- methoxypyridin-3- dichlorobenzensulfonyl chloride. yl)benzenesulfonamide

Example 201 2-(trifluoromethyl)-N-(6-(trifluoromethyl)pyridin-3-yl)benzenesulfonamide Method 1 To a cooled solution of 6-(trifluoromethyl)pyridin-3-amine (50 g , 308 mmol) in acetonitrile (500 mL) and pyridine (75 mL) was added 2-trifluoromethylbenzenesulfonyl chloride (52.4 mL, 340 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with 20% citric acid (500 mL) and extracted into ethyl acetate (2 x 500 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (500 mL), brine (500 mL) , dried over magnesium sulphate and concentrated in vacuo. The residue was dissolved in hot (60°C) TBM E (300 mL) , followed by the addition of heptanes (300 mL). The mixture was stirred at 60°C and left to stand at room temperature overnight. The resulting crystals were collected and recrystallised as described above. The resulting crystals were washed with 1:1 TBM E/heptanes (2 x 200 mL), filtered and dried to afford the title compound . The mother liquors were concentrated in vacuo and crystallised as above followed by elution through a plug of silica with DCM . Following one further recrystallisation as above, the total materials were combined to afford the title compound as an orange solid in 70% yield (80 g) . 1 δ H NM R (400M Hz, CDCI3) : ppm 7 .10 (br s , 1H), 7.60 (d, 1H), 7.68-7.80 (m, 3H), 7.92 (d, 1H), 8 .15 (d, 1H), 8.37 (d, 1H).

19 δ F NMR (400M Hz, CDCI3) : ppm -58 (s, 3F), -67 (s, 3F). MS m/z 369 [M-H]

Example 202 2-(trifluoromethyl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzenesulfonamide

Method 2

To a cooled solution (0°C) of 5-(trifluoromethyl)pyridin-3-amine hydrochloride ( 14 g ,

70.5 mmol) in acetonitrile ( 140 mL) and pyridine (28.4 mL, 352 mmol) was added a solution of 2-(trifluoromethyl)benzenesulfonyl chloride ( 18 .11 g , 74 mmol) in acetonitrile (30 mL) dropwise, maintaining the internal temperature below 5°C. The reaction mixture was stirred at room temperature for 72 hours before concentrating in vacuo. The residue was dissolved in EtOAc (250 mL) and washed with 1M citric acid (2 x 250 mL). The combined aqueous layers were washed with EtOAc (250 mL) and the organic extracts were combined and washed with saturated aqueous NaHCC>3 solution (250 mL), brine (250 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was crystallised from TBM E (290 mL) and heptanes (60 mL). The resulting solid was dissolved in EtOAc (600 mL), washed with water (3 x 600 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was dissolved in methanol (420 mL), treated with charcoal ( 10.5 g) and heated to 50°C for 1 hour. The mixture was cooled, filtered through arbocel and concentrated in vacuo to afford the title compound as an off-white solid ( 15 .19 g , 59%). 1 δ H NMR (400M Hz, DMSO-d 6) : ppm 7.72 (s, 1H), 7.84-7.91 (m, 2H), 8.00 (dd, 1H), 8 .17 (d, 1H) , 8.57 (d, 1H), 8.64 (s, 1H), 11.44 (br s , 1H).

19 δ F NMR (400M Hz, DMSO-d 6) : ppm -56 (s, 3F), -61 (s, 3F). MS m/z 369 [M-H]

Example 203 N-(5-bromopyridin-3-yl)-2-(trifluoromethyl)benzenesulfonamide

Method 3

To a solution of 2-(trifluoromethyl)benzenesulfonyl chloride ( 1 g , 4.09 mmol) and

5-bromopyridin-3-amine (707 mg, 4.09 mmol) in acetonitrile ( 15 mL) was added pyridine (660 µ , 8 .18 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water (25 mL) and extracted into EtOAc (2 x 40 mL) . The organic layers were combined, washed with saturated aqueous ammonium chloride solution (20 mL), brine (20 mL), dried over sodium sulphate and concentrated in vacuo. The residue was triturated with DCM to afford the title compound as a white solid (335 mg, 2 1%). 1 δ H NMR (400M Hz, DMSO-d 6) : ppm 7.65 (t, 1H), 7.84-7.92 (m, 2H), 8.01 (dd, 1H), 8 .14 (dd, 1H), 8.29 (d, 1H), 8.38 (d, 1H), 11.24 (br s , 1H)

19 δ F NMR (400M Hz, DMSO-d 6) : ppm -56 (s, 3F). MS m/z 381 [M+H] + Example 204 N-(4-chloro-5-cvano-2-fluorophenyl)-2-(trifluoromethyl)benzenesulfonarnide

Method 4 To a solution of 5-amino-2-chloro-4-fluorobenzonitrile (640 mg, 3.75 mmol) in THF (50 mL) was added a 1M solution of lithium bis(trimethylsilyl)amide in THF (6 mL, 6 mmol) over 5 minutes at 4°C and the reaction mixture was stirred at this temperature for 15 minutes. A solution of 2-(trifluoromethyl)benzenesulfonyl chloride ( 1 .01 g , 4 .13 mmol) in

THF ( 10 mL) was added dropwise over 5 minutes and the reaction mixture stirred at this temperature for 40 minutes. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution ( 100 mL) and the mixture extracted into EtOAc (3 x 70 mL). The organic layers were combined, dried over sodium sulphate and concentrated in vacuo. The residue was purified using reverse phase silica gel column chromatography eluting with from 20-80% acetonitrile (with 0 .1% formic acid) in water (with 0 .1% formic acid) to afford the title compound as a colourless solid (861 mg, 6 1%) . 1 δ H NM R (400M Hz, DMSO-d 6) : ppm 7.83-7.88 (m , 4H), 7.99-8.04 (m, 2H), 10.87 (br s , 1H).

19 δ F NMR (400M Hz, DMSO-d 6) : ppm -56 (s, 3F), - 110 (s, 1F). MS m/z 377 [M-H]

Example 205 3,5-dichloro-2-hvdroxy-N-r6-(trifluoromethyl)pyridin-3-yl1benzenesulfonamide

Method 5 6-(Trifluoromethyl)pyridin-3-amine (3. 10 g , 19 .1 mmol) was dissolved in acetonitrile (80 mL) and the resulting solution was heated to 80°C. A solution of 3,5-dichloro-2- hydroxybenzenesulfonyl chloride (5.00 g , 19 .1 mmol) in acetonitrile (20 mL) was added at 80°C and the reaction mixture was stirred at this temperature for 48 hours. The reaction mixture was cooled, and concentrated in vacuo. The residue was treated with

2M NaOH (aq) ( 100 mL) , stirred at room temperature for 5 minutes and filtered. The filtrate was washed with DCM (3 x 50 mL) before acidifying with cHCI. The resulting precipitate was collected and dried under vacuum to afford the title compound as a white solid (3.78 g , 5 1%). 1 δ H NMR (400M Hz, DMSO-d 6) : ppm 7.70 (dd, 1H), 7.77-7.80 (m, 2H) , 7.87 (d, 1H), 8.49 (d, 1H) , 11.29 (br s , 1H) . 19 δ F NMR (400M Hz, DMSO-d 6) : ppm -66 (s, 3F). MS m/z 385 [M-H]

Example 206 N-r3-cvano-4-(trifluoromethyl)phenyll-2-(trifluoromethyl)benzenesulfonamide

Method 6 To a solution of 5-amino-2-trifluoromethylbenzonitrile (380 mg, 2.04 mmol) in pyridine (5 mL) was added 2-trifluoromethylbenzenesulfonyl chloride (500 mg, 2.04 mmol) and DMAP (25 mg, 0.204 mmol) . The reaction mixture was stirred at room temperature for 48 hours. The reaction was quenched by the addition of 2M HCI (aq) (50 mL) and the mixture extracted into EtOAc (50 mL). The organic layer was collected, washed with 2M HCI (aq) (50 mL) and concentrated in vacuo. The residue was purified using reverse phase chromatography eluting with 10-60% (0. 1% ammonium hydroxide in MeCN) in water to afford the title compound as a colourless solid (31 8 mg, 40%) . 1 δ H NM R (400M Hz, CDCI3) : ppm 7 .19 (d, 1H), 7.40 (d, 1H), 7.56 (d, 1H) , 7.62 (d, 1H) , 7.64-7.78 (m, 2H), 7.91 (dd, 1H) , 8.20 (dd, 1H).

MS m/z 393 [M-H]

The compounds of Examples 207-21 7 were prepared according to the method indicated (i.e. one of the Methods 3-6 described above) using the appropriate sulfonyl chloride and amine and, where specified and unless otherwise indicated, purified using one of the following Preparative HPLC conditions: Preparative Method A :

Column: Gemini C18 11OA, 100 x 21.2 mm, 5 micron

Mobile Phase A : 0.1% formic acid in water, Mobile phase B : 0.1% formic acid in MeCN Gradient: from 5% B to 95% B at 7 minutes and return to 5% B at 9.1 minutes. Flow rate: 18 mL/min, run time = 10 minutes.

Preparative Method B :

Column: Gemini C18 11OA, 100 x 21.2 mm, 5 micron

Mobile Phase A : 0.1% DEA in water, Mobile phase B : 0.1% DEA in MeCN Gradient: from 5% B to 95% B at 7 minutes and return to 5% B at 9.1 minutes. Flow rate: 18 mL/min, run time = 10 minutes.

Where LCMS data is quoted the following method was used: Column: RESTEK C18 30 x 2.1 mm, 3 micron Mobile phase A : 0.05% formic acid in water; Mobile phase B : MeCN Gradient: from 2-10% B at 1 minute, to 98% B at 2 mins and returning to 2% B at 2.9- 3.0 mins. Flow rate: 1.5 mL/min.

Ex Name SM/Method Data/SM 207 3,5-dichloro-N-(4- 3,5-dichloro-2- MS m/z 377 [M+H]+; 1 δ chloro-3- hydroxybenzene H NMR (400MHz, DMSO-d 6) : cyanophenyl)-2- sulfonyl chloride and 5- ppm 7.40 (d, 1H), 7.55 (s, 1H), hydroxybenzene amino-2- 7.60 (d, 1H), 7.70 (s, 1H), 7.85 sulfonamide chlorobenzonitrile; (s, 1H), 11.00-1 1.20 (br s , 1H). Method 5 208 N-(4-cyano-3- 2-(trifluoromethyl) MS m/z 355 [M-H] ; 1 δ methoxyphenyl)- benzenesulfonyl H NMR (400MHz, CDCI3) : 2-(trifluoromethyl) chloride and 4-amino- ppm 3.90 (s, 3H), 6.60-6.65 (m, benzene 2-methoxybenzonitrile; 1H), 6.80 (s, 1H), 7.20-7.40 (m, sulfonamide Method 3 2H), 7.60-7.80 (m, 2H), 7.90 (d, Purification by silica 1H), 8.10 (d, 1H). gel column chromatography eluting with 20% EtOAc in heptanes.

Ex Name SM/Method Data/SM 216 2-fluoro-N-(6- 2-fluorobenzene LCMS Rt = 1.29 minutes methylpyridin-3- sulfonyl chloride and 6- MS m/z 267 [M+H]+ yl)benzene methylpyridin-3-amine; sulfonamide Method 6 , at 60°C. Purified using Preparative HPLC.

Example 2 17 3-cvano-N-(5-fluoropyridin-2-yl)-4-hvdroxybenzenesulfonamide

To a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(5-fluoropyridin-2- yl)benzenesulfonamide (0.2 g , 0.448 mmol) in NMP (5 mL) was added drop-wise 2- (methylsulfonyl)ethanol (42 µ , 0.448 mmol). Sodium hydride (36 mg, 0.896 mmol) was added in 1 portion and the reaction mixture left to stir at room temperature for 18 hours.

The reaction was quenched by the addition of water ( 10 mL) and the mixture extracted into diethyl ether (3 x 5 mL) . The pH of the aqueous layer was adjusted to pH=4 by the addition of 2M HCI (aq) and was re-extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. The residue (0.448 mmol) was dissolved in dioxane (2 mL) and treated with 4M HCI in dioxane (2 mL). The reaction mixture was stirred at room temperature for 72 hours. The resulting precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 10-60% EtOAc in heptanes to afford the title compound (24 mg, 18%) as a white solid. 1 δ H NMR (400M Hz, MeOH-d4) : ppm 7.00 (d , 1H) , 7 .18-7.20 (m, 1H), 7.50-7.58 (m, 1H), 7.98 (d, 1H), 8.05-8. 10 (m, 2H). MS m/z 294 [M+H]+ Example 2 18 6-(trifluoromethyl)-3-({r2-(trifluoromethyl)ph

To a solution of N-(2-cyano-6-(trifluoromethyl)pyridin-3-yl)-2- (trifluoromethyl)benzenesulfonamide (Example 209, 2 12 mg, 0.540 mmol) in dimethylsulfoxide (6 ml_) was added potassium carbonate (224 mg, 1.62 mmol) followed by hydrogen peroxide (30% w/w, 2 ml_, 2 1.6 mmol) . The reaction mixture was stirred at room temperature for 3 hours before the addition of 2M HCI until adjusted to pH= 1. The resulting precipitate was filtered and dried to afford the title compound as a yellow solid

( 164 mg, 74%) . 1 δ H NMR (400M Hz, DMSO-d 6) : ppm 7.91 (m, 2H), 7.96-8. 13 (m, 3H), 8.35 (t, 1H), 8.39 (br s , 1H), 8.48 (br s , 1H), 13 .17 (br s , 1H) . MS m/z 4 12 [M-H]

Example 2 19 3-cvano-N-(5-fluoropyridin-2-yl)-4-propoxybenzenesulfonamide

To a 0.2M solution of 3-cyano-4-fluoro-N-(5-fluoro-2-pyridyl)benzenesulfonyl chloride

(WO 201 0079443, 500 µ Ι_, 100 µηιοΙ) in DMSO was added a 0.2M solution of propan-1 - ol (500 µ Ι_, 100 µηιοΙ) in DMSO followed by potassium phosphate (64 mg, 300 µηιοΙ). The reaction mixture was heated at 80°C for 16 hours. The reaction mixture was cooled, concentrated in vacuo and purified using preparative HPLC as described below to yield the title compound . Preparative HPLC: Column: Phenomenex Gemini C 18 100 x 20 mm, 5 micron.

Mobile phase A : MeCN . Mobile phase B : 10 mM ammonium formate in water. Gradient: From 10-70% organic over a run time of 10 mins. Flow rate: 20 mL/min. LCMS QC: Column: RESTEK C18 30 x 2.1 mm, 3 micron Mobile phase A : 0.05% formic acid in water; Mobile phase B : MeCN Gradient: from 2-10% B at 1 minute, to 98% B at 2 mins and returning to 2% B at 2.9- 3.0 mins. Flow rate: 1.5 mL/min. LCMS Rt = 1.62 minutes MS m/z 336 [M+H]+

Example 220

To a 0.25M solution of 2-chlorobenzenesulfonyl chloride in DCE (200 µ , 0.05 mmol) was added a 0.25M solution of 5-amino-pyridin-2-ol in DME (200 µ , 0.05 mmol) followed by a 1M solution of triethylamine in DME (50 µ , 0.05 mmol). The reaction mixture was shaken and allowed to stand at room temperature for 18 hours. The reaction mixture was treated with a 1M solution of sodium methoxide in MeOH (50 µ ) and concentrated in vacuo. The residue was eluted through a plug of silica using 1:1 DCM:EtOAc to afford the title compound . LCMS QC: Phenomenex Gemini C18 4.6 X 50 mm 5 micron; (Mobile phase A : 0.01%

TFA in water, mobile phase B : 0.01% TFA in MeCN). LCMS Rt = 1.130 minutes MS m/z 285 [M+H] +

Example 221 Racemic-N-r6-(1-hvdroxypropyl)pyridin-2-yll-2-(trifluoromethyl)benzenesulfonamide trifluoroacetate salt

TFA The title compound was prepared according to the method described for Example 220 using 2-trifluoromethylbenzenesulfonyl chloride and racemic-1 -(6-aminopyridin-2- yl)propan-1 -ol . LCMS QC: YMC ODS-AQ 2.0 x 50 mm, 5 micron; (Mobile phase A : 0.05% TFA in water, mobile phase B : 0.05% TFA in MeCN). LCMS Rt = 2.576 minutes MS m/z 361 [M+H]+

The compounds of formula (I) that follow were prepared from appropriate precursors by procedures described in the aforementioned Schemes and/or Methods, as further illustrated by the preceding Examples and corresponding Preparations, or by processes similar thereto.

The compounds of formula (I) below are commercially available or may be prepared from appropriate precursors by procedures described in the aforementioned Schemes and/or Methods, as further illustrated by the preceding Examples and corresponding Preparations , or by processes similar thereto.

Ex Name CAS Reg No: 228 3,4-difluoro-N-[4-(trifluoromethoxy) 871 922-96-2 phenyl]benzenesulfonamide 229 2,6-dichloro-N-(3-chloropyridin-4-yl)benzenesulfonamide 851 175-1 0-5 230 2,3-dichloro-N-(3-chloropyridin-4-yl)benzenesulfonamide 778620-71 -6 Preparation 1 3-cvano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(5-fluoropyridin-2-yl)benzenesulfonarnide

To a solution of N-(2,4-dimethoxybenzyl)-5-fluoropyridin-2-amine (Preparation 2 , 3.25 g , 12.4 mmol) in THF (50 ml_) at -40°C was slowly added LiHM DS ( 1 M in THF, 12.4 ml_, 12.4 mmol). The solution was slowly warmed to 0°C and left to stir for 50 minutes. The reaction mixture was then cooled to -40°C and 3-cyano-4-fluorobenzene-1 -sulfonyl chloride (2.47 g , 11.3 mmol) dissolved in THF (40 ml_) was slowly added. The reaction mixture was warmed to room temperature and left to stir for 18 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution ( 100 ml_) and the mixture extracted with EtOAc ( 100 ml_). The organic layer was washed with brine ( 100 ml_), dried over MgS0 4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with DCM followed by a second chromatography eluting with 20% EtOAc in heptanes to afford the title compound as a gummy oil (2.68 g , 53%). 1 δ H NMR (400 MHz, DMSO-d6) : ppm 3.54 (s, 3H), 3.68 (s, 3H), 4.79 (s, 2H), 6.37 ( , 2H) , 7.04 (d, 1H), 7.37 (dd, 1H) , 7.70 (t, 1H) , 7.76 (td, 1H), 8.04 (m, 1H) , 8.31 (dd, 1H) , 8.36 (d, 1H). MS m/z 446 [M+H]+

Preparation 2 N-(2,4-dimethoxybenzyl)-5-fluoropyridin-2-amine

To a solution of 2,5-difluoropyridine (5 g , 43.5 mmol) in DMSO (40 ml_) was added

K2C0 3 ( 18 g , 0 .13 mol) and (2,4-dimethoxyphenyl)methanamine ( 10.9 g , 62.2 mmol). The reaction mixture was heated to 100°C for 3 days. The reaction mixture was cooled to room temperature, diluted with water ( 150 ml_) and extracted with EtOAc ( 150 ml_ and 100 ml_) . The organic layers were combined and washed with brine (3 x 100 ml_), dried over MgS0 4 and concentrated in vacuo to afford the title compound as a colourless solid (3.25 g , 28%) . 1 δ H NM R (400 MHz, DMSO-d 6) : ppm 3.71 (s, 3H), 3.77 (s, 3H), 4.27 (d, 2H), 6.42 (dd, 1H), 6.50 (dd, 1H), 6.52 (br s , 1H),6.70 (t, 1H), 7.09 (d, 1H), 7.31 (td, 1H), 7.88 (d, 1H). MS m/z 263 [M+H]+

Biological Assay 1. Generation of a custom clonal cell line for URAT1 transporter activity assay The nucleotide sequence for the long isoform of URAT1 (NM_1 44585) was C-terminally fused to that of enhanced green fluorescent protein (eGFP) (hereinafter referred to as URATI (L)GFP). The combined sequence was codon-optimised and custom synthesized. The synthesized sequence was generated in pDON R22 1 Gateway entry vector (Invitrogen Life Technologies) prior to cloning in pLenti6.3/V5 Gateway destination vector ( Invitrogen Life Technologies). A schematic of the URAT1(L)GFP construct follows.

The nucleotide and amino acid sequence of the URAT1(L)GFP construct is set out below, which also shows alignment of the nucleotide sequence with NM_1 44585 .

Alignment row 1 is the sequence from accession NM_1 44585. Alignment row 2 is the sequence of the construct in the Gateway destination vector pLenti6.3V5/DEST (encoding URATI (L)GFP) with the nucleotide alignment indicated with NM_1 44585 above and the nucleotide numbering below. Alignment row 3 is the amino acid translation with sequence annotation indicated in italics below. GGGCCCCTCTTCTGGGCCCCTTGAGTAGGTTCCATGGCATTTTCTGAACTCCTGGACCTC

I I I I I I I I I I I I I I I I I I ACAAGTTTGTACAAAAAAGCAGGCTTCGCCACCATGGCCTTCAGCGAGCTGCTGGACCTG + + + + + +60 M A F S E L L D L attBl-5 ' URAT1 Initiation co on

G GGG GGCC GGGCAGG CCAGG C CCAGACGA GGC C GA GG C CCA CA G

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I G GGGAGGCC GGGCAGA CCAGG GC GCAGACCA GGCCC GA GG G CCATCA G + + + + + +120 V G G L G F V L T A L V S

TGGCTGTGTACCCAGAGCATGCTGGAGAACTTCTCGGCCGCCGTGCCCAGCCACCGCTGC

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I TGGCTGTGCACCCAGAGCATGCTGGAAAACTTCTCTGCCGCCGTGCCCAGCCACAGATGC + + + + + +180 L C T S M L E N F S A A V P S H R C

TGGGCACCCCTCCTGGACAACAGCACGGCTCAGGCCAGCATCCTAGGGAGCTTGAGTCCT

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I TGGGCCCCTCTGCTGGACAACAGCACCGCCCAGGCCAGCATCCTGGGCAGCCTGTCTCCA + + + + + +240 A P L L D N S T A A S I L G S L S P

GAGGCCCTCCTGGCTATTTCCATCCCGCCGGGCCCCAACCAGAGGCCCCACCAGTGCCGC

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I GAGGCCCTGCTGGCCAT CAGCATCCCCCCTGGCCCCAACCAGAGGCCCCACCAGTGCAGA + + + + + +300 E A L L A I S I P P G P N R P H C R

CGCTTCCGCCAGCCACAGTGGCAGCTCTTGGACCCCAATGCCACGGCCAC CAGCTGGAGC

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I CGGTTCCGGCAGCCTCAGTGGCAGCTGCTGGATCCCAACGCCACCGCCACCTCTTGGAGC + + + + + +360 R F R P L L D P N A T A T S S GAGGCCGACACGGAGCCGTGTGTGGATGGCTGGGTCTATGACCGCAGCATCTTCACCTCC

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I GAGGCCGACACCGAGCCCTGTGTGGACGGCTGGGTGTACGACCGGTCCATCTTCACCAGC + + + + + + 4 E A D T E P C V D G V Y D S I F T S

ACAATCGTGGCCAAGTGGAACCTCGTGTGTGACTCTCATGCTCTGAAGCCCATGGCCCAG

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I ACCATCGTGGCCAAGTGGAACCTGGTGTGCGACAGTCACGCCCTGAAGCCCATGGCCCAG + + + + + + 4 8 0 T I V A K N L V C D S H A L K P A

TCCATCTACCTGGCTGGGATTCTGGTGGGAGCTGCTGCGTGCGGCCCTGCCTCAGACAGG

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I AGCATCTACCTGGCCGGCATTCTGGTGGGAGCCGCCGCTTGTGGCCCTGCCAGCGATAGA + + + + + + 5 4 0 S I Y L A G I L V G A A A C G P A S D R

TTTGGGCGCAGGCTGGTGCTAACCTGGAGCTACCTTCAGATGGCTGTGATGGGTACGGCA

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I TTCGGCAGACGGCTGGTGCTGACCTGGTCCTACCTGCAGATGGCCGTGATGGGCACCGCC + + + + + + 6 0 0 F G R R L V L T S Y L A V G T A

GCTGCCTTCGCCCCTGCCTTCCCCGTGTACTGCCTGTTCCGCTTCCTGTTGGCCTTTGCC

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I GCAGCCTTTGCCCCTGCCTTCCCTGTGTACTGCCTGTTCCGGTTCCTGCTGGCCTTCGCC + + + + + + 6 6 0 A A F A P A F P V Y C L F R F L L A F A

GTGGCAGGCGTCATGATGAACACGGGCACTCTCCTGATGGAGTGGACGGCGGCACGGGCC

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I GTGGCCGGCGTGATGATGAACACCGGCACCCTGCTGATGGAATGGACCGCCGCCAGAGCC + + + + + + 7 2 0 V A G V N T G T L L E T A A R A

CGACCCTTGGTGATGACCTTGAACTCTCTGGGCTTCAGCTTCGGCCATGGCCTGACAGCT

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I AGACCCCTGGTGATGACCCTGAACAGCCTGGGCTTCAGCTTCGGACATGGCCTCACAGCC + + + + + + 7 8 0 R P L V T L N S L G F S F G H G L T A GCAGTGGCCTACGGTGTGCGGGACTGGACACTGCTGCAGCTGGTGGTCTCGGTCCCCTTC

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I GCTGTGGCTTATGGCGTGCGGGACTGGACACTGCTGCAGCTGGTGGTGTCCGTGCCCTTC + + + + + +8 A V A Y G V D T L L L V V S V P F

TTCCTCTGCTTTTTGTACTCCTGGTGGCTGGCAGAGTCGGCACGATGGCTCCTCACCACA

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I TTCCTGTGCTTCCTGTACAGCTGGTGGCTCGCTGAGAGCGCCCGGTGGCTGCTGACCACA + + + + + +900 F L C F L Y S L A E S A R L L T T

GGCA GGC GGA GGGGCC GCA GGA GC G GGAGGG GGC GCCA CAACGGAAAGGGG

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I GGCAGACTGGACTGGGGCCTGCAGGAACTGTGGCGGGTCGCCGCCAT CAATGGCAAGGGC + + + + + +960 G R L D G L E L R V A A I N G G

GCAGTGCAGGACACCCTGACCCCTGAGGTCTTGCTTTCAGCCATGCGGGAGGAGCTGAGC

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I GCCGTGCAGGACACCCTGACCCCTGAGGTGCTGCTGAGCGCCATGCGCGAGGAACTGAGC + + + + + +1020 A V D T L T P E V L L S A R E E L S

ATGGGCCAGCCTCCTGCCAGCCTGGGCACCCTGCTCCGCATGCCCGGACTGCGCTTCCGG

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I ATGGGCCAGCCTCCAGCCAGCCTGGGCACACTGCTGAGAATGCCCGGCCTGCGGTTCCGG + + + + + +1080 G P P A S L G T L L R P G L R F R

ACCTGTATCTCCACGTTGTGCTGGTTCGCCTTTGGCTTCACCTTCTTCGGCCTGGCCCTG

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I A CC GCA CA GCACCC G G GG CGCC CGGC CA CC C CGGCC GGCCC G

+ + + + + +1140 T C I S T L C F A F G F T F F G L A L

GACCTGCAGGCCCTGGGCAGCAACATCTTCCTGCTCCAAATGTTCATTGGTGTCGTGGAC

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I GACCTCCAGGCCCTGGGCAGCAACATCTTCCTGCTGCAGATGTTCATCGGCGTGGTGGAC + + + + + +1200 D L A L G S N I F L L F I G V V D ATCCCAGCCAAGATGGGCGCCCTGCTGCTGCTGAGCCACCTGGGCCGCCGCCCCACGCTG

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I ATCCCCGCCAAGATGGGCGCCCTGCTGCTGCTGTCTCACCTGGGCAGAAGGCCTACCCTG

+ + + + + + 12 6 0 I P A M G A L L L L S H L G R R P T L

GCCGCATCCCTGTTGCTGGCAGGGCTCTGCATTCTGGCCAACACGCTGGTGCCCCACGAA

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I GCCGCCTCTCTGCTGCTGGCCGGACTGTGCATCCTGGCCAACACCCTGGTGCCCCACGAG

+ + + + + + 132 0 A A S L L L A G L C I L A N T L V P H E

ATGGGGGCTCTGCGCTCAGCCTTGGCCGTGCTGGGGCTGGGCGGGGTGGGGGCTGCCTTC

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I ATGGGAGCCCTGAGATCTGCCCTGGCCGTCCTGGGACTGGGAGGCGTGGGAGCTGCCTTC + + + + + + 1 3 8 0 M G A L R S A L A V L G L G G V G A A F

ACCTGCAT CACCA CTACAGCAGCGAGC C CCCCAC G GC CAGGA GACGGCAG G

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I ACCTGTAT CACCA CTACAGCAGCGAGC G CCCCACCG GC GCGGA GACAGCCG G + + + + + + 1 4 4 0 T C I T I Y S S E L F P T V L T A V

GGCTTGGGCCAGATGGCAGCCCGTGGAGGAGCCATCCTGGGGCCTCTGGTCCGGCTGCTG

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I GGCCTGGGACAGATGGCCGCCAGAGGCGGAGCCATCCTGGGACCTCTGGTGCGCCTGCTG + + + + + + 1 5 0 0 G L G M A A R G G A I L G P L V R L L

GGTGTCCATGGCCCCTGGCTGCCCTTGCTGGTGTATGGGACGGTGCCAGTGCTGAGTGGC

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I GGAGTGCACGGACCTTGGCTCCCTCTGCTGGTGTACGGCACCGTGCCTGTGCTGTCTGGA + + + + + + 1 5 6 0 G V H G P L P L L V Y G T V P V L S G

CTGGCCGCACTGCTTCTGCCCGAGACCCAGAGCTTGCCGCTGCCCGACACCATCCAAGAT

I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I C GGC GC C GC GC GCCCGAGACACAGAGCC GCCCC GCCCGACACCATCCAGGAC

+ + + + + + 162 0 L A A L L L P E T S L P L P D T I D GTGCAGAACCAGGCAGTAAAGAAGGCAACACATGGCACGCTGGGGAACTCTGTCCTAAAA

IIIIIIIIIIIIII I I IIIIIIII I I I I IIIII IIIII III I I I I I I GTGCAGAACCAGGCCGTGAAGAAGGCCACCCACGGCACCCTGGGCAACAGCGTGCTGAAG + + + + + +1680 V N A V K K A T H G T L G N S V L K

CCA CA CA GT C IIIII IIIIII TCCACCCAGTTCATGGTGTCCAAGGGGGAGGAACTGTTTACCGGCGTGGTGCCCATCCTG

+ + + + + +1740 S T F V S K G E E L F T G V V P I L End of RA 1 sequence Initiation fox: eGFP

GTGGAACTGGACGGCGACGTGAACGGCCACAAGTTCAGCGTGTCCGGCGAGGGCGAAGGC + + + + + +1800 V E L D G D V N G H F S V S G E G E G

GACGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCCGTG + + + + + +1860 D A T Y G K L T L K F I C T T G K L P V

CCTTGGCCCACCCTGGTGACAACCTTCACCTACGGCGTGCAGTGCTTCGCCAGATACCCC + + + + + +1920 P P T L V T T F T Y G V C F A Y P

GACCACATGAAGCAGCACGATTTCTTCAAGTCCGCCATGCCCGAGGGCTACGTGCAGGAA + + + + + +1980 D H H D F F S A P E G Y V E

CGGAC CAT CTTCTTCAAG GAC GACGG CAACTACAAGAC CAGAG CCGAAGT GAA G CGAG + + + + + +2040 R T I F F K D D G N Y K T R A E V K F E

GGCGATACCCTGGTGAACCGGATCGAGCTGAAGGGCATCGACTTCAAAGAGGACGGCAAT + + + + + +2100 G D T L V N R I E L K G I D F K E D G N ATCCTGGGCCACAAGCTGGAGTACAACTACAACAGCCACAAGGTGTACATCACCGCCGAC

+ + + + + +2160 I L G H L E Y N Y N S H V Y I T A D

AAG CAGAAAAAC GGCAT CAAAGT GAA C CAAGAC CCGGCACAACAT CGAGGAC GGAAGC + + + + + +2220 N G I V N F T H N I E D G S

GTGCAGCTGGCCGACCACTAC CAGCAGAACACCCCCATCGGCGACGGCCCCGTGCTGCTG + + + + + +2280 V L A D H Y N T P I G D G P V L L

CCTGACAAC CACTACCTGAGCACCCAGTCCGCCCTGAG CAAGGAC CCCAAC GAGAAG CGG + + + + + +2340 P D N H Y L S T S A L S D P N E R

GACCACATGGTGCTGCTGGAATTCGTGACCGCCGCTGGCATCACACTGGGCATGGACGAG + + + + + +2400 D H V L L E F V T A A G I T L G D E

attB2-3 ' CTGTACAAGTACCCAGCTTTCTTGTACAAAGTGGTTGATATCCAGCACAGTGGCGGCCGC + + + + + +2460 L Y K P A F L Y K V V N I H S G G R End of Egfp

TCGAGTCTAGAGGGCCCGCGGTTCGAAGGTAAGCCTATCCCTAACCCTCTCCTCGGTCTC + + + + + +2520 S S L E G P R F E G K P I P N P L L G L V5 EPITOPE

GAT TCTACGCGTACCGGT TAGTAAT GA

+ + 2547 D S T R T G * * * STOP

Lentiviral particles were generated according to ViraPower HiPerform expression system procedure (Invitrogen Life Technologies) and used to transduce CHO cells. Blasticidin selection enabled the generation of a stable clonal pool of cells, confirmed by expression of GFP and V5 epitope. The clonal pools were sorted using fluorescence- activated cell sorting (FACS) on the basis of GFP expression with the gating set at the top 50% of expression into single cells which were subsequently expanded to generate clonal lines. One clone was identified with the best assay performance as determined by maximal separation between complete inhibition of uric acid transport (with 10 µΜ benzbromarone) and no inhibition (DMSO). This cell line was used for all screening activities and is referred to as CHO-U RAT1(L)GFP#8 or CHO#8.

2. URAT1 Inhibitor activity The potency of the compounds of formula (I) as inhibitors of the URAT1 transporter was determined as follows.

CHO#8 cells were cultured in cell line maintenance flasks in medium consisting of Dulbecco's modified Eagle medium (DM EM) with high glucose and sodium pyruvate (4.5 g of glucose per litre, Invitrogen Life Technologies), supplemented with heat- inactivated foetal bovine serum (FBC, 10 % v/v), 1x NEAA (non-essential amino acids) and blasticidin ( 10 µg/ml). Cultures were grown in 175 cm2 tissue culture flasks in a humidified incubator at approximately 37°C in approximately 95% air/5% CO2. Near confluent CHO#8 cell cultures were harvested by trypsinisation, re-suspended in culture medium and the process was repeated once or twice weekly to provide sufficient cells for use.

Assay ready flasks were generated by the same method, except the cells were not cultured in blasticidin.

Assay ready frozen cells were generated by freezing 40,000,000 cells in 1ml of FBS (without blasticidin) containing 10% DMSO per vial . One vial was sufficient for 5 assay plates. Each vial was thawed rapidly to 37°C, washed and re-suspended in pre- warmed culture medium for seeding onto assay plates.

CHO#8 cells were seeded onto Cytostar™ 96-well plates at a density of 5 x 105 cells per well. The cells were cultured for 1 day at approximately 37°C in a humidified incubator containing approximately 5% CO2 in air. After approximately 24 hours culture, cells were used for uptake experiments. On the day of assay, culture medium was removed from the wells and the cells were washed once with 50 µ Ι_ of chloride-containing buffer ( 136.7 mM NaCI, 5.36 mM KCI,

0.952 mM CaCI 2, 0.441 mM KH2P0 4, 0.81 2 mM MgS0 4, 5.6 mM D-glucose, 0.383 mM

Na2HP0 4.2H 20 , 10 mM HEPES, pH 7.4 with NaOH) . The cells were pre-incubated with another 50 µ Ι_ of chloride-containing buffer for one hour at approximately 37°C in a humidified incubator containing approximately 5% C0 2 in air.

Assay compound plates were prepared by diluting the compounds of formula (I) with chloride-free buffer ( 125 mM Na-gluconate, 4.8 mM K-gluconate, 1.3 mM Ca-gluconate,

1.2 mM KH2P0 4, 1.2 mM MgS0 4, 5.6 mM D-glucose, 25 mM HEPES, pH 7.4 with NaOH) in 100% DMSO to a final concentration of 1% DMSO. [14C]-Uric acid working stock was made by addition of radiolabeled compound to a final concentration of 120 nM in chloride-free buffer. In all wells, the final assay concentration of solvent (DMSO) was 0.25%; the final assay concentration of [14C]-uric acid was 30nM in chloride-free buffer and the final compound of formula (I) concentrations ranged from 0 to 10 µΜ. The vehicle comparator was DMSO (i.e. no inhibition of uric acid transport) and the pharmacological blockade (i.e. 100% inhibition of uric acid transport) was defined by benzbromarone at 10 µ Μ final assay concentration.

After pre-incubation, cells were washed with 50 µ Ι_ of chloride-free buffer and another 50 µ Ι_ of chloride-free buffer was added. Thereafter, 25 µ Ι_ of compound of formula (I) was added from the prepared compound plate and the cells were pre-incubated for 15 minutes prior to the addition of 25 m l_ of [14C] uric acid. The plate was incubated at room temperature and protected from light for three hours prior to measuring proximity- induced scintillation on a Wallac microbeta at 1 minute/well.

The accumulation of [14C]-uric acid into CHO#8 cells was calculated and the IC50 (nM) values, defined as the concentration of inhibitor required for 50% inhibition of transport, were determined from a 4 parameter logistic fit to generate sigmoid curves from dose response data. Ex. ICso (nM) Ex. ICso (nM) Ex. ICso (nM) Ex. ICso (nM) 1 185 3 1 366 6 1 1750 9 1 2351 2 44 32 111 62 382 92 60 3 64 33 360 63 2836 93 1572 4 388 34 1243 64 513 94 331 5 156 35 5 1 65 29 95 783 6 1264 36 10 66 1156 96 233 7 >10000 37 1974 67 718 97 673 8 405 38 >10000 68 940 98 780 9 3918 39 166 69 440 99 249 10 446 40 87 70 846 100 397 11 86 4 1 >10000 7 1 14 101 2409 12 3609 42 1499 72 2 11 102 5 11 13 188 43 3641 73 6 103 1049 14 >10000 44 >10000 74 151 104 282 15 89 45 >10000 75 20 105 8 1 16 >10000 46 >10000 76 641 106 8 1 17 88 47 4412 77 1969 107 817 18 1031 48 >10000 78 593 108 2803 19 2 11 49 5622 79 3927 109 167 20 1938 50 >10000 80 785 110 631 2 1 1171 5 1 2891 8 1 89 111 222 22 2491 52 >10000 82 283 112 88 23 171 53 569 83 156 113 266 24 616 54 >10000 84 127 114 101 25 24 55 1353 85 706 115 429 26 >10000 56 >10000 86 574 116 98 27 112 57 >10000 87 265 117 315 28 79 58 >10000 88 3397 118 199 29 234 59 >10000 89 203 119 6597 30 23 60 3153 90 67 120 >10000 Ex. ICso (nM) Ex. ICso (nM) Ex. ICso (nM) Ex. ICso (nM) 121 2561 151 2026 181 >4028 2 11 42 122 374 152 1973 182 612 212 39 123 32 153 7 1 183 188 213 18 124 95 154 434 184 244 214 520 125 2659 155 246 185 603 215 18 126 4434 156 8 186 2089 216 >10000 127 1382 157 158 187 1237 217 >6717 128 2961 158 484 188 >10000 218 210 129 752 159 78 189 50 219 >10000 130 137 160 2041 190 >10000 220 >10000 131 >10000 161 476 191 >9030 221 1614 132 407 162 587 192 >10000 222 475 133 27 163 47 193 >91 16 223 926 134 8 164 510 194 >8923 224 1523 135 236 165 4032 195 >10000 225 >10000 136 4 166 >10000 196 >10000 226 251 137 18 167 659 197 1061 227 >10000 138 187 168 528 198 >10000 228 >10000 139 801 169 467 199 >10000 229 306 140 12 170 2148 200 >10000 230 666 141 393 171 2051 201 42 225 >10000 142 84 172 166 202 36 226 251 143 119 173 198 203 35 227 >10000 144 1485 174 290 204 12 228 >10000 145 73 175 374 205 115 229 306 146 225 176 477 206 32 230 666 147 14 177 757 207 2 1 148 145 178 337 208 33 149 156 179 1274 209 NT 150 >10000 180 >1822 210 47

NT = not tested Claims

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof for use as a medicament, wherein:

1 each R is independently: halogen; OH; CN; (Ci-C 4)alkyl optionally substituted by one, two or three F ; or (Ci-C 4)alkyloxy optionally substituted by one, two or three F ;

X1 is phenyl or pyridinyl, wherein said phenyl or pyridinyl is substituted on a ring carbon atom by one, two or three R2;

2 each R is independently: halogen; OH; CN; (Ci-C 4)alkyl optionally substituted by one, two or three F ; (Ci-C 4)alkyl substituted by OH; (Ci-C 4)alkyloxy optionally substituted by 3 4 5 one, two or three F ; -0(CH 2)n(C3-C4)cycloalkyl; -CONR R ; or -S0 2R ;

3 4 each R and R is independently H or (Ci-C 4)alkyl or, together with the nitrogen atom to which they are attached, form a saturated 4- to 6-membered nitrogen containing monocycle;

5 each R is independently (Ci-C 4)alkyl optionally substituted by one, two or three F ; m is 1 , 2 or 3 ; and n is 1 or 2 .

2 . A compound according to claim 1 of formula (Ic)

(Ic) or a pharmaceutically acceptable salt thereof for use as a medicament, wherein:

1 is

2 each R is independently: halogen; (Ci-C4)alkyl optionally substituted by one, two or three F ; (Ci-C4)alkyloxy optionally substituted by one, two or three F ; -OCH (C -C )cycloalkyl or-0(CH (C -C )cycloalkyl. 2 3 4 2 ) 2 3 4

A compound according to claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament wherein X1 is phenyl substituted on a ring carbon atom by one, two or three R2.

A compound according to either claim 1 or 3 of formula (Ic)

or a pharmaceutically acceptable salt thereof for use as a medicament, wherein X1 is phenyl substituted on a ring carbon atom by one, two or three R2.

A compound according to any one of claims 1 , 3 or 4 or a pharmaceutically acceptable salt thereof for use as a medicament, wherein:

2 each R is independently: halogen; CN; (Ci-C4)alkyl optionally substituted by one, two or three F ; (C C4)alkyloxy optionally substituted by one, two or three 3 4 5 F ; -CONR R ; or -S0 2R ; 3 4 each R and R is independently H or (Ci-C 4)alkyl; and

5 each R is independently (Ci-C 4)alkyl optionally substituted by one, two or three F.

6 . A compound according to any one of claims 1 to 5 for use in the treatment of a disorder for which a URAT1 inhibitor is indicated.

7 . A compound according to claim 6 wherein the disorder for which a URAT1 inhibitor is indicated is gout.

8 . A compound of formula (la)

or a pharmaceutically acceptable salt thereof, wherein each -CF 3 may be attached at any available carbon atom of the respective phenyl or pyridinyl ring.

9 . A compound according to claim 10 of formula (lb)

or a pharmaceutically acceptable salt thereof wherein the pyridinyl substituent is attached at either the 5- or 6- position pyridinyl carbon.

The compound according to either claim 8 or 9 that is: 2-(trifluoromethyl)-N-(6-(trifluoromethyl)pyridin-3-yl)benzenesulfonamide; or 2-(trifluoromethyl)-N-(5-(trifluoromethyl)pyridin-3-yl)benzenesulfonamide; or a pharmaceutically acceptable salt thereof. 11. A pharmaceutical composition comprising a compound according to any one of claims 8 to 10 and a pharmaceutically acceptable excipient.

12. A pharmaceutical composition according to claim 11 including one or more additional therapeutic agents.

13. A compound according to any one of claims 8 to 10 for use as a medicament.

14. A compound according to any one of claims 8 to 10 for use in the treatment of a disorder for which a URAT1 inhibitor is indicated.

15. A compound according to claim 14 wherein the disorder for which a URAT1 inhibitor is indicated is gout.

16. Use of a compound according to any of claims 8 to 10 for the preparation of a medicament for the treatment of a disorder for which a URAT1 inhibitor is indicated.

17. A method of treating a disorder in a human or animal for which a URAT1 inhibitor is indicated, comprising administering to said human or animal a therapeutically effective amount of a compound according to any of claims 8 to 10. A . CLASSIFICATION O F SUBJECT MATTER INV. C07C311/21 A61K31/18 C07D213/76 A61P19/06 A61K31/44 ADD.

According to International Patent Classification (IPC) o r t o both national classification and IPC

B . FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) C07C C07D A61K

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)

EPO-Internal , WPI Data, CHEM ABS Data

C . DOCUMENTS CONSIDERED T O B E RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

Hi toshi Nakayama ET AL: "Synthesi s of 1,8, N- [2- (2 ,4-Di f l uorophenoxy) tri f l uoromethyl - 11-13 3-pyri dyl ] - sul fonami des and Thei r Inhi bi tory Acti v i t i es agai nst Secretory Phosphol i pase A2" , Chem. Pharm. Bul l . 59 (8, 1 August 2011 (2011-08-01) , pages 1069-1072 , XP055229305 , Retri eved from the Internet: URL: https ://www.j stage.j st.go.Jp/arti cl e/c pb/59/8/59_8_1069/_pdf [retri eved on 2015-11-18] page 1069 ; f i gure 1; compound 2a -/-

X| Further documents are listed in the continuation of Box C . See patent family annex.

* Special categories of cited documents : "T" later document published after the international filing date o r priority date and not in conflict with the application but cited to understand "A" document defining the general state of the art which is not considered the principle o r theory underlying the invention to be of particular relevance "E" earlier application o r patent but published o n o r after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel o r cannot b e considered to involve a n inventive "L" documentwhich may throw doubts o n priority claim(s) orwhich is step when the document is taken alone cited to establish the publication date of another citation o r other "Y" document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve a n inventive step when the document is "O" document referring to a n oral disclosure, use, exhibition o r other combined with one o r more other such documents, such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

20 November 2015 27/11/2015

Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 N L - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 Bedel , Chri sti an C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

X SIU M ET AL: "N- (Pyri di n-2-yl ) 1 aryl sul fonami e i nhi bi tors of llbeta-hydroxysteroi d dehydrogenase type 1: Di scovery of PF-915275" , BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON , AMSTERDAM, NL, vol . 19 , no. 13 , 1 July 2009 (2009-07-01) , pages 3493-3497 , XP026155094, ISSN : 0960-894X, D0I : 10. 1016/J . BMCL.2009 .05 .011 [retri eved on 2009-05-07] page 3494 - page 3495 ; f i gure 4 ; tabl e 2 ; compounds 11-15

A 0 2013/057722 Al (PFIZER LTD [GB] ) 1-17 25 Apri l 2013 (2013-04-25) c i ted i n the appl i cati on c l aims ; exampl es Patent document Publication Patent family Publication cited in search report date member(s) date

W0 2013057722 Al 25-04-2013 AU 2012324405 Al 08 -05 -2014 CA 2852039 Al 25 -04 -2013 CN 103889420 A 25 -06 -2014 EP 2768505 Al 27 -08 -2014 P 5363636 B2 11 -12 -2013 P 2013087119 A 13 -05 -2013 P 2013127010 A 27 -06 -2013 KR 20140072099 A 12 -06 -2014 SG 11201401238T A 3 -07 -2014 T 201317235 A 0 1-05 -2013 T 201514177 A 16 -04 -2015 US 2014248252 Al 04 -09 -2014 O 2013057722 Al 25 -04 -2013