Compounds

Abstract

The present disclosure relates to a compound of formula (Ia), or a pharmaceutically acceptable salt or hydrate thereof, ##STR00001## The present disclosure further relates to pharmaceutical compositions comprising a compound of formula (Ia) and methods of treating a disease or disorder (e.g., cancer) by administering a compound of formula (Ia).

Claims

1. A compound of formula (Id), or a pharmaceutically acceptable salt or hydrate thereof, ##STR00893## wherein: the group XY is NHSO.sub.2 or SO.sub.2NH; R.sub.1 is H or alkyl; R.sub.2 is selected from COOH and a tetrazolyl group; R.sub.3 is selected from H, Cl and alkyl; R.sub.4 is selected from H, Cl and F; R.sub.5 is selected from alkyl, alkenyl, alkynyl, haloalkyl, SO.sub.2-alkyl, Cl, alkoxy, OH, CN, hydroxyalkyl, alkylthio, heteroaryl, cycloalkyl, heterocycloalkyl and haloalkoxy; R.sub.6 is H; R.sub.7 is CN, SO.sub.2-alkyl, SO.sub.2NR.sub.13R.sub.14 or a heteroaryl group, wherein said heteroaryl group is optionally substituted by one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH; R.sub.8 is selected from H, alkyl, haloalkyl and halo; R.sub.9 is H, C.sub.1-C.sub.3-alkyl or halo; R.sub.10 and R.sub.11, together with the nitrogen to which they are attached, form a 4, 5, 6 or 7-membered monocyclic heterocycloalkyl group, wherein one or two carbons in the monocyclic heterocycloalkyl group are optionally replaced by a group selected from O, NH, S and CO, and said monocyclic heterocycloalkyl group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halo, haloalkyl and heteroaryl, wherein said heteroaryl group is in turn optionally further substituted with one or more groups selected from halo and alkyl; or R.sub.10 and R.sub.11, together with the nitrogen to which they are attached, form an 8, 9 or 10-membered bicyclic heterocycloalkyl group, wherein one or two carbons in the bicyclic heterocycloalkyl ring are optionally replaced by a group selected from O, NH, S and CO, and said bicyclic heterocycloalkyl group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halo, haloalkyl and heteroaryl; or R.sub.10 and R.sub.11, together with the nitrogen to which they are attached, form a 6 to 12-membered bicyclic group containing a spirocyclic carbon atom, wherein one or two carbons in the bicyclic group are optionally replaced by a group selected from O, NH, S and CO, and said bicyclic group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halo, haloalkyl and heteroaryl, or said bicyclic group is optionally fused to a 5 or 6-membered aryl or heteroaryl group; and R.sub.13 and R.sub.14 are each H.

2. The compound according to claim 1, wherein R.sub.10 and R.sub.11, together with the nitrogen to which they are attached, form a 6-membered monocyclic heterocycloalkyl group, wherein one or two carbons in the monocyclic heterocycloalkyl group are optionally replaced by a group selected from O, NH, S and CO, and said monocyclic heterocycloalkyl group is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halo, haloalkyl and heteroaryl, wherein said heteroaryl group is in turn optionally further substituted with one or more groups selected from halo and alkyl.

3. The compound of claim 1, wherein R.sub.10 and R.sub.11, together with the nitrogen to which they are attached, form a piperidinyl group which is optionally substituted by one or more groups selected from alkyl, CN, cycloalkyl, OH, alkoxy, halo, haloalkyl, and heteroaryl, wherein said heteroaryl group is in turn optionally further substituted with one or more groups selected from halo and alkyl.

4. The compound of claim 1, wherein R.sub.10 and R.sub.11, together with the nitrogen to which they are attached, form an unsubstituted piperidinyl group.

5. The compound according to claim 1, wherein R.sub.7 is a heteroaryl group selected from imidazolyl, pyrazolyl, pyrazinyl, pyradizinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl and triazolyl, each of which is optionally substituted by one or more substituents selected from alkyl, halo, alkoxy, CN, haloalkyl and OH.

6. The compound of claim 1, wherein R.sub.7 is CN.

7. The compound of claim 1, wherein R.sub.8 is selected from H, Me, CF.sub.3, Cl, Br, and F.

8. The compound of claim 1, wherein R.sub.2 is COOH.

9. The compound according to claim 1, wherein the compound of formula (Id) is selected from the following: TABLE-US-00017 (182) (207) (214) (215) (241) (242) (259) (261) (273) (274) (275) (276) (277) (278) (279) (280) (281) (282) (286) (287) (288) (289) (290) (291) (292) (293) (295) (296) (297) (298) (299) (300) (301) (302) (303) (304) (305) (306) (323) (324) (327) (329) (330) (331) (332) (333) (334) (335) (336) (337) (338) and pharmaceutically acceptable salts and hydrates thereof.

10. The compound of claim 1, having the following structure: ##STR00944## or a pharmaceutically acceptable salt or hydrate thereof.

11. A pharmaceutical composition comprising a compound according to claim 1 admixed with a pharmaceutically acceptable diluent, excipient or carrier.

Description

(1) FIG. 1 shows the cellular effect of representative compounds 1 and 242 according to the invention on antigen presentation as measured by assessing their effect on the presentation of an ovalbumin-specific peptide (SIINFEKL). More specifically, FIG. 1 shows representative IC.sub.50 curve for exemplar compounds according to the invention. Data was normalized to the signal obtained in the absence of compound (high) and absence of antigen (low) and presented as the meanSTD (n=2).

(2) FIG. 2 shows a summary of the IC.sub.50 data generated for exemplar compounds 1 and 242 according to the invention, as determined by the above OVA antigen presentation assay. The data is presented as the meanSEM (n=6).

(3) FIG. 3 shows the effect of compound 1 according to the invention on global antigen processing as determined using an unbiased proteomics pipeline. More specifically, FIG. 3 shows the effects of ERAP1 siRNA and compound inhibition (at 1 and 10 M) compared to a control on the immunopeptidome of SiHa cells as measured by the effect on the total proportion of 8, 9, 10, 11, 12 and 13 amino acid peptides.

EXAMPLES

(4) Where the preparation of starting materials is not described, these are commercially available, known in the literature, or readily obtainable by those skilled in the art using standard procedures. Where it is indicated that compounds were prepared analogously to earlier examples or intermediates, it will be appreciated by the skilled person that the reaction time, number of equivalents of reagents, solvent, concentration and temperature can be modified for each specific reaction and that it may be necessary or desirable to employ different work-up or purification techniques.

(5) General Schemes

(6) Abbreviations

(7) A list of some common abbreviations is shown belowwhere other abbreviations are used which are not listed, these will be understood by the person skilled in the art.

(8) Aq: aqueous; br: broad; ca.: circa; d: doublet; DCM: dichloromethane; dioxane: 1,4-dioxane; DMAP: 4-dimethylaminopyridine; DMF: dimethylformamide; EDC: 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride; Et.sub.3N: triethylamine; EtOAc: ethyl acetate; EtOH: ethanol; h: hours; HPLC: high performance liquid chromatography; IPA, isopropanol; LC: liquid chromatography; m: multiplet; M: molar, molecular ion; MeCN: actetonitrile; MeOH: methanol; min: minutes; MS: mass spectrometry; NMR: nuclear magnetic resonance; PDA: photodiode array; q: quartet; RT: room temperature (ca. 20 C.); RT: retention time; s: singlet, solid; t: triplet; TBME: tert-butyl methyl ether; TFA: trifluoroacetic acid; THF: tetrahydrofuran; UPLC: ultra performance liquid chromatography; UV: ultraviolet; quant.: quantitative; SEM: [2-(trimethylsilyl) ethoxy]methyl acetal; dppf: 1,1-ferrocenediyl-bis(diphenylphosphine); NBS: n-bromosuccinimide; XantPhos-Pd-G3: [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2-amino-1,1-biphenyl)]palladium (II) methanesulfonate (CAS: 1445085-97-1); Xphos Pd G3: (2-Dicyclohexylphosphino-2,4,6-triisopropyl-1, 1-biphenyl) [2-(2-amino-1,1-biphenyl)]palladium (II) methanesulfonate (CAS: 1445085-55-1); Pd-174: allyl(2-di-tert-butylphosphino-2,4,6-triisopropyl-1,1-biphenyl) palladium (II) triflate (CAS: 1798782-25-8); TBAF: tetra-n-butylammonium fluoride.

(9) Other abbreviations are intended to convey their generally accepted meaning.

(10) ##STR00442##
wherein R.sup.a=R.sub.6, R.sub.7, R.sub.8, R.sub.9, NR.sub.10R.sub.11 and R.sup.b=R.sub.1, R.sub.3, R.sub.4, R.sub.5 of formulae (I)

(11) Reagents: (a) CISO.sub.3H, 100 C.; (b) Amine, pyridine, DCM, RT Chlorosulfonylation of I-1 using chlorosulfonic acid provided sulfonyl chloride I-2. This was reacted with the appropriate amine in the presence of pyridine to afford sulfonamide I-3.

(12) ##STR00443##
wherein R.sup.b=R.sub.1, R.sub.3, R.sub.4, R.sub.5 of formulae (I)

(13) Reagents: (a) Amine, DCM; (b) H.sub.2, 10% Pd/C, EtOH; (c) Fe, NH.sub.4Cl, IPA, water; (d) NH.sub.4OH (aq), Na.sub.2S.sub.2O.sub.4, THF, H.sub.2O, RT; I sulfonyl chloride, pyridine, DCM, RT; (f) LiOH (aq), THF, MeOH; (g) LiOH (aq), dioxane.

(14) Fluoro-2-nitro-4-(trifluoromethyl)benzene (1-4) was reacted with the appropriate amine in a nucleophilic substitution reaction, followed by reduction of the resultant nitro-compound I-5 to aniline 1-6. This was reacted with the appropriate sulfonyl chloride to afford sulfonamide I-7. Ester hydrolysis provided the corresponding carboxylic acid I-8.

(15) ##STR00444##

(16) Reagents: (a) Aniline, pyridine, DCM, RT; (b) amine, THF, 60 C.; (c) LiOH(aq), THF, 50 C. Sulfonyl chloride 1-9 was reacted with the appropriate aniline to provide sulfonamide I-10. Nucleophilic substitution with the appropriate amine gave I-11, which was hydrolysed to provide the corresponding carboxylic acid I-12.

(17) ##STR00445##
wherein R.sup.a=R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sup.b=R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 of formulae (I)

(18) Reagents: (a) Sulfonyl chloride, pyridine, DCM, RT; (b) LiOH(aq), dioxane or THF, RT. Sulfonamide I-14 was prepared by the reaction of aniline I-13 with the appropriate sulfonyl chloride. Ester hydrolysis afforded the corresponding carboxylic acid I-15.

(19) ##STR00446##

(20) Reagents: (a) Aniline, pyridine, DCM, RT; (b) NaOH (aq), MeOH, H.sub.2O, RT; (c) LiOH(aq), THF, RT.

(21) Sulfonamide I-17 was prepared by the reaction of sulfonyl chloride I-16 with the appropriate aniline. Ester hydrolysis provided the corresponding carboxylic acid I-18.

(22) ##STR00447##

(23) Reagents: (a) Amine, MeCN; (b) Bis(pinacolato)diboron, PdCl.sub.2(dppf).Math.DCM, KOAc, dioxane; (c) H2, Pd/C, MeOH; (d) sulfonyl chloride, pyridine, DCM, RT; I Aryl halide, Xphos Pd G3, K.sub.3PO.sub.4, dioxane, water; (f) LiOH(aq), THF, MeOH; (g) HCl, dioxane.

(24) 4-Bromo-1-fluoro-2-nitrobenzene (I-19) was reacted with the appropriate amine in a nucleophilic substitution reaction, followed by conversion of the resultant aryl bromide to boronate ester I-20. The nitro group was then reduced to afford the corresponding aniline I-21. This was reacted with the appropriate sulfonyl chloride to afford sulfonamide I-22. The remaining substituent was introduced by Suzuki coupling prior to ester hydrolysis to provide the corresponding carboxylic acid I-24. Alternatively, the steps may be carried out in an alternative sequence as indicated.

(25) General Experimental Conditions

(26) All starting materials and solvents were obtained either from commercial sources or prepared according to the literature citation. Reaction mixtures were magnetically stirred and reactions performed at room temperature (ca. 20 C.) unless otherwise indicated. Column chromatography was performed on an automated flash chromatography system, such as a CombiFlash Rf system, using pre-packed silica (40 m) cartridges, unless otherwise indicated. .sup.1H NMR spectra were recorded using a Bruker Avance III HD spectrometer at 500 MHz, equipped with a Bruker 5 mm SmartProbe. Chemical shifts are expressed in parts per million using either the central peaks of the residual protic solvent or an internal standard of tetramethylsilane as references. The spectra were recorded at 298 K unless otherwise indicated. Analytical UPLC-MS experiments to determine retention times and associated mass ions were performed using a Waters ACQUITY UPLC H-Class system, equipped with ACQUITY PDA Detector and ACQUITY Qda Mass Detector, running one of the analytical methods described below. Analytical LC-MS experiments to determine retention times and associated mass ions were performed using an Agilent 1200 series HPLC system coupled to an Agilent 1956, 6100 or 6120 series single quadrupole mass spectrometer running one of the analytical methods described below. Preparative HPLC purifications were performed either using a Waters X-Select CSH C18, 5 m, 1950 mm column using a gradient of MeCN and water, both modified with 0.1% v/v formic acid, or on a Waters X-Bridge BEH C18, 5 m, 1950 mm column using a gradient of MeCN and 10 mM ammonium bicarbonate (aq). Fractions were collected following detection by UV at a single wavelength measured by a variable wavelength detector. Nomenclature of structures was generated using Structure to Name conversion from ChemDraw Professional 17 (PerkinElmer).

(27) Analytical Methods

(28) Method 1Acidic 3 Min Method

(29) Column: Waters ACQUITY UPLC CSH C18, 1.7 m, 2.130 mm at 40 C. Detection: UV at 254 nm unless otherwise indicated, MS by electrospray ionisation Solvents: A: 0.1% v/v Formic acid in water, B: 0.1% v/v Formic acid in MeCN Gradient:

(30) TABLE-US-00007 Time % A % B Flow rate (ml/min) 0.00 95 5 0.77 0.11 95 5 0.77 2.15 5 95 0.77 2.56 5 95 0.77 2.83 95 5 0.77 3.00 95 5 0.77
Method 2Basic 3 Min Method Column: Waters ACQUITY UPLC BEH C18, 1.7 m, 2.130 mm at 40 C. Solvents: A: 10 mM ammonium bicarbonate (aq), B: MeCN (other parameters the same as Method 1)
Method 3Acidic 4 Min Method Column: Waters X-Select CSH C18, 2.5 m, 4.630 mm at 40 C. Detection: UV at 254 nm unless otherwise indicated, MS by electrospray ionisation Solvents: A: 0.1% v/v Formic acid in water, B: 0.1% v/v Formic acid in MeCN Gradient:

(31) TABLE-US-00008 Time % A % B Flow rate (ml/min) 0.0 95.0 5.0 2.5 3.0 5.0 95.0 2.5 3.01 5.0 95.0 4.5 3.6 5.0 95.0 4.5 3.7 95.0 5.0 2.5 4.0 95.0 5.0 2.5
Method 4Basic 4 Min Method Column: Waters X-Bridge BEH C18, 2.5 m, 4.630 mm at 40 C. Solvents: A: 10 mM ammonium bicarbonate (aq), B: MeCN (other parameters the same as Method 3)

Example 1:4-Ethyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

(32) ##STR00448##

(33) Step 1: 3-(chlorosulfonyl)-4-ethylbenzoic acid: 4-ethylbenzoic acid (1 g, 6.66 mmol) in chlorosulfonic acid (10 ml, 149 mmol) was heated at 100 C. overnight. The mixture was cooled and carefully added to stirred ice. The resultant precipitate was collected by filtration to afford the title compound (1.58 g, 6.04 mmol, 91% yield, 95% purity) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.34 (d, J=1.9 Hz, 1H), 7.82 (dd, J=7.9, 2.0 Hz, 1H), 7.32 (d, J=7.9 Hz, 1H), 3.08 (q, J=7.5 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H). One exchangeable proton not observed.

(34) Step 2: 4-Ethyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: A solution of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (0.200 g, 0.819 mmol) in pyridine (3 ml, 37.1 mmol) was treated with the product from step 1 above (0.244 g, 0.983 mmol) and the solution was stirred at RT for 24 h. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexanes followed by 0-50% EtOAc/DCM) to afford the title compound (36.3 mg, 0.076 mmol, 9.23% yield, 97% purity) as a tan solid. UPLC-MS (Method 1) m/z 457.4 (M+H).sup.+, 455.2 (MH).sup. at 1.87 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.28 (bs, 1H), 9.44 (bs, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.0, 1.8 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.42 (dd, J=8.4, 2.2 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 3.04 (q, J=7.4 Hz, 2H), 2.72 (t, J=4.9 Hz, 4H), 1.57 (p, J=5.0 Hz, 4H), 1.50-1.45 (m, 2H), 1.21 (t, J=7.4 Hz, 3H).

Example 3:4-isopropyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(35) ##STR00449##

(36) Step 1: 3-(chlorosulfonyl)-4-isopropylbenzoic acid: 4-isopropylbenzoic acid (1 g, 6.09 mmol) in chlorosulfonic acid (5 ml, 74.7 mmol) was heated at 100 C. overnight. The mixture was cooled and carefully added to stirred ice. The resultant precipitate was collected by filtration and dried under vacuum to give the title compound (1.28 g, 4.63 mmol, 76% yield, 95% purity) as a tan solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.50 (bs, 1H), 8.36 (d, J=1.9 Hz, 1H), 7.83 (dd, J=8.1, 1.9 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 4.20 (septet, J=6.8 Hz, 1H), 1.16 (d, J=6.9 Hz, 6H).

(37) Step 2: 4-isopropyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: A solution of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (0.070 g, 0.287 mmol) in DCM (1 ml) and pyridine (0.139 ml, 1.720 mmol) were added to a solution of the product from step 1 above (0.090 g, 0.344 mmol) in DCM (1 ml) and the solution was stirred at RT for 16 h. The solvent was removed in vacuo and the residue purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/DCM) to afford the title compound (14.3 mg, 0.029 mmol, 10% yield, 95% purity) as a light tan solid. UPLC-MS (Method 1) m/z 471.4 (M+H).sup.+, 469.3 (MH).sup. at 1.93 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.29 (bs, 1H), 9.40 (bs, 1H), 8.45 (d, J=1.9 Hz, 1H), 8.13 (dd, J=8.3, 1.9 Hz, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.42 (dd, J=8.2, 1.9 Hz, 1H), 7.27 (d, J=8.3 Hz, 1H), 7.19 (d, J=1.9 Hz, 1H), 3.86 (septet, J=6.8 Hz, 1H), 2.78 (t, J=5.2 Hz, 4H), 1.58 (p, J=5.5 Hz, 4H), 1.51-1.45 (m, 2H), 1.24-1.10 (m, 6H).

Example 4: 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-(trifluoromethoxy)benzoic acid

(38) ##STR00450##

(39) Step 1: 3-(chlorosulfonyl)-4-(trifluoromethoxy)benzoic acid: 4-(trifluoromethoxy)benzoic acid (1 g, 4.85 mmol) in chlorosulfonic acid (5 ml, 74.7 mmol) was heated at 100 C. overnight. The mixture was cooled and carefully added to stirred ice. The resultant precipitate was collected by filtration and dried under vacuum to give the title compound (0.770 g, 2.28 mmol, 46.9% yield, 90% purity) as a cream solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.50 (bs, 1H), 8.40 (d, J=2.2 Hz, 1H), 8.00 (dd, J=8.5, 2.2 Hz, 1H), 7.41 (dq, J=8.5, 1.8 Hz, 1H).

(40) Step 2: 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-(trifluoromethoxy)benzoic acid: A solution of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (0.070 g, 0.287 mmol) in DCM (1 ml) and pyridine (0.139 ml, 1.72 mmol) were added to a solution of the product from step 1 above (0.105 g, 0.344 mmol) in DCM (1 ml) and the solution was stirred at RT for 16 h. The solvent was removed in vacuo and the residue purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/DCM) to afford the title compound (5.6 mg, 10.4 mol, 3.6% yield, 95% purity) as a cream solid. UPLC-MS (Method 1) m/z 513.3 (M+H).sup.+, 511.1 (MH).sup. at 1.94 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.68 (bs, 1H), 9.50 (bs, 1H), 8.45 (d, J=1.7 Hz, 1H), 8.27 (dd, J=8.2, 1.5 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.46-7.44 (m, 2H), 7.27 (d, J=8.2 Hz, 1H), 2.71 (t, J=5.0 Hz, 4H), 1.62-1.34 (m, 6H).

Example 6:3-(N-(2-(cis-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(41) ##STR00451##

(42) Step 1: cis-3,5-dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et.sub.3N (0.5 ml, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (201 l, 1.44 mmol) and cis-3,5-dimethylpiperidine (211 mg, 1.87 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 20 h. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc in isohexanes then 0-10% MeOH/DCM) to afford the title compound (356 mg, 1.12 mmol, 78% yield, 95% purity) as a light orange solid. UPLC-MS (Method 1) m/z 303.4 (M+H).sup.+ at 2.01 min.

(43) Step 2: 2-(cis-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)aniline: The product from Step 1 above (150 mg, 0.496 mmol) was dissolved in EtOH (9.9 ml) and the reaction mixture was hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm cartridge, full hydrogen mode, 40 C., 1 ml/min flow rate, 2 passes). The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to afford the title compound (133 mg, 0.479 mmol, 96% yield, 98% purity) as a pale brown oil. UPLC-MS (Method 2) m/z 273.3 (M+H).sup.+, 271.1 (MH).sup. at 2.00 min.

(44) Step 3: methyl 3-(N-(2-(cis-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from Step 2 above (51.4 mg, 0.189 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (50 l, 0.618 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (60 mg, 0.227 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 3 days. The reaction mixture was loaded directly and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexanes) to afford the title compound (63 mg, 0.120 mmol, 63.3% yield, 95% purity) as a cream solid. UPLC-MS (Method 1) m/z 501.4 (M+H).sup.+, 498.9 (MH).sup. at 2.05 min.

(45) Step 4: 3-(N-(2-(cis-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from Step 3 above (61 mg, 0.122 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (443 l, 0.487 mmol). MeOH was added dropwise until a clear solution formed. The reaction mixture was heated at 40 C. for 24 h, then cooled to RT overnight. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (5 ml). 1 M HCl(aq) was added dropwise to ca. pH 6. The resultant white precipitate was collected by filtration, washing with water. The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (55 mg, 0.113 mmol, 88% yield, 95% purity) as a pale yellow solid. UPLC-MS (Method 1) m/z 487.4 (M+H).sup.+, 485.2 (MH).sup. at 1.89 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.16 (s, 1H), 8.82 (s, 1H), 8.34 (d, J=2.3 Hz, 1H), 8.15 (dd, J=8.7, 2.3 Hz, 1H), 7.47 (d, J=2.1 Hz, 1H), 7.36 (dd, J=8.5, 2.1 Hz, 1H), 7.30 (d, J=8.7 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 3.84 (s, 3H), 2.89-2.80 (m, 2H), 2.14 (t, J=11.0 Hz, 2H), 1.82-1.65 (m, 3H), 0.81 (d, J=6.4 Hz, 6H), 0.67-0.59 (m, 1H).

Example 7: 3-(N-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)-4-methoxybenzoic acid

(46) ##STR00452##

(47) Step 1: 3-(2-nitro-4-(trifluoromethyl)phenyl)-8-oxa-3-azabicyclo[3.2.1]octane: Et.sub.3N (0.583 ml, 4.18 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.167 ml, 1.20 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (221 mg, 1.44 mmol) in DCM (5 ml) and the resultant solution stirred at RT for 2 h. 1 M HCl(aq) (2 ml) was added, the organic phase separated by passage through a phase separator and concentrated in vacuo to afford the title compound (384 mg, 1.08 mmol) as a yellow solid. UPLC-MS (Method 2) m/z 303.2 (M+H).sup.+ at 1.54 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.13-8.08 (m, 1H), 7.84 (dd, J=8.9, 2.3 Hz, 1H), 7.46 (d, J=8.9 Hz, 1H), 4.39-4.32 (m, 2H), 3.16-3.11 (m, 2H), 3.02-2.97 (m, 2H), 1.89-1.77 (m, 4H).

(48) Step 2: 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)aniline: The product from Step 1 above (323 mg, 1.07 mmol) was dissolved in EtOH (21.2 ml) and the reaction mixture was hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm cartridge, full hydrogen mode, 40 C., 1 ml/min flow rate, 4 passes). The reaction mixture was concentrated in vacuo and azeotroped with MeOH (8 ml) to afford the title compound (310 mg, 1.059 mmol, 100% yield, 93% purity) as an off-white solid. UPLC-MS (Method 2) m/z 273.3 (M+H).sup.+ at 1.43 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.05 (d, J=8.2 Hz, 1H), 7.02 (d, J=2.2 Hz, 1H), 6.86 (dd, J=8.2, 2.2 Hz, 1H), 5.01 (br s, 2H), 4.36-4.31 (m, 2H), 2.88-2.82 (m, 2H), 2.79 (dd, J=11.5, 2.0 Hz, 2H), 2.09-2.03 (m, 2H), 1.88-1.80 (m, 2H).

(49) Step 3: methyl 3-(N-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl) phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (58 l, 0.72 mmol) was added to a solution of the product from step 2 above (66.5 mg, 0.239 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.287 mmol) in DCM (2 ml) at RT. The resultant solution was stirred at 40 C. for 4 h before additional methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.287 mmol) and pyridine (58 l, 0.718 mmol) were added and the mixture stirred at 40 C. for a further 19 h. The reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (25 g cartridge, 0-80% EtOAc/isohexanes) to afford the title compound (88.3 mg, 0.173 mmol, 72.3% yield, 98% purity) as an off-white solid. UPLC-MS (Method 2) m/z 501.3 (M+H).sup.+, 499.2 (MH).sup. at 1.59 min.

(50) Step 4: 3-(N-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1 M LiOH (aq) (0.699 ml, 0.699 mmol) was added to a solution of the product from step 3 above (87.4 mg, 0.175 mmol) in THF (1.4 ml) at RT and the resultant solution was stirred at RT for 24 h. The reaction mixture was concentrated in vacuo and the residue was redissolved in water (3 ml) and acidified using 1 M HCl(aq) until pH 4-5. The precipitate was isolated by filtration and then dried to afford the title compound (74 mg, 0.152 mmol, 87% yield, 100% purity) as a white solid. UPLC-MS (Method 1) m/z 487.3 (M+H).sup.+, 485.1 (MH).sup. at 1.45 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.13 (br s, 1H), 8.88 (br s, 1H), 8.24 (d, J=2.2 Hz, 1H), 8.18 (dd, J=8.7, 2.2 Hz, 1H), 7.46-7.34 (m, 2H), 7.27 (d, J=8.5 Hz, 1H), 6.98 (d, J=2.1 Hz, 1H), 4.40-4.33 (m, 2H), 3.95 (s, 3H), 3.01 (d, J=11.2 Hz, 2H), 2.95 (dd, J=11.6, 2.0 Hz, 2H), 2.13-2.05 (m, 2H), 1.92-1.84 (m, 2H).

Example 8: 4-methoxy-3-(N-(2-(cis-5-methylhexahydropyrrolo[3,4-c]pyrrol-2 (1H)-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

(51) ##STR00453##

(52) Step 1: cis-2-methyl-5-(2-nitro-4-(trifluoromethyl)phenyl) octahydropyrrolo[3,4-c]pyrrole: Et.sub.3N (0.417 ml, 2.99 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.167 ml, 1.20 mmol) and cis-2-methyloctahydropyrrolo[3,4-c]pyrrole (187 mg, 1.44 mmol) in DCM (5 ml) at RT and the resultant solution was stirred at RT for 2 h. 1 M HCl(aq) (2 ml) was added, the organic phase was dried by passage through a phase separator and concentrated in vacuo to afford the title compound (402 mg, 1.20 mmol, quant. Yield, 93% purity) as an orange solid. UPLC-MS (Method 2) m/z 316.3 (M+H).sup.+ at 1.40 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.04-8.01 (m, 1H), 7.72 (dd, J=9.1, 2.4 Hz, 1H), 7.22 (d, J=9.0 Hz, 1H), 3.49-3.42 (m, 2H), 3.13 (dd, J=10.8, 3.4 Hz, 2H), 2.94-2.85 (m, 2H), 2.53-2.44 (m, 4H), 2.24 (s, 3H). Signal at 2.49 ppm is obscured by DMSO signal.

(53) Step 2: 2-(cis-5-methylhexahydropyrrolo[3,4-c]pyrrol-2 (1H)-yl)-5-(trifluoromethyl)aniline: The product from step 1 above (376 mg, 1.19 mmol) was dissolved in EtOH (23.9 ml) and the reaction mixture was hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm cartridge, full hydrogen mode, 40 C., 1 ml/min flow rate, 2 passes). The reaction mixture was concentrated in vacuo and azeotroped with MeOH (12 ml) to afford the title compound (355 mg, 1.17 mmol, 98% yield, 94% purity) as an off-white solid. UPLC-MS (Method 2) 286.3 (M+H).sup.+ at 1.24 min.

(54) Step 3: methyl 4-methoxy-3-(N-(2-(cis-5-methylhexahydropyrrolo[3,4-c]pyrrol-2 (1H)-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: Pyridine (58 l, 0.72 mmol) was added to a slurry of the product from step 2 above (72.6 mg, 0.239 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.287 mmol) in DCM (2 ml) at RT. The resultant solution was stirred at 40 C. for 4 h before additional methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.287 mmol) and pyridine (0.058 ml, 0.718 mmol) were added and the mixture stirred at 40 C. for a further 19 h. The reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on silica gel (25 g cartridge, 0-10% MeOH/DCM) to afford the title compound (158 mg, 0.193 mmol, 81% yield, 63% purity) as an off-white solid. UPLC-MS (Method 2) m/z 514.4 (M+H).sup.+, 512.2 (MH).sup. at 1.26 min.

(55) Step 4: 4-methoxy-3-(N-(2-(cis-5-methylhexahydropyrrolo[3,4-c]pyrrol-2 (1H)-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (1.23 ml, 1.23 mmol) was added to a solution of the product from step 3 above (158 mg, 0.308 mmol) in THF (2.5 ml) at RT and the solution was stirred at RT for 26 h. The reaction mixture was concentrated in vacuo, the residue was redissolved in water (3 ml) and acidified using 1 M HCl(aq) until pH 4-5. The precipitate was isolated by filtration and then dried in vacuo to afford the title compound (63.5 mg, 0.127 mmol, 41.3% yield, 98% purity) as an off-white solid. UPLC-MS (Method 2) m/z 500.3 (M+H).sup.+, 498.3 (MH).sup. at 0.83 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.22 (d, J=2.2 Hz, 1H), 8.13 (dd, J=8.7, 2.2 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 7.28-7.24 (m, 1H), 6.97-6.91 (m, 2H), 3.90 (s, 3H), 3.36 (dd, J=9.8, 6.5 Hz, 2H), 3.22 (dd, J=10.0, 2.7 Hz, 2H), 2.86-2.80 (m, 2H), 2.75-2.69 (m, 2H), 2.64-2.59 (m, 2H), 2.38 (s, 3H). Two exchangeable protons not seen.

Example 9: 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(56) ##STR00454##

(57) Step 1: 3,3-difluoro-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et.sub.3N (0.500 ml, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) and 3,3-difluoropiperidine hydrochloride (271 mg, 1.72 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 20 h. Water (3 ml) was added and the phases were separated using a phase separator. The aqueous phase was extracted with DCM (23 ml) and the organic phases were combined, dried by passage through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexanes) to afford the title compound (399 mg, 1.26 mmol, 87.8% yield, >98% purity) as a bright yellow solid. UPLC-MS (Method 2) m/z 309.0 (MH).sup. at 1.64 min.

(58) Step 2: 2-(3, 3-difluoropiperidin-1-yl)-5-(trifluoromethyl)aniline: The product from step 1 above (156 mg, 0.503 mmol) was dissolved in EtOH (10.1 ml) and the reaction mixture was hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm, full hydrogen mode, 40 C., 1 ml/min flow rate, 2 passes). The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to afford the title compound (119 mg, 0.408 mmol, 81% yield, 96% purity) as a colourless oil. UPLC-MS (Method 2) m/z 280.8 (M+H).sup.+ at 1.64 min.

(59) Step 3: methyl 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from step 2 above (53.0 mg, 0.189 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (0.05 ml, 0.618 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (60.0 mg, 0.227 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 4 days. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-10% MeOH/DCM) to afford the title compound (39.9 mg, 0.075 mmol, 39.4% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 509.4 (M+H).sup.+, 507.2 (MH).sup. at 1.75 min.

(60) Step 4: 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 3 above (38 mg, 0.075 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (272 l, 0.299 mmol) and MeOH was added dropwise until the mixture was a solution. The reaction mixture was stirred at 30 C. for 4 days. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to ca. 5 ml) and neutralised to ca. pH 6 with 1 M HCl. The resultant lumpy suspension was sonicated to afford a cloudy solution. The white precipitate was collected by filtration, washing with water and the solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (34 mg, 0.065 mmol, 87% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 495.1 (M+H).sup.+, 493.1 (MH).sup. at 1.59 min, 98% purity (254 nm). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.18 (br s, 1H), 8.60 (br s, 1H), 8.37 (d, J=2.2 Hz, 1H), 8.16 (dd, J=8.7, 2.2 Hz, 1H), 7.41-7.36 (m, 3H), 7.32 (d, J=8.8 Hz, 1H), 3.91 (s, 3H), 3.17 (t, J=11.1 Hz, 2H), 2.95 (t, J=5.3 Hz, 2H), 2.13-2.00 (m, 2H), 1.88-1.84 (m, 2H).

Example 10:3-(N-(2-(8-azabicyclo[3.2.1]octan-8-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)-4-methoxybenzoic acid

(61) ##STR00455##

(62) Step 1: 8-(2-nitro-4-(trifluoromethyl)phenyl)-8-azabicyclo[3.2.1]octane: Et.sub.3N (0.236 ml, 1.69 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.095 ml, 0.677 mmol) and 8-azabicyclo[3.2.1]octane hydrochloride (100 mg, 0.677 mmol) in DCM (2 ml) and the resultant solution was stirred at RT for 20 h. Water (3 ml) was added and the phases were separated using a phase separator. The aqueous phase was extracted with DCM (23 ml) and the organic phases were combined, dried by passage through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexanes) to afford the title compound (183 mg, 0.597 mmol, 88.2% yield, 98% purity). UPLC-MS (Method 2) m/z 301.3 (M+H).sup.+ at 1.85 min.

(63) Step 2: 2-(8-azabicyclo[3.2.1]octan-8-yl)-5-(trifluoromethyl)aniline: The product from step 1 above (134 mg, 0.446 mmol) was dissolved in EtOH (8.9 ml) and the reaction mixture was hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm, full hydrogen mode, 40 C., 1 ml/min flow rate, 2 passes). The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to afford the title compound (104 mg, 0.366 mmol, 82% yield, 95% purity) as a colourless oil. UPLC-MS (Method 2) m/z 271.3 (M+H).sup.+ at 1.83 min.

(64) Step 3: methyl 3-(N-(2-(-8-azabicyclo[3.2.1]octan-8-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from step 2 above (51.1 mg, 0.189 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (0.05 ml, 0.618 mmol) and treated with a solution methyl 3-(chlorosulfonyl)-4-methoxybenzoate (60.0 mg, 0.227 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 4 days. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-10% MeOH/DCM) to afford the title compound (32.1 mg, 0.061 mmol, 32.4% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 499.3 (M+H).sup.+, 497.2 (MH).sup. at 1.90 min.

(65) Step 4: 3-(N-(2-(-8-azabicyclo[3.2.1]octan-8-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 3 above (30 mg, 0.060 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (219 l, 0.241 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 4 days. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to ca. 5 ml) and neutralised to ca. pH 6 with 1 M HCl. The resultant lumpy suspension was sonicated to afford a cloudy solution and the precipitate was collected by filtration, washing with water. The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. The crude product was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 50-80% MeCN in Water) to afford the title compound (9.0 mg, 0.018 mmol, 29.3% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 485.2 (M+H).sup.+, 483.3 (MH).sup. at 1.74 min. 1H NMR (500 MHz, DMSO-d.sub.6) 13.12 (br s, 1H), 8.96 (br s, 1H), 8.21 (d, J=2.2 Hz, 1H), 8.16 (dd, J=8.8, 2.2 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.27 (dd, J=8.7, 2.3 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 6.95-6.92 (m, 1H), 4.29 (s, 2H), 3.93 (s, 3H), 1.91-1.86 (m, 2H), 1.79-1.68 (m, 6H), 1.55-1.46 (m, 1H), 1.45-1.37 (m, 1H).

Example 11: 3-(N-(2-(5-oxa-2-azaspiro[3.4]octan-2-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)-4-methoxybenzoic acid

(66) ##STR00456##

(67) Step 1: 2-(2-nitro-4-(trifluoromethyl)phenyl)-5-oxa-2-azaspiro[3.4]octane: Et.sub.3N (500 l, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (201 l, 1.44 mmol) and 5-oxa-2-azaspiro[3.4]octane hemioxalate (349 mg, 2.21 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 20 h. 1 M HCl(aq) (2 ml) was added and the organic phase was dried by passage through a phase separator. The organic phase was concentrated in vacuo to afford the title compound (438 mg, 1.44 mmol, 100% yield, 99% purity) as a light yellow sticky oil. UPLC-MS (Method 2) m/z 303.3 (M+H).sup.+ at 1.59 min.

(68) Step 2: 2-(5-oxa-2-azaspiro[3.4]octan-2-yl)-5-(trifluoromethyl)aniline: The product from step 1 above (217 mg, 0.718 mmol) was dissolved in EtOH (14.4 ml) and the reaction mixture was hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm, full hydrogen mode, 40 C., 1 ml/min flow rate, 2 passes). The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to give the title compound (198 mg, 0.691 mmol, 96% yield, 95% purity) as a white solid. UPLC-MS (Method 2) m/z 273.3 (M+H).sup.+ at 1.37 min.

(69) Step 3: methyl 3-(N-(2-(5-oxa-2-azaspiro[3.4]octan-2-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from step 2 above (0.073 g, 0.268 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (0.087 ml, 1.07 mmol) and treated with a solution methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.085 g, 0.321 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexanes) to afford the title compound (93.7 mg, 0.178 mmol, 70.0% yield, 95% purity) as an off white solid. UPLC-MS (Method 1) m/z 501.4 (M+H).sup.+, 498.8 (MH).sup. at 1.54 min.

(70) Step 4: 3-(N-(2-(5-oxa-2-azaspiro[3.4]octan-2-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 3 above (92 mg, 0.184 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (668 l, 0.735 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 3 days. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to ca. 5 ml) and neutralised to ca. pH 6 with 1 M HCl. The resultant lumpy suspension was sonicated to afford a cloudy solution. The white precipitate was collected by filtration, washing with water and the solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. The crude product was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 35-65% MeCN in Water) to afford the title compound (3 mg, 5.98 mol, 3.25% yield, 97% purity) as a fluffy white solid. UPLC-MS (Method 1) m/z 487.0 (M+H).sup.+, 485.2 (MH).sup. at 1.37 min. .sup.1H NMR (500 MHz, Methanol-d.sub.4) 8.33 (d, J=2.2 Hz, 1H), 8.29 (dd, J=8.7, 2.2 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.30 (dd, J=8.6, 2.2 Hz, 1H), 6.70 (d, J=2.1 Hz, 1H), 6.55 (d, J=8.6 Hz, 1H), 4.21 (d, J=9.0 Hz, 2H), 4.08 (d, J=9.0 Hz, 2H), 4.02 (s, 3H), 3.88 (t, J=7.0 Hz, 2H), 2.20 (t, J=7.0 Hz, 2H), 2.00 (p, J=7.0 Hz, 2H). Two exchangeable protons not observed.

Example 12: 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(71) ##STR00457##

(72) Step 1: 4,4-difluoro-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et.sub.3N (0.47 ml, 3.37 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.188 ml, 1.34 mmol) and 4,4-difluoropiperidine (196 mg, 1.62 mmol) in DCM (5 ml) and the resultant solution was stirred at RT for 19 h. Water (2.5 ml) was added, the organic phase was isolated using a phase separator and concentrated in vacuo to afford the title compound (434 mg, 1.04 mmol, 77% yield, 74% purity) as an orange oil. UPLC (Method 2) 1.67 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.20 (d, J=2.3 Hz, 1H), 7.89 (dd, J=8.9, 2.4 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 3.28-3.23 (m, 4H), 2.16-2.06 (m, 4H).

(73) Step 2: 2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)aniline: The product from step 1 above (180 mg, 0.580 mmol) was dissolved in EtOH (23.2 ml) and the reaction mixture was hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm, full hydrogen mode, 21 C., 1 ml/min flow rate, 1 pass). The reaction mixture was concentrated in vacuo and azeotroped with MeOH (8 ml) to afford the title compound (159 mg, 0.545 mmol, 94% yield, 96% purity) as an off-white solid. UPLC-MS (Method 2) m/z 281.3 (M+H).sup.+ at 1.63 min. 1H NMR (500 MHz, DMSO-d.sub.6) 7.04 (d, J=8.1 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.82 (dd, J=8.2, 2.1 Hz, 1H), 5.27 (s, 2H), 2.93 (br t, J=5.5 Hz, 4H), 2.24-2.09 (m, 4H).

(74) Step 3: methyl 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (0.058 ml, 0.718 mmol) was added to a solution of the product from step 2 above (69.8 mg, 0.239 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.287 mmol) in DCM (2.0 ml) at RT. The reaction mixture was stirred and heated at 40 C. for 18 h. Additional methyl 3-(chlorosulfonyl)-4-methoxybenzoate (33 mg, 0.120 mmol) was added and the resultant solution was stirred at 40 C. for a further 3 h. The reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on silica gel (10 g cartridge, 0-30% EtOAc/isohexanes) to afford the title compound (107 mg, 0.196 mmol, 82% yield, 93% purity) as an off-white solid. UPLC-MS (Method 2) m/z 509.3 (M+H).sup.+, 507.2 (MH).sup. at 1.72 min.

(75) Step 4: 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1 M LiOH(aq) (0.632 ml, 0.632 mmol) was added to a solution of the product from step 3 above (107 mg, 0.210 mmol) in THF (1.26 ml) at RT. The resultant clear solution was stirred at RT for 20 h. Additional 1 M LiOH(aq) (0.211 ml, 0.211 mmol) was added and the solution was stirred for a further 1 h. The reaction mixture was concentrated in vacuo and the residue was redissolved in water (3 ml) and acidified using 1 M HCl(aq) until pH 4-5. The precipitate was dissolved in DCM (10 ml) and the phases were separated. The aqueous phase was extracted with DCM (23 ml). The combined organic phases were dried by passage through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (10 g cartridge, 0-3.5% MeOH/DCM) to afford an off-white solid (40.1 mg). The product was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 50-80% MeCN in Water) to afford the title compound (19 mg, 0.038 mmol, 18.3% yield, 100% purity) as a white solid. UPLC-MS (Method 1) m/z 495.3 (M+H).sup.+, 493.2 (MH).sup. at 1.61 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.15 (br s, 1H), 9.30 (br s, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.16 (dd, J=8.7, 2.3 Hz, 1H), 7.48-7.44 (m, 1H), 7.41-7.35 (m, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 3.87 (s, 3H), 2.96-2.86 (m, 4H), 2.18-2.08 (m, 4H).

Example 13: 3-(N-(2-(8-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)-4-methoxybenzoic acid

(76) ##STR00458##

(77) Step 1: 3-(2-nitro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.2.1]octan-8-ol: Et.sub.3N (500 l, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (201 l, 1.44 mmol) and 3-azabicyclo[3.2.1]octan-8-ol hydrochloride (250 mg, 1.53 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 20 h. 1 M HCl(aq) (2 ml) was added and the organic phase was dried by passage through a phase separator and concentrated in vacuo to afford the title compound (468 mg, 1.44 mmol, 100% yield, 97% purity) as a light orange solid. UPLC-MS (Method 2) m/z 315.1 (MH).sup. at 1.53 min.

(78) Step 2: 3-(2-amino-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.2.1]octan-8-ol: The product from step 1 above (227 mg, 0.718 mmol) was dissolved in EtOH (14.4 ml) and the reaction mixture was hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm, full hydrogen, 40 C., 1 ml/min flow rate, 2 passes). The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to afford the title compound (186 mg, 0.585 mmol, 81% yield, 90% purity) as a light pink solid. UPLC-MS (Method 2) m/z 287.3 (M+H).sup.+, 285.2 (MH).sup. at 1.38 min.

(79) Step 3: methyl 3-(N-(2-(8-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)-4-methoxybenzoate: The product from step 2 above (63.1 mg, 0.220 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (71.3 l, 0.882 mmol) and treated with a solution methyl 3-(chlorosulfonyl)-4-methoxybenzoate (70 mg, 0.264 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexanes) to afford the title compound (51 mg, 0.087 mmol, 39.6% yield, 88% purity) as a white solid. UPLC-MS (Method 1) m/z 515.4 (M+H).sup.+, 513.2 (MH).sup. at 1.60 min.

(80) Step 4: 3-(N-(2-(8-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 3 above (49 mg, 0.095 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (346 l, 0.381 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to ca. 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to ca. pH 6 with 1 M HCl. The resultant lumpy suspension was sonicated to afford a cloudy solution which was concentrated in vacuo to ca. 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml) and concentrated in vacuo and dried at 45 C. to afford the title compound (21.9 mg, 0.042 mmol, 44.6% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m/z 501.3 (M+H).sup.+, 499.2 (MH).sup. at 1.42 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.17 (s, 1H), 8.69 (s, 1H), 8.34 (d, J=2.2 Hz, 1H), 8.17 (dd, J=8.7, 2.2 Hz, 1H), 7.40-7.32 (m, 3H), 7.17 (d, J=1.6 Hz, 1H), 5.07 (s, 1H), 3.93 (s, 3H), 3.90-3.82 (m, 1H), 3.33-3.31 (m, 2H), 2.61 (dd, J=10.7, 3.6 Hz, 2H), 2.01-1.97 (m, 2H), 1.86-1.73 (m, 4H).

(81) The following examples were prepared by methods analogous to Example 13, substituting appropriate starting materials and intermediates where necessary:

(82) TABLE-US-00009 Example Structure Name/Analytical Data 14 3-(N-(2-(3,3-difluoro-4-hydroxypiperidin-1-yl)- 5-(trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 511.3 (M + H).sup.+, 509.1 (M H).sup. at 1.37 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.18 (br s, 1H), 8.62 (br s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.15 (dd, J = 8.7, 2.2 Hz, 1H), 7.44- 7.23 (m, 4H), 5.74 (d, J = 5.5 Hz, 1H), 3.93-3.83 (m, 4H), 3.15-3.01 (m, 2H), 2.92 (t, J = 9.8 Hz, 1H), 2.04-1.94 (m, 1H), 1.87-1.77 (m, 1H). One proton obscured by solvent. 15 0 3-(N-(2-(4-ethyl-4-hydroxypiperidin-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 503.4 (M + H).sup.+, 501.2 (M H).sup. at 1.46 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.27 (s, 1H), 8.74 (s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 8.7, 2.2 Hz, 1H), 7.46 (s, 1H), 7.33 (s, 2H), 7.26 (d, J = 8.7 Hz, 1H), 4.09 (s, 1H), 3.88 (s, 3H), 2.92 (td, J = 11.1, 3.4 Hz, 2H), 2.72 (d, J = 10.9 Hz, 2H), 1.65-1.50 (m, 4H), 1.45 (q, J = 7.4 Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H). 16 4-methoxy-3-(N-(2-(4-methoxy-3,3- dimethylpiperidin-1-yl)-5-(trifluoromethyl) phenyl)sulfamoyl)benzoic acid UPLC-MS (Method 1) m/z 515.2 (M H).sup. at 1.75 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.18 (br s, 1H), 8.57 (br s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.16 (dd, J = 8.7, 2.2 Hz, 1H), 7.42-7.26 (m, 4H), 3.88 (s, 3H), 3.31 (s, 3H), 3.08-2.99 (m, 1H), 2.94 (dd, J = 9.1, 3.9 Hz, 1H), 2.85-2.76 (m, 1H), 2.67-2.60 (m, 1H), 2.37 (d, J = 11.7 Hz, 1H), 2.05-1.96 (m, 1H), 1.73-1.61 (m, 1H), 1.02 (s, 3H), 0.96 (s, 3H). 17 3-(N-(2-(4-hydroxy-4-(trifluoromethyl) piperidin-1-yl)-5-(trifluoromethyl) phenyl)sulfamoyl)-4-methoxybenzoic acid UPLC-MS (Method 1) m/z 543.4 (M + H).sup.+, 541.1 (M H).sup. at 1.50 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.14 (br s, 1H), 9.18 (br s, 1H), 8.34 (d, J = 2.2 Hz, 1H), 8.15 (dd, J = 8.7, 2.2 Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.33- 7.31 (m, 2H), 5.94 (s, 1H), 3.85 (s, 3H), 2.94- 2.83 (m, 4H), 1.94-1.84 (m, 2H), 1.66 (d, J = 12.7 Hz, 2H). 18 3-(N-(2-(3-hydroxy-3-methylazetidin-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 461.3 (M + H).sup.+, 459.1 (M H).sup. at 1.19 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.06 (br s, 1H), 9.27 (s, 1H), 8.19 (dd, J = 8.7, 2.3 Hz, 1H), 8.12 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.31 (dd, J = 8.6, 1.6 Hz, 1H), 6.52- 6.46 (m, 2H), 5.51 (s, 1H), 4.00 (d, J = 8.2 Hz, 2H), 3.94 (s, 3H), 3.88 (d, J = 8.2 Hz, 2H), 1.41 (s, 3H). 19 3-(N-(2-(1-oxa-6-azaspiro[3.3]heptan-6-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 473.3 (M + H).sup.+, 471.1 (M H).sup. at 1.27 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.07 (br s, 1H), 9.29 (br s, 1H), 8.19 (dd, J = 8.7, 2.3 Hz, 1H), 8.11 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.35-7.29 (m, 1H), 6.53-6.47 (m, 2H), 4.44 (t, J = 7.5 Hz, 2H), 4.36 (d, J = 9.8 Hz, 2H), 4.16 (d, J = 9.8 Hz, 2H), 3.95 (s, 3H), 2.85 (t, J = 7.5 Hz, 2H). 20 3-(N-(2-(3-hydroxy-3-methylpyrrolidin-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 475.4 (M + H).sup.+, 473.2 (M H).sup. at 1.24 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.03 (br s, 1H), 9.29 (br s, 1H), 8.17 (dd, J = 8.7, 2.2 Hz, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.28 (dd, J = 8.8, 1.9 Hz, 1H), 6.72 (d, J = 8.9 Hz, 1H), 6.52 (d, J = 1.9 Hz, 1H), 4.77 (br s, 1H), 3.97 (s, 3H), 3.63-3.56 (m, 1H), 3.53 (d, J = 10.5 Hz, 1H), 3.50-3.44 (m, 1H), 3.39 (d, J = 10.5 Hz, 1H), 1.91-1.84 (m, 1H), 1.81-1.73 (m, 1H), 1.31 (s, 3H). 21 3-(N-(2-(3-cyclopropyl-3-hydroxyazetidin-1-yl)- 5-(trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 487.0 (M + H).sup.+, 485.1 (M H).sup. at 1.28 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.07 (br s, 1H), 9.25 (br s, 1H), 8.18 (dd, J = 8.7, 2.2 Hz, 1H), 8.11 (d, J = 2.2 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.30 (dd, J = 8.7, 2.1 Hz, 1H), 6.51-6.47 (m, 2H), 5.47 (s, 1H), 3.97 (d, J = 8.4 Hz, 2H), 3.95 (s, 3H), 3.83 (d, J = 8.5 Hz, 2H), 1.22-1.14 (m, 1H), 0.45-0.31 (m, 4H). 22 4-methoxy-3-(N-(2-(3-methoxy-3- methylazetidin-1-yl)-5-(trifluoromethyl) phenyl)sulfamoyl)benzoic acid UPLC-MS (Method 1) m/z 475.4 (M + H).sup.+, 473.2 (M H).sup. at 1.36 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.04 (br s, 1H), 9.29 (br s, 1H), 8.19 (dd, J = 8.7, 2.3 Hz, 1H), 8.13 (d, J = 2.2 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.33 (dd, J = 8.7, 2.1 Hz, 1H), 6.55 (d, J = 2.1 Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H), 3.99 (d, J = 8.6 Hz, 2H), 3.94 (s, 3H), 3.93 (d, J = 8.6 Hz, 2H), 3.18 (s, 3H), 1.44 (s, 3H). 23 3-(N-(2-(endo-3-hydroxy-8-azabicyclo [3.2.1]octan-8-yl)-5-(trifluoromethyl) phenyl)sulfamoyl)-4-methoxybenzoic acid UPLC-MS (Method 1) m/z 501.3 (M + H).sup.+, 499.1 (M H).sup. at 1.40 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.98 (s, 1H), 8.20 (d, J = 2.2 Hz, 1H), 8.16 (dd, J = 8.6, 2.2 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.27 (dd, J = 8.7, 2.3 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 2.2 Hz, 1H), 4.55 (br s, 1H), 4.32- 4.24 (m, 2H), 3.92 (s, 3H), 3.88 (t, J = 5.0 Hz, 1H), 2.23-2.20 (m, 2H), 2.04-1.94 (m, 2H), 1.83-1.77 (m, 2H), 1.71-1.58 (m, 2H). One exchangeable proton not observed. 24 3-(N-(2-(4-hydroxy-3,3-dimethylpiperidin-1-yl)- 5-(trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 503.1 (M + H).sup.+, 501.2 (M H).sup. at 1.47 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.19 (br s, 1H), 8.53 (br s, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.15 (dd, J = 8.7, 2.2 Hz, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.36-7.29 (m, 3H), 4.67 (d, J = 4.8 Hz, 1H), 3.88 (s, 3H), 3.29-3.23 (m, 1H), 3.04-2.95 (m, 1H), 2.84-2.77 (m, 1H), 2.68- 2.60 (m, 1H), 2.31 (d, J = 11.8 Hz, 1H), 1.84- 1.76 (m, 1H), 1.76-1.64 (m, 1H), 1.02 (s, 3H), 0.92 (s, 3H). 25 0 4-methoxy-3-(N-(2-(cis-octahydroisoindol-2- yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid UPLC-MS (Method 1) m/z 499.4 (M + H).sup.+, 497.2 (M H).sup. at 1.72 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.07 (br s, 1H), 9.28 (br s, 1H), 8.17 (dd, J = 8.7, 2.2 Hz, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.28 (dd, J = 8.9, 2.0 Hz, 1H), 6.72 (d, J = 8.9 Hz, 1H), 6.55 (d, J = 1.9 Hz, 1H), 3.96 (s, 3H), 3.51-3.40 (m, 4H), 2.27-2.17 (m, 2H), 1.61-1.44 (m, 4H), 1.45-1.30 (m, 4H). 26 3-(N-(2-(3-hydroxy-3-(trifluoromethyl)azetidin- 1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 515.2 (M + H).sup.+, 513.1 (M H).sup. at 1.33 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.04 (br s, 1H), 9.31 (br s, 1H), 8.16 (d, J = 8.7 Hz, 1H), 8.14-8.09 (m, 1H), 7.42-7.24 (m, 3H), 6.63-6.49 (m, 2H), 4.39 (d, J = 9.7 Hz, 2H), 4.10 (d, J = 9.7 Hz, 2H), 3.94 (s, 3H). 27 3-(N-(2-((3S,4R)-3-fluoro-4-hydroxypiperidin-1- yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 493.1 (M + H).sup.+, 491.2 (M H).sup. at 1.29 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.18 (br s, 1H), 8.71 (br s, 1H), 8.38(d, J = 2.2 Hz, 1H), 8.15 (dd, J = 8.7, 2.3 Hz, 1H), 7.44 (s, 1H), 7.37-7.26 (m, 3H), 5.15 (d, J = 5.3 Hz, 1H), 4.83-4.65 (m, 1H), 3.91 (s, 3H), 3.84-3.72 (m, 1H), 3.21-3.14 (m, 1H), 3.00-2.82 (m, 3H), 1.95- 1.74 (m, 2H). 28 3-(N-(2-(4-hydroxy-4-methylpiperidin-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 489.3 (M + H).sup.+, 487.2 (M H).sup. at 1.37 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.17 (br s, 1H), 8.80 (br s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.15 (dd, J = 8.7, 2.2 Hz, 1H), 7.44 (s, 1H), 7.37-7.33 (m, 2H), 7.31 (d, J = 8.8 Hz, 1H), 4.31 (s, 1H), 3.90 (s, 3H), 2.92 (td, J = 11.0, 3.3 Hz, 2H), 2.73-2.65 (m, 2H), 1.66-1.54 (m, 4H), 1.18 (s, 3H).

Example 29: 3-(N-(2-(3-hydroxy-3-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)-4-methoxybenzoic acid

(83) ##STR00474##

(84) Step 1: 3-methyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ol: Et.sub.3N (0.500 ml, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) and 3-methylpiperidin-3-ol (198 mg, 1.72 mmol) in DCM (6 ml) at RT. The clear solution was stirred at RT for 17 h. The organic phase was washed with 1 M HCl(aq) (3 ml) and the organic phase was dried by passage through a phase separator and concentrated in vacuo to afford the title compound (452 mg, 1.35 mmol, 94% yield, 91% purity) as a red/orange oil. UPLC-MS (Method 1) m/z 305.2 (M+H).sup.+ at 1.49 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.07 (d, J=2.3 Hz, 1H), 7.76 (dd, J=9.0, 2.4 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 4.51 (s, 1H), 3.16 (ddd, J=13.2, 6.1, 3.7 Hz, 1H), 3.08 (ddd, J=12.8, 8.3, 3.2 Hz, 1H), 3.00 (d, J=12.6 Hz, 1H), 2.90 (d, J=12.7 Hz, 1H), 1.87-1.76 (m, 1H), 1.60-1.55 (m, 2H), 1.55-1.48 (m, 1H), 1.10 (s, 3H).

(85) Step 2: 1-(2-amino-4-(trifluoromethyl)phenyl)-3-methylpiperidin-3-ol: 5% Pd/C (50% w/w water) Type 87L (50 mg, 0.012 mmol) in EtOH (0.5 ml) was added to a solution of the product from step 1 above (224 mg, 0.670 mmol) in EtOH (3.0 ml) at RT. The reaction mixture was hydrogenated at 4 bar at RT for 19 h. The catalyst was removed by filtration through Celite and washed with MeOH (20 ml). The organic phase was concentrated in vacuo and the residue was redissolved in EtOAc (10 ml). The organic phase was washed with water (5 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to the title compound (112 mg, 0.404 mmol, 60.3% yield, 99% purity) as a pale orange solid. UPLC-MS (Method 1) m/z 275.3 (M+H).sup.+ at 1.42 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 6.94 (d, J=8.1 Hz, 1H), 6.92 (d, J=1.8 Hz, 1H), 6.81 (dd, J=8.1, 1.8 Hz, 1H), 5.27 (br s, 2H), 4.58 (s, 1H), 2.91-2.81 (m, 1H), 2.73-2.67 (m, 1H), 2.60-2.51 (m, 2H), 1.95-1.84 (m, 1H), 1.60-1.50 (m, 2H), 1.47-1.38 (m, 1H), 1.15 (s, 3H).

(86) Step 3: methyl 3-(N-(2-(3-hydroxy-3-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (0.075 ml, 0.933 mmol) was added to a cloudy solution of the product from step 2 above (64.6 mg, 0.233 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (78 mg, 0.280 mmol) in DCM (2.0 ml) at RT. The resultant clear solution was stirred at RT for 20 h. The reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on silica gel (12 g cartridge, 30-100% EtOAc/isohexanes) to afford the title compound (98.5 mg, 0.196 mmol, 84% yield, 100% purity) as an off-white foam. UPLC-MS (Method 1) m/z 503.4 (M+H).sup.+, 501.2 (MH).sup. at 1.66 min.

(87) Step 4: 3-(N-(2-(3-hydroxy-3-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1 M LiOH(aq) (0.784 ml, 0.784 mmol) was added to a solution of the product from step 3 above (98.5 mg, 0.196 mmol) in THF (1.57 ml) at RT. The solution was stirred at RT for 18 h and then concentrated in vacuo. The residue was redissolved in water (3 ml) and acidified using 1 M HCl(aq) until pH 4-5. The precipitate was isolated by filtration and then redissolved in EtOAc (5 ml). The organic phase was washed with water (3 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to afford the title compound (64 mg, 0.130 mmol, 73.4% yield, 99% purity) as an off-white solid. UPLC-MS (Method 1) m/z 489.4 (M+H).sup.+, 487.3 (MH).sup. at 1.49 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.14 (br s, 1H), 9.44 (br s, 1H), 8.41 (d, J=2.2 Hz, 1H), 8.14 (dd, J=8.7, 2.2 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.30 (dd, J=8.4, 1.7 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 5.02 (br s, 1H), 3.78 (s, 3H), 2.93-2.85 (m, 1H), 2.63 (td, J=11.1, 2.4 Hz, 1H), 2.56-2.52 (m, 1H), 2.52-2.48 (m, 1H), 2.03-1.90 (m, 1H), 1.62-1.55 (m, 1H), 1.54-1.46 (m, 1H), 1.37 (td, J=12.6, 4.5 Hz, 1H), 1.02 (s, 3H).

Example 30:3-(N-(2-(cis-3,5-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl sulfamoyl)-4-ethylbenzoic acid

(88) ##STR00475##

(89) A solution of the product from example 6, step 2, (72 mg, 0.264 mmol) in DCM (1 ml) and pyridine (0.128 ml, 1.59 mmol) were added to a suspension of the product from example 1, step 1, (79 mg, 0.317 mmol) in DCM (1 ml) and the solution was stirred at RT for 4 days. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-10% MeOH/DCM). The product from chromatography was partitioned between isohexanes (3 ml) and MeCN (3 ml). The phases were separated, the MeCN phase was washed with isohexanes (23 ml) and concentrated in vacuo. The product was loaded onto a silica plug in the minimum amount of DCM, the column was eluted with DCM (5 ml), isohexanes (5 ml), 5% MeOH in EtOAc (5 ml) then 5% MeOH in EtOAc (5 ml) to afford the title compound (26.7 mg, 0.052 mmol, 19.80% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 485.4 (M+H).sup.+, 483.3 (MH).sup. at 2.06 min. .sup.1H NMR (500 MHz, Methanol-d.sub.4) 8.54 (d, J=1.8 Hz, 1H), 8.15 (dd, J=8.0, 1.8 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.36-7.27 (m, 2H), 3.07 (q, J=7.5 Hz, 2H), 2.79-2.72 (m, 2H), 2.18 (t, J=11.1 Hz, 2H), 1.89-1.76 (m, 3H), 1.28 (t, J=7.5 Hz, 3H), 0.90 (d, J=6.5 Hz, 6H), 0.75-0.64 (m, 1H). Two exchangeable protons not observed.

Example 31: 3-(N-(2-(2,2-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(90) ##STR00476##

(91) Step 1: 2,2-dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et.sub.3N (0.500 ml, 3.59 mmol) was added to a solution of 2,2-dimethylpiperidine (195 mg, 1.72 mmol) and 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 96 h. Additional 2,2-dimethylpiperidine (75 mg, 0.663 mmol) was added and the reaction was stirred at RT for 1 day. Water (3 ml) was added and the phases were separated before the aqueous phase was extracted with DCM (23 ml). The organic phases were combined, dried by passage through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexanes) to afford the title compound (163 mg, 0.512 mmol, 35.7% yield, 95% purity) as a dark orange viscous oil. UPLC-MS (Method 2) m/z 303.3 (M+H).sup.+ at 1.96 min.

(92) Step 2: 2-(2,2-dimethylpiperidin-1-yl)-5-(trifluoromethyl)aniline: Iron powder (297 mg, 5.33 mmol) was added to a solution of the product from step 1 above (161 mg, 0.533 mmol) and ammonium chloride (34.2 mg, 0.639 mmol) in IPA (5 ml) and water (2.5 ml) at RT. The resultant suspension was heated and stirred at 90 C. for 1 h then cooled to RT overnight. Additional iron powder (297 mg, 5.33 mmol) was added and the reaction was heated at 90 C. for a further 2 h then cooled to RT. The reaction mixture was filtered through Celite, washed with excess MeOH (100 ml) and concentrated in vacuo. The residue was redissolved in DCM (25 ml) and washed with water (5 ml). The aqueous phase was extracted with DCM (25 ml) and the combined organic phases were washed with brine (10 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to afford the title compound (78 mg, 0.215 mmol, 40.3% yield, 75% purity) as a pale yellow oil. UPLC-MS (Method 2) m/z 273.3 (M+H).sup.+ at 1.95 min.

(93) Step 3: methyl 3-(N-(2-(2,2-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from step 2 above (51.4 mg, 0.189 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (0.05 ml, 0.618 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (60 mg, 0.227 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 18 h. The reaction mixture was loaded directly on to silica gel and purified by column chromatography (12 g cartridge, 0-100% EtOAc/isohexanes) to afford the title compound (64 mg, 0.121 mmol, 64.3% yield, 100% purity) as a white sticky solid. UPLC-MS (Method 1) m/z 501.4 (M+H).sup.+, 499.1 (MH).sup. at 1.95 min.

(94) Step 4: 3-(N-(2-(2,2-dimethylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 3 above (62 mg, 0.124 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (450 l, 0.495 mmol). The reaction was stirred at RT for 1 day. MeOH was added dropwise until the mixture was a solution, the reaction mixture was heated at 40 C. for 4 h and then cooled to RT overnight. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (5 ml). 1 M HCl(aq) was added dropwise to ca. pH 6. The resultant white precipitate was collected by filtration, washing with water. The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (57 mg, 0.111 mmol, 90% yield, 99% purity) as a white solid. UPLC-MS (Method 1) m/z 487.3 (M+H).sup.+, 485.2 (MH).sup. at 1.80 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.20 (br s, 1H), 8.96 (s, 1H), 8.41 (d, J=2.2 Hz, 1H), 8.14 (dd, J=8.7, 2.2 Hz, 1H), 7.59 (s, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.33-7.27 (m, 2H), 3.93 (s, 3H), 1.73-1.55 (m, 6H), 1.32-0.62 (m, 8H).

Example 32: 3-(N-(2-(1,4-oxazepan-4-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(95) ##STR00477##

(96) Step 1: 4-(2-nitro-4-(trifluoromethyl)phenyl)-1,4-oxazepane: Et.sub.3N (0.500 ml, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) and 1,4-oxazepane hydrochloride (237 mg, 1.72 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 7 days. Water (3 ml) was added and the phases were separated using a phase separator. The aqueous phase was extracted with DCM (23 ml) and the organic phases were combined, dried by passage through a phase separator and concentrated in vacuo to afford the title compound as a viscous orange oil (429 mg, 1.14 mmol, 98% yield, 95% purity). UPLC-MS (Method 2) m/z 290.8 (M+H).sup.+ at 1.48 min.

(97) Step 2: 2-(1,4-oxazepan-4-yl)-5-(trifluoromethyl)aniline: Iron powder (822 mg, 14.71 mmol) was added to a solution of the product from step 1 above (427 mg, 1.471 mmol) and ammonium chloride (94 mg, 1.765 mmol) in IPA (5 ml) and water (2.5 ml) at RT. The resultant suspension was heated and stirred at 90 C. for 1 h then cooled to RT. The reaction mixture was filtered through Celite, washed with excess MeOH (100 ml) and concentrated in vacuo. The residue was redissolved In DCM (25 ml) and washed with water (5 ml). The aqueous phase was extracted with DCM (25 ml) and the combined organic phases were washed with brine (10 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexanes) to afford the title compound (186 mg, 0.700 mmol, 47.6% yield, 98% purity) as a dark orange solid. UPLC-MS (Method 2) m/z 261.3 (M+H).sup.+ at 1.39 min.

(98) Step 3: methyl 3-(N-(2-(1,4-oxazepan-4-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from step 2 above (54.8 mg, 0.189 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (0.05 ml, 0.618 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (60 mg, 0.227 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 18 h. The reaction mixture was loaded directly on silica gel and purified by column chromatography (12 g cartridge, 0-100% EtOAc/isohexanes) to afford the title compound (66 mg, 0.132 mmol, 70.1% yield, 98% purity) as a cream solid. UPLC-MS (Method 1) m/z 489.3 (M+H).sup.+, 487.2 (MH).sup. at 1.59 min.

(99) Step 4: 3-(N-(2-(1,4-oxazepan-4-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 3 above (64 mg, 0.131 mmol) was dissolved in THF (2 ml), treated with 1.1 M LiOH(aq) (476 l, 0.524 mmol) and stirred at RT for 1 day. MeOH was added dropwise until the mixture was a solution, the reaction mixture was heated at 40 C. for 4 h then cooled to RT overnight. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to ca. 5 ml) and neutralised to ca. pH 6 with 1 M HCl. The resultant lumpy suspension was sonicated to afford a cloudy solution and the white precipitate was collected by filtration, washing with water. The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (60 mg, 0.120 mmol, 92% yield, 95% purity) as a pale grey solid. UPLC-MS (Method 1) m/z 475.4 (M+H).sup.+, 473.3 (MH).sup. at 1.43 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.12 (s, 1H), 9.11 (s, 1H), 8.23 (s, 1H), 8.16 (dd, J=8.7, 2.2 Hz, 1H), 7.38-7.32 (m, 2H), 7.23 (d, J=8.5 Hz, 1H), 7.10 (s, 1H), 3.93 (s, 3H), 3.76-3.70 (m, 4H), 3.29-3.20 (m, 4H), 1.91 (t, J=5.8 Hz, 2H).

Example 33: 3-(N-(2-(spiro[isobenzofuran-1,4-piperidin]-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)-4-methoxybenzoic acid

(100) ##STR00478##

(101) Step 1: 1-(2-nitro-4-(trifluoromethyl)phenyl)spiro[isobenzofuran-1,4-piperidine]: Et.sub.3N (0.417 ml, 2.99 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.167 ml, 1.20 mmol) and spiro[isobenzofuran-1,4-piperidine]hydrochloride (324 mg, 1.44 mmol) in DCM (6 ml) at RT and the reaction mixture was stirred at RT for 68 h. Water (2 ml) was added and the phases were separated. The aqueous phase was extracted with DCM (23 ml) and the combined organic phases were dried by passage through a phase separator and concentrated in vacuo to afford the title compound (536 mg, 0.907 mmol, 76% yield, 64% purity) as an orange oil. UPLC-MS (Method 1) m/z 379.2 (M+H).sup.+ at 1.91 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.17 (d, J=1.6 Hz, 1H), 7.86 (dd, J=8.9, 2.3 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.34-7.27 (m, 4H), 5.04 (s, 2H), 3.39-3.29 (m, 4H), 2.06 (dt, J=17.4, 5.8 Hz, 2H), 1.74 (dd, J=13.9, 2.5 Hz, 2H).

(102) Step 2: 2-(spiro[isobenzofuran-1,4-piperidin]-1-yl)-5-(trifluoromethyl)aniline: Iron powder (335 mg, 6.00 mmol) was added to a solution of the product from step 1 above (227 mg, 0.600 mmol) and ammonium chloride (38.5 mg, 0.720 mmol) in IPA (3.5 ml) and water (1.25 ml) and heated to 90 C. for 2 h. The reaction mixture was cooled to RT, filtered and washed with excess MeOH (100 ml). The filtrate was concentrated in vacuo, redissolved in DCM (25 ml) and washed with water (5 ml). The aqueous phase was extracted with DCM (25 ml) and the combined organic phases were washed with brine (10 ml), dried by passage through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-35% EtOAc/isohexanes) to afford the title compound (144 mg, 0.401 mmol, 66.8% yield, 97% purity) as an orange powder. UPLC-MS (Method 1) m/z 349.2 (M+H).sup.+ at 1.83 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.36-7.24 (m, 4H), 7.07 (d, J=8.1 Hz, 1H), 6.98 (d, J=2.1 Hz, 1H), 6.85 (dd, J=8.2, 2.1 Hz, 1H), 5.22 (s, 2H), 5.03 (s, 2H), 3.12-3.01 (m, 2H), 2.91 (td, J=12.0, 2.3 Hz, 2H), 2.18 (td, J=12.9, 4.5 Hz, 2H), 1.79-1.67 (m, 2H).

(103) Step 3: methyl 3-(N-(2-(spiro[isobenzofuran-1,4-piperidin]-1-yl)-5-(trifluoromethyl) phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (0.058 ml, 0.718 mmol) was added to a solution of the product from step 2 above (86 mg, 0.239 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.287 mmol) in DCM (2 ml) at RT. The reaction mixture was stirred and heated at 40 C. for 18 h. Additional methyl 3-(chlorosulfonyl)-4-methoxybenzoate (33 mg, 0.120 mmol) was added and the reaction mixture was stirred at 40 C. for a further 3 h. The reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on silica gel (25 g cartridge, 0-45% EtOAc/isohexanes) to afford the title compound (117 mg, 0.187 mmol, 78% yield, 92% purity) as an off-white solid. UPLC-MS (Method 2) m/z 577.4 (M+H).sup.+ 575.2, (MH).sup. at 1.89 min.

(104) Step 4: 3-(N-(2-(spiro[isobenzofuran-1,4-piperidin]-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1 M LiOH(aq) (0.812 ml, 0.812 mmol) was added to a solution of the product from step 3 above (117 mg, 0.203 mmol) in THF (1.6 ml) at RT. The solution was stirred at RT for 25 h before concentrating in vacuo. The residue was redissolved in water (3 ml) and acidified using 1 M HCl(aq) until pH 4-5. The precipitate was isolated by filtration and dried in vacuo to afford the title compound (92 mg, 0.164 mmol, 81% yield, 94% purity) as an off-white solid. UPLC-MS (Method 1) m/z 563.3 (M+H).sup.+, 561.1 (MH).sup. at 1.80 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.02 (br s, 1H), 8.39 (d, J=2.3 Hz, 1H), 8.15 (dd, J=8.7, 2.2 Hz, 1H), 7.51 (d, J=1.7 Hz, 1H), 7.39-7.27 (m, 7H), 5.02 (s, 2H), 3.88 (s, 3H), 3.01 (t, J=11.9 Hz, 2H), 2.96-2.90 (m, 2H), 2.19-2.08 (m, 2H), 1.73-1.65 (m, 2H). One exchangeable proton not seen.

(105) The following examples were prepared by methods analagous to Example 33, substituting appropriate starting materials and intermediates where necessary:

(106) TABLE-US-00010 Example Structure Name/Analytical Data 34 3-(N-(2-(4-acetylpiperazin-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 502.3 (M + H).sup.+, 500.2 (M H).sup. at 1.28 min. .sup.1H NMR (500 MHz, DMSO- d.sub.6) 13.00 (s, 1H), 9.14 (s, 1H), 8.35 (d, J = 2.1 Hz, 1H), 8.16 (dd, J = 8.7, 2.2 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.5, 2.0 Hz, 1H), 7.32 (m, 2H), 3.91 (s, 3H), 3.64-3.53 (m, 4H), 2.83 (t, J = 4.8 Hz, 2H), 2.74 (t, J = 5.0 Hz, 2H), 2.04 (s, 3H). 35 0 3-(N-(2-(4-hydroxypiperidin-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 475.4 (M + H).sup.+, 473.2 (M H).sup. at 1.31 min. .sup.1H NMR (500 MHz, DMSO- d.sub.6) 13.16 (br s, 1H), 8.80 (br s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.15 (dd, J = 8.7, 2.2 Hz, 1H), 7.46-7.40 (m, 1H), 7.37-7.28 (m, 3H), 4.71 (d, J = 4.1 Hz, 1H), 3.92 (s, 3H), 3.68-3.59 (m, 1H), 2.94 (dt, J = 10.4, 4.5 Hz, 2H), 2.66 (ddd, J = 12.1, 9.6, 2.9 Hz, 2H), 1.90-1.79 (m, 2H), 1.63-1.51 (m, 2H). 36 3-(N-(2-(3-hydroxypyrrolidin-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 461.3 (M + H).sup.+, 459.2 (M H).sup. at 1.18 min. .sup.1H NMR (500 MHz, DMSO- d.sub.6) 13.03 (br s, 1H), 9.28 (br s, 1H), 8.17 (dd, J = 8.7, 2.2 Hz, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.29 (dd, J = 8.8, 2.3 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.51 (d, J = 2.3 Hz, 1H), 4.96 (br s, 1H), 4.34 (p, J = 4.2 Hz, 1H), 3.98 (s, 3H), 3.79 (dd, J = 10.9, 4.7 Hz, 1H), 3.59-3.52 (m, 1H), 3.49-3.44 (m, 1H), 3.38-3.33 (m, 1H), 1.97-1.83 (m, 1H), 1.84 (td, J = 7.7, 3.4 Hz, 1H). 37 3-(N-(2-(3-hydroxyazetidin-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 447.3 (M + H).sup.+, 445.2 (M H).sup. at 1.12 min. .sup.1H NMR (500 MHz, DMSO- d.sub.6) 13.05 (br s, 1 H), 9.23 (br s, 1H), 8.18 (dd, J = 8.7, 2.3 Hz, 1H), 8.12 (d, J = 2.2 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.30 (dd, J = 8.6, 2.1 Hz, 1H), 6.52-6.44 (m, 2H), 5.62 (br s, 1H), 4.55-4.49 (m, 1H), 4.35 (dd, J = 8.6, 6.6 Hz, 2H), 3.95 (s, 3H), 3.80 (dd, J = 8.8, 4.8 Hz, 2H). 39 3-(N-(2-(3,3-dimethylpyrrolidin-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 473.4 (M + H).sup.+, 471.2 (M H).sup. at 1.63 min. .sup.1H NMR (500 MHz, DMSO- d.sub.6) 13.12 (s, 1H), 9.11 (s, 1H), 8.23 (d, J = 2.2 Hz, 1H), 8.16 (dd, J = 8.7, 2.2 Hz, 1H), 7.38- 7.32 (m, 2H), 7.26-7.20 (m, 1H), 7.10 (s, 1H), 3.93 (s, 3H), 3.77-3.70 (m, 4H), 3.29-3.20 (m, 4H), 1.91 (t, J = 5.8 Hz, 2H). Two protons obscured by solvent. 40 (R)-3-(N-(2-(hexahydropyrrolo[1,2-a]pyrazin- 2(1H)-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)-4-methoxybenzoic acid UPLC-MS (Method 1) m/z 500.3 (M + H).sup.+, 498.4 (M H).sup. at 0.87 min. .sup.1H NMR (500 MHz, DMSO- d.sub.6) 13.13 (s, 1H), 9.40 (s, 1H), 8.34 (d, J = 2.2 Hz, 1H), 8.17 (dd, J = 8.7, 2.2 Hz, 1H), 7.47- 7.41 (m, 2H), 7.39-7.30 (m, 2H), 3.86 (s, 3H), 3.21-2.83 (m, 6H), 2.04-1.88 (m, 3H), 1.23 (s, 2H). Two protons obscured by solvent.

Example 41: 4-methoxy-3-(N-(2-(2-oxopiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(107) ##STR00485##

(108) Step 1: 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-2-one: NaH (63.1 mg, 1.58 mmol, 60% w/w in mineral oil) was added to a solution of piperidin-2-one (142 mg, 1.44 mmol) in anhydrous DMF (3 ml) at 0 C. under N.sub.2. The reaction was stirred at this temperature for 10 min then a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) in anhydrous DMF (3 ml) was added dropwise at 0 C. The reaction was stirred at RT overnight. The reaction mixture was diluted with EtOAc (100 ml) and washed sequentially with water (50 ml) and brine (250 ml). The organic phase was separated, dried over MgSO.sub.4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (245 mg, 0.808 mmol, 56.3% yield, 100% purity) as a light yellow solid. UPLC-MS (Method 2) m/z 289.5 (M+H).sup.+ at 1.23 min.

(109) Step 2: 1-(2-amino-4-(trifluoromethyl)phenyl)piperidin-2-one: Iron powder (508 mg, 9.09 mmol) was added to a suspension of the product from step 1 above (131 mg, 0.455 mmol) and ammonium chloride (29.2 mg, 0.545 mmol) in propan-2-ol (5 ml) and water (2.5 ml) at RT. The resulting suspension was heated and stirred at 90 C. for 2 h. The reaction was filtered through Celite, washed with excess MeOH (100 ml) and concentrated in vacuo. The residue was redissolved in DCM (25 ml) and washed sequentially with water (10 ml) and brine (10 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (22 mg, 0.076 mmol, 16.7% yield, 89% purity) as a cream solid. UPLC-MS (Method 2) m/z 259.3 (M+H).sup.+ at 1.07 min.

(110) Step 3: methyl 4-methoxy-3-(N-(2-(2-oxopiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoate: The product from step 2 above (22 mg, 0.085 mmol) was dissolved in a mixture of DCM (0.5 ml) and pyridine (22.5 l, 0.279 mmol) and treated with a solution methyl 3-(chlorosulfonyl)-4-methoxybenzoate (27.1 mg, 0.102 mmol) in DCM (0.5 ml). The resultant solution was stirred at RT for 18 h. More methyl 3-(chlorosulfonyl)-4-methoxybenzoate (11.3 mg, 0.043 mmol) and pyridine (6.89 l, 0.085 mmol) were added and the reaction mixture was stirred at RT for 1 h. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (18.6 mg, 0.037 mmol, 43.5% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m/z 487.6 (M+H).sup.+, 484.8 (MH).sup. at 1.40 min.

(111) Step 4: 4-methoxy-3-(N-(2-(2-oxopiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: The product from step 3 above (18.6 mg, 0.038 mmol) was dissolved in THF (1 ml) and treated with 1.1 M LiOH(aq) (139 l, 0.153 mmol). The reaction was stirred at RT for 1 day then MeOH was added dropwise until the mixture was a solution and the reaction mixture was heated at 40 C. for 20 h before cooling to RT. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml) and neutralised to pH 6 with 1 M HCl. The white precipitate was collected by filtration, washing with water. The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (17.1 mg, 0.034 mmol, 90% yield, 95% purity) as a pale yellow solid. UPLC-MS (Method 1) m/z 473.0 (M+H).sup.+, 471.1 (MH).sup. at 1.23 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.12 (s, 1H), 9.70 (s, 1H), 8.33 (d, J=2.2 Hz, 1H), 8.15 (dd, J=8.7, 2.2 Hz, 1H), 7.65 (s, 1H), 7.54-7.39 (m, 2H), 7.31 (d, J=8.8 Hz, 1H), 3.80 (s, 3H), 3.09-3.23 (m, 2H), 2.44-2.22 (m, 2H), 1.90-1.70 (m, 4H).

Example 42: 3-(N-(2-(1,4-oxazepan-4-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methylbenzoic acid

(112) ##STR00486##

(113) A solution of the product from example 32, step 2 above 62 mg, 0.238 mmol) in DCM (1 ml) and pyridine (0.116 ml, 1.43 mmol) were added to a solution of 3-(chlorosulfonyl)-4-methylbenzoic acid (67.1 mg, 0.286 mmol) in DCM (1 ml) and the solution was stirred at RT for 4 days. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-10% MeOH/DCM) to afford a cream solid (23 mg). 8 mg of this crude product was loaded onto a silica plug in the minimal amount of DCM, the column was eluted with DCM (5 ml), isohexanes (5 ml), 5% MeOH in EtOAc (5 ml) then 20% MeOH in EtOAc (5 ml) to afford the title compound (7.0 mg, 0.015 mmol, 6.09% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 459.4 (M+H).sup.+, 457.3 (MH).sup. at 1.64 min. .sup.1H NMR (500 MHz, Methanol-d.sub.4) 8.58 (d, J=2.1 Hz, 1H), 8.48 (s, 1H), 8.00 (dd, J=7.9, 2.1 Hz, 1H), 7.52-7.42 (m, 3H), 3.97 (t, J=6.2 Hz, 2H), 3.94-3.89 (m, 2H), 3.28-3.22 (m, 4H), 2.79 (s, 3H), 2.15-2.07 (m, 2H). Two exchangeable protons not observed.

Example 43: 3-(N-(2-(1,4-oxazepan-4-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(114) ##STR00487##

(115) A solution of the product from example 32, step 2 above (62 mg, 0.238 mmol) in DCM (1 ml) and pyridine (0.116 ml, 1.429 mmol) were added to a solution of the product from example 1, step 1 above (71.1 mg, 0.286 mmol) in DCM (1 ml) and the solution was stirred at RT for 4 days. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-10% MeOH/DCM) to afford a cream solid. This was loaded onto a silica plug in the minimal amount of DCM, the column was eluted sequentially with DCM (5 ml), isohexanes (5 ml), 5% MeOH in EtOAc (5 ml) then 5% MeOH in EtOAc (5 ml) to afford the title compound (11.7 mg, 0.024 mmol, 9.87% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 473.4 (M+H).sup.+, 471.2 (MH).sup. at 1.61 min. .sup.1H NMR (500 MHz, Methanol-d.sub.4) 8.53 (d, J=1.8 Hz, 1H), 8.17 (dd, J=8.0, 1.8 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.34-7.28 (m, 3H), 3.90 (t, J=5.9 Hz, 2H), 3.86-3.81 (m, 2H), 3.23-3.16 (m, 4H), 3.08 (q, J=7.5 Hz, 2H), 2.02 (p, J=5.8 Hz, 2H), 1.29 (t, J=7.5 Hz, 3H). Two exchangeable protons not observed.

Example 46: 4-methoxy-3-(N-(2-(2-(3-methylisoxazol-5-yl) pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

(116) ##STR00488##

(117) Step 1: 3-methyl-5-(1-(2-nitro-4-(trifluoromethyl)phenyl) pyrrolidin-2-yl) isoxazole: Et.sub.3N (302 mg, 2.99 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.167 ml, 1.20 mmol) and 3-methyl-5-(pyrrolidin-2-yl) isoxazole (218 mg, 1.44 mmol) in DCM (5 ml) and the resultant solution was stirred at RT for 19 h. Water (2.5 ml) was added and the organic phase was dried by passage through a phase separator and concentrated in vacuo to give the title compound (489 mg, 1.19 mmol, 99% yield, 83% purity) as a yellow oil. UPLC-MS (Method 2) m/z 342.4 (M+H).sup.+ at 1.61 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.07 (m, 1H), 7.71 (dd, J=9.1, 2.0 Hz, 1H), 7.17 (d, J=9.1 Hz, 1H), 6.18 (s, 1H), 5.34 (t, J=7.3 Hz, 1H), 3.55-3.50 (m, 1H), 3.02-2.98 (m, 1H), 2.54-2.51 (m, 1H), 2.16 (s, 3H), 2.08-2.02 (m, 1H), 2.02-1.89 (m, 2H).

(118) Step 2: 2-(2-(3-methylisoxazol-5-yl) pyrrolidin-1-yl)-5-(trifluoromethyl)aniline: Ammonium hydroxide (28% aq. Solution) (0.319 ml, 2.30 mmol) and sodium dithionite (1.18 g, 5.74 mmol) were added to a solution of the product from step 1 above (236 mg, 0.574 mmol) in THF (2.5 ml) and water (2.5 ml) at RT and then stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the residue was redissolved in DCM (10 ml) and washed with water (5 ml). The aqueous phase was extracted with DCM (25 ml) and the organic phases were combined, washed with brine (5 ml), dried by passage through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (10 g cartridge, 0-50% EtOAc/isohexanes) to afford the title compound (95 mg, 0.302 mmol, 52.6% yield, 99% purity) as a red/brown oil. UPLC-MS (Method 1) m/z 312.1 (M+H).sup.+ at 1.52 min. 1H NMR (500 MHz, DMSO-d.sub.6) 7.03 (d, J=8.2 Hz, 1H), 6.92 (d, J=2.2 Hz, 1H), 6.74 (dd, J=8.3, 2.1 Hz, 1H), 6.05 (s, 1H), 5.17 (s, 2H), 4.98 (dd, J=7.9, 5.9 Hz, 1H), 3.72-3.65 (m, 1H), 2.76-2.68 (m, 1H), 2.45-2.37 (m, 1H), 2.10 (s, 3H), 2.08-1.99 (m, 1H), 1.98-1.87 (m, 2H).

(119) Step 3: methyl 4-methoxy-3-(N-(2-(2-(3-methylisoxazol-5-yl) pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: Pyridine (0.069 ml, 0.852 mmol) was added to a solution of the product from step 2 above (88 mg, 0.284 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (95 mg, 0.341 mmol) in DCM (2.5 ml) at RT. The reaction mixture was stirred at RT for 65 h and then at 40 C. for 5 h. The crude reaction mixture was filtered and the filtered product was redissolved in MeCN (10 ml) and concentrated in vacuo to afford the title compound (69 mg, 0.123 mmol, 43.2% yield, 96% purity) as an off-white solid. UPLC-MS (Method 2) m/z 540.3 (M+H).sup.+, 538.2 (MH).sup. at 1.58 min.

(120) Step 4: 4-methoxy-3-(N-(2-(2-(3-methylisoxazol-5-yl) pyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (0.384 ml, 0.384 mmol) was added to a suspension of the product from step 3 above (69 mg, 0.128 mmol) in THF (0.768 ml) at RT. The resultant clear solution was stirred at RT for 20 h. Additional 1 M LiOH(aq) (0.128 ml, 0.128 mmol) was added and the solution was stirred for a further 1 h. The reaction mixture was concentrated in vacuo and the residue was redissolved in water (2 ml) and acidified using 1 M HCl(aq) until pH 4-5. The precipitate was dissolved in DCM (10 ml) and the phases were separated. The aqueous phase was extracted with DCM (23 ml) and the combined organic phases were dried by passage through a phase separator and concentrated in vacuo to afford the title compound (47.9 mg, 0.091 mmol, 71.3% yield, 97% purity) as a light yellow solid. UPLC-MS (Method 1) m/z 526.3 (M+H).sup.+, 524.2 (MH).sup. at 1.46 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.08 (br s, 1H), 9.39 (br s, 1H), 8.17 (dd, J=8.7, 2.3 Hz, 1H), 8.10 (d, J=2.2 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.27 (dd, J=8.8, 2.3 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 6.67 (d, J=2.3 Hz, 1H), 6.02 (s, 1H), 5.35 (t, J=6.4 Hz, 1H), 4.01 (app. Dt, J=9.7, 7.0 Hz, 1H), 3.95 (s, 3H), 3.45 (ddd, J=9.9, 7.3, 5.2 Hz, 1H), 2.40-2.35 (m, 1H), 2.13 (s, 3H), 2.01-1.85 (m, 3H).

Example 49 Methyl Ester: methyl 4-methoxy-3-((2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfonamido)benzoate

(121) ##STR00489##

(122) Step 1: methyl 3-(2-bromo-5-(trifluoromethyl)phenylsulfonamido)-4-methoxybenzoate: A mixture of 2-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride (230 l, 1.32 mmol), methyl 3-amino-4-methoxybenzoate (200 mg, 1.10 mmol) and pyridine (268 l, 3.31 mmol) in DCM (4 ml) was stirred at RT over the weekend. The mixture was concentrated onto silica and purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexanes) to afford the title compound (510 mg, 1.07 mmol, 97% yield, 98% purity) as a pale beige solid. UPLC-MS (Method 2) m/z 468.0/470.0 (M/M+2).sup.+ at 1.43 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 10.26 (s, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.10 (d, J=2.2 Hz, 1H), 7.92 (dd, J=8.3, 2.2 Hz, 1H), 7.83-7.77 (m, 2H), 7.08 (d, J=8.6 Hz, 1H), 3.80 (s, 3H), 3.56 (s, 3H).

(123) Step 2: methyl 4-methoxy-3-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenylsulfonamido)benzoate: A mixture of the product from step 1 above (100 mg, 0.214 mmol) and piperidine (25 l, 0.253 mmol) in THF (1 ml) was heated to 60 C. and stirred overnight. Additional piperidine (25 l, 0.253 mmol) was added and stirring at 60 C. was continued for 7 h. Additional piperidine (25 l, 0.253 mmol) was added and stirring at 60 C. was continued overnight. Upon cooling to RT the mixture was concentrated in vacuo and the residue was loaded onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexanes) to afford the title compound (82 mg, 0.165 mmol, 78% yield, 95% purity) as a white solid. UPLC-MS (Method 2) m/z 473.3 (M+H).sup.+ at 1.84 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.04 (s, 1H), 8.05 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 2.92 (t, J=5.3 Hz, 4H), 1.77-1.65 (m, 4H), 1.57-1.51 (m, 2H).

Example 49:4-methoxy-3-((2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfonamido)benzoic acid

(124) ##STR00490##

(125) A mixture of the product from example 49 methyl ester, step 2 above 70 mg, 0.148 mmol) in THF (1.25 ml) and 2 M LiOH(aq) (0.25 ml, 0.500 mmol) was stirred at 50 C. overnight. Additional 2 M LiOH(aq) (0.25 ml, 0.500 mmol) was added and stirring at 50 C. was continued for 5 h. The mixture was diluted with H.sub.2O (5 ml), acidified to ca. pH 4 with 1 M HCl(aq) and extracted with EtOAc (310 ml). The combined organic extracts were washed with brine (10 ml), passed through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (4 g cartridge, 0-10% MeOH/DCM) and triturated with TBME to afford the title compound (44.3 mg, 0.093 mmol, 62.6% yield, 96% purity) as a white solid. UPLC-MS (Method 2) m/z 459.3 (M+H).sup.+, 457.2 (MH).sup. at 1.19 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.71 (s, 1H), 8.99 (s, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.93 (dd, J=8.5, 2.3 Hz, 1H), 7.89 (d, J=2.1 Hz, 1H), 7.64 (dd, J=8.7, 2.1 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.02 (d, J=8.7 Hz, 1H), 3.71 (s, 3H), 2.92 (t, J=5.1 Hz, 4H), 1.76-1.65 (m, 4H), 1.59-1.48 (m, 2H).

General Compound A: 4-methoxy-2-((2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfonamido)benzoic acid

(126) ##STR00491##

(127) Step 1: methyl 2-(2-fluoro-5-(trifluoromethyl)phenylsulfonamido)-4-methoxybenzoate: A mixture of 2-fluoro-5-(trifluoromethyl)benzene-1-sulfonyl chloride (87 mg, 0.331 mmol), methyl 2-amino-4-methoxybenzoate (50 mg, 0.276 mmol) and pyridine (0.067 ml, 0.828 mmol) in DCM (2 ml) was stirred at RT overnight. The mixture was concentrated onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexanes) to afford the title compound (98 mg, 0.180 mmol, 65.4% yield, 75% purity) as a white solid. UPLC-MS (Method 2) 405.5 (MH).sup. at 1.67 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.13 (s, 1H), 8.24-8.12 (m, 2H), 7.87 (d, J=8.9 Hz, 1H), 7.73 (t, J=9.5 Hz, 1H), 6.94 (d, J=2.5 Hz, 1H), 6.83-6.76 (m, 1H), 3.79 (s, 3H), 3.77 (s, 3H).

(128) Step 2: methyl 4-methoxy-2-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl sulfonamido)benzoate: A mixture of the product from step 1 above (98 mg, 0.180 mmol) and piperidine (0.06 ml, 0.606 mmol) in THF (2 ml) was stirred at 60 C. for 6 days. The mixture was concentrated onto silica and purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexanes) to afford the title compound (52 mg, 0.109 mmol, 60.4% yield, 99% purity) as a white solid. UPLC-MS (Method 2) m/z 473.3 (M+H).sup.+ at 2.01 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 11.11 (s, 1H), 8.28 (d, J=2.3 Hz, 1H), 8.06-7.95 (m, 1H), 7.85 (d, J=8.9 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 6.73 (d, J=2.5 Hz, 1H), 6.63 (dd, J=8.9, 2.5 Hz, 1H), 3.84 (s, 3H), 3.66 (s, 3H), 2.84 (t, J=5.3 Hz, 4H), 1.74-1.64 (m, 4H), 1.58-1.49 (m, 2H).

(129) Step 3: 4-methoxy-2-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenylsulfonamido)benzoic acid: A mixture of the product from step 2 above (52 mg, 0.109 mmol) and 2 M LiOH(aq) (250 l, 0.500 mmol) in THF (1.25 ml) was stirred at 50 C. overnight. The mixture was diluted with H.sub.2O (2 ml) and acidified to ca. pH 4 with 1 M HCl. The mixture was extracted with EtOAc (315 ml), the combined organic extracts were washed with brine, passed through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (4 g cartridge, 0-5% MeOH/DCM) to afford the title compound (14.1 mg, 0.030 mmol, 27.1% yield, 96% purity) as a white solid. UPLC-MS (Method 2) m/z 459.3 (M+H).sup.+, 457.2 (MH).sup. at 1.22 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.63 (s, 1H), 11.65 (s, 1H), 8.29 (d, J=2.3 Hz, 1H), 7.99 (dd, J=8.5, 2.3 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 6.65 (d, J=2.4 Hz, 1H), 6.57 (dd, J=8.9, 2.4 Hz, 1H), 3.64 (s, 3H), 2.86 (t, J=5.1 Hz, 4H), 1.77-1.66 (m, 4H), 1.60-1.46 (m, 2H).

(130) The following examples were prepared by methods analogous to General Compound A substituting appropriate starting materials and intermediates where necessary:

(131) TABLE-US-00011 Example Structure Name/Analytical Data 51 3-((2-(dimethylamino)-5-(trifluoromethyl) phenyl)sulfonamido)-4-methoxybenzoic acid UPLC-MS (Method 2) m/z 419.2 (M + H).sup.+, 417.1 (M H).sup. at 1.02 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.65 (s, 1H), 9.51 (s, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.86-7.79 (m, 2H), 7.67 (dd, J = 8.6, 2.1 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 3.74 (s, 3H), 2.80 (s, 6H). 52 4-methoxy-3-((2-morpholino-5- (trifluoromethyl)phenyl)sulfonamido)benzoic acid UPLC-MS (Method 2) m/z 461.3 (M + H).sup.+, 459.1 (M H).sup. at 0.90 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.74 (s, 1H), 9.23 (s, 1H), 8.06 (d, J = 2.3 Hz, 1H), 7.95 (dd, J = 8.5, 2.3 Hz, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.66 (dd, J = 8.6, 2.1 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 3.79- 3.72 (m, 4H), 3.65 (s, 3H), 2.99-2.92 (m, 4H).

Example 54 Methyl Ester: methyl 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate

(132) ##STR00494##

(133) A solution of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (0.100 g, 0.409 mmol) in DCM (1 ml) and pyridine (0.1 ml, 1.236 mmol) were added to a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.130 g, 0.491 mmol) in DCM (1 ml) and the solution was stirred at RT for 23 h. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexanes) to afford an orange oil. This was repurified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexanes) to afford the title compound (0.143 g, 0.294 mmol, 71.7% yield, 97% purity) as a pale yellow slowly cystallising oil. UPLC-MS (Method 2) m/z 473.2 (M+H).sup.+, 471.1 (MH).sup. at 1.83 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.81 (br s, 1H), 8.37 (d, J=2.3 Hz, 1H), 8.19 (dd, J=8.7, 2.3 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.40-7.30 (m, 3H), 3.94 (s, 3H), 3.86 (s, 3H), 2.78-2.75 (m, 4H), 1.68-1.64 (m, 4H), 1.56-1.52 (m, 2H).

Example 54: 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(134) ##STR00495##

(135) 1 M LiOH(aq) (3 ml, 3.00 mmol) was added to a solution of the product from example 54 methyl ester (0.068 g, 0.144 mmol) in dioxane (3 ml) and the solution was stirred at RT overnight. The solvent was removed in vacuo and the residue was redissolved in water (5 ml) and extracted with EtOAc (35 ml). The aqueous phase was acidified with 1 M HCl(aq) and the product was extracted into EtOAc (310 ml). The combined organic phases were dried over MgSO.sub.4, filtered and the solvent was removed in vacuo to give the title compound (0.047 g, 0.100 mmol, 69.8% yield, 98% purity) as an off-white solid. UPLC-MS (Method 2) m/z 459.2 (M+H).sup.+, 457.0 (MH).sup. at 1.15 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.16 (s, 1H), 8.76 (s, 1H), 8.37 (d, J=2.2 Hz, 1H), 8.16 (dd, J=8.7, 2.2 Hz, 1H), 7.45 (d, J=1.9 Hz, 1H), 7.38-7.30 (m, 3H), 3.93 (s, 3H), 2.76 (t, J=5.3 Hz, 4H), 1.67 (p, J=5.3 Hz, 4H), 1.55 (p, J=5.3 Hz, 2H).

Example 55: 3-(N-(2-(azepan-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-isopropylbenzoic acid

(136) ##STR00496##

(137) A solution of 2-(azepan-1-yl)-5-(trifluoromethyl)aniline (50 mg, 0.194 mmol) in DCM (1 ml) and pyridine (0.094 ml, 1.16 mmol) were added to a solution of 3-(chlorosulfonyl)-4-isopropylbenzoic acid (61.0 mg, 0.232 mmol) in DCM (1 ml) and the solution was stirred at RT for 4 days. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-10% MeOH/DCM) to afford a light yellow solid (11.1 mg). 9 mg of this was loaded onto a silica plug in the minimal amount of DCM, the column was eluted with DCM (5 ml), isohexanes (5 ml), 5% MeOH in EtOAc (5 ml) then 5% MeOH in EtOAc (5 ml) to afford the title compound (5.4 mg, 10.6 mol, 5.47% yield, 95% purity) as a light yellow solid. UPLC-MS (Method 2) m/z 485.4 (M+H).sup.+, 483.1 (MH).sup. at 1.99 min. .sup.1H NMR (500 MHz, Methanol-d.sub.4) 8.58 (d, J=1.8 Hz, 1H), 8.20 (dd, J=8.2, 1.8 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.33-7.21 (m, 3H), 3.90 (septet, J=6.8 Hz, 1H), 3.20-3.13 (m, 4H), 1.86-1.77 (m, 4H), 1.76-1.71 (m, 4H), 1.24 (d, J=6.7 Hz, 6H). Two exchangeable protons not observed.

(138) The following examples were prepared by methods analogous to Example 55, substituting appropriate starting materials and intermediates where necessary:

(139) TABLE-US-00012 Example Structure Name/Analytical Data 59 3-fluoro-5-(N-(2-(piperidin-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)benzoic acid UPLC-MS (Method 1) m/z 447.4 (M + H).sup.+, 445.2 (M H).sup. at 1.86 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.75 (br s, 1H), 9.69 (br s, 1H), 8.13 (s, 1H), 7.96 (d, J = 9.0 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.32 (s, 1H), 7.23 (d, J = 8.3 Hz, 1H), 2.70 (t, J = 5.1 Hz, 4H), 1.56-1.52 (m, 4H), 1.48-1.44 (m, 2H). 61 3-(N-(2-(azepan-1-yl)-5-(trifluoromethyl) phenyl)sulfamoyl)-4-ethylbenzoic acid UPLC-MS (Method 1) m/z 471.3 (M + H).sup.+, 469.3 (M H).sup. at 2.27 min. .sup.1H NMR (500 MHz, Methanol- d.sub.4) 8.59 (d, J = 2.1 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.01 (dd, J = 8.0, 2.1 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.46-7.34 (m, 2H), 3.25 (q, J = 7.5 Hz, 2H), 3.22-3.17 (m, 4H), 1.89-1.82 (m, 4H), 1.81-1.75 (m, 4H), 1.36 (t, J = 7.5 Hz, 3H). Two exchangeable protons not observed. 62 3-(N-(2-(azepan-1-yl)-5-(trifluoromethyl) phenyl)sulfamoyl)-4-methylbenzoic acid UPLC-MS (Method 1) m/z 457.4 (M + H).sup.+, 455.0 (M H).sup. at 1.86 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.12 (br s, 1H), 9.46 (br s, 1H), 8.22 (d, J = 1.8 Hz, 1H), 8.03 (dd, J = 7.9, 1.9 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 6.61 (s, 1H), 3.39-3.26 (m, 4H), 2.55 (s, 3H), 1.75-1.66 (m, 4H), 1.58-1.49 (m, 4H). 63 00 N-(2-methoxy-5-(tetrazol-5-yl)phenyl)-2- (piperidin-1-yl)-5-(trifluoromethyl) benzenesulfonamide UPLC-MS (Method 1) m/z 483.4 (M + H).sup.+, 481.2 (M H).sup. at 1.66 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.11 (s, 1H), 8.11 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.93 (dd, J = 8.4, 2.2 Hz, 1H), 7.75 (dd, J = 8.6, 2.2 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 3.72 (s, 3H), 2.94 (t, J = 5.1 Hz, 4H), 1.71 (p, J = 5.8 Hz, 4H), 1.58-1.50 (m, 2H). One exchangeable proton not observed.

Example 64: 4-methoxy-3-(N-(2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid

(140) ##STR00501##

(141) Step 1: methyl 4-methoxy-3-(N-(2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: A solution of 2-(piperidin-1-yl)aniline hydrochloride (0.050 g, 0.235 mmol) in DCM (1 ml) and pyridine (0.114 ml, 1.410 mmol) was added to a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.075 g, 0.282 mmol) in DCM (1 ml) and the solution was stirred at RT for 96 h. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexanes) to afford the title compound (0.095 g, 0.169 mmol, 71.9% yield, 72% purity) as a pale yellow slowly cystallising oil. UPLC-MS (Method 2) m/z 405.2 (M+H).sup.+, 403.4 (MH).sup. at 1.69 min.

(142) Step 2: 4-methoxy-3-(N-(2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (0.470 ml, 0.470 mmol) was added to a solution of the product from step 1 above (0.095 g, 0.235 mmol) in dioxane (3 ml) and the solution was stirred at RT overnight. The solvent was removed in vacuo and the residue redissolved in water (5 ml) and extracted with EtOAc (35 ml). The aqueous phase was acidified with 1 M HCl(aq) and the product was extracted into EtOAc (310 ml). The combined organic phases were dried over MgSO.sub.4, filtered and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-70% EtOAc/isohexanes) to afford the title compound (40 mg, 0.097 mmol, 41.4% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 391.3 (M+H).sup.+, 389.3 (MH).sup. at 1.41 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.23 (bs, 1H), 8.60 (s, 1H), 8.39 (d, J=2.3 Hz, 1H), 8.14 (dd, J=8.7, 2.3 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.25 (dd, J=7.4, 2.1 Hz, 1H), 7.22 (dd, J=7.5, 2.2 Hz, 1H), 7.12-6.85 (m, 2H), 3.96 (s, 3H), 2.75-2.63 (m, 4H), 1.69 (p, J=5.5 Hz, 4H), 1.58-1.52 (m, 2H).

Example 65: 3-(N-(4-chloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(143) ##STR00502##

(144) Step 1: methyl 3-(N-(4-chloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoate: A solution of 4-chloro-2-(piperidin-1-yl)aniline (0.050 g, 0.237 mmol) in DCM (1 ml) and pyridine (0.115 ml, 1.42 mmol) were added to a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.075 g, 0.285 mmol) in DCM (1 ml) and the solution was stirred at RT for 96 h. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexanes) to afford the title compound (0.093 g, 0.165 mmol, 69.6% yield) as a pale yellow slowly cystallising oil. UPLC-MS (Method 2) m/z 439.3 (M+H).sup.+, 437.2 (MH).sup. at 1.81 min.

(145) Step 2: 3-(N-(4-chloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1 M LiOH(aq) (0.424 ml, 0.424 mmol) was added to a solution of the product from step 1 above (0.093 g, 0.212 mmol) in dioxane (3 ml) and the solution was stirred at RT overnight. The solvent was removed in vacuo and the residue redissolved in water (5 ml) and extracted with EtOAc (35 ml). The aqueous phase was acidified with 1 M HCl(aq) and the product was extracted into EtOAc (310 ml). The combined organic phases were dried over MgSO.sub.4, filtered and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-80% EtOAc/isohexanes) to afford the title compound (34 mg, 0.076 mmol, 35.9% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 425.3 (M+H).sup.+, 423.2 (MH).sup. at 1.69 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6).Math. 13.24 (bs, 1H), 8.58 (s, 1H), 8.36 (d, J=2.3 Hz, 1H), 8.16 (dd, J=8.7, 2.2 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.28-7.14 (m, 2H), 7.07 (dd, J=8.8, 2.4 Hz, 1H), 3.96 (s, 3H), 2.72-2.68 (m, 4H), 1.66 (p, J=5.5 Hz, 4H), 1.56-1.50 (m, 2H).

Example 66: 3-(N-(5-chloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(146) ##STR00503##

(147) Step 1: methyl 3-(N-(5-chloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoate: A solution of 5-chloro-2-(piperidin-1-yl)aniline hydrochloride (0.050 g, 0.202 mmol) in DCM (1 ml) and pyridine (0.098 ml, 1.21 mmol) were added to a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.064 g, 0.243 mmol) in DCM (1 ml) and the solution was stirred at RT for 96 h. The solvent was removed in vacuo the crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexanes) to afford the title compound (0.066 g, 0.143 mmol, 70.6% yield, 95% purity) as a pale yellow slowly cystallising oil. UPLC-MS (Method 2) m/z 439.3 (M+H).sup.+, 437.3 (MH).sup. at 1.81 min.

(148) Step 2: 3-(N-(5-chloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1 M LiOH(aq) (0.301 ml, 0.301 mmol) was added to a solution of the product from step 1 above (0.066 g, 0.150 mmol) in dioxane (3 ml) and the solution was stirred at RT overnight. The solvent was removed in vacuo and the residue redissolved in water (5 ml) and extracted with EtOAc (35 ml). The aqueous phase was acidified with 1 M HCl(aq) and the product was extracted into EtOAc (310 ml). The combined organic phases were dried over MgSO.sub.4, filtered and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-70% EtOAc/isohexanes) to afford the title compound (22 mg, 0.049 mmol, 32.7% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 425.1 (M+H).sup.+, 423.2 (MH).sup. at 1.67 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6).Math. 13.25 (br s, 1H), 8.69 (br s, 1H), 8.38 (d, J=2.2 Hz, 1H), 8.17 (dd, J=8.7, 2.2 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.25 (d, J=2.5 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.05 (dd, J=8.5, 2.5 Hz, 1H), 3.96 (s, 3H), 2.75-2.61 (m, 4H), 1.67 (p, J=5.5 Hz, 4H), 1.56-1.50 (m, 2H).

Example 67:4-methyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(149) ##STR00504##

(150) Step 1: methyl 4-methyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (50 mg, 0.205 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (0.05 ml, 0.618 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methylbenzoate (52 mg, 0.209 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 18 h. Additional methyl 3-(chlorosulfonyl)-4-methylbenzoate (15 mg, 0.060 mmol) was added and the reaction was stirred for a further 24 h at RT. The reaction mixture was loaded directly on to silica gel (12 g cartridge, 0-50% EtOAc/isohexanes) and purified to afford the title compound (73 mg, 0.155 mmol, 76% yield, 97% purity) as a colourless oil, which crystallised upon standing. UPLC-MS (Method 1) m/z 457.1 (M+H).sup.+, 455.3 (MH).sup. at 1.95 min.

(151) Step 2: 4-methyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: The product from step 1 above (71 mg, 0.151 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (499 l, 0.549 mmol). MeOH was added to give a clear solution, which was allowed to stand at RT. After 2 days, the solution was diluted with water (2 ml) and was allowed to stand at RT for a further 24 h. The solution was further diluted with water (2 ml) and concentrated in vacuo. The resultant aqueous suspension was diluted with water (2 ml) and filtered, washing with water (1 ml). The resultant solution was neutralised with 1 M HCl(aq) (0.4 ml) and sonicated, then adjusted to ca. pH 6 with 1 M HCl(aq) (2 drops). The resultant off-white precipitate was collected by filtration, washing with water. The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (55 mg, 0.122 mmol, 81% yield, 98% purity) as a tan powder. UPLC-MS (Method 1) m/z 443.3 (M+H).sup.+ 441.3 (MH).sup. at 1.81 min.

Example 68: 3-(N-(2-(azepan-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(152) ##STR00505##

(153) Step 1: methyl 3-(N-(2-(azepan-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: 2-(azepan-1-yl)-5-(trifluoromethyl)aniline (48.8 mg, 0.189 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (0.05 ml, 0.618 mmol) and treated with a solution methyl 3-(chlorosulfonyl)-4-methoxybenzoate (60 mg, 0.227 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 18 h. The reaction mixture was loaded directly on to silica gel and purified by chromatography on silica gel (12 g cartridge, 0-70% EtOAc/isohexanes) to afford the title compound (44 mg, 0.084 mmol, 44.5% yield, 93% purity) as a sticky light yellow solid. UPLC-MS (Method 1) m/z 487.4 (M+H).sup.+, 485.2 (MH).sup. at 1.91 min.

(154) Step 2: 3-(N-(2-(azepan-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 1 above (42 mg, 0.086 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (235 l, 0.259 mmol). The reaction mixture was stirred at RT for 2 days. Additional 1.1 M LiOH(aq) (78 l, 0.086 mmol) was added and the reaction warmed to 30 C. for 18 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to ca. 5 ml) and neutralised with 1 M HCl(aq) (0.4 ml). The resultant lumpy suspension was sonicated to afford a cloudy solution and neutralised to ca. pH 6 with 1 M HCl. The aqueous phase was acidified with 1 M HCl(aq) and the product was extracted into EtOAc (310 ml). The combined organic phases were dried over MgSO.sub.4, filtered and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-70% EtOAc/isohexanes) to afford the title compound (2.2 mg, 4.42 mol, 5.12% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 473.4 (M+H).sup.+, 471.1 (MH).sup. at 1.79 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6).Math. 13.13 (br s, 1H), 8.76 (br s, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.14 (dd, J=8.7, 2.2 Hz, 1H), 7.44 (d, J=1.9 Hz, 1H), 7.38-7.26 (m, 3H), 3.91 (s, 3H), 2.92 (d, J=11.4 Hz, 2H), 2.67-2.57 (m, 2H), 1.72-1.65 (m, 1H), 1.55-1.43 (m, 1H), 1.34-1.20 (m, 3H), 0.97 (d, J=6.5 Hz, 3H).

Example 69: 4-chloro-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(155) ##STR00506##

(156) Step 1: methyl 4-chloro-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (45.4 mg, 0.186 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (0.05 ml, 0.618 mmol) and treated with a solution methyl 4-chloro-3-(chlorosulfonyl)benzoate (60 mg, 0.223 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 18 h. The reaction mixture was loaded directly on to silica and purified by chromatography on silica gel (12 g cartridge, 0-70% EtOAc/isohexanes) to afford the title compound (45.5 mg, 0.094 mmol, 50.3% yield, 98% purity) as a tan solid. UPLC-MS (Method 1) m/z 477.3 (M+H).sup.+, 475.1 (MH).sup. at 2.00 min.

(157) Step 2: 4-chloro-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: The product from step 1 above (43 mg, 0.090 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (328 l, 0.361 mmol). The reaction was stirred at RT for 2 days. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to ca. 5 ml) and neutralised with 1 M HCl(aq) (0.4 ml). The resultant lumpy suspension was sonicated to afford a cloudy solution and neutralised to ca. pH 6 with 1 M HCl(aq). The aqueous phase was acidified with 1 M HCl(aq) and the product was extracted into EtOAc (310 ml). The combined organic phases were dried over MgSO.sub.4, filtered and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-10% MeOH/DCM) to afford the title compound (20.5 mg, 0.042 mmol, 46.7% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 463.3 (M+H).sup.+, 461.2 (MH).sup. at 1.88 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6).Math. 13.48 (br s, 1H), 9.54 (br s, 1H), 8.44 (d, J=2.0 Hz, 1H), 8.12 (dd, J=8.3, 2.1 Hz, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.34 (s, 1H), 7.29 (d, J=8.4 Hz, 1H), 2.77 (t, J=5.1 Hz, 4H), 1.58-1.51 (m, 4H), 1.50-1.43 (m, 2H).

(158) The following examples were prepared by methods analogous to Example 69, substituting appropriate starting materials and intermediates where necessary:

(159) TABLE-US-00013 Example Structure Name/Analytical Data 70 07 2-methyl-5-(N-(2-(piperidin-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)benzoic acid UPLC-MS (Method 1) 443.3 (M + H).sup.+, 441.2 (M H) at 1.81 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.34 (br s, 1H), 9.34 (br s, 1H), 8.23 (d, J = 2.2 Hz, 1H), 7.81 (dd, J = 8.0, 2.2 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.47-7.35 (m, 2H), 7.22 (d, J = 8.3 Hz, 1H), 2.67-2.63 (m, 4H), 2.57 (s, 3H), 1.57 (p, J = 5.5 Hz, 4H), 1.56-1.47 (m, 2H). 71 08 4-methoxy-3-(N-(5-methyl-2-(piperidin-1- yl)phenyl)sulfamoyl)benzoic acid UPLC-MS (Method 1) 405.4 (M + H).sup.+, 403.4 (M H).sup. at 1.43 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.20 (s, 1H), 8.56 (s, 1H), 8.39 (d, J = 2.1 Hz, 1H), 8.14 (dd, J = 8.7, 2.2 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.16-7.02 (m, 2H), 6.78 (dd, J = 8.2, 1.9 Hz, 1H), 3.96 (s, 3H), 2.71-2.58 (m, 4H), 2.13 (s, 3H), 1.67 (p, J = 5.5 Hz, 4H), 1.56- 1.50 (m, 2H). 72 09 4-methoxy-3-(N-(2-morpholino-5- (trifluoromethyl)phenyl)sulfamoyl)benzoic acid UPLC-MS (Method 1) 461.3 (M + H).sup.+, 459.2 (M H).sup. at 1.38 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.15 (br s, 1H), 9.06 (br s, 1H), 8.34 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.46 (s, 1H), 7.43-7.26 (m, 3H), 3.91 (s, 3H), 3.72 (t, J = 4.5 Hz, 4H), 2.83 (t, J = 4.5 Hz, 4H). 73 0 3-(N-(5-fluoro-2-(piperidin-1-yl)phenyl) sulfamoyl)-4-methoxybenzoic acid UPLC-MS (Method 1) m/z 409.4 (M + H).sup.+, 407.2 (M H).sup. at 1.57 min. .sup.1H NMR (500 MHz, DMSO- d.sub.6) 13.26 (s, 1H), 8.74 (s, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.17 (dd, J = 8.7, 2.2 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.29 (dd, J = 8.8, 5.8 Hz, 1H), 7.05 (dd, J = 10.6, 2.9 Hz, 1H), 6.82 (app. td, J = 8.6, 3.0 Hz, 1H), 3.97 (s, 3H), 2.65-2.61 (m, 4H), 1.68 (p, J = 5.5 Hz, 4H), 1.57-1.51 (m, 2H). 74 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl) phenyl)sulfamoyl)benzoic acid UPLC-MS (Method 1) m/z 429.4 (M + H).sup.+, 427.2 (M H).sup. at 1.77 min. 75 4-methoxy-3-(N-(2-(pyrrolidin-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)benzoic acid UPLC-MS (Method 1) 445.3 (M + H).sup.+, 443.5 (M H).sup. at 1.46 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.17 (dd, J = 8.7, 2.3 Hz, 1H), 8.07 (d, J = 2.2 Hz, 1H), 7.44-7.34 (m, 1H), 7.29 (dd, J = 8.8, 2.4 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.55 (d, J = 2.3 Hz, 1H), 3.98 (s, 3H), 3.52-3.46 (m, 4H), 2.00-1.79 (m, 4H). 2 exchangeable protons not observed. 77 3-(N-(2-(dimethylamino)-5-(trifluoromethyl) phenyl)sulfamoyl)-4-methoxybenzoic acid UPLC-MS (Method 1) m/z 419.4 (M + H).sup.+, 417.2 (M H).sup. at 1.47 min. .sup.1H NMR (500 MHz, DMSO- d.sub.6) 13.10 (br s, 1H) 9.15 (br s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 8.15 (dd, J = 8.7, 2.2 Hz, 1H), 7.40-7.28 (m, 3H), 7.22 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 2.61 (s, 6H). 78 4-methoxy-3-(N-(2-(4-methylpiperazin-1-yl)- 5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid UPLC-MS (Method 1) m/z 474.4 (M + H).sup.+, 472.2 (M H).sup. at 0.83 min. .sup.1H NMR (500 MHz, DMSO- d.sub.6) 9.10 (br s, 2H), 8.35 (d, J = 2.2 Hz, 1H), 8.15 (dd, J = 8.7, 2.2 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.5, 2.1 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 3.91 (s, 3H), 2.91 (t, J = 4.9 Hz, 4H), 2.75-2.67 (m, 4H), 2.39 (s, 3H). 80 3-chloro-5-(N-(2-(piperidin-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)benzoic acid UPLC-MS (Method 1) m/z 463.3 (M + H).sup.+, 461.2 (M H).sup. at 1.96 min. .sup.1H NMR (500 MHz, DMSO- d.sub.6) 13.78 (br s, 1H), 9.72 (br s, 1H), 8.19 (app. t, J = 1.6 Hz, 1H), 8.13 (app. t, J = 1.7 Hz, 1H), 7.99 (app. t, J = 1.9 Hz, 1H), 7.47 (dd, J = 8.5, 2.2 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 2.69 (t, J = 5.2 Hz, 4H), 1.56-1.49 (m, 4H), 1.48-1.41 (m, 2H). 83 2-chloro-5-(N-(2-(piperidin-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)benzoic acid UPLC-MS (Method 1) m/z 463.3 (M + H).sup.+, 461.0 (M H).sup. at 1.85 min. .sup.1H NMR (500 MHz, DMSO- d.sub.6) 13.88 (br s, 1H), 9.59 (br s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.87 (dd, J = 8.5, 2.4 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.47 (dd, J = 8.5, 2.2 Hz, 1H), 7.34 (d, J = 2.2 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 2.68 (t, J = 5.2 Hz, 4H), 1.56-1.50 (m, 4H), 1.48-1.38 (m, 2H). 84 4-methoxy-3-(N-(2-(4-methylpiperidin-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)benzoic acid UPLC-MS (Method 1) m/z 473.4 (M + H)+ (ES+); 471.3 (M H) (ES), at 1.80 min, 100% purity (254 nm). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.13 (br s, 1H), 8.78 (br s, 1H), 8.37 (d, J = 2.3 Hz, 1H), 8.15 (dd, J = 8.7, 2.3 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.38-7.27 (m, 3H), 3.92 (s, 3H), 2.93 (d, J = 11.7 Hz, 2H), 2.63 (t, J = 11.8, 2.3 Hz, 2H), 1.73-1.64 (m, 2H), 1.56-1.41 (m, 1H), 1.35-1.20 (m, 2H), 0.97 (d, J = 6.5 Hz, 3H). 86 3-(N-(2-(azepan-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)-4- chlorobenzoic acid UPLC-MS (Method 1) m/z 477.4 (M + H).sup.+, 474.9 (M H).sup. at 1.93 min. .sup.1H NMR (500 MHz, DMSO- d.sub.6) 13.59 (br s, 1H), 9.74 (br s, 1H), 8.28 (d, J = 2.1 Hz, 1H), 8.14 (dd, J = 8.3, 2.1 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.36 (dd, J = 8.8, 2.4 Hz, 1H), 7.11 (d, J = 8.7 Hz, 1H), 6.74 (d, J = 2.3 Hz, 1H), 3.36-3.29 (m, 4H), 1.75-1.67 (m, 4H), 1.58-1.50 (m, 4H).

Example 161: 4-hydroxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(160) ##STR00519##

(161) Step 1: methyl 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoate: A solution of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (0.130 g, 0.532 mmol) in DCM (1 ml) and pyridine (0.258 ml, 3.19 mmol) was added to a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.169 g, 0.639 mmol) in DCM (1 ml) and the solution was stirred at RT for 16 h. The solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/DCM) to afford the title compound (0.230 g, 0.433 mmol, 81% yield, 89% purity) as a white solid. UPLC-MS (Method 1) m/z 473.4 (M+H).sup.+, 471.3 (MH).sup. at 1.86 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.81 (s, 1H), 8.37 (d, J=2.3 Hz, 1H), 8.19 (dd, J=8.7, 2.3 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.41-7.28 (m, 3H), 3.94 (s, 3H), 3.86 (s, 3H), 2.84-2.69 (m, 4H), 1.66 (p, J=5.6 Hz, 4H), 1.57-1.51 (m, 2H).

(162) Step 2: methyl 4-hydroxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoate: A solution of the product from step 1 above (0.230 g, 0.438 mmol) in DCM (10 ml) was treated with 1.0 M BBr.sub.3 in DCM (0.166 ml, 1.75 mmol) and the solution was stirred at RT for 16 h. The solvent was removed in vacuo to give the title compound as a yellow oil (0.200 g, 0.393 mmol, 90% yield, 90% purity). UPLC-MS (Method 1) m/z 459 (M+H).sup.+ at 1.7 min.

(163) Step 3: 4-hydroxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (1.31 ml, 1.31 mmol) was added to a solution of the product from step 2 above (0.2 g, 0.436 mmol) in MeOH (10 ml) and the solution was stirred at RT overnight. The solvent was removed in vacuo and the residue redissolved in water (5 ml) and extracted with EtOAc (35 ml). The aqueous phase was acidified with 1 M HCl(aq) and the product was extracted into EtOAc (310 ml). The combined organic phases were dried over MgSO.sub.4, filtered and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/DCM) to afford the title compound (60 mg, 0.128 mmol, 29.4% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 445.3 (M+H).sup.+, 443.2 (MH).sup. at 1.56 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 12.96 (br s, 1H), 8.29 (d, J=2.3 Hz, 1H), 7.98 (dd, J=8.6, 2.3 Hz, 1H), 7.52 (d, J=1.8 Hz, 1H), 7.37-7.33 (m, 2H), 7.04 (d, J=8.6 Hz, 1H), 2.75 (t, J=5.2 Hz, 4H), 1.68 (p, J=5.5 Hz, 4H), 1.58-1.51 (m, 2H). 2 exchangeable protons not observed.

Example 165: 4-methoxy-3-(N-methyl-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(164) ##STR00520##

(165) Step 1: methyl 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoate: A mixture of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (100 mg, 0.409 mmol), methyl 3-(chlorosulfonyl)-4-methoxybenzoate (130 mg, 0.491 mmol) and pyridine (100 l, 1.24 mmol) in DCM (1.5 ml) was stirred at RT overnight. The mixture was concentrated onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (189 mg, 0.384 mmol, 94% yield, 96% purity) as a white solid. UPLC-MS (Method 2) m/z 473.3 (M+H).sup.+ at 1.80 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.80 (s, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.18 (dd, J=8.8, 2.2 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.40-7.29 (m, 3H), 3.93 (s, 3H), 3.85 (s, 3H), 2.76 (t, J=5.2 Hz, 4H), 1.70-1.61 (m, 4H), 1.59-1.49 (m, 2H).

(166) Step 2: methyl 4-methoxy-3-(N-methyl-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoate: To a suspension of sodium hydride (12 mg, 0.500 mmol) in THF (1 ml) at 0 C. was added the product from step 1 above (189 mg, 0.384 mmol) in THF (1 ml). The mixture was warmed to RT and stirred for 30 min before iodomethane (30 l, 0.480 mmol) was added and mixture was stirred at RT overnight. The mixture was quenched with H.sub.2O (10 ml) and extracted with EtOAc (320 ml). The combined organic extracts were washed with brine (15 ml), passed through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexanes) to afford the title compound (172 mg, 0.283 mmol, 73.7% yield, 80% purity) as a clear colourless oil. UPLC-MS (Method 2) m/z 487.3 (M+H).sup.+ at 1.83 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.25 (dd, J=8.7, 2.2 Hz, 1H), 8.22 (d, J=2.2 Hz, 1H), 7.54 (dd, J=8.6, 2.2 Hz, 1H), 7.48 (d, J=8.7 Hz, 1H), 7.21 (d, J=8.6 Hz, 1H), 7.02 (d, J=2.2 Hz, 1H), 4.00 (s, 3H), 3.83 (s, 3H), 3.27 (s, 3H), 3.06 (t, J=5.1 Hz, 4H), 1.64-1.57 (m, 4H), 1.57-1.50 (m, 2H).

(167) Step 3: 4-methoxy-3-(N-methyl-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid: A mixture of the product from step 2 above (170 mg, 0.349 mmol) and 2 M LiOH(aq) (0.35 ml, 0.700 mmol) in THF (1.5 ml) was stirred at 50 C. overnight. The mixture was diluted with H.sub.2O (5 ml), acidified to ca. pH 4 with 1 M HCl(aq) and extracted with EtOAc (310 ml). The combined organic extracts were washed with brine (10 ml), passed through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (4 g cartridge, 0-10% MeOH/DCM) to give the title compound (66.1 mg, 0.134 mmol, 38.3% yield, 96% purity) as a white solid. UPLC-MS (Method 2) m/z 473.3 (M+H).sup.+, 471.2 (MH).sup. at 1.17 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.10 (s, 1H), 8.22 (m, 2H), 7.53 (dd, J=8.5, 2.3 Hz, 1H), 7.48-7.41 (m, 1H), 7.20 (d, J=8.5 Hz, 1H), 7.01 (d, J=2.2 Hz, 1H), 3.99 (s, 3H), 3.28 (s, 3H), 3.09-3.02 (m, 4H), 1.65-1.57 (m, 4H), 1.57-1.48 (m, 2H).

Example 171:2-methoxy-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrazol-5-yl)benzenesulfonamide

(168) ##STR00521##

(169) Step 1: 5-cyano-2-methoxy-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)benzenesulfonamide: 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (200 mg, 0.819 mmol) was dissolved in a mixture of DCM (2 ml) and pyridine (0.15 ml, 1.86 mmol) and treated with a solution of the 5-cyano-2-methoxybenzenesulfonyl chloride (237 mg, 1.02 mmol) in DCM (1 ml). The resultant solution was allowed to stand at RT for 18 h, then diluted with water (ca. 0.1 ml) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexanes) to afford the title compound (325 mg, 0.717 mmol, 88% yield, 99% purity) as a pale yellow solid. UPLC-MS (Method 1) m/z 440.4 (M+H).sup.+, 438.1 (MH).sup. at 1.82 min.

(170) Step 2: 2-methoxy-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)-5-(tetrazol-5-yl)benzenesulfonamide: The product from step 1 above (100 mg, 0.228 mmol) was combined with sodium azide (74.0 mg, 1.14 mmol) and zinc bromide (102 mg, 0.455 mmol) in IPA (1 ml) and water (0.3 ml). The resultant mixture was heated at 80 C. overnight then concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexanes followed by 0-10% MeOH/DCM) to afford the title compound (7.9 mg, 0.016 mmol, 6.84% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 483.4 (M+H).sup.+, 481.2 (MH).sup. at 1.67 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.79 (s, 1H), 8.55 (d, J=2.2 Hz, 1H), 8.27 (dd, J=8.7, 2.2 Hz, 1H), 7.51 (s, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.37-7.33 (m, 2H), 3.94 (s, 3H), 2.78 (t, J=5.3 Hz, 4H), 1.70-1.65 (m, 4H), 1.57-1.50 (m, 2H). One exchangeable proton not observed.

Example 177: 3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(171) ##STR00522##

(172) Step 1: 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ol: Et.sub.3N (0.500 ml, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) and piperidin-3-ol (174 mg, 1.72 mmol) in DCM (6 ml) at RT. The clear solution was stirred at RT for 17 h. The organic phase was washed with 1 M HCl (3 ml) and dried by passage through a phase separator and concentrated in vacuo to afford the title compound (468 mg, 1.40 mmol, 98% yield, 87% purity) as a red/orange oil. UPLC-MS (Method 1) m/z 291.5 (M+H).sup.+ at 1.39 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.12-8.07 (m, 1H), 7.80 (dd, J=9.0, 2.4 Hz, 1H), 7.41 (d, J=8.9 Hz, 1H), 4.91 (d, J=4.3 Hz, 1H), 3.65-3.57 (m, 1H), 3.26 (dd, J=12.4, 3.9 Hz, 1H), 3.21 (dt, J=13.0, 4.5 Hz, 1H), 2.98-2.91 (m, 1H), 2.75 (dd, J=12.3, 8.5 Hz, 1H), 1.93-1.85 (m, 1H), 1.81-1.73 (m, 1H), 1.56-1.46 (m, 1H), 1.40-1.30 (m, 1H).

(173) Step 2: 1-(2-amino-4-(trifluoromethyl)phenyl)piperidin-3-ol: 5% Pd/C (50% w/w water) Type 87L (50 mg, 0.012 mmol) in EtOH (0.5 ml) was added to a solution of the product from step 1 above (234 mg, 0.701 mmol) in EtOH (3.0 ml) at RT. The reaction mixture was hydrogenated (4 bar) at RT for 19 h. The catalyst was removed by filtration through Celite, washing with MeOH (15 ml). The filtrate was concentrated in vacuo and the residue was dissolved in MeOH (10 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to afford a white solid. MeCN (10 ml) was added and the resultant slurry was dried again with a large excess of MgSO.sub.4, filtered and concentrated in vacuo to afford the title compound (153 mg, 0.576 mmol, 82% yield, 98% purity) as a yellow solid. UPLC-MS (Method 1) m/z 261.4 (M+H).sup.+ at 1.29 min. 1H NMR (500 MHz, DMSO-d.sub.6) 6.96 (d, J=8.1 Hz, 1H), 6.94 (d, J=2.2 Hz, 1H), 6.84-6.80 (m, 1H), 5.14 (s, 2H), 4.79 (d, J=5.4 Hz, 1H), 3.74-3.66 (m, 1H), 3.04-2.96 (m, 1H), 2.92-2.85 (m, 1H), 2.58-2.50 (m, 1H), 2.49-2.41 (m, 1H), 1.86-1.75 (m, 2H), 1.65-1.55 (m, 1H), 1.37-1.28 (m, 1H).

(174) Step 3: methyl 3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (0.075 ml, 0.933 mmol) was added to a cloudy solution of the product from step 2 above (62.0 mg, 0.233 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (78 mg, 0.280 mmol) in DCM (2.0 ml) at RT. The resultant clear solution was stirred at RT for 20 h and the reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (10 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (88.1 mg, 0.177 mmol, 76% yield, 98% purity) as a yellow oil. UPLC-MS (Method 1) m/z 489.3 (M+H).sup.+, 487.2 (MH).sup. at 1.59 min.

(175) Step 4: 3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1 M LiOH(aq) (0.707 ml, 0.707 mmol) was added to a solution of the product from step 3 above (88.1 mg, 0.177 mmol) in THF (1.4 ml) at RT. The reaction mixture was stirred at RT for 18 h and then concentrated in vacuo. The residue was dissolved in water (3 ml) and acidified using 1 M HCl until pH 4-5. The precipitate was isolated by filtration and then dissolved in EtOAc (5 ml). The organic phase was washed with water (3 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to afford the title compound (50 mg, 0.104 mmol, 59% yield, 99% purity) as a pale pink solid. UPLC-MS (Method 1) m/z 475.4 (M+H).sup.+, 473.1 (MH).sup. at 1.38 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.16 (br s, 1H), 9.14 (br s, 1H), 8.39 (d, J=2.2 Hz, 1H), 8.14 (dd, J=8.7, 2.2 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.33-7.27 (m, 2H), 7.25 (d, J=8.3 Hz, 1H), 5.09 (br s, 1H), 3.89 (s, 3H), 3.79-3.73 (m, 1H), 2.87-2.79 (m, 2H), 2.74-2.68 (m, 1H), 2.67-2.62 (m, 1H), 1.93-1.85 (m, 1H), 1.77-1.69 (m, 1H), 1.60-1.51 (m, 1H), 1.51-1.43 (m, 1H).

Example 178: (S)-3-(N-(2-(3-hydroxypyrrolidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)-4-methoxybenzoic acid

(176) ##STR00523##

(177) Step 1: (S)-1-(2-nitro-4-(trifluoromethyl)phenyl) pyrrolidin-3-ol: Et.sub.3N (0.500 ml, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) and(S)-pyrrolidin-3-ol (0.139 ml, 1.72 mmol) in DCM (6 ml) at RT. The clear solution was stirred at RT for 17 h. The organic phase was washed with 1 M HCl (3 ml), dried by passage through a phase separator and concentrated in vacuo to afford the title compound (445 mg, 1.37 mmol, 95% yield, 85% purity) as an orange oil. UPLC-MS (Method 1) m/z 277.2 (M+H).sup.+ at 1.33 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.06-8.03 (m, 1H), 7.72 (dd, J=9.1, 2.3 Hz, 1H), 7.19 (d, J=9.1 Hz, 1H), 5.05 (d, J=3.4 Hz, 1H), 4.41-4.36 (m, 1H), 3.50 (app. Td, J=9.8, 6.8 Hz, 1H), 3.41 (dd, J=11.1, 4.3 Hz, 1H), 3.25-3.19 (m, 1H), 2.85-2.80 (m, 1H), 2.04-1.96 (m, 1H), 1.94-1.88 (m, 1H).

(178) Step 2: (S)-1-(2-amino-4-(trifluoromethyl)phenyl) pyrrolidin-3-ol: 5% Pd/C (50% w/w water) Type 87L (50 mg, 0.012 mmol) in EtOH (0.5 ml) was added to a solution of the product from step 1 above (220 mg, 0.677 mmol) in EtOH (3.0 ml) at RT. The reaction mixture was hydrogenated (4 bar) at RT for 19 h. The catalyst was removed by filtration through Celite, washing with MeOH (20 ml). The organic phase was concentrated in vacuo and the residue was dissolved in DCM (10 ml). The organic phase was washed with water (5 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to afford the title compound (134 mg, 0.522 mmol, 77% yield, 96% purity) as a dark brown oil. UPLC-MS (Method 1) m/z 247.3 (M+H).sup.+ at 1.08 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 6.92 (d, J=1.8 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.80 (dd, J=8.2, 1.5 Hz, 1H), 4.97 (br s, 2H), 4.86 (d, J=4.9 Hz, 1H), 4.35-4.28 (m, 1H), 3.31-3.22 (m, 2H), 2.99 (ddd, J=9.1, 7.9, 5.0 Hz, 1H), 2.90 (dd, J=10.0, 3.0 Hz, 1H), 2.12-2.04 (m, 1H), 1.79-1.71 (m, 1H).

(179) Step 3: (S)-methyl 3-(N-(2-(3-hydroxypyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (0.075 ml, 0.933 mmol) was added to a cloudy solution of the product from step 2 above (60.5 mg, 0.233 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (78 mg, 0.280 mmol) in DCM (2.0 ml) at RT. The resultant clear solution was stirred at RT for 20 h then concentrated in vacuo. The crude product was purified by chromatography on silica gel (10 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (96.7 mg, 0.196 mmol, 84% yield, 96% purity) as an orange oil. UPLC-MS (Method 1) m/z 475.4 (M+H).sup.+, 473.2 (MH).sup. at 1.35 min.

(180) Step 4: (S)-3-(N-(2-(3-hydroxypyrrolidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1 M LiOH (aq) (0.783 ml, 0.783 mmol) was added to a solution of the product from step 3 above (96.7 mg, 0.196 mmol) in THF (1.6 ml) at RT. The reaction mixture was stirred at RT for 20 h then concentrated in vacuo. The residue was dissolved in water (3 ml) and acidified using 1 M HCl until pH 4-5. The precipitate was isolated by filtration and then dissolved in EtOAc (5 ml). The organic phase was washed with water (3 ml), dried over MgSO.sub.4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (10 g cartridge, 0-5% MeOH/DCM) to afford the title compound (22.3 mg, 0.046 mmol, 26.3% yield, 96% purity) as an off-white solid. UPLC-MS (Method 1) m/z 461.3 (M+H).sup.+, 459.2 (MH).sup. at 1.17 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.06 (br s, 1H), 9.30 (br s, 1H), 8.17 (dd, J=8.7, 2.2 Hz, 1H), 8.06 (d, J=2.2 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.29 (dd, J=8.8, 2.4 Hz, 1H), 6.74 (d, J=8.9 Hz, 1H), 6.50 (d, J=2.3 Hz, 1H), 4.96 (br s, 1H), 4.37-4.31 (m, 1H), 3.99 (s, 3H), 3.79 (dd, J=11.0, 4.8 Hz, 1H), 3.59-3.52 (m, 1H), 3.49-3.43 (m, 1H), 3.38-3.34 (m, 1H), 1.96-1.88 (m, 1H), 1.87-1.81 (m, 1H).

Example 179:4-methoxy-3-(N-(2-(3-methoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(181) ##STR00524##

(182) Step 1: 3-methoxy-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et.sub.3N (0.500 ml, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) and 3-methoxypiperidine (198 mg, 1.72 mmol) in DCM (6 ml) at RT. The clear solution was stirred at RT for 16 h. The organic phase was washed with 1 M HCl (3 ml), dried by passage through a phase separator and concentrated in vacuo to afford the title compound (438 mg, 1.41 mmol, 98% yield, 98% purity) as an orange oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.13-8.10 (m, 1H), 7.81 (dd, J=8.9, 2.4 Hz, 1H), 7.43 (d, J=8.9 Hz, 1H), 3.42-3.33 (m, 2H), 3.24 (s, 3H), 3.19 (app. Dt, J=12.9, 4.7 Hz, 1H), 3.03-2.96 (m, 1H), 2.86 (dd, J=12.2, 7.5 Hz, 1H), 2.00-1.93 (m, 1H), 1.82-1.73 (m, 1H), 1.57-1.47 (m, 1H), 1.47-1.38 (m, 1H).

(183) Step 2: 2-(3-methoxypiperidin-1-yl)-5-(trifluoromethyl)aniline: 5% Pd/C (50% w/w water) Type 87L (50 mg, 0.012 mmol) in EtOH (0.5 ml) was added to a solution of the product from step 1 above (214 mg, 0.689 mmol) in EtOH (3.0 ml) at RT. The reaction mixture was hydrogenated (4 bar) at RT for 18 h. The catalyst was removed by filtration through a pad of Celite, washing with EtOH (15 ml). The filtrate was concentrated in vacuo and azeotroped with MeOH (6 ml) to afford the title compound (151 mg, 0.484 mmol, 70% yield, 88% purity) as an off-white solid. UPLC-MS (Method 1) m/z 275.3 (M+H)+ (ES+), at 1.58 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 6.99 (d, J=8.1 Hz, 1H), 6.95 (d, J=2.2 Hz, 1H), 6.83 (dd, J=8.1, 1.5 Hz, 1H), 5.12 (br s, 2H), 3.46-3.40 (m, 1H), 3.29 (s, 3H), 3.17-3.09 (m, 1H), 2.99-2.93 (m, 1H), 2.57-2.46 (m, 2H), 1.98-1.90 (m, 1H), 1.80-1.73 (m, 1H), 1.67-1.58 (m, 1H), 1.40-1.29 (m, 1H).

(184) Step 3: methyl 4-methoxy-3-(N-(2-(3-methoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoate: Pyridine (0.081 ml, 1.01 mmol) was added to a cloudy solution of the product from step 2 above (79 mg, 0.252 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (2.0 ml) at RT. The resultant clear solution was stirred at RT for 18 h then concentrated in vacuo. The crude product was purified by chromatography on silica gel (10 g cartridge, 0-60% EtOAc/isohexane) to afford the title compound (84 mg, 0.167 mmol, 66% yield, 100% purity) as a cream solid. UPLC-MS (Method 1) m/z 503.4 (M+H).sup.+, 501.2 (MH).sup. at 1.77 min.

(185) Step 4: 4-methoxy-3-(N-(2-(3-methoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid: 1 M LiOH (aq) (0.669 ml, 0.669 mmol) was added to a solution of the product from step 3 above (84 mg, 0.167 mmol) in THF (1.3 ml) at RT. The reaction mixture was stirred at RT for 18 h then concentrated in vacuo. The residue was dissolved in water (3 ml) and washed with EtOAc (5 ml). The aqueous phase was acidified using 1 M HCl until pH 4-5 and the product was extracted into EtOAc (5 ml3). The combined organic phases were dried over MgSO.sub.4 and concentrated in vacuo to afford the title compound (63 mg, 0.128 mmol, 77% yield, 100% purity) as a white solid. UPLC-MS (Method 1) m/z 489.3 (M+H).sup.+, 487.1 (MH).sup. at 1.60 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.19 (br s, 1H), 9.06 (br s, 1H), 8.39 (d, J=2.2 Hz, 1H), 8.15 (dd, J=8.7, 2.2 Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.35-7.23 (m, 3H), 3.89 (s, 3H), 3.47-3.41 (m, 1H), 3.35 (s, 3H), 2.98-2.88 (m, 2H), 2.78-2.71 (m, 2H), 1.85-1.70 (m, 2H), 1.69-1.55 (m, 2H).

Example 180:3-(N-(2-(4-ethoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(186) ##STR00525##

(187) Step 1: 4-ethoxy-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et.sub.3N (0.500 ml, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) and 4-ethoxypiperidine (222 mg, 1.72 mmol) in DCM (6 ml) at RT. The clear solution was stirred at RT for 16 h. The organic phase was washed with 1 M HCl (3 ml), dried by passage through a phase separator and concentrated in vacuo to afford the title compound (471 mg, 1.435 mmol, 100% yield, 97% purity) as an orange oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.13-8.10 (m, 1H), 7.81 (dd, J=8.9, 2.4 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 3.55-3.45 (m, 3H), 3.30-3.25 (m, 2H), 3.03-2.97 (m, 2H), 1.95-1.87 (m, 2H), 1.59-1.51 (m, 2H), 1.12 (t, J=7.0 Hz, 3H).

(188) Step 2: 2-(4-ethoxypiperidin-1-yl)-5-(trifluoromethyl)aniline: 5% Pd/C (50% w/w water) Type 87L (50 mg, 0.012 mmol) in EtOH (0.5 ml) was added to a solution of the product from step 1 above (228 mg, 0.695 mmol) in EtOH (3.0 ml) at RT. The reaction mixture was hydrogenated (4 bar) at RT for 18 h. The catalyst was removed by filtration through a pad of Celite, washing with EtOH (15 ml). The filtrate was concentrated in vacuo and azeotroped with MeOH (6 ml) to afford the title compound (179 mg, 0.559 mmol, 80% yield, 90% purity) as an off-white solid. UPLC-MS (Method 1) m/z 289.3 (M+H).sup.+ at 1.66 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 6.99 (d, J=8.1 Hz, 1H), 6.95 (d, J=2.2 Hz, 1H), 6.82 (dd, J=8.2, 1.6 Hz, 1H), 5.10 (br s, 2H), 3.48 (q, J=7.0 Hz, 2H), 3.45-3.38 (m, 1H), 3.06-2.99 (m, 2H), 2.65-2.57 (m, 2H), 1.99-1.91 (m, 2H), 1.68-1.59 (m, 2H), 1.12 (t, J=7.0 Hz, 3H).

(189) Step 3: methyl 3-(N-(2-(4-ethoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (0.081 ml, 1.01 mmol) was added to a cloudy solution of the product from step 2 above (81 mg, 0.252 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (2.0 ml) at RT. The resultant clear solution was stirred at RT for 18 h then concentrated in vacuo. The crude product was purified by chromatography on silica gel (10 g cartridge, 0-60% EtOAc/isohexane) to afford the title compound (92.5 mg, 0.159 mmol, 63% yield, 89% purity) as a colourless oil. UPLC-MS (Method 1) m/z 517.4 (M+H).sup.+, 515.2 (MH).sup. at 1.80 min.

(190) Step 4: 3-(N-(2-(4-ethoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1 M LiOH (aq) (0.634 ml, 0.634 mmol) was added to a solution of the product from step 3 above (92 mg, 0.159 mmol) in THF (1.3 ml) at RT. The reaction mixture was stirred at RT for 18 h then concentrated in vacuo. The residue was dissolved in water (3 ml) and washed with EtOAc (25 ml). The aqueous phase was acidified using 1 M HCl until pH 4-5 and the product was extracted into EtOAc (35 ml). The combined organic phases were dried over MgSO.sub.4 and concentrated in vacuo to afford the title compound (61 mg, 0.118 mmol, 74% yield, 97% purity) as an off-white solid. UPLC-MS (Method 1) m/z 503.3 (M+H).sup.+, 501.3 (MH).sup. at 1.63 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.18 (br s, 1H), 8.87 (br s, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.16 (dd, J=8.7, 2.2 Hz, 1H), 7.44 (d, J=1.7 Hz, 1H), 7.36 (dd, J=8.4, 1.6 Hz, 1H), 7.34-7.30 (m, 2H), 3.91 (s, 3H), 3.52-3.42 (m, 3H), 2.99-2.91 (m, 2H), 2.72-2.64 (m, 2H), 1.98-1.90 (m, 2H), 1.67-1.58 (m, 2H), 1.14 (t, J=7.0 Hz, 3H).

Example 181: 4-methoxy-3-(N-(2-(4-methoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(191) ##STR00526##

(192) Step 1: 4-methoxy-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et.sub.3N (318 l, 2.28 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (128 l, 0.912 mmol) and 4-methoxypiperidine (105 mg, 0.912 mmol) in DCM (3 ml) and the resultant solution was stirred at RT for 20 h. 1 M HCl (2 ml) was added and the organic phase was dried by passage through a phase separator. The organic phase was concentrated in vacuo to afford the title compound (277 mg, 0.912 mmol, 100% yield, 100% purity) as a light orange oil. UPLC-MS (Method 1) m/z 305.6 (M+H).sup.+ at 1.60 min.

(193) Step 2: 2-(4-methoxypiperidin-1-yl)-5-(trifluoromethyl)aniline: The product from step 1 above (277 mg, 0.912 mmol) was dissolved in EtOH (14.2 ml) and hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm, full hydrogen mode, 40 C., 1 ml/min flow rate, 2 passes). The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to afford the title compound (239 mg, 0.854 mmol, 94% yield, 98% purity) as a cream solid. UPLC-MS (Method 2) m/z 275.3 (M+H).sup.+, 273.3 (MH).sup. at 1.53 min.

(194) Step 3: methyl 4-methoxy-3-(N-(2-(4-methoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoate: The product from step 2 above (69.1 mg, 0.252 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (81 l, 1.01 mmol) and treated with a solution methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 4 days. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (52.8 mg, 0.103 mmol, 40.9% yield, 98% purity) as a white solid. UPLC-MS (Method 1) m/z 503.4 (M+H)+(ES+); 501.2 (MH)(ES), at 1.71 min.

(195) Step 4: 4-methoxy-3-(N-(2-(4-methoxypiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid: The product from step 3 above (50 mg, 0.100 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH (aq) (362 l, 0.398 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 with 1 M HCl. The resultant lumpy suspension was sonicated to afford a cloudy mixture. The cloudy mixture was concentrated in vacuo to 2 ml. The resultant precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (38.8 mg, 0.078 mmol, 78% yield, 98% purity) as a white solid. UPLC-MS (Method 1) m/z 489.2 (M+H).sup.+, 487.1 (MH).sup. at 1.53 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.16 (s, 1H), 8.88 (s, 1H), 8.35 (d, J=2.2 Hz, 1H), 8.15 (dd, J=8.7, 2.2 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.38-7.28 (m, 3H), 3.91 (s, 3H), 3.35-3.28 (m, 1H), 3.27 (s, 3H), 2.98-2.90 (m, 2H), 2.71-2.62 (m, 2H), 1.99-1.90 (m, 2H), 1.67-1.57 (m, 2H).

Example 182: 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(196) ##STR00527##

(197) Step 1: 3-nitro-4-(piperidin-1-yl)benzonitrile: A mixture of 4-fluoro-3-nitrobenzonitrile (300 mg, 1.81 mmol), piperidine (0.2 ml, 2.02 mmol) and Et.sub.3N (0.65 ml, 4.66 mmol) in DCM (6 ml) was stirred at RT overnight. The mixture was washed with water (10 ml), passed through a phase separator, concentrated onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (400 mg, 1.73 mmol, 96% yield, 100% purity) as a pale orange solid. UPLC-MS (Method 2) m/z 232.1 (M+H).sup.+ at 1.60 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.28 (d, J=2.1 Hz, 1H), 7.84 (dd, J=8.9, 2.1 Hz, 1H), 7.34 (d, J=8.9 Hz, 1H), 3.18-3.10 (m, 4H), 1.65-1.54 (m, 6H).

(198) Step 2: 3-amino-4-(piperidin-1-yl)benzonitrile: A solution of the product from step 1 above (398 mg, 1.72 mmol) in EtOH (35 ml) was hydrogenated in a ThalesNano H-cube flow reactor (10% Pt/C, 304 mm, full hydrogen mode, 25 C., 1 ml/min flow rate, 1 pass). The mixture was concentrated onto silica and purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (118 mg, 0.542 mmol, 32% yield, 93% purity) as a thick red oil. UPLC-MS (Method 2) m/z 202.2 (M+H).sup.+ at 1.58 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 6.96-6.95 (m, 3H), 5.07 (s, 2H), 2.79 (t, J=5.1 Hz, 4H), 1.71-1.63 (m, 4H), 1.57-1.48 (m, 2H).

(199) Step 3: methyl 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoate: A mixture of the product from step 2 above (118 mg, 0.542 mmol), methyl 3-(chlorosulfonyl)-4-methoxybenzoate (172 mg, 0.651 mmol) and pyridine (130 l, 1.61 mmol) in DCM (5 ml) was stirred at RT over the weekend. The mixture was concentrated onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (172 mg, 0.394 mmol, 73% yield, 98% purity) as a white solid. UPLC-MS (Method 2) m/z 430.2 (M+H).sup.+, 428.1 (MH).sup. at 1.58 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.94 (s, 1H), 8.33 (d, J=2.3 Hz, 1H), 8.20 (dd, J=8.7, 2.3 Hz, 1H), 7.50 (dd, J=8.5, 2.0 Hz, 1H), 7.41-7.35 (m, 2H), 7.24 (d, J=8.5 Hz, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 2.82 (t, J=5.3 Hz, 4H), 1.65-1.57 (m, 4H), 1.55-1.46 (m, 2H).

(200) Step 4: 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: A mixture of the product from step 3 above (170 mg, 0.390 mmol) and LiOH (40 mg, 1.67 mmol) in THF/H.sub.2O (4:1, 4 ml) was stirred at RT for 1 h and then at 35 C. overnight. The mixture was diluted with H.sub.2O (10 ml) and EtOAc (15 ml) and acidified to pH 4 with 1 M HCl. The phases were separated and the aqueous was extracted with EtOAc (215 ml). The combined organic extracts were washed with brine (15 ml), passed through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (105 mg, 0.243 mmol, 62% yield, 96% purity) as a white solid. UPLC-MS (Method 1) m/z 416.2 (M+H).sup.+, 413.7 (MH).sup. at 1.47 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.18 (s, 1H), 8.88 (s, 1H), 8.33 (d, J=2.2 Hz, 1H), 8.17 (dd, J=8.7, 2.2 Hz, 1H), 7.50 (dd, J=8.3, 2.0 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.24 (d, J=8.3 Hz, 1H), 3.92 (s, 3H), 2.81 (t, J=5.2 Hz, 4H), 1.67-1.56 (m, 4H), 1.56-1.45 (m, 2H).

Example 183:4-ethyl-3-(N-(2-(3-hydroxyazetidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(201) ##STR00528##

(202) Step 1: methyl 3-(chlorosulfonyl)-4-ethylbenzoate: Thionyl chloride (5 ml, 68.5 mmol) was added portionwise to the product from example 1, step 1, 3-((chlorosulfonyl)-4-ethylbenzoic acid) (0.888 g, 3.57 mmol) at RT. The mixture was heated to 75 C. for 1 h. The solution was cooled to RT and concentrated in vacuo. The residue was dissolved in DCM (5 ml), treated with MeOH (0.144 ml, 3.57 mmol) followed by Et&N (0.536 ml, 3.93 mmol) and stirred at RT overnight. The mixture was diluted with DCM (50 ml), washed with water (50 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to give the title compound (0.450 g, 1.37 mmol, 38% yield, 80% purity) as a light brown oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.73 (d, J=1.8 Hz, 1H), 8.32 (dd, J=8.1, 1.8 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 3.99 (s, 3H), 3.28 (q, J=7.3 Hz, 2H), 1.40 (t, J=7.4 Hz, 3H).

(203) Step 2: 1-(2-nitro-4-(trifluoromethyl)phenyl) azetidin-3-ol: Et.sub.3N (0.700 ml, 5.02 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (0.201 ml, 1.44 mmol) and azetidin-3-ol hydrochloride (189 mg, 1.72 mmol) in DCM (6 ml) at RT. The clear solution was stirred at RT for 16 h. The organic phase was washed with 1 M HCl (3 ml) and the organic phase was dried via hydrophobic frit and concentrated in vacuo to afford the title compound (461 mg, 1.39 mmol, 97% yield, 79% purity) as an orange oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.09-8.05 (m, 1H), 7.73 (dd, J=9.0, 2.3 Hz, 1H), 6.90 (d, J=8.9 Hz, 1H), 5.79 (d, J=6.3 Hz, 1H), 4.55-4.49 (m, 1H), 4.19 (ddd, J=9.7, 6.7, 1.4 Hz, 2H), 3.77 (ddd, J=9.7, 4.1, 1.3 Hz, 2H).

(204) Step 3: 1-(2-amino-4-(trifluoromethyl)phenyl) azetidin-3-ol: The product from step 2 above (455 mg, 1.37 mmol) was dissolved in EtOH (27.4 ml) and hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm, full hydrogen mode, 40 C., 1 ml/min flow rate, 1 pass). The reaction mixture was concentrated in vacuo and azeotroped with MeOH (12 ml) to afford the title compound (395 mg, 1.37 mmol, 100% yield, 81% purity) as a pale yellow oil. UPLC-MS (Method 1) m/z 233.3 (M+H).sup.+ at 1.00 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 6.86 (d, J=2.1 Hz, 1H), 6.83-6.79 (m, 1H), 6.50 (d, J=8.1 Hz, 1H), 5.52 (d, J=6.5 Hz, 1H), 4.74 (br s, 2H), 4.46 (sextet, J=6.2 Hz, 1H), 4.19-4.13 (m, 2H), 3.45-3.40 (m, 2H).

(205) Step 4: methyl 4-ethyl-3-(N-(2-(3-hydroxyazetidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoate: Pyridine (0.072 ml, 0.896 mmol) was added to a solution of the product from step 3 above (65 mg, 0.224 mmol) and the product from step 1 above (92 mg, 0.280 mmol) in DCM (2.0 ml) at RT. The resultant cloudy solution was stirred at RT for 21 h. The reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on silica gel (10 g cartridge, 0-65% EtOAc/isohexane) to afford the title compound (51 mg, 0.102 mmol, 46% yield, 92% purity) as a red oil. UPLC-MS (Method 1) m/z 459.4 (M+H).sup.+, 457.2 (MH).sup. at 0.66 min.

(206) Step 5: 4-ethyl-3-(N-(2-(3-hydroxyazetidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH (aq) (0.409 ml, 0.409 mmol) was added to a solution of the product from step 4 above (51 mg, 0.102 mmol) in THF (0.82 ml) at RT. The solution was stirred at RT for 17 h then concentrated in vacuo. The residue was dissolved in water (3 ml) and washed with EtOAc (5 ml). The aqueous phase was acidified using 1 M HCl until pH 4-5 and the product was extracted into EtOAc (35 ml). The organic phases were combined, dried over MgSO.sub.4 and concentrated in vacuo. The crude product was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 35-65% MeCN in Water) to afford the title compound (7.3 mg, 0.016 mmol, 16% yield, 99% purity) as a white solid. UPLC-MS (Method 1) m/z 445.3 (M+H).sup.+, 443.2 (MH).sup. at 1.32 min. 1H NMR (500 MHz, DMSO-d.sub.6) 13.24 (br s, 1H), 9.55 (br s, 1H), 8.25 (d, J=1.8 Hz, 1H), 8.11 (dd, J=8.0, 1.5 Hz, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.31 (br d, J=8.7 Hz, 1H), 6.51 (d, J=8.6 Hz, 1H), 6.24 (br s, 1H), 5.63 (br d, J=5.9 Hz, 1H), 4.58-4.48 (m, 1H), 4.40-4.33 (m, 2H), 3.82 (dd, J=8.7, 4.8 Hz, 2H), 2.94 (q, J=7.4 Hz, 2H), 1.17 (t, J=7.4 Hz, 3H).

Example 184: 3-(N-(3-fluoro-2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(207) ##STR00529##

(208) Step 1: 1-(2-fluoro-6-nitro-4-(trifluoromethyl)phenyl)piperidine: Et.sub.3N (0.767 ml, 5.50 mmol) was added to a solution of 1,2-difluoro-3-nitro-5-(trifluoromethyl)benzene (500 mg, 2.20 mmol) and piperidine (0.261 ml, 2.64 mmol) in DCM (6 ml) at RT. The clear solution was stirred at RT for 23 h. The organic phase was washed with 1 M HCl (3 ml), dried by passage through a phase separator and concentrated in vacuo to afford the title compound (676 mg, 2.20 mmol, 100% yield, 98% purity) as a brown oil. UPLC-MS (Method 1) m/z 293.5 (M+H).sup.+ at 1.93 min.

(209) Step 2: 3-fluoro-2-(piperidin-1-yl)-5-(trifluoromethyl)aniline: The product from step 1 above (0.642 g, 2.20 mmol) was dissolved in EtOH (44 ml) and hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm, full hydrogen mode, RT, 1 ml/min flow rate, 1 pass). The crude product was concentrated in vacuo and azeotroped with MeOH (12 ml) to afford the title compound (0.543 g, 1.97 mmol, 90% yield, 95% purity) as a pale yellow oil. UPLC-MS (Method 1) m/z 263.3 (M+H).sup.+ at 1.89 min.

(210) Step 3: methyl 3-(N-(3-fluoro-2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (0.139 ml, 1.72 mmol) was added to a solution of the product from step 2 above (0.15 g, 0.572 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.189 g, 0.715 mmol) in DCM (10 ml) and the solution was stirred at RT for 18 h. The solution was concentrated in vacuo and the crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.372 g, 0.546 mmol, 95% yield, 72% purity) as a white solid. UPLC-MS (Method 1) m/z 491.3 (M+H).sup.+, 489.2 (MH).sup. at 1.96 min.

(211) Step 4: 3-(N-(3-fluoro-2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1 M LiOH (aq) (3.28 ml, 3.28 mmol) was added to a solution of the product from step 3 above (0.268 g, 0.547 mmol) in THF (12 ml) and MeOH (3 ml) and the solution was stirred at RT overnight. The solvent was removed in vacuo and the residue dissolved in water (5 ml) and extracted with TBME (35 ml). The aqueous phase was acidified with conc. HCl and the product was extracted into TBME (310 ml). The organic phases were combined and dried by passage through a phase separator. The solvent was removed in vacuo to afford the title compound (0.184 g, 0.378 mmol, 69% yield, 98% purity) as an off white solid. UPLC-MS (Method 1) m/z 477.3 (M+H).sup.+, 474.9 (MH).sup. at 1.81 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.19 (s, 1H), 8.99 (s, 1H), 8.38 (d, J=2.2 Hz, 1H), 8.17 (dd, J=8.7, 2.2 Hz, 1H), 7.37-7.31 (m, 3H), 3.94 (s, 3H), 2.91-2.81 (m, 4H), 1.69-1.62 (m, 4H), 1.58-1.51 (m, 2H).

(212) The following examples were prepared by methods analogous to Example 184, substituting appropriate starting materials and intermediates where necessary:

(213) TABLE-US-00014 Example Structure Name/Analytical Data 185 0 3-(N-(2-(4-cyclopropyl-4-hydroxypiperidin-1- yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 515.4 (M + H).sup.+, 512.9 (M H).sup. at 1.50 min. .sup.1H NMR (500 MHz, DMSO- d.sub.6) 13.17 (s, 1H), 8.84 (s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.15 (dd, J = 8.7, 2.2 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.39-7.28 (m, 3H), 3.91-3.89 (m, 4H), 2.91 (td, J = 11.5, 2.6 Hz, 2H), 2.78- 2.72 (m, 2H), 1.68 (td, J = 12.5, 4.2 Hz, 2H), 1.57- 1.49 (m, 2H), 0.94-0.86 (m, 1H), 0.39-0.34 (m, 2H), 0.28-0.18 (m, 2H). 186 3-(N-(2-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 501.3 (M + H).sup.+, 499.3 (M H).sup. at 1.46 min. .sup.1H NMR (500 MHz, DMSO- d.sub.6) 13.17 (s, 1H), 8.90 (s, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.14 (dd, J = 8.7, 2.2 Hz, 1H), 7.44 (d, J = 2.1 Hz, 1H), 7.37-7.25 (m, 3H), 4.41 (t, J = 7.7 Hz, 2H), 3.89 (s, 3H), 2.89-2.78 (m, 2H), 2.74- 2.67 (m, 2H), 2.39 (t, J = 7.7 Hz, 2H), 1.92 (t, J = 5.5 Hz, 4H). 187 3-(N-(2-(4-isopropoxypiperidin-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 517.3 (M + H).sup.+, 515.2 (M H).sup. at 1.72 min. .sup.1H NMR (500 MHz, DMSO- d.sub.6) 13.15 (br s, 1H), 8.86 (br s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.16 (dd, J = 8.7, 2.2 Hz, 1H), 7.43 (d, J = 1.7 Hz, 1H), 7.36 (dd, J = 8.5, 1.6 Hz, 1H), 7.32 (app. d, J = 8.7 Hz, 2H), 3.91 (s, 3H), 3.73 (hept, J = 6.1 Hz, 1H), 3.57-3.50 (m, 1H), 2.98- 2.91 (m, 2H), 2.72-2.65 (m, 2H), 1.93-1.86 (m, 2H), 1.64-1.55 (m, 2H), 1.10 (d, J = 6.1 Hz, 6H). 188 (R)-3-(N-(2-(3-hydroxypyrrolidin-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 461.4 (M + H).sup.+, 459.2 (M H).sup. at 1.17 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.15 (dd, J = 8.6, 2.2 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.28 (dd, J = 8.9, 2.3 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.56 (d, J = 2.3 Hz, 1H), 4.96 (br s, 1H), 4.37-4.32 (m, 1H), 3.97 (s, 3H), 3.80 (dd, J = 10.9, 4.9 Hz, 1H), 3.60-3.53 (m, 1H), 3.49-3.43 (m, 1H), 3.38-3.33 (m, 1H), 1.97- 1.89 (m, 1H), 1.88-1.81 (m, 1H). Two exchangeable protons not observed. 189 3-(N-(2-(3-ethyl-3-hydroxyazetidin-1-yl)-5- (trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 475.4 (M + H).sup.+, 472.9 (M H).sup. at 1.27 min. .sup.1H NMR (500 MHz, DMSO- d.sub.6) 13.03 (br s, 1H), 9.26 (br s, 1H), 8.18 (dd, J = 8.7, 2.2 Hz, 1H), 8.12 (d, J = 2.2 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.31 (dd, J = 8.8, 2.2 Hz, 1H), 6.57-6.44 (m, 2H), 5.41 (br s, 1H), 4.01 (d, J = 8.4 Hz, 2H), 3.93 (s, 3H), 3.83 (d, J = 8.3 Hz, 2H), 1.66 (q, J = 7.3 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H). 190 3-(N-(2-(trans-3-fluoro-4-hydroxypyrrolidin-1- yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4- methoxybenzoic acid UPLC-MS (Method 1) m/z 479.4 (M + H).sup.+, 477.1 (M H).sup. at 1.22 min. .sup.1H NMR (500 MHz, DMSO- d.sub.6) 13.07 (br s, 1H), 9.31 (br s, 1H), 8.18 (dd, J = 8.7, 2.2 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.32 (dd, J = 8.8, 1.6 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.57-6.52 (m, 1H), 5.56 (br s, 1H), 5.11-4.99 (m, 1H), 4.31 (dd, J = 9.1, 4.1 Hz, 1H), 4.02-3.83 (m, 5H), 3.72 (dd, J = 25.7, 12.7 Hz, 1H), 3.45 (d, J = 11.3 Hz, 1H).

Example 200: 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-(trifluoromethyl)benzoic acid

(214) ##STR00536##

(215) Step 1: methyl 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-(trifluoromethyl)benzoate: A mixture of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (75 mg, 0.307 mmol), methyl 3-(chlorosulfonyl)-4-(trifluoromethyl)benzoate (101 mg, 0.335 mmol) and pyridine (75 l, 0.927 mmol) in DCM (4 ml) was stirred at RT overnight and then at 35 C. for 11 days. The mixture was concentrated onto silica and purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (91 mg, 0.178 mmol, 58.1% yield, 100% purity) as a pale yellow solid. UPLC-MS (Method 1) m/z 511.2 (M+H).sup.+, 509.0 (MH).sup. at 1.99 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.73 (s, 1H), 8.46 (s, 1H), 8.34 (d, J=8.2 Hz, 1H), 8.19 (d, J=8.2 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.37 (d, J=2.2 Hz, 1H), 7.26 (dd, J=8.4, 2.2 Hz, 1H), 3.89 (s, 3H), 2.71-2.65 (m, 4H), 1.48-1.36 (m, 6H). Step 2: 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-(trifluoro-methyl)benzoic acid: A mixture of the product from step 1 above (91 mg, 0.178 mmol) and LiOH (17 mg, 0.710 mmol) in THE/MeOH/water (4:1:1, 2.4 ml) was stirred at 35 C. overnight. The mixture was diluted with water (10 ml) and EtOAc (15 ml) and acidified to pH 4 with 1 M HCl(aq). The phases were separated and the aqueous phase was extracted with EtOAc (215 ml). The organic extracts were combined and washed with brine (15 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The residue was triturated with isohexane/TBME (5:1) to give the title compound (33.4 mg, 0.066 mmol, 37.0% yield, 98% purity) as a beige solid. UPLC-MS (Method 1) m/z 497.2 (M+H).sup.+, 495.1 (MH).sup. at 1.92 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.89 (s, 1H), 9.69 (s, 1H), 8.48 (d, J=1.6 Hz, 1H), 8.32 (dd, J=8.2, 1.6 Hz, 1H), 8.16 (d, J=8.2 Hz, 1H), 7.49 (dd, J=8.5, 2.2 Hz, 1H), 7.35 (d, J=2.2 Hz, 1H), 7.26 (d, J=8.5 Hz, 1H), 2.73-2.64 (m, 4H), 1.49-1.35 (m, 6H).

Example 201: 4-ethoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(216) ##STR00537##

(217) Step 1: methyl 4-ethoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: A solution of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (0.100 g, 0.409 mmol) in DCM (5 ml) and pyridine (0.199 ml, 2.46 mmol) were added to a solution of methyl 3-(chlorosulfonyl)-4-ethoxybenzoate (0.114 g, 0.409 mmol) in DCM (10 ml) and the solution was stirred at RT for 24 h. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (0.160 g, 0.326 mmol, 80% yield, 99% purity) as a cream waxy solid. UPLC-MS (Method 1) m/z 487.4 (M+H).sup.+, 485.2 (MH).sup. at 1.93 min.

(218) Step 2: 4-ethoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH (aq) (0.024 g, 0.987 mmol) was added to a solution of the product from step 1 (0.160 g, 0.329 mmol) in THF (5 ml) and the solution was stirred at RT overnight. The reaction mixture was concentrated in vacuo to water. The pH was adjusted to pH 6 with 1 M HCl(aq) to form a precipitate which was filtered and washed with water (10 ml) and isohexane (20 ml) to give the title compound (0.151 g, 0.304 mmol, 92% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 473.4 (M+H).sup.+, 471.2 (MH).sup. at 1.78 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.20 (br s, 1H), 8.55 (br s, 1H), 8.40 (d, J=2.2 Hz, 1H), 8.13 (dd, J=8.7, 2.2 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.39-7.34 (m, 1H), 7.32-7.30 (m, 2H), 4.22 (q, J=7.0 Hz, 2H), 2.76 (t, J=5.3 Hz, 4H), 1.62 (p, J=5.5 Hz, 4H), 1.52 (p, J=6.3 Hz, 2H), 1.27 (t, J=7.0 Hz, 3H).

Example 202: 3-(N-(4,5-dichloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(219) ##STR00538##

(220) Step 1: methyl 3-(N-(4,5-dichloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (0.166 ml, 2.06 mmol) was added to a solution of 4,5-dichloro-2-(piperidin-1-yl)aniline (0.168 g, 0.685 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.227 g, 0.857 mmol) in DCM (10 ml). The solution was stirred at RT for 18 h and then concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.257 g, 0.543 mmol, 79% yield, 81% purity) as a white solid. UPLC-MS (Method 1) m/z 475.4 (M+H).sup.+, 472.8 (MH).sup. at 1.75 min.

(221) Step 2: 3-(N-(4,5-dichloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1 M LiOH (aq) (3.26 ml, 3.26 mmol) was added to a solution of the product from step 1 above (0.257 g, 0.543 mmol) in THF (13 ml) and MeOH (3 ml) and the solution was stirred at RT overnight. The solvent was removed in vacuo and the residue dissolved in water (5 ml) and washed with TBME (35 ml). The aqueous phase was acidified with conc. HCl and extracted with TBME (310 ml). The combined organic phases were dried by passage through a phase separator and the solvent was removed in vacuo to afford the title compound (0.229 g, 0.494 mmol, 91% yield, 97% purity) as an off white solid. UPLC-MS (Method 1) m/z 459.3/461.3 (M+H).sup.+, 457.2/459.2 (MH).sup. at 1.82 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.22 (s, 1H), 8.75 (s, 1H), 8.35 (d, J=2.2 Hz, 1H), 8.17 (dd, J=8.7, 2.2 Hz, 1H), 7.42 (s, 1H), 7.38 (s, 1H), 7.34 (d, J=8.8 Hz, 1H), 3.94 (s, 3H), 2.70-2.64 (m, 4H), 1.67-1.56 (m, 4H), 1.56-1.42 (m, 2H).

Example 203:3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(222) ##STR00539##

(223) Step 1: 3-(chlorosulfonyl)-4-ethylbenzoic acid: 4-ethylbenzoic acid (7 g, 46.6 mmol) in chlorosulfonic acid (20 ml, 299 mmol) was heated at 100 C. for 5 h. The mixture was cooled and carefully added to stirred ice-water (200 ml). The solid precipitated out was collected by filtration, washed with water (100 ml) and dried in vacuo to give the title compound (10.9 g, 41.5 mmol, 89% yield, 95% purity) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.65 (br s, 1H), 8.34 (d, J=1.9 Hz, 1H), 7.82 (dd, J=7.9, 2.0 Hz, 1H), 7.32 (d, J=7.9 Hz, 1H), 3.08 (q, J=7.5 Hz, 2H), 1.18 (t, J=7.5 Hz, 3H).

(224) Step 2: methyl 3-(chlorosulfonyl)-4-ethylbenzoate: Thionyl Chloride (10 ml, 137 mmol) was added portionwise to the product from step 1 above (4 g, 16.1 mmol) at RT. The mixture was heated to 75 C. for 2 h, cooled to RT, concentrated in vacuo and azeotroped with toluene. The solid was dissolved in DCM (10 ml) and treated with MeOH (0.716 ml, 17.7 mmol) followed by Et.sub.3N (2.41 ml, 17.7 mmol) and stirred at RT overnight. The mixture was diluted with DCM (50 ml), washed with water (50 ml), dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (3.60 g, 13.02 mmol, 81% yield, 95% purity) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.74 (d, J=1.8 Hz, 1H), 8.32 (dd, J=8.0, 1.8 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 3.99 (s, 3H), 3.28 (q, J=7.5 Hz, 2H), 1.41 (t, J=7.5 Hz, 3H).

(225) Step 3: methyl 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoate: Pyridine (0.069 ml, 0.856 mmol) was added to a solution of the product from Example 12 step 2 (0.08 g, 0.285 mmol) and the product from step 2 above (0.094 g, 0.357 mmol) in DCM (10 ml) and the solution was stirred at RT for 18 h. The solution was concentrated in vacuo and the crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.137 g, 0.227 mmol, 80% yield, 84% purity) as a white solid. UPLC-MS (Method 1) m/z 507.4 (M+H).sup.+, 505.2 (MH).sup. at 1.90 min.

(226) Step 4: 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoic acid: 1 M LiOH (aq) (1.35 ml, 1.35 mmol) was added to a solution of the product from step 3 above (0.137 g, 0.225 mmol) in THF (6 ml) and MeOH (1.3 ml) and the solution was stirred at RT overnight. The solvent was removed in vacuo and the residue dissolved in water (5 ml) and washed with TBME (35 ml). The aqueous phase was acidified with conc. HCl and extracted with TBME (310 ml). The organic phases were combined and dried by passage through a phase separator and the solvent removed in vacuo to give the title compound (0.105 g, 0.209 mmol, 93% yield, 98% purity) as an off white solid. UPLC-MS (Method 1) m/z 493.3 (M+H).sup.+, 490.9 (MH).sup. at 1.76 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.31 (s, 1H), 9.85 (s, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.10 (dd, J=8.0, 1.8 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.44 (dd, J=8.5, 2.1 Hz, 1H), 7.36-7.31 (m, 2H), 3.03 (q, J=7.4 Hz, 2H), 2.89-2.80 (m, 4H), 2.13-2.00 (m, 4H), 1.18 (t, J=7.4 Hz, 3H).

Example 204:3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(227) ##STR00540##

(228) Step 1: methyl 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoate: Pyridine (0.052 ml, 0.642 mmol) was added to a solution of the product from Example 9 step 2 (60 mg, 0.214 mmol) and the product from Example 203 step 2 (70 mg, 0.268 mmol) in DCM (10 ml). The solution was stirred at RT for 18 h then concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.057 g, 0.113 mmol, 52.6% yield, 100% purity) as a white solid. UPLC-MS (Method 1) m/z 507.7 (M+H).sup.+, 505.2 (MH).sup. at 1.89 min.

(229) Step 2: 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoic acid: 1 M LiOH (aq) (0.675 ml, 0.675 mmol) was added to a solution of the product from step 1 above (0.057 g, 0.113 mmol) in THF (8 ml) and MeOH (2 ml). The solution was stirred at RT overnight and then concentrated in vacuo. The residue was dissolved in water (5 ml) and washed with TBME (35 ml). The aqueous phase was acidified with conc. HCl and extracted with TBME (310 ml). The organic phases were combined, dried by passage through a phase separator and concentrated in vacuo to afford the title compound (0.056 g, 0.110 mmol, 98% yield, 97% purity) as an off white solid. UPLC-MS (Method 1) m/z 493.7 (M+H).sup.+, 491.1 (MH).sup. at 1.74 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.30 (s, 1H), 9.30 (s, 1H), 8.35 (d, J=1.8 Hz, 1H), 8.11 (dd, J=8.0, 1.8 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.45 (dd, J=8.5, 2.1 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.12 (d, J=2.1 Hz, 1H), 3.21 (t, J=11.4 Hz, 2H), 3.00 (q, J=7.4 Hz, 2H), 2.98-2.94 (m, 2H), 2.08-1.96 (m, 2H), 1.84-1.75 (m, 2H), 1.19 (t, J=7.4 Hz, 3H).

Example 205:4-ethyl-3-(N-(2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(230) ##STR00541##

(231) Step 1: 4-fluoro-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et.sub.3N (500 l, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (201 l, 1.44 mmol) and 4-fluoropiperidine (192 mg, 1.87 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 3 days. 1 M HCl(aq) (2 ml) was added and the organic phase was separated by passage through a phase separator. The organic phase was concentrated in vacuo to afford the title compound (419 mg, 1.44 mmol, 100% yield, 100% purity) as a pale yellow viscous oil. UPLC-MS (Method 2) m/z 293.3 (M+H).sup.+ at 1.62 min.

(232) Step 2: 2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)aniline: The product from step 1 above (419 mg, 1.44 mmol) was dissolved in EtOH (28.8 ml) and the reaction mixture was hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm, full hydrogen mode, 40 C., 1 ml/min flow rate, 2 passes). The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to afford the title compound (371 mg, 1.27 mmol, 89% yield, 90% purity) as a clear viscous oil. UPLC-MS (Method 2) m/z 263.3 (M+H).sup.+ at 1.59 min.

(233) Step 3: methyl 4-ethyl-3-(N-(2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: The product from step 2 above (66.5 mg, 0.254 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (82 l, 1.02 mmol) and treated with a suspension of the product from Example 203 step 2 (80 mg, 0.305 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The reaction mixture was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (61 mg, 0.112 mmol, 44.3% yield, 90% purity) as a cream solid. UPLC-MS (Method 1) m/z 489.3 (M+H).sup.+, 487.2 (MH).sup. at 1.87 min.

(234) Step 4: 4-ethyl-3-(N-(2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: The product from step 3 above (59 mg, 0.121 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH (aq) (439 l, 0.483 mmol). MeOH was added dropwise to afford a solution, which was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 with 1 M HCl. The lumpy suspension was sonicated to afford a cloudy solution which was concentrated in vacuo to 2 ml. The resultant precipitate was collected by filtration and washed with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (38.4 mg, 0.078 mmol, 64.3% yield, 96% purity) as a white solid. UPLC-MS (Method 1) m/z 475.4 (M+H).sup.+, 473.2 (MH).sup. at 1.74 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.29 (br s, 1H), 9.68 (br s, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.0, 1.8 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.46-7.40 (m, 1H), 7.31-7.24 (m, 2H), 4.85-4.70 (m, 1H), 3.03 (q, J=7.4 Hz, 2H), 2.89 (t, J=9.9 Hz, 2H), 2.74-2.67 (m, 2H), 2.00-1.87 (m, 2H), 1.85-1.73 (m, 2H), 1.19 (t, J=7.4 Hz, 3H).

Example 206:3-(N-(2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(235) ##STR00542##

(236) Step 1: methyl 3-(N-(2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from Example 205 step 2 (66.1 mg, 0.252 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (81 l, 1.01 mmol) and treated with a solution methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The reaction mixture was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (88 mg, 0.161 mmol, 64.1% yield, 90% purity) as a sticky cream solid. UPLC-MS (Method 1) m/z 491.4 (M+H).sup.+, 489.1 (MH).sup. at 1.73 min.

(237) Step 2: 3-(N-(2-(4-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 1 above (86 mg, 0.175 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH (aq) (638 l, 0.701 mmol). MeOH was added dropwise to afford a solution, which was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 with 1 M HCl. The lumpy suspension was sonicated to afford a cloudy solution which was concentrated in vacuo to 2 ml. The resultant precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (52.7 mg, 0.108 mmol, 61.8% yield, 98% purity) as a white solid. UPLC-MS (Method 1) m/z 477.3 (M+H).sup.+, 475.1 (MH).sup. at 1.56 min. .sup.1H NMR (500 MHz, DMSO-d6) 13.16 (br s, 1H), 9.00 (br s, 1H), 8.35 (d, J=2.2 Hz, 1H), 8.16 (dd, J=8.7, 2.2 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.40-7.29 (m, 3H), 4.93-4.75 (m, 1H), 3.90 (s, 3H), 2.94 (t, J=9.8 Hz, 2H), 2.79-2.73 (m, 2H), 2.10-1.94 (m, 2H), 1.93-1.79 (m, 2H).

Example 207:4-methoxy-3-(N-(5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid

(238) ##STR00543##

(239) Step 1: 1-(4-(methylsulfonyl)-2-nitrophenyl)piperidine: Et.sub.3N (0.795 ml, 5.70 mmol) was added to a solution of 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (500 mg, 2.28 mmol) and piperidine (0.226 ml, 2.28 mmol) in DCM (6 ml) at RT. The clear solution was stirred at RT for 23 h. The organic phase was washed with 1 M HCl(aq) (3 ml), dried by passage through a phase separator and concentrated in vacuo to afford the title compound (0.676 g, 2.28 mmol, 100% yield, 100% purity) as a brown oil. UPLC-MS (Method 1) m/z 285.2 (M+H).sup.+ at 1.32 min.

(240) Step 2: 5-(methylsulfonyl)-2-(piperidin-1-yl)aniline: The product from step 1 above (0.676 g, 2.38 mmol) was dissolved in EtOH (44 ml) and the reaction mixture was hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm, full hydrogen mode, RT, 1 ml/min flow rate, 1 pass). The reaction mixture was concentrated in vacuo and then azeotroped with MeOH (12 ml) to afford the title compound (0.615 g, 2.370 mmol, 100% yield, 98% purity) as a pale yellow oil. UPLC-MS (Method 1) m/z 255.3 (M+H).sup.+ at 1.20 min.

(241) Step 3: methyl 4-methoxy-3-(N-(5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: Pyridine (0.143 ml, 1.77 mmol) was added to a solution of the product from step 2 above (0.15 g, 0.590 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.195 g, 0.737 mmol) in DCM (10 ml). The resultant solution was stirred at RT for 18 h. The solution was concentrated in vacuo and the crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.201 g, 0.412 mmol, 69.9% yield, 99% purity) as a white solid. UPLC-MS (Method 1) m/z 483.3 (M+H).sup.+, 481.0 (MH).sup. at 1.49 min.

(242) Step 4: 4-methoxy-3-(N-(5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH (aq) (2.47 ml, 2.47 mmol) was added to a solution of the product from step 3 above (0.199 g, 0.412 mmol) in THF (10 ml) and MeOH (2.5 ml) and the solution was stirred at RT overnight. The solvent was removed in vacuo and the residue dissolved in water (5 ml) and washed with TBME (35 ml). The aqueous phase was acidified with conc. HCl and extracted with TBME (310 ml). The organic phases were combined and dried by passage through a phase separator. The solvent was removed in vacuo to afford the title compound (0.176 g, 0.372 mmol, 90% yield, 99% purity) as an off white solid. UPLC-MS (Method 1) m/z 469.4 (M+H).sup.+, 467.0 (MH).sup. at 1.36 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.17 (s, 1H), 8.82 (s, 1H), 8.35 (d, J=2.2 Hz, 1H), 8.15 (dd, J=8.7, 2.2 Hz, 1H), 7.65 (d, J=2.2 Hz, 1H), 7.55 (dd, J=8.4, 2.2 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.33 (d, J=8.7 Hz, 1H), 3.94 (s, 3H), 3.00 (s, 3H), 2.85-2.78 (m, 4H), 1.71-1.60 (m, 4H), 1.58-1.50 (m, 2H).

Example 208: I-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(243) ##STR00544##

(244) Step 1: I-3-fluoro-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et.sub.3N (500 l, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (300 mg, 1.44 mmol) and I-3-fluoropiperidine (250 mg, 2.42 mmol) in DCM (6 ml). The resultant solution was stirred at RT for 20 h. 1 M HCl(aq) (2 ml) was added and the organic phase was separated by passage through a phase separator. The organic phase was concentrated in vacuo to afford the title compound (488 mg, 1.44 mmol, 100% yield, 86% purity) as a pale orange viscous oil. UPLC-MS (Method 2) m/z 293.0 (M+H).sup.+ at 1.59 min.

(245) Step 2: I-2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)aniline: The product from step 1 above (419 mg, 1.44 mmol) was dissolved in EtOH (28.8 ml) and the reaction mixture was hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm, full hydrogen mode, 40 C., 1 ml/min flow rate, 2 passes). The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to afford the title compound (457 mg, 1.394 mmol, 97% yield, 80% purity) as a cream coloured gel. UPLC-MS (Method 2) m/z 263.3 (M+H).sup.+ at 1.59 min.

(246) Step 3: I-methyl 3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from step 3 above (66.1 mg, 0.252 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (81 l, 1.01 mmol) and treated with a solution methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 3 days. The reaction mixture was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (72.4 mg, 0.118 mmol, 46.9% yield, 80% purity) as an off-white solid. UPLC-MS (Method 1) m/z 491.3 (M+H).sup.+, 489.1 (MH).sup. at 1.73 min.

(247) Step 4: I-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 3 above (69 mg, 0.141 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH (aq) (512 l, 0.563 mmol). MeOH was added dropwise to afford a solution, which was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 with 1 M HCl. The lumpy suspension was sonicated to afford a cloudy solution which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (55.2 mg, 0.110 mmol, 78% yield) as a white solid. UPLC-MS (Method 1) m/z 477.4 (M+H).sup.+, 475.1 (MH).sup. at 1.57 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.19 (br s, 1H), 8.75 (br s, 1H), 8.38 (d, J=2.2 Hz, 1H), 8.16 (dd, J=8.7, 2.2 Hz, 1H), 7.44 (s, 1H), 7.38-7.33 (m, 2H), 7.31 (d, J=8.8 Hz, 1H), 4.95-4.79 (m, 1H), 3.91 (s, 3H), 3.09-2.86 (m, 3H), 2.85-2.75 (m, 1H), 1.95-1.75 (m, 3H), 1.74-1.63 (m, 1H).

Example 209: (S)-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(248) ##STR00545##

(249) Step 1: (S)-3-fluoro-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: Et.sub.3N (500 l, 3.59 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (300 mg, 1.44 mmol) and(S)-3-fluoropiperidine (250 mg, 2.42 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 20 h. 1 M HCl(aq) (2 ml) was added and the organic phase was separated and concentrated in vacuo to afford the title compound (461 mg, 1.44 mmol, 100% yield, 91% purity) as a pale orange viscous oil. UPLC-MS (Method 2) m/z 293.1 (M+H).sup.+ at 1.60 min.

(250) Step 2: (S)-2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)aniline: The product from step 1 above (419 mg, 1.44 mmol) was dissolved in EtOH (28.8 ml). The reaction mixture was hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm, full hydrogen mode, 40 C., 1 ml/min flow rate, 2 passes). The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to afford the title compound (475 mg, 1.43 mmol, 100% yield, 79% purity) as a cream coloured gel. UPLC-MS (Method 2) m/z 263.3 (M+H).sup.+ at 1.59 min.

(251) Step 3: (S)-methyl 3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from step 2 above (66.1 mg, 0.252 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (81 l, 1.01 mmol) and treated with a solution methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 3 days. The reaction mixture was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (81.4 mg, 0.133 mmol, 52.7% yield, 80% purity) as an off white solid. UPLC-MS (Method 1) m/z 491.4 (M+H).sup.+, 489.3 (MH).sup. at 1.74 min.

(252) Step 4: (S)-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 3 above (78 mg, 0.159 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH (aq) (578 l, 0.636 mmol). MeOH was added dropwise to afford a solution, which was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). This was washed with EtOAc (25 ml) and neutralised to pH 6 with 1 M HCl. The lumpy suspension was sonicated to afford a cloudy solution which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (55.2 mg, 0.110 mmol, 69.2% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 477.3 (M+H).sup.+, 475.2 (MH).sup. at 1.57 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6).Math. 13.18 (br s, 1H), 8.74 (br s, 1H), 8.37 (d, J=2.2 Hz, 1H), 8.15 (dd, J=8.7, 2.2 Hz, 1H), 7.44 (s, 1H), 7.39-7.27 (m, 3H), 4.95-4.79 (m, 1H), 3.91 (s, 3H), 3.08-2.86 (m, 3H), 2.83-2.76 (m, 1H), 1.95-1.75 (m, 3H), 1.74-1.63 (m, 1H).

Example 210: (S)-4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(253) ##STR00546##

(254) Step 1: (S)-methyl 4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: The product from Example 209 step 2 (67 mg, 0.255 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (83 l, 1.02 mmol) and treated with a suspension of the product from Example 203 step 2 (124 mg, 0.307 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 3 days. The reaction mixture was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (65.9 mg, 0.108 mmol, 42.2% yield, 80% purity) as an off white solid. UPLC-MS (Method 1) m/z 489.4 (M+H).sup.+, 487.2 (MH).sup. at 1.89 min.

(255) Step 2: (S)-4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: The product from step 1 above (63 mg, 0.129 mmol) was dissolved in THF (2 ml) and treated with 1.1 LiOH (aq) (469 l, 0.516 mmol). MeOH was added dropwise to afford a solution, which was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 with 1 M HCl. The lumpy suspension was sonicated to afford a cloudy solution which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (35.9 mg, 0.072 mmol, 55.7% yield) as a cream solid. UPLC-MS (Method 1) m/z 475.3 (M+H).sup.+, 473.2 (MH).sup. at 1.74 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.31 (br s, 1H), 9.36 (br s, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.0, 1.8 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.42 (dd, J=8.4, 2.1 Hz, 1H), 7.33-7.24 (m, 2H), 1.98-1.85 (m, 1H), 3.13-2.97 (m, 3H), 2.89-2.79 (m, 2H), 2.71 (td, J=8.1, 4.0 Hz, 1H), 1.98-1.85 (m, 1H), 1.82-1.71 (m, 1H), 1.71-1.55 (m, 2H), 1.19 (t, J=7.4 Hz, 3H).

Example 211: I-4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(256) ##STR00547##

(257) Step 1: I-methyl 4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: The product from Example 208 step 2 (67 mg, 0.255 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (83 l, 1.02 mmol) and treated with a suspension of the product from Example 203 step 2 (124 mg, 0.307 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 3 days. The reaction mixture was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (76.7 mg, 0.126 mmol, 49.2% yield, 80% purity) as an off white solid. UPLC-MS (Method 1) m/z 489.3 (M+H).sup.+, 487.2 (MH).sup. at 1.89 min.

(258) Step 2: I-4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: The product from step 1 above (74 mg, 0.151 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH (aq) (551 l, 0.606 mmol). MeOH was added dropwise to afford a solution, which was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 with 1 M HCl. The lumpy suspension was sonicated to afford a cloudy solution which was concentrated in vacuo to 2 ml. The resultant precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (43.5 mg, 0.087 mmol, 57.5% yield, 95% purity) as a cream solid. UPLC-MS (Method 1) m/z 475.4 (M+H).sup.+, 473.2 (MH).sup. at 1.74 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.31 (br s, 1H), 9.36 (br s, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.0, 1.8 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.45-7.38 (m, 1H), 7.33-7.25 (m, 2H), 4.84-4.68 (m, 1H), 3.13-2.96 (m, 3H), 2.89-2.79 (m, 2H), 2.75-2.67 (m, 1H), 1.98-1.85 (m, 1H), 1.82-1.72 (m, 1H), 1.70-1.54 (m, 2H), 1.19 (t, J=7.4 Hz, 3H).

Example 212: 3-(N-(5-(difluoromethyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(259) ##STR00548##

Synthesis of 3-(chlorosulfonyl)-4-methoxybenzoic acid

(260) 4-methoxybenzoic acid (6.5 g, 42.7 mmol) was added portionwise to chlorosulfonic acid (30 ml, 448 mmol) at RT. The mixture was heated to 80 C. for 2 h, then cooled to RT and added cautiously to ice-water (300 ml), then stirred for 1 h. The solid was collected, washed with water (200 ml) and dried in vacuo to give the title compound (7.92 g, 30.0 mmol, 70.3% yield, 95% purity) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.31 (br s, 1H), 8.30 (d, J=2.3 Hz, 1H), 7.90 (dd, J=8.6, 2.4 Hz, 1H), 7.07 (d, J=8.6 Hz, 1H), 3.83 (s, 3H).

Synthesis of 3-(N-(5-(difluoromethyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(261) Step 1: 1-(4-(difluoromethyl)-2-nitrophenyl)piperidine: Et.sub.3N (547 l, 3.92 mmol) was added to a solution of 4-(difluoromethyl)-1-fluoro-2-nitrobenzene (300 mg, 1.57 mmol) and piperidine (202 l, 2.04 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 20 h. 1 M HCl(aq) (2 ml) was added and the organic phase was separated by passage through a phase separator. The organic phase was concentrated in vacuo to afford the title compound (402 mg, 1.57 mmol, 100% yield, 100% purity) as a yellow viscous oil. UPLC-MS (Method 1) m/z 257.3 (M+H).sup.+ at 1.63 min.

(262) Step 2: 5-(difluoromethyl)-2-(piperidin-1-yl)aniline: The product from step 1 above (402 mg, 1.57 mmol) was dissolved in EtOH (14.4 ml). The reaction mixture was hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm, full hydrogen mode, 40 C., 1 ml/min flow rate, 2 passes). The reaction mixture was concentrated in vacuo and azeotroped with MeOH (6 ml) to afford the title compound (324 mg, 1.403 mmol, 89% yield, 98% purity) as a light yellow oil. UPLC-MS (Method 1) m/z 227.3 (M+H).sup.+ at 1.58 min.

(263) Step 3: 3-(N-(5-(difluoromethyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 2 above (60.2 mg, 0.266 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (86 l, 1.06 mmol) and treated with a suspension of 3-(chlorosulfonyl)-4-methoxybenzoic acid (80 mg, 0.319 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The reaction mixture was filtered and the filtrate was purified directly by chromatography on silica gel (12 g cartridge, 100% isohexane then 0-100% 10% MeOH in EtOAc/isohexane). The crude product was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 35-65% MeCN in Water) to afford the title compound (18 mg, 0.040 mmol, 14.9% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m/z 441.2 (M+H).sup.+, 439.1 (MH).sup. at 1.57 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.15 (br s, 1H), 8.66 (br s, 1H), 8.39 (d, J=2.2 Hz, 1H), 8.14 (dd, J=8.7, 2.2 Hz, 1H), 7.42 (s, 1H), 7.30 (d, J=8.9 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.18 (d, J=8.2, 1H), 6.89 (t, J=55.9 Hz, 1H), 3.93 (s, 3H), 2.71 (t, J=5.2 Hz, 4H), 1.67 (p, J=5.5 Hz, 4H), 1.57-1.50 (m, 2H).

Example 213: 3-(N-(5-(difluoromethyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(264) ##STR00549##

(265) Step 1: methyl 3-(N-(5-(difluoromethyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoate: The product of Example 212 step 2 (57.4 mg, 0.254 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (82 l, 1.02 mmol) and treated with a suspension of the product of Example 203 step 2 (80 mg, 0.305 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The reaction mixture was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (54 mg, 0.119 mmol, 47.0% yield, 100% purity) as a light yellow solid. UPLC-MS (Method 1) m/z 453.4 (M+H).sup.+, 451.1 (MH).sup. at 1.91 min.

(266) Step 2: 3-(N-(5-(difluoromethyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid: Conc. HCl (2.2 ml, 72.4 mmol) was added to water (0.737 ml) and this solution was added to a solution of the product from step 1 above (52 mg, 0.115 mmol) in dioxane (2.2 ml). The reaction mixture was heated at 50 C. for 2 days. The solution was concentrated in vacuo and the crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% 10% MeOH in EtOAc/pentane) to afford the title compound (18 mg, 0.039 mmol, 33.9% yield, 95% purity) as a cream solid. UPLC-MS (Method 1) m/z 439.4 (M+H).sup.+, 437.3 (MH).sup. at 1.75 min. 1H NMR (500 MHz, DMSO-d.sub.6) 13.28 (br s, 1H), 9.21 (br s, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.07 (dd, J=8.0, 1.8 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.32-7.18 (m, 3H), 7.02-6.08 (m, 1H), 3.03 (q, J=7.4 Hz, 2H), 2.67-2.61 (m, 4H), 1.59-1.50 (m, 4H), 1.49-1.42 (m, 2H), 1.20 (t, J=7.4 Hz, 3H).

Example 214: 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(1H-tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid

(267) ##STR00550##

(268) Step 1: 1-(4-fluoro-3-nitrophenyl)tetrazole: Trimethylsilyl azide (1.70 ml, 12.8 mmol) was added to 4-fluoro-3-nitroaniline (0.4 g, 2.56 mmol) and triethyl orthoformate (2.13 ml, 12.8 mmol) in acetic acid (9.97 ml) at 0 C. The resultant mixture was stirred for 30 min then heated to 80 C. over 1 h and stirred for 20 h. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel (12 g cartridge, 0-10% MeOH/DCM) to afford the title compound (0.469 g, 2.220 mmol, 87% yield, 99% purity) as a white solid. UPLC-MS (Method 1) m/z no ionisation at 1.75 min. .sup.1H NMR (500 MHz, CDCl.sub.3) 9.16 (s, 1H), 8.50 (dd, J=6.1, 2.8 Hz, 1H), 8.15-8.09 (m, 1H), 7.61 (app. T, J=9.4 Hz, 1H).

(269) Step 2: 1-(2-nitro-4-(1H-tetrazol-1-yl)phenyl)piperidine: Et.sub.3N (0.781 ml, 5.61 mmol) was added to a solution of the product from step 1 above (0.469 g, 2.24 mmol) and piperidine (0.266 ml, 2.69 mmol) in DCM (6 ml) at RT. The clear solution was stirred at RT for 23 h. The organic phase was washed with 1 M HCl(aq) (3 ml), dried by passage through a phase separator and concentrated in vacuo to afford the title compound (0.609 g, 2.20 mmol, 98% yield, 99% purity) as a brown oil. UPLC-MS (Method 1) m/z 1.39 min. .sup.1H NMR (500 MHz, CDCl.sub.3) 8.98 (s, 1H), 8.12 (d, J=2.7 Hz, 1H), 7.78 (dd, J=9.0, 2.7 Hz, 1H), 7.27 (d, J=9.0 Hz, 1H), 3.22-3.05 (m, 4H), 1.81-1.71 (m, 4H), 1.69-1.61 (m, 2H).

(270) Step 3: 2-(piperidin-1-yl)-5-(1H-tetrazol-1-yl)aniline: The product from step 2 above (0.609 g, 2.22 mmol) was dissolved in EtOH (48 ml) and the reaction mixture was hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm, full hydrogen mode, RT, 1 ml/min flow rate, 1 pass). The reaction mixture was concentrated in vacuo and azeotroped with MeOH (12 ml) to afford the title compound (0.531 g, 2.15 mmol, 97% yield, 99% purity) as a pale yellow oil. UPLC-MS (Method 1) m/z no 1.18 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.91 (s, 1H), 7.14 (d, J=2.5 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.98 (dd, J=8.3, 2.6 Hz, 1H), 5.21 (s, 2H), 2.91-2.69 (m, 4H), 1.75-1.62 (m, 4H), 1.60-1.47 (m, 2H).

(271) Step 4: methyl 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(1H-tetrazol-1-yl)phenyl)sulfamoyl)benzoate: Pyridine (0.199 ml, 2.46 mmol) was added to a solution of the product from step 3 above (200 mg, 0.819 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (260 mg, 0.982 mmol) in DCM (8 ml) and the solution was stirred at RT for 18 h. The solution was concentrated in vacuo and the crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.221 g, 0.468 mmol, 57.1% yield, 100% purity) as a white solid. UPLC-MS (Method 1) m/z 473.3 (M+H).sup.+, 471.3 (MH).sup. at 1.52 min.

(272) Step 5: 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(1H-tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH (aq) (2.81 ml, 2.81 mmol) was added to a solution of the product from step 4 above (0.221 g, 0.468 mmol) in THF (11 ml) and MeOH (3 ml) and the solution was stirred at RT overnight. The solvent was removed in vacuo and the residue was dissolved in water (5 ml) and washed with TBME (35 ml). The aqueous phase was acidified with conc. HCl and extracted with TBME (310 ml). The organic phases were combined and dried by passage through a phase separator and the solvent was removed in vacuo to give the title compound (0.171 g, 0.369 mmol, 79% yield, 99% purity) as an off white solid. UPLC-MS (Method 1) m/z 459.3 (M+H).sup.+, 457.2 (MH).sup. at 1.40 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.16 (s, 1H), 9.95 (s, 1H), 8.83 (s, 1H), 8.41 (d, J=2.2 Hz, 1H), 8.14 (dd, J=8.7, 2.2 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.53 (dd, J=8.6, 2.5 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 3.95 (s, 3H), 2.77-2.68 (m, 4H), 1.74-1.61 (m, 4H), 1.60-1.49 (m, 2H).

Example 215: 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(273) ##STR00551##

(274) Step 1: methyl 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoate: A mixture of the product from Example 182 step 2 (90 mg, 0.443 mmol), the product from Example 203 step 2 (174 mg, 0.664 mmol) and pyridine (150 l, 1.86 mmol) in DCM (3 ml) was stirred at 35 C. for 2 days. The mixture was concentrated onto silica and the crude product was purified by chromatography on silica gel (12 g cartridge, 0-25% EtOAc/isohexane) to afford the title compound (129 mg, 0.272 mmol, 61.3% yield, 90% purity) as a pale brown oil. UPLC-MS (Method 1) m/z 428.2 (M+H).sup.+, 426.2 (MH).sup. at 1.80 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.62 (s, 1H), 8.30 (d, J=1.9 Hz, 1H), 8.12 (dd, J=8.0, 1.9 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.56 (dd, J=8.4, 2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 3.86 (s, 3H), 3.02 (q, J=7.4 Hz, 2H), 2.82-2.73 (m, 4H), 1.53-1.39 (m, 6H), 1.21 (t, J=7.4 Hz, 3H).

(275) Step 2: 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid: A mixture of the product from step 1 above (129 mg, 0.272 mmol) and LiOH (26.0 mg, 1.09 mmol) in THF/MeOH/water (4:1:1, 3.6 ml) was stirred at 40 C. overnight. The mixture was diluted with water (5 ml) and EtOAc (15 ml) and acidified to pH 4 with 1 M HCl(aq). The phases were separated and the aqueous extracted with EtOAc (215 ml). The organic extracts were combined, washed with brine (10 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The residue was triturated with hexane/TBME (2:1) to give the title compound (50.3 mg, 0.121 mmol, 44.4% yield, 99% purity) as a beige solid. UPLC-MS (Method 1) m/z 414.2 (M+H).sup.+, 412.0 (MH).sup. at 1.65 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6).Math. 13.30 (s, 1H), 9.58 (s, 1H), 8.30 (d, J=1.9 Hz, 1H), 8.10 (dd, J=8.0, 1.9 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.56 (dd, J=8.4, 2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 3.01 (q, J=7.4 Hz, 2H), 2.84-2.69 (m, 4H), 1.54-1.39 (m, 6H), 1.21 (t, J=7.4 Hz, 3H).

Example 216:3-(N-(5-chloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(276) ##STR00552##

(277) Step 1: methyl 3-(N-(5-chloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoate: A mixture of 5-chloro-2-(piperidin-1-yl)aniline (212 mg, 0.956 mmol), the product from Example 203 step 2 (300 mg, 1.14 mmol) and pyridine (0.34 ml, 4.20 mmol) in DCM (7 ml) was stirred at 35 C. overnight. The mixture was concentrated onto silica and purified by chromatography on silica gel (12 g cartridge, 0-20% EtOAc/isohexane) to afford the title compound (326 mg, 0.671 mmol, 70.2% yield, 90% purity) as a dark purple oil. UPLC-MS (Method 1) m/z 437.2 (M+H).sup.+, 435.2 (MH).sup. at 2.01 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.29 (s, 1H), 8.34 (d, J=1.9 Hz, 1H), 8.11 (dd, J=8.0, 1.9 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.19-7.10 (m, 3H), 3.86 (s, 3H), 3.06 (q, J=7.4 Hz, 2H), 2.54 (t, J=5.3 Hz, 4H), 1.59-1.48 (m, 4H), 1.47-1.37 (m, 2H), 1.22 (t, J=7.4 Hz, 3H).

(278) Step 2: 3-(N-(5-chloro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid: A mixture of the product from step 1 above (326 mg, 0.671 mmol) and 2 M LiOH (aq) (0.336 ml, 0.671 mmol) in THF/MeOH/water (4:1:1, 8.4 ml) was stirred at 40 C. overnight. The mixture was diluted with water (10 ml) and EtOAc (25 ml) and acidified to pH 4 with 1 M HCl. The phases were separated and the aqueous extracted with EtOAc (225 ml). The combined organic extracts were washed with brine (15 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (89.7 mg, 0.207 mmol, 30.8% yield, 98% purity) as a light grey solid. UPLC-MS (Method 1) m/z 423.3 (M+H).sup.+, 421.2 (MH).sup. at 1.86 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.33 (s, 1H), 9.23 (s, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.0, 1.8 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.19-7.09 (m, 3H), 3.05 (q, J=7.4 Hz, 2H), 2.55 (t, J=5.3 Hz, 4H), 1.60-1.50 (m, 4H), 1.48-1.38 (m, 2H), 1.21 (t, J=7.4 Hz, 3H).

Example 217:3-(N-(5-chloro-2-(4,4-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(279) ##STR00553##

(280) Step 1: 1-(4-chloro-2-nitrophenyl)-4,4-difluoropiperidine: Et.sub.3N (0.992 ml, 7.12 mmol) was added to a solution of 4-chloro-1-fluoro-2-nitrobenzene (500 mg, 2.85 mmol) and 4,4-difluoropiperidine (414 mg, 3.42 mmol) in DCM (6 ml) at RT. The clear solution was stirred at RT for 23 h. The organic phase was washed with 1 M HCl(aq) (3 ml), separated by passage through a phase separator and concentrated in vacuo to afford the title compound (803 mg, 2.76 mmol, 97% yield, 95% purity) as a brown oil. UPLC-MS (Method 1) m/z 277.2 (M+H).sup.+ at 1.67 min.

(281) Step 2: 5-chloro-2-(4,4-difluoropiperidin-1-yl)aniline: Iron powder (1.62 g, 28.9 mmol) was added to a suspension of the product from step 1 above (400 mg, 1.45 mmol) and ammonium chloride (93 mg, 1.74 mmol) in IPA (10 ml) and water (5 ml) at RT. The resultant suspension was heated and stirred at 90 C. for 2 h. The reaction was filtered through Celite, washed with MeOH (100 ml) and concentrated in vacuo. The residue was dissolved in DCM (25 ml) and washed with water (10 ml) and brine (10 ml), dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.152 g, 0.592 mmol, 40.9% yield, 96% purity) as a cream solid. UPLC-MS (Method 1) m/z 247.3 (M+H).sup.+ at 1.58 min.

(282) Step 3: methyl 3-(N-(5-chloro-2-(4,4-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoate: Pyridine (0.074 ml, 0.912 mmol) was added to a solution of the product from step 2 above (0.075 g, 0.304 mmol) and the product from Example 203 step 2 (0.100 g, 0.380 mmol) in DCM (10 ml) and the solution was stirred at RT for 18 h. The solution was concentrated in vacuo and the crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.096 g, 0.189 mmol, 62.1% yield, 93% purity) as a white solid. UPLC-MS (Method 1) m/z 473.0 (M+H).sup.+, 470.9 (MH).sup. at 1.89 min.

(283) Step 4: 3-(N-(5-chloro-2-(4,4-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid: 1 M LiOH (aq) (1.13 ml, 1.13 mmol) was added to a solution of the product from step 3 above (0.089 g, 0.189 mmol) in THF (4.5 ml) and MeOH (1.1 ml) and the solution was stirred at RT overnight. The solvent was removed in vacuo and the residue dissolved in water (5 ml) and washed with TBME (35 ml). The aqueous phase was acidified with conc. HCl and extracted with TBME (310 ml). The organic phases were combined and dried by passage through a phase separator and the solvent was removed in vacuo to give the title compound (0.073 g, 0.156 mmol, 82% yield, 98% purity) as an off white solid. UPLC-MS (Method 1) m/z 459.6 (M+H).sup.+, 456.9 (MH).sup. at 1.76 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.34 (s, 1H), 9.70 (s, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.0, 1.8 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.26-7.19 (m, 2H), 7.14 (dd, J=8.5, 2.5 Hz, 1H), 3.04 (q, J=7.4 Hz, 2H), 2.69 (t, J=5.6 Hz, 4H), 2.10-1.97 (m, 4H), 1.19 (t, J=7.4 Hz, 3H).

Example 218:3-(N-(5-chloro-2-(4,4-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(284) ##STR00554##

(285) Step 1: Methyl 3-(N-(5-chloro-2-(4,4-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (0.074 ml, 0.912 mmol) was added to a solution of the product from Example 217 step 2 (0.075 g, 0.304 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.101 g, 0.380 mmol) in DCM (10 ml) and the solution was stirred at RT for 18 h. The solution was concentrated in vacuo and the crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.113 g, 0.193 mmol, 63.4% yield, 81% purity) as a white solid. UPLC-MS (Method 1) m/z 475.4 (M+H).sup.+, 472.8 (MH).sup. at 1.75 min.

(286) Step 2: 3-(N-(5-chloro-2-(4,4-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1 M LiOH (aq) (1.16 ml, 1.16 mmol) was added to a solution of the product from step 1 above (0.092 g, 0.193 mmol) in THF (4.5 ml) and MeOH (1.1 ml) and the solution was stirred at RT overnight. The solvent was removed in vacuo and the residue dissolved in water (5 ml) and washed with TBME (35 ml). The aqueous phase was acidified with conc. HCl and extracted with TBME (310 ml). The organic phases were combined and dried by passage through a phase separator and the solvent was removed in vacuo to give the title compound (0.078 g, 0.166 mmol, 86% yield, 98% purity) as an off white solid. UPLC-MS (Method 1) m/z 461.0 (M+H).sup.+, 459.0 (MH).sup. at 1.59 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.19 (s, 1H), 9.13 (s, 1H), 8.37 (d, J=2.2 Hz, 1H), 8.17 (dd, J=8.7, 2.2 Hz, 1H), 7.33 (d, J=8.7 Hz, 1H), 7.29-7.23 (m, 2H), 7.07 (dd, J=8.5, 2.5 Hz, 1H), 3.90 (s, 3H), 2.78 (t, J=5.6 Hz, 4H), 2.18-2.06 (m, 4H).

Example 219:3-(N-(5-chloro-2-(3,3-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(287) ##STR00555##

(288) Step 1: 1-(4-chloro-2-nitrophenyl)-3,3-difluoropiperidine: Et.sub.3N (1.79 ml, 12.8 mmol) was added to a solution of 4-chloro-1-fluoro-2-nitrobenzene (0.335 ml, 2.85 mmol) and 3,3-difluoropiperidine hydrochloride (539 mg, 3.42 mmol) in DCM (6 ml) at RT. The mixture was stirred at RT for 23 h. The solvent was removed in vacuo and the residue was dissolved in THF (6 ml) and heated to 50 C. for 18 h. DMF (6 ml) was added and the mixture was heated to 90 C. for 18 h. The solvents were removed in vacuo and DCM (6 ml) and 1 M HCl(aq) (3 ml) were added. The organic phase was dried by passage through a phase separator and concentrated in vacuo to afford the title compound (0.490 g, 1.68 mmol, 59.1% yield, 95% purity) as a brown oil. UPLC-MS (Method 1) m/z 277.2 (M+H).sup.+ at 1.63 min.

(289) Step 2: 5-chloro-2-(3,3-difluoropiperidin-1-yl)aniline: Iron powder (1.62 g, 28.9 mmol) was added to a suspension of the product from step 1 above (0.490 g, 1.77 mmol) and ammonium chloride (0.093 g, 1.74 mmol) in IPA (10 ml) and water (5 ml) at RT. The resultant suspension was heated and stirred at 90 C. for 2 h. The reaction mixture was filtered through Celite, washed with MeOH (100 ml) and concentrated in vacuo. The residue was dissolved in DCM (25 ml) and washed sequentially with water (10 ml) and brine (10 ml), dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.252 g, 1.02 mmol, 70.6% yield, 100% purity) as a cream solid. UPLC-MS (Method 1) m/z 247.2 (M+H).sup.+ at 1.59 min.

(290) Step 3: methyl 3-(N-(5-chloro-2-(3,3-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoate: Pyridine (0.123 ml, 1.52 mmol) was added to a solution of the product from step 2 above (0.125 g, 0.507 mmol) and methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.168 g, 0.633 mmol) in DCM (10 ml) and the solution was stirred at RT for 18 h. The solution was concentrated in vacuo and the crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.241 g, 0.502 mmol, 99% yield, 99% purity) as a white solid. UPLC-MS (Method 1) m/z 475.3 (M+H).sup.+, 472.8 (MH).sup. at 1.73 min.

(291) Step 4: 3-(N-(5-chloro-2-(3,3-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: 1 M LiOH (aq) (3.04 ml, 3.04 mmol) was added to a solution of the product from step 3 above (0.241 g, 0.507 mmol) in THF (12 ml) and MeOH (3 ml) and the solution was stirred at RT overnight. The solvent was removed in vacuo and the residue dissolved in water (5 ml) and washed with TBME (35 ml). The aqueous phase was acidified with conc. HCl and extracted with TBME (310 ml). The organic phases were combined and dried by passage through a phase separator and the solvent was removed in vacuo to give the title compound (0.211 g, 0.458 mmol, 90% yield, 100% purity) as an off white solid. UPLC-MS (Method 1) m/z 461.3 (M+H).sup.+, 459.1 (MH).sup. at 1.57 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.25 (s, 1H), 8.46 (s, 1H), 8.40 (d, J=2.2 Hz, 1H), 8.19 (dd, J=8.7, 2.2 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 7.09 (dd, J=8.5, 2.4 Hz, 1H), 3.94 (s, 3H), 3.04 (t, J=11.1 Hz, 2H), 2.85-2.76 (m, 2H), 2.11-1.98 (m, 2H), 1.90-1.79 (m, 2H).

Example 220:3-(N-(5-chloro-2-(3,3-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(292) ##STR00556##

(293) Step 1: methyl 3-(N-(5-chloro-2-(3,3-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoate: Pyridine (0.123 ml, 1.52 mmol) was added to a solution of the product from Example 219 step 2 (0.125 g, 0.507 mmol) and the product from Example 203 step 2 (0.166 g, 0.633 mmol) in DCM (10 ml) and the solution was stirred at RT for 18 h. The solution was concentrated in vacuo and the crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.166 g, 0.351 mmol, 69.3% yield, 100% purity) as a white solid. UPLC-MS (Method 1) m/z 473.4 (M+H).sup.+, 471.2 (MH).sup. at 1.89 min.

(294) Step 2: 3-(N-(5-chloro-2-(3,3-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid: 1 M LiOH (aq) (2.11 ml, 2.11 mmol) was added to a solution of the product from step 1 above (0.166 g, 0.351 mmol) in THF (8.5 ml) and MeOH (2.1 ml) and the solution was stirred at RT overnight. The solvent was removed in vacuo and the residue dissolved in water (5 ml) and washed with TBME (35 ml). The aqueous phase was acidified with conc. HCl and extracted with TBME (310 ml). The organic phases were combined and dried by passage through a phase separator and the solvent was removed in vacuo to afford the title compound (0.143 g, 0.308 mmol, 88% yield, 99% purity) as an off white solid. UPLC-MS (Method 1) m/z 459.1 (M+H).sup.+, 457.0 (MH).sup. at 1.75 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.36 (s, 1H), 8.98 (s, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.11 (dd, J=8.0, 1.8 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.6 Hz, 1H), 7.15 (dd, J=8.6, 2.5 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 3.06-2.96 (m, 4H), 2.81-2.72 (m, 2H), 2.06-1.93 (m, 2H), 1.80-1.71 (m, 2H), 1.21 (t, J=7.4 Hz, 3H).

Example 221: 3-(N-(5-cyano-2-(4,4-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(295) ##STR00557##

(296) Step 1: 4-(4,4-difluoropiperidin-1-yl)-3-nitrobenzonitrile: A mixture of 4-fluoro-3-nitrobenzonitrile (500 mg, 3.01 mmol), 4,4-difluoropiperidine (400 mg, 3.30 mmol) and Et.sub.3N (0.65 ml, 4.66 mmol) in DMF (5 ml) was stirred at 90 C. overnight. The mixture was diluted with water (20 ml) and extracted with EtOAc (335 ml). The combined organic extracts were washed with brine (230 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (24 g cartridge, 0-10% EtOAc/isohexane) to afford the title compound (541 mg, 2.02 mmol, 67.3% yield, 100% purity) as a bright yellow solid. UPLC-MS (Method 2) m/z 1.39 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.37 (d, J=2.1 Hz, 1H), 7.94 (dd, J=8.7, 2.1 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 3.31-3.25 (m, 4H), 2.15-2.04 (m, 4H).

(297) Step 2: 3-amino-4-(4,4-difluoropiperidin-1-yl)benzonitrile: A mixture of the product from step 1 above (541 mg, 2.02 mmol), iron powder (2.5 g, 44.8 mmol), ammonium chloride (130 mg, 2.43 mmol), IPA (16 ml) and water (8 ml) was heated at 90 C. overnight. The mixture was filtered over Celite, rinsing with MeOH and the solvent was removed in vacuo. The residue was diluted with DCM (20 ml), dried by passage through a phase separator and concentrated onto silica. The crude product was purified by chromatography on silica gel (24 g cartridge, 100% DCM) to afford the title compound (260 mg, 1.10 mmol, 54.1% yield, 100% purity) as a light yellow solid. UPLC-MS (Method 2) m/z 238.2 (M+H).sup.+, 236.0 (MH).sup. at 1.34 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.04-6.90 (m, 3H), 5.29 (s, 2H), 2.94 (t, J=5.5 Hz, 4H), 2.24-2.08 (m, 4H).

(298) Step 3: methyl 3-(N-(5-cyano-2-(4,4-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoate: A mixture of the product from step 2 above (130 mg, 0.548 mmol), methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.160 g, 0.603 mmol), pyridine (140 l, 1.73 mmol) and DCM (3.5 ml) was stirred at RT overnight. The mixture was concentrated onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (148 mg, 0.312 mmol, 56.9% yield, 98% purity) as a white solid. UPLC-MS (Method 1) m/z 466.3 (M+H).sup.+, 464.1 (MH).sup. at 1.54 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.43 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 8.21 (dd, J=8.7, 2.3 Hz, 1H), 7.54 (dd, J=8.3, 1.9 Hz, 1H), 7.42-7.35 (m, 2H), 7.28 (d, J=8.3 Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 2.98 (t, J=5.6 Hz, 4H), 2.13-2.01 (m, 4H).

(299) Step 4: 3-(N-(5-cyano-2-(4,4-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: A mixture of the product from step 3 above (0.148 g, 0.312 mmol) and LiOH (30 mg, 1.253 mmol) in THF/MeOH/water (4:1:1, 3.6 ml) was stirred at 40 C. overnight. The mixture was diluted with water (5 ml) and acidified to pH 4 with 1 M HCl(aq). The mixture was extracted with EtOAc (320 ml) and the combined organic extracts were washed with brine (10 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (85.6 mg, 0.185 mmol, 59.3% yield, 97% purity) as a white solid after trituration with TBME. UPLC-MS (Method 1) m/z 452.2 (M+H).sup.+, 450.2 (MH).sup. at 1.40 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.17 (s, 1H), 9.40 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 8.18 (dd, J=8.8, 2.3 Hz, 1H), 7.53 (dd, J=8.3, 2.0 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 3.89 (s, 3H), 3.04-2.92 (m, 4H), 2.15-2.01 (m, 4H).

Example 222: 3-(N-(5-cyano-2-(4,4-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(300) ##STR00558##

(301) Step 1: methyl 3-(N-(5-cyano-2-(4,4-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoate: A mixture of the product from Example 221 step 2 (130 mg, 0.548 mmol), the product from Example 203 step 2 (0.244 g, 0.603 mmol), pyridine (140 l, 1.73 mmol) and DCM (3.5 ml) was stirred at RT overnight. The mixture was concentrated onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (102 mg, 0.211 mmol, 38.6% yield, 96% purity) as a white solid. UPLC-MS (Method 1) m/z 464.3 (M+H).sup.+, 462.1 (MH).sup. at 1.68 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.91 (s, 1H), 8.33 (d, J=1.9 Hz, 1H), 8.13 (dd, J=8.0, 1.9 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.59 (dd, J=8.4, 1.9 Hz, 1H), 7.33 (d, J=1.9 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 3.86 (s, 3H), 3.01 (q, J=7.4 Hz, 2H), 2.91 (t, J=5.6 Hz, 4H), 2.05-1.94 (m, 4H), 1.20 (t, J=7.4 Hz, 3H).

(302) Step 2: 3-(N-(5-cyano-2-(4,4-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid: A mixture of the product from step 3 above (0.102 g, 0.211 mmol) and LiOH (30 mg, 1.253 mmol) in THF/MeOH/water (4:1:1, 3.6 ml) was stirred at 40 C. overnight. The mixture was diluted with water (5 ml) and acidified to pH 4 with 1 M HCl. The mixture was extracted with EtOAc (320 ml) and the combined organic extracts were washed with brine (10 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (32.6 mg, 0.070 mmol, 33.2% yield, 97% purity) as a white solid after trituration with TBME. UPLC-MS (Method 1) m/z 450.2 (M+H).sup.+, 448.2 (MH).sup. at 1.56 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.33 (s, 1H), 9.88 (s, 1H), 8.33 (d, J=1.9 Hz, 1H), 8.11 (dd, J=8.1, 1.9 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.58 (dd, J=8.4, 2.0 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 3.01 (q, J=7.4 Hz, 2H), 2.94-2.88 (m, 4H), 2.06-1.97 (m, 4H), 1.20 (t, J=7.3 Hz, 3H).

Example 223:3-(N-(5-cyano-2-(3-hydroxypiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(303) ##STR00559##

(304) Step 1: 4-(3-hydroxypiperidin-1-yl)-3-nitrobenzonitrile: A mixture of 4-fluoro-3-nitrobenzonitrile (500 mg, 3.01 mmol), piperidin-3-ol (350 mg, 3.46 mmol) and Et.sub.3N (0.65 ml, 4.66 mmol) in DCM (10 ml) was stirred at RT overnight. The mixture was concentrated onto silica and purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (698 mg, 2.63 mmol, 87% yield, 93% purity) as a thick orange oil. UPLC-MS (Method 2) m/z 248.2 (M+H).sup.+, 246.4 (MH).sup. at 1.02 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6).Math. 8.28 (d, J=2.1 Hz, 1H), 7.83 (dd, J=8.9, 2.1 Hz, 1H), 7.35 (d, J=8.9 Hz, 1H), 4.92 (d, J=4.2 Hz, 1H), 3.67-3.57 (m, 1H), 3.29-3.21 (m, 2H), 3.01 (ddd, J=12.8, 9.6, 3.1 Hz, 1H), 2.81 (dd, J=12.8, 8.2 Hz, 1H), 1.91-1.84 (m, 1H), 1.82-1.73 (m, 1H), 1.54-1.44 (m, 1H), 1.43-1.33 (m, 1H).

(305) Step 2: 3-amino-4-(3-hydroxypiperidin-1-yl)benzonitrile: A mixture of the product from step 1 above (698 mg, 2.65 mmol), iron powder (3 g, 53.7 mmol), ammonium chloride (170 mg, 3.18 mmol), IPA (20 ml) and water (10 ml) was heated to 90 C. overnight. The mixture was filtered over Celite, rinsing with MeOH and the filtrate was concentrated in vacuo. The residue was diluted with DCM (20 ml), dried by passage through a phase separator and concentrated onto silica. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-5% MeOH/DCM) to afford the title compound (381 mg, 1.72 mmol, 64.8% yield, 98% purity) as a light orange solid. UPLC-MS (Method 2) m/z 218.2 (M+H).sup.+, 216.2 (MH).sup. at 0.94 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 6.98-6.90 (m, 3H), 5.15 (s, 2H), 4.80 (d, J=5.4 Hz, 1H), 3.75-3.66 (m, 1H), 3.06-2.97 (m, 1H), 2.96-2.87 (m, 1H), 2.56 (t, J=10.3 Hz, 1H), 2.49-2.42 (m, 1H), 1.89-1.74 (m, 2H), 1.67-1.54 (m, 1H), 1.41-1.27 (m, 1H).

(306) Step 3: methyl 3-(N-(5-cyano-2-(3-hydroxypiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoate: A mixture of the product from step 2 above (100 mg, 0.451 mmol), methyl 3-(chlorosulfonyl)-4-methoxybenzoate (131 mg, 0.496 mmol), pyridine (110 l, 1.36 mmol) and DCM (3 ml) was stirred at RT overnight. The mixture was concentrated onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (111 mg, 0.219 mmol, 48.6% yield, 88% purity) as a white solid. UPLC-MS (Method 1) m/z 446.3 (M+H).sup.+, 444.1 (MH).sup. at 1.31 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.28 (s, 1H), 8.36 (d, J=2.3 Hz, 1H), 8.23-8.17 (m, 1H), 7.49-7.43 (m, 1H), 7.43-7.39 (m, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 5.09 (d, J=5.2 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.75-3.67 (m, 1H), 2.96-2.86 (m, 2H), 2.78-2.70 (m, 1H), 2.70-2.61 (m, 1H), 1.90-1.80 (m, 1H), 1.76-1.66 (m, 1H), 1.57-1.40 (m, 2H).

(307) Step 4: 3-(N-(5-cyano-2-(3-hydroxypiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: A mixture of the product from step 3 above (111 mg, 0.219 mmol) and LiOH (21.0 mg, 0.877 mmol) in THF/MeOH/water (4:1:1, 3 ml) was stirred at 40 C. overnight. The mixture was diluted with water (5 ml), acidified to pH 4 with 1 M HCl(aq) and extracted with EtOAc (320 ml). The combined organic extracts were washed with brine (10 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (4 g cartridge, 0-5% MeOH/DCM) to afford the title compound (69.3 mg, 0.157 mmol, 71.8% yield, 98% purity) as a white solid. UPLC-MS (Method 1) m/z 432.2 (M+H).sup.+, 430.2 (MH).sup. at 1.14 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6).Math. 13.19 (s, 1H), 9.24 (s, 1H), 8.36 (d, J=2.3 Hz, 1H), 8.16 (dd, J=8.7, 2.3 Hz, 1H), 7.45 (dd, J=8.3, 2.0 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 5.10 (br s, 1H), 3.89 (s, 3H), 3.72 (br s, 1H), 2.96-2.84 (m, 2H), 2.78-2.71 (m, 1H), 2.67 (dd, J=11.6, 6.3 Hz, 1H), 1.91-1.80 (m, 1H), 1.75-1.67 (m, 1H), 1.56-1.44 (m, 2H).

Example 224: 3-(N-(5-cyano-2-(3-hydroxypiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(308) ##STR00560##

(309) Step 1: methyl 3-(N-(5-cyano-2-(3-hydroxypiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoate: A mixture of the product from Example 223 step 2 (100 mg, 0.451 mmol), the product from Example 203 step 2 (201 mg, 0.496 mmol), pyridine (110 l, 1.36 mmol) and DCM (3 ml) was stirred at RT overnight. The mixture was concentrated onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (108 mg, 0.219 mmol, 48.6% yield, 90% purity) as a white solid. UPLC-MS (Method 1) m/z 444.2 (M+H).sup.+, 442.1 (MH).sup. at 1.49 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.79 (s, 1H), 8.35 (d, J=1.9 Hz, 1H), 8.15-8.09 (m, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.32 (d, J=1.9 Hz, 1H), 7.15 (d, J=8.2 Hz, 1H), 5.15 (d, J=5.5 Hz, 1H), 3.87 (s, 3H), 3.71-3.66 (m, 1H), 3.11-3.00 (m, 2H), 2.98-2.93 (m, 1H), 2.93-2.87 (m, 1H), 2.67-2.59 (m, 2H), 1.84-1.74 (m, 1H), 1.71-1.62 (m, 1H), 1.52-1.40 (m, 2H), 1.20 (t, J=7.4 Hz, 3H).

(310) Step 2: 3-(N-(5-cyano-2-(3-hydroxypiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid: A mixture of the product from step 2 above (108 mg, 0.219 mmol) and LiOH (21.0 mg, 0.877 mmol) in THF/MeOH/water (4:1:1, 3 ml) was stirred at 40 C. overnight. The mixture was diluted with water (5 ml), acidified to pH 4 with 1 M HCl(aq) and extracted with EtOAc (320 ml). The combined organic extracts were washed with brine (10 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (4 g cartridge, 0-5% MeOH/DCM) to afford the title compound (75 mg, 0.169 mmol, 77% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m/z 430.3 (M+H).sup.+, 428.2 (MH).sup. at 1.33 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.33 (s, 1H), 9.76 (s, 1H), 8.35 (d, J=1.9 Hz, 1H), 8.10 (dd, J=8.0, 1.9 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.48 (dd, J=8.4, 2.0 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 5.16 (br s, 1H), 3.70 (br s, 1H), 3.13-2.98 (m, 2H), 2.98-2.93 (m, 1H), 2.93-2.85 (m, 1H), 2.70-2.61 (m, 2H), 1.85-1.75 (m, 1H), 1.72-1.62 (m, 1H), 1.52-1.41 (m, 2H), 1.20 (t, J=7.4 Hz, 3H).

Example 225:4-(methylsulfonyl)-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(311) ##STR00561##

(312) Step 1: methyl 4-fluoro-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: Pyridine (0.199 ml, 2.46 mmol) was added to a solution of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (200 mg, 0.819 mmol) and methyl 3-(chlorosulfonyl)-4-fluorobenzoate (259 mg, 1.02 mmol) in DCM (10 ml) and the solution was stirred at RT for 18 h. The solution was concentrated in vacuo and the crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.183 g, 0.389 mmol, 47.6% yield, 98% purity) as a white solid. UPLC-MS (Method 1) m/z 461.3 (M+H).sup.+, 459.2 (MH).sup. at 1.91 min.

(313) Step 2: methyl 4-(methylthio)-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: Sodium thiomethoxide (0.084 g, 1.19 mmol) was added to a solution of the product from step 1 above (0.183 g, 0.397 mmol) in DMF (4 ml) and stirred at RT for 18 h. The mixture was partitioned between DCM (10 ml) and water (10 ml) and the organic phase was separated. The aqueous phase was extracted with DCM (210 ml) and the combined organic phases were dried by passage through a phase separator. The solvent was removed in vacuo to give the title compound (0.095 g, 0.193 mmol, 48.4% yield, 99% purity) as an off white solid. UPLC-MS (Method 1) m/z 489.3 (M+H).sup.+, 486.8 (MH).sup. at 1.95 min.

(314) Step 3: methyl 4-(methylsulfonyl)-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate and methyl 4-(methylsulfinyl)-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: 3-Chloroperoxybenzoic acid (0.044 g, 0.194 mmol, 77% w/w) was added to the product from step 2 above (0.095 g, 0.194 mmol) in DCM (4 ml) and stirred at RT for 72 h. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford methyl 4-(methylsulfonyl)-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate (0.060 g, 0.112 mmol, 57.5% yield, 97% purity) as an off white solid. UPLC-MS (Method 1) m/z 521.3 (M+H).sup.+, 518.9 (MH).sup. at 1.28 min. Methyl 4-(methylsulfinyl)-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate (0.032 g, 0.058 mmol, 30.0% yield, 92% purity) was also isolated as an off white solid. UPLC-MS (Method 1) m/z 505.3 (M+H).sup.+, 503.1 (MH).sup. at 1.69 min.

(315) Step 4: 4-(methylsulfonyl)-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH (aq) (0.692 ml, 0.692 mmol) was added to a solution of methyl 4-(methylsulfonyl)-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate from step 3 above (0.06 g, 0.115 mmol) in THF (3 ml) and MeOH (0.7 ml) and the solution was stirred at RT overnight. The solvent was removed in vacuo and the residue dissolved in water (5 ml) and washed with TBME (35 ml). The aqueous phase was acidified with conc. HCl and extracted with TBME (310 ml). The organic phases were combined and dried by passage through a phase separator and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-10% MeOH/DCM) to afford the title compound (0.049 g, 0.096 mmol, 83% yield, 99% purity) as an off white solid. UPLC-MS (Method 1) m/z 507.3 (M+H).sup.+, 504.8 (MH).sup. at 1.13 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 15.98 (s, 1H), 13.59 (s, 1H), 8.43 (d, J=1.7 Hz, 1H), 8.30 (dd, J=8.1, 1.7 Hz, 1H), 8.24 (d, J=8.1 Hz, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.23 (dd, J=8.9, 2.1 Hz, 1H), 4.37-4.25 (m, 2H), 3.92 (d, J=11.8 Hz, 1H), 3.72 (d, J=11.8 Hz, 1H), 2.85 (s, 3H), 2.28-2.15 (m, 2H), 1.87-1.72 (m, 3H), 1.59-1.44 (m, 1H).

Example 227: 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-(2,2,2-trifluoroethoxy)benzoic acid

(316) ##STR00562##

(317) Step 1: 3-(chlorosulfonyl)-4-(2,2,2-trifluoroethoxy)benzoic acid: 4-(2,2,2-trifluoroethoxy)benzoic acid (1 g, 4.54 mmol) in chlorosulfonic acid (5 ml, 74.7 mmol) was heated at 80 C. for 2 h. The mixture was cooled and carefully added to stirred ice-water (100 ml). The solid precipitated out was collected under filtration, washed with water (100 ml) and dried in vacuo to give the title compound (1.20 g, 3.58 mmol, 79% yield, 95% purity) as a cream solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.34 (d, J=2.3 Hz, 1H), 7.89 (dd, J=8.5, 2.4 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 4.82 (q, J=8.9 Hz, 2H). One exchangeable proton not observed.

(318) Step 2: 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-(2,2,2-trifluoroethoxy)benzoic acid (2393-12): A solution of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (0.100 g, 0.409 mmol) in DCM (5 ml) and pyridine (0.199 ml, 2.46 mmol) were added to a solution of the product from step 1 above (0.130 g, 0.409 mmol) in DCM (10 ml) and the solution was stirred at RT for 24 h. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (42.8 mg, 0.077 mmol, 18.9% yield, 95% purity) as a cream waxy solid. UPLC-MS (Method 1) m/z 527.4 (M+H).sup.+, 525.1 (MH).sup. at 1.82 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.36 (br s, 1H), 8.50 (br s, 1H), 8.44 (d, J=2.2 Hz, 1H), 8.22 (dd, J=8.7, 2.2 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.40-7.35 (m, 2H), 7.31 (d, J=8.6 Hz, 1H), 5.02 (q, J=8.6 Hz, 2H), 2.77 (t, J=5.2 Hz, 4H), 1.61 (p, J=5.7 Hz, 4H), 1.52 (p, J=6.2 Hz, 2H).

Example 228: 4-(2-hydroxypropan-2-yl)-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

(319) ##STR00563##

(320) Step 1: methyl 4-bromo-2-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: A solution of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (0.200 g, 0.819 mmol) in DCM (1 ml) and pyridine (0.397 ml, 4.91 mmol) were added to a solution of methyl 4-bromo-2-(chlorosulfonyl)benzoate (0.257 g, 0.819 mmol) in DCM (10 ml) and the solution was stirred at RT for 24 h. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (0.33 g, 0.601 mmol, 73.4% yield, 95% purity) as a cream waxy solid. UPLC-MS (Method 1) m/z 521.2 (M+H).sup.+, 518.7 (MH).sup. at 2.07 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.43 (s, 1H), 8.06 (d, J=2.0 Hz, 1H), 8.01 (dd, J=8.2, 2.0 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.50-7.45 (m, 1H), 7.33 (d, J=8.4 Hz, 1H), 3.81 (s, 3H), 2.69 (t, J=5.2 Hz, 4H), 1.56 (p, J=5.5 Hz, 4H), 1.51-1.42 (m, 2H).

(321) Step 2: 5-bromo-2-(2-hydroxypropan-2-yl)-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)benzenesulfonamide: A solution of the product from step 1 above (0.150 g, 0.288 mmol) in dry THF (10 ml) was treated with 3.0 M methylmagnesium bromide in Et.sub.2O (0.384 ml, 1.15 mmol) and the solution was stirred at RT for 16 h. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (91 mg, 0.150 mmol, 52.2% yield, 87% purity) as a colourless waxy solid. UPLC-MS (Method 1) m/z 521.2 (M+H).sup.+, 519.1 (MH).sup. at 2.11 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.76 (br s, 1H), 8.15 (d, J=2.2 Hz, 1H), 7.79 (dd, J=8.5, 2.2 Hz, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.38-7.23 (m, 2H), 6.15 (s, 1H), 2.71 (t, J=5.3 Hz, 4H), 1.67 (p, J=5.3 Hz, 4H), 1.58 (s, 6H), 1.54-1.49 (m, 2H).

(322) Step 3: methyl 4-(2-hydroxypropan-2-yl)-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: A solution of the product from step 2 above (0.091 g, 0.175 mmol), Et.sub.3N (0.049 ml, 0.349 mmol) and PdCl2 (dppf).Math.DCM (0.029 g, 0.035 mmol) in MeOH (10 ml) was stirred under a CO atmosphere (4 bar) overnight at 100 C. After 24 h, the reaction was cooled, filtered through Celite and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (0.090 g, 0.171 mmol, 98% yield, 95% purity) as a blue oil. UPLC-MS (Method 1) m/z 501.4 (M+H).sup.+, 499.3 (MH).sup. at 1.97 min.

(323) Step 4: 4-(2-hydroxypropan-2-yl)-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH (aq) (0.013 g, 0.539 mmol) was added to a solution of the product from step 3 above (0.090 g, 0.180 mmol) in THF (5 ml) and the solution was stirred at RT overnight. The reaction mixture was concentrated in vacuo and the resultant aqueous phase was adjusted to pH 6 with 1M HCl. The precipitate was filtered and washed with water (10 ml) and isohexane (20 ml) to give the title compound (54.3 mg, 0.106 mmol, 59.0% yield, 95% purity) as a light grey solid. UPLC-MS (Method 1) m/z 487.3 (M+H).sup.+, 485.3 (MH).sup. at 1.82 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.38 (br s, 1H), 9.74 (br s, 1H), 8.66 (d, J=1.9 Hz, 1H), 8.06 (dd, J=8.3, 1.9 Hz, 1H), 7.78 (s, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.33-7.28 (m, 2H), 6.20 (br s, 1H), 2.70 (t, J=5.3 Hz, 4H), 1.67 (p, J=5.2 Hz, 4H), 1.62 (s, 6H), 1.55-1.48 (m, 2H).

Example 229:4-(hydroxymethyl)-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(324) ##STR00564##

(325) Step 1: 5-bromo-2-(hydroxymethyl)-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)benzenesulfonamide: A solution of the product from Example 228 step 1 (0.285 g, 0.547 mmol) in THF (5 ml) was cooled to 0 C., then treated with 2.0 M LiBH.sub.4 in THF (0.273 ml, 0.547 mmol). The mixture was stirred at RT for 16 h and then the mixture was diluted with water (100 ml), extracted with EtOAc (100 ml), dried (MgSO.sub.4) and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (0.212 g, 0.408 mmol, 74.7% yield, 95% purity) as a colourless solid. UPLC-MS (Method 1) m/z 493.2 (M+H).sup.+, 491.1 (MH).sup. at 1.86 min. 1H NMR (500 MHz, DMSO-d.sub.6) 9.53 (br s, 1H), 7.87 (dd, J=8.3, 2.1 Hz, 1H), 7.83 (d, J=2.1 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.45 (dd, J=8.5, 2.2 Hz, 1H), 7.38 (d, J=2.2 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 5.67 (br s, 1H), 4.82 (s, 2H), 2.71 (t, J=5.3 Hz, 4H), 1.58-1.54 (m, 4H), 1.48-1.45 (m, 2H).

(326) Step 2: methyl 4-(hydroxymethyl)-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: A solution of the product from step 1 above (0.210 g, 0.426 mmol), Et.sub.3N (0.119 ml, 0.851 mmol) and PdCl.sub.2 (dppf).Math. DCM (0.070 g, 0.085 mmol) in MeOH (10 ml) was stirred under a CO atmosphere (4 bar) overnight at 100 C. After 24 h, the reaction was cooled, filtered through Celite and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (0.180 g, 0.376 mmol, 88% yield, 99% purity) as a cream waxy solid. UPLC-MS (Method 1) m/z 473.3 (M+H).sup.+, 471.3 (MH).sup. at 1.73 min.

(327) Step 3: 4-(hydroxymethyl)-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH (aq) (0.027 g, 1.14 mmol) was added to a solution of the product from step 2 above (0.180 g, 0.381 mmol) in THF (5 ml) and the solution was stirred at RT overnight. The reaction mixture was concentrated in vacuo and the resultant aqueous phase was extracted with EtOAc (50 ml). The aqueous phase was then adjusted to pH 6 with 1 M HCl(aq) to form a precipitate which was filtered and washed with water (10 ml) and isohexane (20 ml) to afford the title compound (134 mg, 0.277 mmol, 72.8% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 459.3 (M+H).sup.+, 457.3 (MH).sup. at 1.58 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.33 (br s, 1H), 9.49 (br s, 1H), 8.30 (d, J=1.8 Hz, 1H), 8.17 (dd, J=8.0, 1.8 Hz, 1H), 7.90 (d, J=8.1 Hz, 1H), 7.42 (dd, J=8.4, 2.2 Hz, 1H), 7.37 (d, J=2.2 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 5.74-5.30 (m, 1H), 4.94 (s, 2H), 2.69 (t, J=5.2 Hz, 4H), 1.55 (p, J=5.4 Hz, 4H), 1.46 (p, J=6.0 Hz, 2H).

Example 230:4-ethyl-3-(N-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

(328) ##STR00565##

(329) Step 1: 1-(2-nitro-5-(trifluoromethyl)phenyl)piperidine: 2-fluoro-1-nitro-4-(trifluoromethyl)benzene (1.1 g, 5.26 mmol) was dissolved in DMSO (10 ml) and treated with K.sub.2CO.sub.3 (0.872 g, 6.31 mmol) followed by piperidine (0.779 ml, 7.89 mmol) and the mixture was heated at 100 C. for 2 h. The reaction mixture was added to ice water (100 ml) and extracted with EtOAc (100 ml). The organic phase was washed with water (100 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (1.32 g, 4.81 mmol, 91% yield, 95% purity) as a red oil. UPLC-MS (Method 1) m/z 275.2 (M+H).sup.+ at 1.82 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.97 (d, J=8.4 Hz, 1H), 7.53 (d, J=1.8 Hz, 1H), 7.36 (dd, J=8.5, 1.8 Hz, 1H), 3.05-3.03 (m, 4H), 1.62-1.52 (m, 6H).

(330) Step 2: 2-(piperidin-1-yl)-4-(trifluoromethyl)aniline: The product from step 1 above (1.32 g, 4.81 mmol) was added to a suspension of 10% Pd/C (0.051 g, 0.481 mmol) in EtOH (40 ml, 685 mmol) and the mixture was stirred at RT under H.sub.2 (3 bar pressure) for 2 h. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to afford the title compound (1.15 g, 4.61 mmol, 96% yield, 99% purity) as a light brown oil. UPLC-MS (Method 1) m/z 245.3 (M+H).sup.+ at 1.69 min.

(331) Step 3: methyl 4-ethyl-3-(N-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)sulfamoyl)benzoate: A solution of the product from step 2 above (0.100 g, 0.409 mmol) in DCM (1 ml) and pyridine (0.199 ml, 2.46 mmol) were added to a solution of the product from Example 203 step 2 (0.108 g, 0.409 mmol) in DCM (10 ml) and the resultant mixture stirred at RT for 24 h. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (86 mg, 0.174 mmol, 42.4% yield, 96% purity) as a pale yellow oil, which cystallised upon standing. UPLC-MS (Method 2) m/z 471.4 (M+H).sup.+, 469.2 (MH).sup. at 2.02 min.

(332) Step 4: 4-ethyl-3-(N-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH (aq) (0.555 ml, 0.555 mmol) was added to a solution of the product from step 3 above (0.087 g, 0.185 mmol) in THF (5 ml, 61.0 mmol) and the solution was stirred at RT overnight. The reaction mixture was concentrated in vacuo and the resultant aqueous solution acidified to pH 6 using 1 M HCl(aq). The precipitate was filtered and washed with water (10 ml) and isohexane (20 ml) to afford the title compound (17.1 mg, 0.036 mmol, 19.3% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 457.4 (M+H).sup.+, 455.2 (MH).sup. at 1.91 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.34 (br s, 1H), 9.38 (br s, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.10 (dd, J=8.0, 1.8 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H), 3.07 (q, J=7.4 Hz, 2H), 2.70 (t, J=5.2 Hz, 4H), 1.62 (p, J=5.7 Hz, 4H), 1.49 (p, J=5.6 Hz, 2H), 1.23 (t, J=7.4 Hz, 3H).

Example 231: 4-methoxy-3-(N-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(333) ##STR00566##

(334) Step 1: methyl 4-methoxy-3-(N-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)sulfamoyl)benzoate: A solution of the product from Example 230 step 2 above (0.100 g, 0.409 mmol) in DCM (1 ml) and pyridine (0.199 ml, 2.46 mmol) was added to a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (0.108 g, 0.409 mmol) in DCM (10 ml) and the resultant solution was stirred at RT for 24 h. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.150 g, 0.317 mmol, 78% yield, 100% purity) as a pale yellow slowly cystallising oil. UPLC-MS (Method 2) m/z 473.4 (M+H).sup.+, 471.2 (MH).sup. at 1.85 min.

(335) Step 2: 4-methoxy-3-(N-(2-(piperidin-1-yl)-4-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH (aq) (0.952 ml, 0.952 mmol) was added to a solution of the product from step 1 above (0.150 g, 0.317 mmol) in THF (5 ml) and the resultant solution was stirred at RT overnight. The reaction mixture was concentrated in vacuo and the resultant aqueous solution acidified to pH 6 using 1 M HCl(aq). The precipitate was filtered and washed with water (10 ml) and isohexane (20 ml) to afford the title compound (41.4 mg, 0.086 mmol, 27.0% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 459.4 (M+H).sup.+, 457.0 (MH).sup. at 1.73 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.20 (br s, 1H), 8.81 (br s, 1H), 8.43 (d, J=2.2 Hz, 1H), 8.17 (dd, J=8.7, 2.2 Hz, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.47-7.39 (m, 2H), 7.33 (d, J=8.8 Hz, 1H), 3.97 (s, 3H), 2.75 (t, J=5.3 Hz, 4H), 1.71 (p, J=5.2 Hz, 4H), 1.57 (p, J=5.4 Hz, 2H).

Example 232:4-(methylthio)-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(336) ##STR00567##

(337) The aqueous phase from the reaction in Example 225 step 2 was acidified with conc. HCl and extracted with DCM (315 ml). The organic phases were combined and extracted with 0.5 M NaOH solution (320 ml). The aqueous extracts were combined, acidified with conc. HCl and extracted with TBME (330 ml). All of the organic phases were then combined, dried by passage through a phase separator and the solvent was removed in vacuo to afford the title compound (0.075 g, 0.156 mmol, 39.4% yield, 99% purity) as an off-white solid. UPLC-MS (Method 1) m/z 475.3 (M+H).sup.+, 472.9 (MH).sup. at 1.79 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.31 (s, 1H), 9.26 (s, 1H), 8.39 (d, J=1.9 Hz, 1H), 8.04 (dd, J=8.3, 1.9 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.39-7.32 (m, 2H), 2.72 (t, J=5.2 Hz, 4H), 2.57 (s, 3H), 1.64 (p, J=5.5 Hz, 4H), 1.54-1.51 (m, 2H).

Example 233:3-(N-(5-cyano-2-(3,3-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(338) ##STR00568##

(339) Step 1: 4-(3,3-difluoropiperidin-1-yl)-3-nitrobenzonitrile: A mixture of 4-fluoro-3-nitrobenzonitrile (500 mg, 3.01 mmol), 3,3-difluoropiperidine hydrochloride (569 mg, 3.61 mmol) and Et.sub.3N (1.6 ml, 11.5 mmol) in DMF (5 ml) was stirred at 90 C. over the weekend. The mixture was diluted with water (20 ml) and extracted with EtOAc (335 ml). The organic extracts were combined, washed with brine (230 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (24 g cartridge, 0-100% DCM/isohexane) to afford the title compound (635 mg, 2.35 mmol, 78% yield, 99% purity) as a bright yellow solid. UPLC-MS (Method 2) m/z no ionisation at 1.34 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.36 (d, J=2.1 Hz, 1H), 7.93 (dd, J=8.8, 2.1 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 3.55 (t, J=11.7 Hz, 2H), 3.18 (t, J=5.4 Hz, 2H), 2.15-2.03 (m, 2H), 1.81-1.72 (m, 2H).

(340) Step 2: 3-amino-4-(3,3-difluoropiperidin-1-yl)benzonitrile: A mixture of the product from step 1 above (635 mg, 2.35 mmol), iron powder (2.6 g, 46.6 mmol), ammonium chloride (151 mg, 2.82 mmol), IPA (18 ml) and water (9 ml) was stirred at 90 C. overnight. The mixture was filtered through Celite, rinsing with MeOH and the filtrate was concentrated in vacuo. The residue was diluted with DCM (20 ml), dried by passage through a phase separator and concentrated onto silica. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% DCM/isohexane) to afford the title compound (334 mg, 1.41 mmol, 60% yield) as a light orange solid. UPLC-MS (Method 2) m/z no ionisation at 1.34 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.05-6.96 (m, 3H), 5.13-5.01 (m, 2H), 3.14 (t, J=11.3 Hz, 2H), 2.88 (t, J=5.4 Hz, 2H), 2.09-1.97 (m, 2H), 1.88-1.81 (m, 2H).

(341) Step 3: methyl 3-(N-(5-cyano-2-(3,3-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoate: A mixture of the product from step 2 above (80 mg, 0.337 mmol), methyl 3-(chlorosulfonyl)-4-methoxybenzoate (100 mg, 0.378 mmol), pyridine (0.1 ml, 1.24 mmol) and DCM (2.2 ml) was stirred at RT for 4 h and then at 35 C. for 5 days. The mixture was concentrated onto silica and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (105 mg, 0.219 mmol, 64.9% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m/z 466.2 (M+H).sup.+, 464.1 (MH).sup. at 1.53 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.85 (s, 1H), 8.32 (d, J=2.2 Hz, 1H), 8.21 (dd, J=8.8, 2.2 Hz, 1H), 7.56-7.51 (m, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.34-7.28 (m, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.26 (t, J=11.2 Hz, 2H), 3.04-3.01 (m, 2H), 2.09-1.99 (m, 2H), 1.84-1.77 (m, 2H).

(342) Step 4: 3-(N-(5-cyano-2-(3,3-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: A mixture of the product from step 3 above (105 mg, 0.219 mmol) and LiOH (21.0 mg, 0.875 mmol) in THF/water/MeOH (4:1:1, 2.7 ml) was stirred at 40 C. overnight. The mixture was diluted with water (5 ml) and acidified to pH 4 using 1 M HCl(aq). The mixture was extracted with EtOAc (320 ml) and the combined organic extracts were washed with brine (10 ml) dried by passage through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (36.1 mg, 0.078 mmol, 36% yield, 98% purity) as a white solid after trituration with TBME. UPLC-MS (Method 1) m/z 452.2 (M+H).sup.+, 450.1 (MH).sup. at 1.37 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.19 (s, 1H), 8.79 (s, 1H), 8.32 (d, J=2.2 Hz, 1H), 8.18 (dd, J=8.7, 2.2 Hz, 1H), 7.52 (dd, J=8.3, 2.0 Hz, 1H), 7.38-7.28 (m, 3H), 3.92 (s, 3H), 3.25 (t, J=11.3 Hz, 2H), 3.02 (t, J=5.5 Hz, 2H), 2.11-2.00 (m, 2H), 1.86-1.77 (m, 2H).

Example 234: 3-(N-(5-cyano-2-(3,3-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(343) ##STR00569##

(344) Step 1: methyl 3-(N-(5-cyano-2-(3,3-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoate: A mixture of the product from Example 233 step 2 (80 mg, 0.337 mmol), the product from Example 203 step 2 (99 mg, 0.378 mmol), pyridine (0.1 ml, 1.24 mmol) and DCM (2.2 ml) was stirred at RT for 4 h and then at 35 C. for 5 days. The mixture was concentrated onto silica and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (59 mg, 0.120 mmol, 36% yield, 94% purity) as a light brown solid. UPLC-MS (Method 1) m/z 464.2 (M+H).sup.+, 462.2 (MH).sup. at 1.68 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.59 (s, 1H), 8.29 (d, J=1.9 Hz, 1H), 8.14 (dd, J=8.0, 1.9 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.59 (dd, J=8.5, 2.1 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.13 (d, J=2.1 Hz, 1H), 3.86 (s, 3H), 3.28-3.24 (m, 2H), 3.05-2.95 (m, 4H), 2.04-1.95 (m, 2H), 1.77-1.69 (m, 2H), 1.20 (t, J=7.4 Hz, 3H).

(345) Step 2: 3-(N-(5-cyano-2-(3,3-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid: A mixture of the product from step 1 above (59 mg, 0.120 mmol) and LiOH (21.0 mg, 0.875 mmol) in THF/water/MeOH (4:1:1, 2.7 ml) was stirred at 40 C. overnight. The mixture was diluted with water (5 ml) and acidified to pH 4 using 1 M HCl(aq). The mixture was extracted with EtOAc (320 ml) and the combined organic extracts were washed with brine (10 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (12.4 mg, 0.028 mmol, 22% yield) as a white solid after trituration with TBME. UPLC-MS (Method 1) m/z 450.2 (M+H).sup.+, 448.1 (MH).sup. at 1.53 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.31 (s, 1H), 9.53 (s, 1H), 8.30 (s, 1H), 8.11 (d, J=8.6 Hz, 1H), 7.65-7.54 (m, 2H), 7.29-7.19 (m, 1H), 7.13 (s, 1H), 3.29-3.23 (m, 2H), 3.05-2.96 (m, 4H), 2.05-1.95 (m, 2H), 1.78-1.72 (m, 2H), 1.20 (t, J=7.4 Hz, 3H).

Example 235: I-4-methoxy-3-(N-(2-(2-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(346) ##STR00570##

(347) Step 1: I-2-methyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: A mixture of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (220 l, 1.57 mmol), I-2-methylpiperidine (220 l, 1.87 mmol) and Et.sub.3N (0.6 ml, 4.30 mmol) in DCM (8 ml) was stirred at RT for 2 h and then at 35 C. overnight. The mixture was washed with 1 M HCl(aq) (10 ml), dried by passage through a phase separator and concentrated onto silica. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% DCM/isohexane) to afford the title compound (439 mg, 1.48 mmol, 94% yield, 97% purity) as an orange oil. UPLC-MS (Method 1) m/z 289.2 (M+H).sup.+ at 1.87 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.14 (d, J=2.3 Hz, 1H), 7.85 (dd, J=8.8, 2.3 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 3.58-3.51 (m, 1H), 3.16 (ddd, J=12.5, 8.5, 4.0 Hz, 1H), 2.81 (dt, J=12.5, 4.6 Hz, 1H), 1.80-1.63 (m, 2H), 1.62-1.47 (m, 3H), 1.45-1.37 (m, 1H), 0.99 (d, J=6.5 Hz, 3H).

(348) Step 2: I-2-(2-methylpiperidin-1-yl)-5-(trifluoromethyl)aniline: A solution of the product from step 1 above (438 mg, 1.47 mmol) in EtOH (35 ml) was hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm cartridge, full hydrogen mode, RT, 1 ml/min flow rate, 1 pass). The resultant solution was concentrated in vacuo to give the title compound (361 mg, 1.34 mmol, 91% yield, 96% purity) as pale yellow oil. UPLC-MS (Method 2) m/z 259.2 (M+H).sup.+ at 1.88 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.09 (d, J=8.1 Hz, 1H), 6.95 (d, J=2.2 Hz, 1H), 6.81 (dd, J=8.1, 2.2 Hz, 1H), 5.24 (s, 2H), 3.09-2.96 (m, 1H), 2.91-2.84 (m, 1H), 2.44-2.35 (m, 1H), 1.81-1.69 (m, 2H), 1.66-1.57 (m, 2H), 1.49-1.28 (m, 2H), 0.78 (d, J=6.1 Hz, 3H).

(349) Step 3: I-methyl 4-methoxy-3-(N-(2-(2-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: A mixture of the product from step 3 above (100 mg, 0.372 mmol), methyl 3-(chlorosulfonyl)-4-methoxybenzoate (113 mg, 0.427 mmol) and pyridine (0.1 ml, 1.24 mmol) in DCM (2.5 ml) was stirred at 35 C. over the weekend. The mixture was concentrated onto silica and purified by chromatography on silica gel (4 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (181 mg, 0.337 mmol, 91% yield, 91% purity) as a pale yellow oil. UPLC-MS (Method 1) m/z 487.3 (M+H).sup.+, 485.2 (MH).sup. at 1.89 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.92 (s, 1H), 8.39 (d, J=2.3 Hz, 1H), 8.19 (dd, J=8.8, 2.3 Hz, 1H), 7.65 (d, J=2.1 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.41-7.34 (m, 2H), 3.96 (s, 3H), 3.85 (s, 3H), 3.01-2.93 (m, 1H), 2.63-2.52 (m, 2H), 1.79-1.74 (m, 2H), 1.69-1.55 (m, 2H), 1.45-1.33 (m, 2H), 0.59 (d, J=6.1 Hz, 3H).

(350) Step 4: I-4-methoxy-3-(N-(2-(2-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: A mixture of the product from step 3 above (181 mg, 0.337 mmol) and LiOH (32.3 mg, 1.35 mmol) in THF/MeOH/water (4:1:1, 4.5 ml) was stirred at 40 C. overnight. The mixture was diluted with water (5 ml) and acidified to pH 4 using 1 M HCl(aq). The mixture was extracted with EtOAc (320 ml) and the combined organic extracts were washed with brine (10 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (15.9 mg, 0.033 mmol, 10% yield, 99% purity) as a white solid. UPLC-MS (Method 1) m/z 473.3 (M+H).sup.+, 471.2 (MH).sup. at 1.74 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6).Math. 13.20 (s, 1H), 8.89 (s, 1H), 8.39 (d, J=2.2 Hz, 1H), 8.16 (dd, J=8.7, 2.2 Hz, 1H), 7.64 (d, J=2.1 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.37 (dd, J=8.3, 2.1 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 3.95 (s, 3H), 3.00-2.93 (m, 1H), 2.63-2.57 (m, 1H), 2.55-2.51 (m, 1H), 1.80-1.74 (m, 2H), 1.70-1.56 (m, 2H), 1.48-1.34 (m, 2H), 0.60 (d, J=6.1 Hz, 3H).

Example 236: I-4-ethyl-3-(N-(2-(2-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(351) ##STR00571##

(352) Step 1: I-methyl 4-ethyl-3-(N-(2-(2-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: A mixture of the product from Example 235 step 2 (100 mg, 0.372 mmol), the product from Example 203 step 2 (112 mg, 0.427 mmol) and pyridine (0.1 ml, 1.24 mmol) in DCM (2.5 ml) was stirred at 35 C. over the weekend. The mixture was concentrated onto silica and purified by chromatography on silica gel (4 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (120 mg, 0.238 mmol, 64% yield, 96% purity) as a pale yellow oil. UPLC-MS (Method 1) m/z 485.3 (M+H).sup.+, 483.2 (MH).sup. at 2.06 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.42 (s, 1H), 8.38 (d, J=1.9 Hz, 1H), 8.10 (dd, J=8.0, 1.9 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.57 (br s, 1H), 7.42 (br s, 2H), 3.84 (s, 3H), 3.16-2.99 (m, 2H), 2.98-2.91 (m, 1H), 2.46-2.38 (m, 2H), 1.72-1.65 (m, 2H), 1.63-1.48 (m, 2H), 1.41-1.32 (m, 2H), 1.23 (t, J=7.4 Hz, 3H), 0.57 (d, J=6.1 Hz, 3H).

(353) Step 2: I-4-ethyl-3-(N-(2-(2-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: A mixture of the product from step 1 above (120 mg, 0.238 mmol) and LiOH (32.3 mg, 1.35 mmol) in THF/MeOH/water (4:1:1, 4.5 ml) was stirred at 40 C. overnight. The mixture was diluted with water (5 ml) and acidified to pH 4 using 1 M HCl(aq). The mixture was extracted with EtOAc (320 ml), the combined organic extracts were washed with brine (10 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (28.6 mg, 0.060 mmol, 27% yield, 99% purity) as a white solid. UPLC-MS (Method 1) m/z 471.2 (M+H).sup.+, 469.2 (MH).sup. at 1.91 min. 1H NMR (500 MHz, DMSO-d.sub.6) 13.31 (s, 1H), 9.36 (s, 1H), 8.39 (d, J=1.9 Hz, 1H), 8.08 (dd, J=8.0, 1.9 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.55 (s, 1H), 7.45-7.38 (m, 2H), 3.15-2.99 (m, 2H), 2.97-2.91 (m, 1H), 2.47-2.38 (m, 2H), 1.73-1.66 (m, 2H), 1.63-1.48 (m, 2H), 1.43-1.33 (m, 2H), 1.22 (t, J=7.4 Hz, 3H), 0.58 (d, J=6.2 Hz, 3H).

Example 237:3-(N-(2-(4-cyanopiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(354) ##STR00572##

(355) Step 1: 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine-4-carbonitrile: A solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (200 l, 1.43 mmol), piperidine-4-carbonitrile (250 l, 2.24 mmol) and Et.sub.3N (500 l, 3.59 mmol) in DCM (6 ml) was allowed to stand at RT for 4 h. The reaction mixture was washed with 1 M HCl(aq) (22 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to afford the title compound (470 mg, 1.54 mmol, quant. Yield, 98% purity) as a bright yellow solid. UPLC-MS (Method 1) m/z 299.7 (M+H).sup.+ at 1.54 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.17 (d, J=2.2 Hz, 1H), 7.87 (dd, J=8.9, 2.3 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 3.29-3.20 (m, 2H), 3.20-3.02 (m, 3H), 2.05-1.94 (m, 2H), 1.91-1.75 (m, 2H).

(356) Step 2: 1-(2-amino-4-(trifluoromethyl)phenyl)piperidine-4-carbonitrile: The product from step 1 above (465 mg, 1.52 mmol) was dissolved in EtOH (40 ml) and hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm cartridge, full hydrogen mode, RT, 1 ml/min flow rate, 1 pass). The resultant colourless solution was concentrated in vacuo to afford the title compound (407 mg, 1.50 mmol, 98% yield, 99% purity) as an off-white solid. UPLC-MS (Method 1) m/z 270.4 (M+H).sup.+ at 1.48 min.

(357) Step 3: methyl 3-(N-(2-(4-cyanopiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from step 2 above (100 mg, 0.371 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (0.1 ml, 1.24 mmol) and treated with methyl 3-(chlorosulfonyl)-4-methoxybenzoate (140 mg, 0.529 mmol). The resultant solution was allowed to stand at RT for 18 h. The mixture was concentrated in vacuo and the residue was dissolved in EtOAc (4 ml) and sequentially washed with saturated NaHCO.sub.3(aq) (3 ml) and brine (2 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (157 mg, 0.309 mmol, 83% yield, 98% purity) as a white solid. UPLC-MS (Method 1) m/z 498.3 (M+H).sup.+, 496.2 (MH).sup. at 1.64 min.

(358) Step 4: 3-(N-(2-(4-cyanopiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 3 above (50 mg, 0.098 mmol) was dissolved in THF (2 ml) and treated with 1 M LiOH (aq) (400 l, 0.400 mmol). MeOH was added to give a clear solution and the resultant mixture was stirred at RT for 3 days. The solution was diluted with water (4 ml) and concentrated in vacuo at 22 C. The resultant aqueous solution was acidified using 1 M HCl(aq). The precipitate was collected by filtration, washing with water, and dried in vacuo to afford the title compound (40 mg, 0.079 mmol, 80% yield, 98% purity) as a white powder. UPLC-MS (Method 2) m/z 484.3 (M+H).sup.+, 482.3 (MH).sup. at 0.98 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.16 (br s, 1H), 9.06 (s, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.17 (dd, J=8.7, 2.3 Hz, 1H), 7.46 (d, J=2.2 Hz, 1H), 7.39 (dd, J=8.6, 2.2 Hz, 1H), 7.35-7.29 (m, 2H), 3.90 (s, 3H), 3.02 (tt, J=8.4, 4.1 Hz, 1H), 2.94-2.86 (m, 2H), 2.82-2.71 (m, 2H), 2.08-1.95 (m, 2H), 1.95-1.80 (m, 2H).

Example 238:3-(N-(2-(4-cyanopiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(359) ##STR00573##

(360) Step 1: methyl 3-(N-(2-(4-cyanopiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoate: The product from Example 237 step 2 (100 mg, 0.371 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (0.1 ml, 1.24 mmol) and treated with the product from Example 203 step 2 (140 mg, 0.533 mmol). The resultant solution was allowed to stand at RT for 18 h. The mixture was concentrated in vacuo, the residue was dissolved in EtOAc (4 ml) and sequentially washed with saturated NaHCO.sub.3(aq) (3 ml) and brine (2 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (105 mg, 0.208 mmol, 56% yield, 98% purity) as a white solid. UPLC-MS (Method 1) m/z 496.3 (M+H).sup.+, 494.3 (MH).sup. at 1.78 min.

(361) Step 2: 3-(N-(2-(4-cyanopiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoic acid: The product from step 1 above (50 mg, 0.099 mmol) was dissolved in THF (2 ml) and treated with 1 M LiOH (aq) (400 l, 0.400 mmol). MeOH was added to give a clear solution and the resultant mixture stirred at RT for 3 days. The solution was diluted with water (4 ml) and concentrated in vacuo at 22 C. The resultant aqueous solution was acidified using 1 M HCl(aq). The precipitate was collected by filtration, washing with water, and dried in vacuo to afford the title compound (44 mg, 0.090 mmol, 91% yield, 98% purity) as a white powder. UPLC-MS (Method 2) m/z 482.3 (M+H).sup.+, 480.2 (MH).sup. at 1.09 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.30 (br s, 1H), 9.70 (br s, 1H), 8.35 (d, J=1.8 Hz, 1H), 8.10 (dd, J=8.0, 1.9 Hz, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.44 (dd, J=8.5, 2.2 Hz, 1H), 7.32 (d, J=2.2 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 3.04 (q, J=7.4 Hz, 2H), 2.96 (tt, J=8.7, 4.2 Hz, 1H), 2.89-2.78 (m, 2H), 2.74-2.64 (m, 2H), 1.99-1.88 (m, 2H), 1.88-1.76 (m, 2H), 1.20 (t, J=7.4 Hz, 3H).

Example 239: (S)-4-methoxy-3-(N-(2-(2-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(362) ##STR00574##

(363) Step 1: (S)-2-methyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: A mixture of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (250 l, 1.79 mmol), (S)-2-methylpiperidine (250 l, 2.13 mmol) and Et.sub.3N (0.6 ml, 4.30 mmol) in DCM (8 ml) was stirred at RT for 2 h and then at 35 C. overnight. The mixture was washed with 1 M HCl(aq) (10 ml), dried by passage through a phase separator and concentrated onto silica. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% DCM/isohexane) to afford the title compound (503 mg, 1.68 mmol, 94% yield, 96% purity) as an orange oil. UPLC-MS (Method 1) m/z 289.2 (M+H).sup.+ at 1.87 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.14 (d, J=2.3 Hz, 1H), 7.85 (dd, J=8.8, 2.3 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 3.58-3.50 (m, 1H), 3.16 (ddd, J=12.5, 8.5, 4.0 Hz, 1H), 2.82 (dt, J=12.5, 4.6 Hz, 1H), 1.80-1.63 (m, 2H), 1.63-1.46 (m, 3H), 1.45-1.37 (m, 1H), 0.99 (d, J=6.5 Hz, 3H).

(364) Step 2: (S)-2-(2-methylpiperidin-1-yl)-5-(trifluoromethyl)aniline: A solution of the product from step 1 above (503 mg, 1.68 mmol) in EtOH (35 ml) was hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm cartridge, full hydrogen mode, RT, 1 ml/min flow rate, 1 pass). The solvent was evaporated to give the title compound (410 mg, 1.38 mmol, 82% yield, 87% purity) as a pale yellow oil. UPLC-MS (Method 2) m/z 259.2 (M+H).sup.+, 257.0 (MH).sup. at 1.86 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.10 (d, J=8.2 Hz, 1H), 6.96 (d, J=2.2 Hz, 1H), 6.82 (dd, J=8.2, 2.2 Hz, 1H), 5.25 (s, 2H), 3.09-2.98 (m, 1H), 2.91-2.85 (m, 1H), 2.45-2.36 (m, 1H), 1.84-1.70 (m, 2H), 1.67-1.58 (m, 2H), 1.50-1.29 (m, 2H), 0.79 (d, J=6.2 Hz, 3H).

(365) Step 3: (S)-methyl 4-methoxy-3-(N-(2-(2-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: A mixture of the product from step 2 above (100 mg, 0.337 mmol), methyl 3-(chlorosulfonyl)-4-methoxybenzoate (103 mg, 0.387 mmol) and pyridine (0.1 ml, 1.24 mmol) in DCM (2.5 ml) was stirred at 35 C. for 4 days. The mixture was concentrated onto silica and purified by chromatography on silica gel (4 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (159 mg, 0.321 mmol, 95% yield, 98% purity) as a light brown oil. UPLC-MS (Method 1) m/z 487.2 (M+H).sup.+, 485.1 (MH).sup. at 1.90 min. 1H NMR (500 MHz, DMSO-d.sub.6) 8.92 (s, 1H), 8.39 (d, J=2.3 Hz, 1H), 8.19 (dd, J=8.8, 2.3 Hz, 1H), 7.65 (d, J=2.1 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.41-7.34 (m, 2H), 3.96 (s, 3H), 3.85 (s, 3H), 2.98-2.95 (m, 1H), 2.62-2.51 (m, 2H), 1.76 (br d, J=10.8 Hz, 2H), 1.70-1.55 (m, 2H), 1.45-1.33 (m, 2H), 0.59 (d, J=6.1 Hz, 3H).

(366) Step 4: (S)-4-methoxy-3-(N-(2-(2-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: A mixture of the product from step 3 above (159 mg, 0.321 mmol) and LiOH.Math.H.sub.2O (55 mg, 1.31 mmol) in THF/MeOH/water (4:1:1, 4.5 ml) was stirred at 40 C. overnight. The mixture was diluted with water (5 ml) and acidified to pH 4 using 1 M HCl(aq). The mixture was extracted with EtOAc (320 ml) and the combined organic extracts were washed with brine (10 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc/isohexane) to afford the product (29.6 mg, 0.062 mmol, 19% yield, 99% purity) as a white solid after trituration with TBME. UPLC-MS (Method 1) m/z 473.2 (M+H).sup.+, 471.1 (MH).sup. at 1.76 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.20 (s, 1H), 8.89 (s, 1H), 8.39 (d, J=2.2 Hz, 1H), 8.16 (dd, J=8.7, 2.2 Hz, 1H), 7.64 (d, J=2.1 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 7.37 (dd, J=8.2, 2.1 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 3.95 (s, 3H), 3.01-2.92 (m, 1H), 2.63-2.51 (m, 2H), 1.80-1.74 (m, 2H), 1.70-1.58 (m, 2H), 1.48-1.31 (m, 2H), 0.60 (d, J=6.1 Hz, 3H).

Example 240: (S)-4-ethyl-3-(N-(2-(2-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(367) ##STR00575##

(368) Step 1: (S)-methyl 4-ethyl-3-(N-(2-(2-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: A mixture of the product from Example 239 step 2 (100 mg, 0.337 mmol), the product from Example 203 step 2 (102 mg, 0.387 mmol) and pyridine (0.1 ml, 1.24 mmol) in DCM (2.5 ml) was stirred at 35 C. for 4 days. The mixture was concentrated onto silica and purified by chromatography on silica gel (4 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (159 mg, 0.320 mmol, 95% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m/z 485.3 (M+H).sup.+, 483.1 (MH).sup. at 2.06 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.42 (s, 1H), 8.38 (d, J=1.9 Hz, 1H), 8.10 (dd, J=8.1, 1.9 Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.59-7.55 (m, 1H), 7.43-7.40 (m, 2H), 3.84 (s, 3H), 3.15-2.99 (m, 2H), 2.98-2.91 (m, 1H), 2.45-2.38 (m, 2H), 1.72-1.66 (m, 2H), 1.63-1.47 (m, 2H), 1.41-1.32 (m, 2H), 1.23 (t, J=7.4 Hz, 3H), 0.57 (d, J=6.2 Hz, 3H).

(369) Step 2: (S)-4-ethyl-3-(N-(2-(2-methylpiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: A mixture of the product from step 1 above (159 mg, 0.320 mmol) and LiOH.Math.H.sub.2O (55 mg, 1.31 mmol) in THF/MeOH/water (4:1:1, 4.5 ml) was stirred at 40 C. overnight. The mixture was diluted with water (5 ml) and acidified to pH 4 using 1 M HCl(aq). The mixture was extracted with EtOAc (320 ml) and the combined organic extracts were washed with brine (10 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (26.1 mg, 0.055 mmol, 17% yield, 99% purity) as a white solid after trituration with TBME. UPLC-MS (Method 1) m/z 471.3 (M+H).sup.+, 469.1 (MH).sup. at 1.94 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.30 (s, 1H), 9.36 (s, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.08 (dd, J=8.0, 1.8 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.55 (s, 1H), 7.45-7.38 (m, 2H), 3.15-2.99 (m, 2H), 2.99-2.91 (m, 1H), 2.48-2.38 (m, 2H), 1.73-1.64 (m, 2H), 1.62-1.48 (m, 2H), 1.42-1.32 (m, 2H), 1.22 (t, J=7.4 Hz, 3H), 0.58 (d, J=6.2 Hz, 3H).

Example 241:4-ethyl-3-(N-(5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid

(370) ##STR00576##

(371) Step 1: methyl 4-ethyl-3-(N-(5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: A solution of the product from Example 207 step 2 (0.120 g, 0.472 mmol) and the product from Example 203 step 2 (0.124 g, 0.472 mmol) in DCM (10 ml) was treated with pyridine (0.229 ml, 2.83 mmol) and the solution was stirred at RT for 24 h and then at reflux for 20 h. The reaction mixture was concentrated in vacuo and the crude product was purified by chromatography on silica gel (24 g cartridge, 0-70% EtOAc/isohexane) to afford the title compound (0.180 g, 0.375 mmol, 79% yield, 100% purity) as a white solid. UPLC-MS (Method 1) m/z 481.3 (M+H).sup.+, 479.3 (MH).sup. at 1.66 min.

(372) Step 2: 4-ethyl-3-(N-(5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH (aq) (1.12 ml, 1.12 mmol) was added to a solution of the product from step 1 above (0.180 g, 0.375 mmol) in THF (5 ml) and the solution was stirred at RT overnight. The solvent was removed in vacuo and the resultant aqueous solution was washed with EtOAc (50 ml). The aqueous phase was adjusted to pH 6 using 1M HCl(aq) to form a precipitate which was filtered and washed with water (10 ml) and isohexane (20 ml) to provide the title compound (142 mg, 0.289 mmol, 77% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 467.3 (M+H).sup.+, 465.3 (MH).sup. at 1.52 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6).Math. 13.23 (br s, 1H), 9.58 (br s, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.58-7.51 (m, 3H), 7.20 (s, 1H), 3.06 (q, J=7.4 Hz, 2H), 3.02 (s, 3H), 2.81-2.80 (m, 4H), 1.58-1.54 (m, 4H), 1.49-1.48 (m, 2H), 1.21 (t, J=7.4 Hz, 3H).

Example 242:4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid

(373) ##STR00577##

(374) Step 1: methyl 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoate: Pyridine (0.099 ml, 1.23 mmol) was added to a solution of the product from Example 214 step 3 (100 mg, 0.409 mmol) and the product from Example 203 step 2 (129 mg, 0.491 mmol) in DCM (10 ml) and the solution was stirred at RT for 18 h. The solution was concentrated in vacuo and the crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.120 g, 0.245 mmol, 60% yield, 96% purity) as a white solid. UPLC-MS (Method 1) m/z 471.3 (M+H).sup.+, 469.4 (MH).sup. at 1.72 min.

(375) Step 2: 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH (aq) (1.5 ml, 1.50 mmol) was added to a solution of the product from step 1 above (0.120 g, 0.245 mmol) in THF (6 ml) and methanol (1.5 ml) and the solution was stirred at RT overnight. The solvent was removed in vacuo and the residue was dissolved in water (5 ml) and washed with TBME (35 ml). The aqueous phase was acidified to pH 2 using conc. HCl and the product was extracted with TBME (310 ml). The organic phases were combined, dried by passage through a phase separator and the solvent was removed in vacuo to give the title compound (0.103 g, 0.220 mmol, 90% yield, 98% purity). UPLC-MS (Method 1) m/z 457.3 (M+H).sup.+, 455.3 (MH).sup. at 1.58 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.27 (s, 1H), 9.97 (s, 1H), 9.44 (s, 1H), 8.38 (d, J=1.8 Hz, 1H), 8.08 (dd, J=8.0, 1.9 Hz, 1H), 7.70 (d, J=2.5 Hz, 1H), 7.66-7.57 (m, 2H), 7.37 (d, J=8.6 Hz, 1H), 3.07 (q, J=7.4 Hz, 2H), 2.71-2.58 (m, 4H), 1.62-1.49 (m, 4H), 1.49-1.40 (m, 2H), 1.22 (t, J=7.4 Hz, 3H).

Example 243: I-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(376) ##STR00578##

(377) Step 1: I-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ol: Et.sub.3N (720 l, 5.17 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (201 l, 1.44 mmol) and I-piperidin-3-ol hydrochloride (257 mg, 1.87 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 20 h. 1 M HCl(aq) (2 ml) was added and the organic phase was dried by passage through a phase separator and concentrated in vacuo to afford the title compound (421 mg, 1.44 mmol, 100% yield, 99% purity) as a dark yellow solid. UPLC-MS (Method 2) m/z 291.2 (M+H).sup.+ at 1.35 min.

(378) Step 2: I-1-(2-amino-4-(trifluoromethyl)phenyl)piperidin-3-ol: 5% Pd/C (50% w/w water) Type 87L (107 mg, 0.025 mmol) in EtOH (1 ml) was added to a solution of the product from step 1 above (416 mg, 1.44 mmol) in EtOH (6.4 ml) at RT. The reaction mixture was stirred at RT under H.sub.2 (4 bar pressure) for 19 h. The catalyst was removed by filtration through Celite and washed with MeOH (20 ml). The filtrate was concentrated in vacuo and the residue was dissolved in EtOAc (10 ml). The organic phase was washed with water (5 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to afford the title compound (384 mg, 1.48 mmol, quant. Yield) as a cream solid. UPLC-MS (Method 2) m/z 261.1 (M+H).sup.+, 259.1 (MH).sup. at 1.28 min.

(379) Step 3: I-methyl 3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from step 3 above (65.6 mg, 0.252 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (81 l, 1.01 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 3 days. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (102 mg, 0.207 mmol, 82% yield, 99% purity) as a white solid. UPLC-MS (Method 2) m/z 489.2 (M+H).sup.+, 487.1 (MH).sup. at 1.54 min.

(380) Step 4: I-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 3 above (100 mg, 0.205 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH (aq) (744 l, 0.819 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (47.8 mg, 0.096 mmol, 47% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 475.3 (M+H).sup.+, 473.2 (MH).sup. at 0.93 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.16 (br s, 1H), 9.16 (s, 1H), 8.40 (d, J=2.2 Hz, 1H), 8.15 (dd, J=8.7, 2.2 Hz, 1H), 7.47 (d, J=2.1 Hz, 1H), 7.38-7.16 (m, 3H), 5.11 (s, 1H), 3.90 (s, 3H), 3.82-3.70 (m, 1H), 2.89-2.78 (m, 2H), 2.77-2.55 (m, 2H), 1.96-1.85 (m, 1H), 1.79-1.68 (m, 1H), 1.63-1.37 (m, 2H).

Example 244: (S)-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(381) ##STR00579##

(382) Step 1: (S)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ol: Et.sub.3N (720 l, 5.17 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (201 l, 1.44 mmol) and(S)-piperidin-3-ol hydrochloride (257 mg, 1.87 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 20 h. 1 M HCl(aq) (2 ml) was added and the organic phase was dried by passage through a phase separator. The filtrate was concentrated in vacuo to afford the title compound (416 mg, 1.44 mmol, 100% yield) as a dark yellow solid. UPLC-MS (Method 2) m/z 291.3 (M+H).sup.+, 289.1 (MH).sup. at 1.35 min.

(383) Step 2: (S)-1-(2-amino-4-(trifluoromethyl)phenyl)piperidin-3-ol: 5% Pd/C (50% w/w water) Type 87L (107 mg, 0.025 mmol) in EtOH (1 ml) was added to a solution of the product from step 1 above (416 mg, 1.44 mmol) in EtOH (6.4 ml) at RT. The reaction mixture was stirred at RT under H.sub.2 (4 bar pressure) for 19 h. The catalyst was removed by filtration through Celite and washed with MeOH (20 ml). The filtrate was concentrated in vacuo and the residue was dissolved in EtOAc (10 ml). The organic phase was washed with water (5 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to afford the title compound (376 mg, 1.43 mmol, 100% yield, 99% purity) as a light yellow viscous oil. UPLC-MS (Method 2) m/z 261.1 (M+H).sup.+, 259.0 (MH).sup. at 1.28 min.

(384) Step 3: (S)-methyl 3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from step 2 above (65.6 mg, 0.252 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (81 l, 1.01 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 3 days. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (93.1 mg, 0.191 mmol, 76% yield) as a light yellow sticky solid. UPLC-MS (Method 2) m/z 489.3 (M+H).sup.+, 487.1 (MH).sup. at 1.55 min.

(385) Step 4: (S)-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 3 above (91 mg, 0.186 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH (aq) (677 l, 0.745 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration and washed with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (79.7 mg, 0.163 mmol, 87% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m/z 475.3 (M+H).sup.+, 473.2 (MH).sup. at 0.94 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.16 (br s, 1H), 9.15 (s, 1H), 8.39 (d, J=2.2 Hz, 1H), 8.15 (dd, J=8.7, 2.2 Hz, 1H), 7.47 (d, J=2.1 Hz, 1H), 7.38-7.10 (m, 3H), 5.10 (s, 1H), 3.90 (s, 3H), 3.80-3.74 (m, 1H), 2.90-2.78 (m, 2H), 2.76-2.58 (m, 2H), 1.96-1.84 (m, 1H), 1.80-1.69 (m, 1H), 1.65-1.37 (m, 2H).

Example 245: I-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(386) ##STR00580##

(387) Step 1: I-1-(4-(methylsulfonyl)-2-nitrophenyl)piperidin-3-ol: Et.sub.3N (687 l, 4.93 mmol) was added to a solution of 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (300 mg, 1.37 mmol) and I-piperidin-3-ol hydrochloride (245 mg, 1.78 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 20 h. 1 M HCl(aq) (2 ml) was added and the organic phase was dried by passage through a phase separator. The filtrate was concentrated in vacuo to afford the title compound (411 mg, 1.37 mmol, 100% yield) as a dark yellow solid. UPLC-MS (Method 2) m/z 301.2 (M+H).sup.+, 299.1 (MH).sup. at 0.87 min.

(388) Step 2: I-1-(2-amino-4-(methylsulfonyl)phenyl)piperidin-3-ol: 5% Pd/C (50% w/w water) Type 87L (107 mg, 0.025 mmol) in EtOH (1 ml) was added to a solution of the product from step 1 above (411 mg, 1.37 mmol) in EtOH (15 ml) at RT. The reaction mixture was stirred at RT under H2 (4 bar pressure) for 19 h. The catalyst was removed by filtration through Celite and washed with MeOH (20 ml). The filtrate was concentrated in vacuo and the residue was dissolved in EtOAc (10 ml). The organic phase was washed with water (5 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to afford the title compound (368 mg, 1.36 mmol, 99% yield) as a light yellow viscous oil. UPLC-MS (Method 2) m/z 271.1 (M+H).sup.+, 269.2 (MH).sup. at 0.78 min.

(389) Step 3: I-methyl 3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from step 2 above (68.1 mg, 0.252 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (81 l, 1.01 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 3 days. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (96 mg, 0.189 mmol, 75% yield, 98% purity) as a cream solid. UPLC-MS (Method 1) m/z 499.3 (M+H).sup.+, 497.2 (MH).sup. at 1.16 min.

(390) Step 4: I-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 3 above (94 mg, 0.185 mmol, 98% purity) was dissolved in THF (2 ml) and treated with 1.1 M LiOH (aq) (686 l, 0.754 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (2 5 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (32.4 mg, 0.062 mmol, 34% yield, 93% purity) as a white solid. UPLC-MS (Method 1) m/z 485.2 (M+H).sup.+, 483.2 (MH).sup. at 0.68 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.19 (br s, 1H), 9.19 (br s, 1H), 8.38 (d, J=2.2 Hz, 1H), 8.14 (dd, J=8.7, 2.2 Hz, 1H), 7.69 (d, J=2.2 Hz, 1H), 7.50 (dd, J=8.4, 2.2 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 5.55-4.80 (m, 1H), 3.91 (s, 3H), 3.80-3.74 (m, 1H), 2.98 (s, 3H), 2.94-2.86 (m, 2H), 2.82-2.61 (m, 2H), 1.95-1.83 (m, 1H), 1.79-1.68 (m, 1H), 1.63-1.38 (m, 2H).

Example 246: (S)-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(391) ##STR00581##

(392) Step 1: (S)-1-(4-(methylsulfonyl)-2-nitrophenyl)piperidin-3-ol: Et.sub.3N (687 l, 4.93 mmol) was added to a solution of 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (300 mg, 1.37 mmol) and (S)-piperidin-3-ol hydrochloride (245 mg, 1.78 mmol) in DCM (6 ml) and the solution was stirred at RT for 20 h. 1 M HCl(aq) (2 ml) was added and the filtrate was dried by passage through a phase separator. The organic phase was concentrated in vacuo to afford the title compound (415 mg, 1.37 mmol, 100% yield, 99% purity) as a dark yellow solid. UPLC-MS (Method 2) m/z 301.1 (M+H).sup.+, 299.1 (MH).sup. at 0.88 min.

(393) Step 2: (S)-1-(2-amino-4-(methylsulfonyl)phenyl)piperidin-3-ol: 5% Pd/C (50% w/w water) Type 87L (107 mg, 0.025 mmol) in EtOH (1 ml) was added to a solution of the product from step 1 above (415 mg, 1.37 mmol) in EtOH (6.4 ml) at RT. The reaction mixture was stirred at RT under H.sub.2 (4 bar pressure) for 3 days. The catalyst was removed by filtration through Celite and washed with MeOH (20 ml). The filtrate was concentrated in vacuo and the residue was dissolved in EtOAc (10 ml). The organic phase was washed with water (5 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to afford the title compound (375 mg, 1.37 mmol, 100% yield, 99% purity) as a pale brown solid. UPLC-MS (Method 2) m/z 269.0 (MH).sup. at 0.76 min.

(394) Step 3: (S)-methyl 3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from step 3 above (68.1 mg, 0.252 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (81 l, 1.01 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (68.4 mg, 0.136 mmol, 54% yield, 99% purity) as a cream solid. UPLC-MS (Method 1) m/z 499.3 (M+H).sup.+, 497.2 (MH).sup. at 1.16 min.

(395) Step 4: (S)-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 3 above (66 mg, 0.132 mmol) was dissolved in THF (5 ml) and treated with 1.1 M LiOH(aq) (481 l, 0.530 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (31.3 mg, 0.063 mmol, 48% yield, 98% purity) as a white solid. UPLC-MS (Method 1) m/z 485.3 (M+H).sup.+, 483.2 (MH).sup. at 0.69 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.16 (s, 1H), 9.21 (s, 1H), 8.38 (d, J=2.2 Hz, 1H), 8.15 (dd, J=8.7, 2.2 Hz, 1H), 7.69 (d, J=2.2 Hz, 1H), 7.51 (dd, J=8.4, 2.2 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 5.11 (s, 1H), 3.91 (s, 3H), 3.80-3.73 (m, 1H), 2.98 (s, 3H), 2.95-2.82 (m, 2H), 2.82-2.63 (m, 2H), 1.98-1.82 (m, 1H), 1.79-1.69 (m, 1H), 1.64-1.41 (m, 2H).

Example 247: (S)-4-ethyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(methylsulfonyl)phenyl) sulfamoyl)benzoic acid

(396) ##STR00582##

(397) Step 1: (S)-methyl 4-ethyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoate: The product from Example 246 step 2 (68.6 mg, 0.254 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (82 l, 1.02 mmol) and treated with a solution of the product from Example 203 step 2 (80 mg, 0.305 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (41.9 mg, 0.084 mmol, 33% yield, 100% purity) as a white solid. UPLC-MS (Method 1) m/z 497.3 (M+H).sup.+, 495.3 (MH).sup. at 1.34 min.

(398) Step 2: (S)-4-ethyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoic acid: The product from step 1 above (40 mg, 0.081 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (293 l, 0.322 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (30.5 mg, 0.058 mmol, 72% yield, 92% purity) as a white solid. UPLC-MS (Method 1) m/z 483.3 (M+H).sup.+, 481.2 (MH).sup. at 0.77 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6).Math. 13.33 (br s, 1H), 9.76 (br s, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.08 (dd, J=8.0, 1.8 Hz, 1H), 7.63-7.58 (m, 2H), 7.54 (dd, J=8.4, 2.2 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 5.21 (s, 1H), 3.87-3.69 (m, 1H), 2.98-3.15 (m, 7H), 2.77-2.59 (m, 2H), 1.90-1.79 (m, 1H), 1.73-1.64 (m, 1H), 1.56-1.45 (m, 2H), 1.21 (t, J=7.4 Hz, 3H).

Example 248: I-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(399) ##STR00583##

(400) Step 1: I-1-(2-nitro-4-(tetrazol-1-yl)phenyl)piperidin-3-ol: Et.sub.3N (720 l, 5.16 mmol) was added to a solution of the product from Example 214 step 1 (300 mg, 1.43 mmol) and I-piperidin-3-ol hydrochloride (257 mg, 1.87 mmol) in DCM (6 ml) and the solution was stirred at RT for 20 h. 1 M HCl(aq) (2 ml) was added and the organic phase was dried by passage through a phase separator and concentrated in vacuo to afford the title compound (421 mg, 1.43 mmol, 100% yield, 99% purity) as a dark red viscous oil. UPLC-MS (Method 2) m/z no ionisation at 0.92 min.

(401) Step 2: I-1-(2-amino-4-(tetrazol-1-yl)phenyl)piperidin-3-ol: 5% Pd/C (50% w/w water) Type 87L (107 mg, 0.025 mmol) in EtOH (1 ml) was added to a solution of the product from step 1 above (421 mg, 1.43 mmol, 99% purity) in EtOH (6.4 ml) at RT. The reaction mixture was stirred at RT under H.sub.2 (4 bar pressure) for 3 days. The catalyst was removed by filtration through Celite and washed with MeOH (20 ml). The filtrate was concentrated in vacuo and the residue was dissolved in EtOAc (10 ml). The organic phase was washed with water (5 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to afford the title compound (369 mg, 1.42 mmol, 99% yield, 100% purity) as a cream solid. UPLC-MS (Method 2) m/z 259.1 (MH).sup. at 0.82 min.

(402) Step 3: I-methyl 3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from step 2 above (65.6 mg, 0.252 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (81 l, 1.01 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (83.9 mg, 0.170 mmol, 68% yield, 99% purity) as a white solid. UPLC-MS (Method 1) m/z 489.3 (M+H).sup.+, 487.3 (MH).sup. at 1.20 min.

(403) Step 4: I-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 3 above (81 mg, 0.166 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (603 l, 0.663 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (30.2 mg, 0.059 mmol, 35% yield, 92% purity) as a white solid. UPLC-MS (Method 1) m/z 475.3 (M+H).sup.+, 473.2 (MH).sup. at 0.73 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.15 (br s, 1H), 9.94 (s, 1H), 9.18 (s, 1H), 8.44 (d, J=2.2 Hz, 1H), 8.14 (dd, J=8.7, 2.2 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.50 (dd, J=8.5, 2.5 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 5.06 (s, 1H), 3.93 (s, 3H), 3.82-3.73 (m, 1H), 2.92-2.56 (m, 4H), 1.99-1.80 (m, 1H), 1.82-1.70 (m, 1H), 1.65-1.51 (m, 1H), 1.52-1.41 (m, 1H).

Example 249: I-4-ethyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(404) ##STR00584##

(405) Step 1: I-methyl 4-ethyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: The product from Example 243 step 2 (66.0 mg, 0.254 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (82 l, 1.02 mmol) and treated with a solution of the product from Example 203 step 2 (80 mg, 0.305 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 3 days. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (93.1 mg, 0.180 mmol, 71% yield, 94% purity) as a dark yellow sticky solid. UPLC-MS (Method 1) m/z 487.3 (M+H).sup.+ at 1.72 min.

(406) Step 2: I-4-ethyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: The product from step 1 above (91 mg, 0.187 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (680 l, 0.748 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension, which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (30.2 mg, 0.062 mmol, 33% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m/z 473.4 (M+H).sup.+, 471.2 (MH).sup. at 1.06 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.22 (br s, 1H), 9.71 (br s, 1H), 8.42 (d, J=1.8 Hz, 1H), 8.08 (dd, J=8.0, 1.8 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.47-7.27 (m, 2H), 7.20 (d, J=8.2 Hz, 1H), 5.31 (s, 1H), 3.84-3.71 (m, 1H), 3.15-3.00 (m, 2H), 2.95-2.75 (m, 2H), 2.71-2.63 (m, 2H), 1.95-1.77 (m, 1H), 1.77-1.59 (m, 1H), 1.57-1.45 (m, 2H), 1.20 (t, J=7.4 Hz, 3H).

Example 250: (S)-4-ethyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(407) ##STR00585##

(408) Step 1: (S)-methyl 4-ethyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: The product from Example 244 step 2 (66.0 mg, 0.254 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (82 l, 1.02 mmol) and treated with a solution of the product from Example 203 step 2 (80 mg, 0.305 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 3 days. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (86.6 mg, 0.174 mmol, 69% yield, 98% purity) as a sticky cream solid. UPLC-MS (Method 1) m/z 485.2 (MH).sup. at 1.71 min.

(409) Step 2: (S)-4-ethyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: The product from step 1 above (84 mg, 0.173 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (628 l, 0.691 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (66.6 mg, 0.133 mmol, 77% yield, 94% purity) as a cream solid. UPLC-MS (Method 1) m/z 473.3 (M+H).sup.+, 471.2 (MH).sup. at 1.05 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6).Math. 13.31 (br s, 1H), 9.71 (br s, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.0, 1.8 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.42-7.27 (m, 2H), 7.21 (d, J=8.1 Hz, 1H), 5.20 (s, 1H), 3.84-3.68 (m, 1H), 3.15-2.99 (m, 2H), 2.94-2.75 (m, 2H), 2.72-2.61 (m, 2H), 1.94-1.74 (m, 1H), 1.73-1.61 (m, 1H), 1.58-1.41 (m, 2H), 1.20 (t, J=7.4 Hz, 3H).

Example 251: I-4-ethyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(methylsulfonyl)phenyl) sulfamoyl)benzoic acid

(410) ##STR00586##

(411) Step 1: I-methyl 4-ethyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoate: The product from Example 245 step 2 (68.6 mg, 0.254 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (82 l, 1.02 mmol) and treated with a solution of the product from Example 203 step 2 (80 mg, 0.305 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 3 days. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (75.4 mg, 0.152 mmol, 60% yield) as a cream solid. UPLC-MS (Method 1) m/z 497.3 (M+H).sup.+, 495.2 (MH).sup. at 1.32 min.

(412) Step 2: I-4-ethyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoic acid: The product from step 1 above (73 mg, 0.147 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (535 l, 0.588 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (28.4 mg, 0.056 mmol, 38% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 483.3 (M+H).sup.+, 481.2 (MH).sup. at 0.78 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.33 (br s, 1H), 9.77 (s, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.0, 1.9 Hz, 1H), 7.65-7.58 (m, 2H), 7.55 (dd, J=8.4, 2.2 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 5.23 (s, 1H), 3.84-3.69 (m, 1H), 3.17-2.96 (m, 5H), 2.96-2.82 (m, 2H), 2.76-2.65 (m, 2H), 1.97-1.78 (m, 1H), 1.73-1.62 (m, 1H), 1.54-1.47 (m, 2H), 1.21 (t, J=7.4 Hz, 3H).

Example 252: I-4-ethyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid

(413) ##STR00587##

(414) Step 1: I-methyl 4-ethyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoate: The product from Example 248 step 2 (66.1 mg, 0.254 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (82 l, 1.02 mmol) and treated with a solution of the product from Example 203 step 2 (80 mg, 0.305 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (96.0 mg, 0.195 mmol, 77% yield, 99% purity) as a cream solid. UPLC-MS (Method 1) m/z 487.3 (M+H).sup.+, 485.3 (MH).sup. at 1.38 min.

(415) Step 2: I-4-ethyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid: The product from step 1 above (94 mg, 0.193 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (703 l, 0.773 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (58.4 mg, 0.120 mmol, 62% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m/z 473.3 (M+H).sup.+, 471.3 (MH).sup. at 0.82 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.29 (br s, 1H), 9.93 (s, 1H), 9.71 (br s, 1H), 8.44 (d, J=1.8 Hz, 1H), 8.08 (dd, J=8.0, 1.8 Hz, 1H), 7.73 (d, J=2.5 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.54 (dd, J=8.6, 2.5 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H), 5.17 (s, 1H), 3.87-3.66 (m, 1H), 3.18-3.03 (m, 2H), 2.80-2.72 (m, 1H), 2.69-2.59 (m, 1H), 2.68-2.60 (m, 2H), 1.92-1.80 (m, 1H), 1.74-1.62 (m, 1H), 1.59-1.38 (m, 2H), 1.22 (t, J=7.4 Hz, 3H).

Example 253: (S)-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(416) ##STR00588##

(417) Step 1: (S)-1-(2-nitro-4-(tetrazol-1-yl)phenyl)piperidin-3-ol: Et.sub.3N (720 l, 5.16 mmol) was added to a solution of the product from Example 214 step 1 (300 mg, 1.43 mmol) and(S)-piperidin-3-ol hydrochloride (257 mg, 1.87 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 20 h. 1 M HCl(aq) (2 ml) was added and the organic phase was dried by passage through a phase separator. The filtrate was concentrated in vacuo to afford the title compound (416 mg, 1.43 mmol, 100% yield) as a dark red viscous oil. UPLC-MS (Method 2) m/z no ionisation at 0.92 min.

(418) Step 2: (S)-1-(2-amino-4-(tetrazol-1-yl)phenyl)piperidin-3-ol: 5% Pd/C (50% w/w water) Type 87L (107 mg, 0.025 mmol) in EtOH (1 ml) was added to a filtered solution of the product from step 1 above (416 mg, 1.43 mmol) in EtOH (6.4 ml) at RT. The reaction mixture was stirred at RT under H.sub.2 (4 bar pressure) for 19 h. The catalyst was removed by filtration through Celite and washed with MeOH (20 ml). The filtrate was concentrated in vacuo and the residue was dissolved in EtOAc (10 ml). The organic phase was washed with water (5 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to afford the title compound (275 mg, 1.05 mmol, 73% yield, 99% purity) as a cream solid. UPLC-MS (Method 2) m/z 258.8 (MH).sup. at 0.82 min.

(419) Step 3: (S)-methyl 3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from step 2 above (65.6 mg, 0.252 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (81 l, 1.01 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (57.8 mg, 0.115 mmol, 46% yield, 97% purity) as a cream solid. UPLC-MS (Method 1) m/z 489.3 (M+H).sup.+, 487.2 (MH).sup. at 1.20 min.

(420) Step 4: (S)-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 1 above (56 mg, 0.115 mmol) was dissolved in THF (5 ml) and treated with 1.1 M LiOH(aq) (417 l, 0.459 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. Additional 1.1 M LiOH(aq) (417 l, 0.459 mmol) was added and the reaction mixture was heated at 40 C. for 4 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (2 5 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (27.3 mg, 0.052 mmol, 45% yield, 90% purity) as a white solid. UPLC-MS (Method 1) m/z 475.3 (M+H).sup.+, 473.3 (MH).sup. at 0.72 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.14 (br s, 1H), 9.94 (s, 1H), 9.18 (br s, 1H), 8.43 (d, J=2.2 Hz, 1H), 8.14 (dd, J=8.7, 2.2 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.50 (dd, J=8.5, 2.5 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 5.08 (s, 1H), 3.93 (s, 3H), 3.83-3.73 (m, 1H), 2.95-2.56 (m, 4H), 1.96-1.85 (m, 1H), 1.82-1.71 (m, 1H), 1.66-1.37 (m, 2H).

Example 254: (S)-4-ethyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(tetrazol-1-yl)phenyl) sulfamoyl)benzoic acid

(421) ##STR00589##

(422) Step 1: (S)-methyl 4-ethyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoate: The product from Example 253 step 2 (66.1 mg, 0.254 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (82 l, 1.02 mmol) and treated with a solution of the product from Example 203 step 2 (80 mg, 0.305 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (99.6 mg, 0.205 mmol, 81% yield) as a white solid. UPLC-MS (Method 1) m/z 487.3 (M+H).sup.+, 485.3 (MH).sup. at 1.37 min.

(423) Step 2: (S)-4-ethyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid: The product from step 1 above (97 mg, 0.199 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (725 l, 0.797 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 24 h. Additional 1.1 M LiOH(aq) (725 l, 0.797 mmol) was added and the reaction was stirred at 40 C. for 24 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (2 5 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (39.9 mg, 0.080 mmol, 40% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 473.4 (M+H).sup.+, 471.3 (MH).sup. at 0.83 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6).Math. 13.22 (br s, 1H), 9.93 (s, 1H), 9.71 (br s, 1H), 8.44 (d, J=1.8 Hz, 1H), 8.07 (dd, J=7.9, 1.8 Hz, 1H), 7.72 (d, J=2.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.52 (dd, J=8.6, 2.5 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 5.17 (s, 1H), 3.82-3.68 (m, 1H), 3.18-3.04 (m, 2H), 2.86 (dd, J=11.5, 2.7 Hz, 1H), 2.81-2.69 (m, 1H), 2.69-2.56 (m, 2H), 1.91-1.80 (m, 1H), 1.73-1.62 (m, 1H), 1.56-1.43 (m, 2H), 1.22 (t, J=7.4 Hz, 3H).

Example 255: 4-ethyl-3-(N-(2-(3-hydroxy-3-methylazetidin-1-yl)-5-(methylsulfonyl)phenyl) sulfamoyl)benzoic acid

(424) ##STR00590##

(425) Step 1: 3-methyl-1-(4-(methylsulfonyl)-2-nitrophenyl) azetidin-3-ol: Et.sub.3N (687 l, 4.93 mmol) was added to a solution of 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (300 mg, 1.37 mmol) and 3-methylazetidin-3-ol hydrochloride (220 mg, 1.78 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 20 h. 1 M HCl(aq) (2 ml) was added and the organic phase was dried by passage through a phase separator. The filtrate was concentrated in vacuo to afford the title compound (392 mg, 1.37 mmol, 100% yield) as a light yellow solid. UPLC-MS (Method 2) m/z no ionisation at 0.83 min.

(426) Step 2: 1-(2-amino-4-(methylsulfonyl)phenyl)-3-methylazetidin-3-ol: 5% Pd/C (50% w/w water) Type 87L (107 mg, 0.025 mmol) in EtOH (1 ml) was added to a fine suspension of the product from step 1 above (392 mg, 1.37 mmol) in EtOH (6.4 ml) at RT. The reaction mixture was stirred at RT under H.sub.2 (4 bar pressure) for 19 h. The catalyst was removed by filtration through Celite and washed with MeOH (20 ml). The filtrate was concentrated in vacuo and the residue was dissolved in EtOAc (10 ml). The organic phase was washed with water (5 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to afford a dark brown oil. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (270 mg, 1.03 mmol, 74% yield, 98% purity) as a dark pink solid. UPLC-MS (Method 2) m/z 257.2 (M+H).sup.+ at 0.61 min.

(427) Step 3: methyl 4-ethyl-3-(N-(2-(3-hydroxy-3-methylazetidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoate: The product from step 2 above (65.0 mg, 0.254 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (82 l, 1.02 mmol) and treated with a solution of the product from Example 203 step 2 (80 mg, 0.305 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (74.7 mg, 0.155 mmol, 61% yield, 100% purity) as a white solid. UPLC-MS (Method 1) m/z 483.2 (M+H).sup.+, 481.1 (MH).sup. at 1.16 min.

(428) Step 4: 4-ethyl-3-(N-(2-(3-hydroxy-3-methylazetidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoic acid: The product from step 1 above (72 mg, 0.149 mmol) was dissolved in THF (2 ml) and treated with 1.1 M LiOH(aq) (543 l, 0.597 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 45 C. to afford the title compound (66.2 mg, 0.137 mmol, 92% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m/z 467.1 (MH).sup. at 1.02 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.29 (br s, 1H), 9.60 (br s, 1H), 8.25 (d, J=1.8 Hz, 1H), 8.12 (dd, J=8.0, 1.9 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.51 (dd, J=8.7, 2.2 Hz, 1H), 6.58-6.50 (m, 2H), 5.58 (s, 1H), 4.07 (d, J=8.5 Hz, 2H), 3.98 (d, J=8.5 Hz, 2H), 2.95 (q, J=7.4 Hz, 2H), 2.80 (s, 3H), 1.43 (s, 3H), 1.20 (t, J=7.4 Hz, 3H).

Example 257: 4-ethyl-3-(N-(2-(3-hydroxy-3-methylazetidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid

(429) ##STR00591##

(430) Step 1: 3-methyl-1-(2-nitro-4-(tetrazol-1-yl)phenyl) azetidin-3-ol: Et.sub.3N (720 l, 5.16 mmol) was added to a solution of the product from Example 214 step 1 (300 mg, 1.43 mmol) and 3-methylazetidin-3-ol hydrochloride (230 mg, 1.87 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 20 h. 1 M HCl(aq) (2 ml) was added, followed by 10% MeOH in DCM (200 ml) and the organic phase was dried by passage through a phase separator. The filtrate was concentrated in vacuo to afford the title compound (413 mg, 1.43 mmol, 100% yield) as a dark orange solid. UPLC-MS (Method 2) m/z no ionisation at 0.87 min.

(431) Step 2: 1-(2-amino-4-(tetrazol-1-yl)phenyl)-3-methylazetidin-3-ol: 5% Pd/C (50% w/w water) Type 87L (214 mg, 0.050 mmol) in EtOH (1 ml) was added to a filtered solution of the product from step 1 above (396 mg, 1.44 mmol) in EtOH (150 ml) at RT. The reaction mixture was stirred at RT under H.sub.2 (4 bar pressure) for 19 h. The catalyst was removed by filtration through Celite and washed with MeOH (20 ml). The filtrate was concentrated in vacuo and the crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (117 mg, 0.474 mmol, 33% yield, 100% purity) as a light purple solid. UPLC-MS (Method 2) m/z no ionisation at 0.65 min.

(432) Step 3: methyl 4-ethyl-3-(N-(2-(3-hydroxy-3-methylazetidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoate: The product from step 2 above (62.5 mg, 0.254 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (82 l, 1.02 mmol) and treated with a solution of the product from Example 203 step 2 (80 mg, 0.305 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 3 days. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (31.0 mg, 0.064 mmol, 25% yield, 98% purity) as a very pale pink solid. UPLC-MS (Method 1) m/z 473.4 (M+H).sup.+, 471.3 (MH).sup. at 1.20 min.

(433) Step 4: 4-ethyl-3-(N-(2-(3-hydroxy-3-methylazetidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid: The product from step 3 above (29 mg, 0.061 mmol) was dissolved in THF (2 ml) and treated with 1 M LiOH(aq) (245 l, 0.245 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 50 C. to afford the title compound (27.5 mg, 0.058 mmol, 94% yield, 96% purity) as a light pink solid. UPLC-MS (Method 1) m/z 459.2 (M+H).sup.+, 457.2 (MH).sup. at 1.05 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.23 (br s, 1H), 9.74 (s, 1H), 9.70 (br s, 1H), 8.32 (d, J=1.9 Hz, 1H), 8.10 (dd, J=7.9, 1.9 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.59-7.52 (m, 1H), 6.82 (d, J=2.6 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 5.48 (s, 1H), 3.92 (d, J=8.0 Hz, 2H), 3.83 (d, J=7.9 Hz, 2H), 2.96 (q, J=7.4 Hz, 2H), 1.38 (s, 3H), 1.18 (t, J=7.4 Hz, 3H).

Example 258: I-3-(N-(5-cyano-2-(3-hydroxypiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(434) ##STR00592##

(435) Step 1: I-4-(3-hydroxypiperidin-1-yl)-3-nitrobenzonitrile: Et.sub.3N (0.252 ml, 1.81 mmol) was added to a solution of 4-fluoro-3-nitrobenzonitrile (300 mg, 1.81 mmol), and I-piperidin-3-ol hydrochloride (249 mg, 1.81 mmol) in DCM (20 ml) and the resultant solution was stirred at RT overnight. 1 M HCl(aq) (10 ml) was added and the organic phase was dried by passage through a phase separator. The filtrate was concentrated in vacuo to afford the title compound (447 mg, 1.81 mmol, 100% yield) as a dark orange viscous oil. UPLC-MS (Method 2) m/z 248.3 (M+H).sup.+, 246.2 (MH).sup. at 1.01 min.

(436) Step 2: I-3-amino-4-(3-hydroxypiperidin-1-yl)benzonitrile: A mixture of the product from step 1 above (447 mg, 1.81 mmol), iron powder (2.48 g, 44.4 mmol), ammonium chloride (116 mg, 2.17 mmol), IPA (15 ml) and water (7.6 ml) was heated at 90 C. for 20 h. The reaction mixture was filtered through Celite, washing with MeOH (25 ml), and the filtrate was concentrated in vacuo. The residue was diluted with DCM (20 ml), dried by passage through a phase separator and the crude product was purified directly by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (191 mg, 0.870 mmol, 48% yield, 99% purity) as a cream solid. UPLC-MS (Method 2) m/z 218.3 (M+H).sup.+ at 0.95 min.

(437) Step 3: I-methyl 3-(N-(5-cyano-2-(3-hydroxypiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from step 2 above (54.7 mg, 0.252 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (81 l, 1.01 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (89.5 mg, 0.201 mmol, 80% yield) as a white solid. UPLC-MS (Method 1) m/z 446.3 (M+H).sup.+, 444.3 (MH).sup. at 1.32 min.

(438) Step 4: I-3-(N-(5-cyano-2-(3-hydroxypiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 3 above (87 mg, 0.195 mmol) was dissolved in THF (2 ml) and treated with 1 M LiOH(aq) (781 l, 0.781 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 50 C. to afford the title compound (74 mg, 0.166 mmol, 85% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m/z 432.2 (M+H).sup.+, 430.3 (MH).sup. at 1.15 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.20 (br s, 1H), 9.25 (br s, 1H), 8.37 (d, J=2.2 Hz, 1H), 8.17 (dd, J=8.7, 2.2 Hz, 1H), 7.45 (dd, J=8.3, 2.0 Hz, 1H), 7.42 (d, J=1.9 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 5.11 (br s, 1H), 3.90 (s, 3H), 3.77-3.70 (m, 1H), 2.95-2.86 (m, 2H), 2.79-2.72 (m, 1H), 2.71-2.63 (m, 1H), 1.91-1.80 (m, 1H), 1.77-1.67 (m, 1H), 1.58-1.41 (m, 2H).

Example 259: 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(tetrazol-5-yl)phenyl)sulfamoyl)benzoic acid

(439) ##STR00593##

(440) Step 1: 1-(2-nitro-4-(tetrazol-5-yl)phenyl)piperidine: Et.sub.3N (720 l, 5.16 mmol) was added to a solution of 5-(4-fluoro-3-nitrophenyl)tetrazole (300 mg, 1.43 mmol) and piperidine (185 l, 1.87 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 20 h. 1 M HCl(aq) (2 ml) was added and the organic phase was dried by passage through a phase separator. The filtrate was concentrated in vacuo to afford the title compound (406 mg, 1.43 mmol, 100% yield, 97% purity) as a dark orange viscous oil. UPLC-MS (Method 2) m/z 275.2 (M+H).sup.+, 273.1 (MH).sup. at 0.92 min.

(441) Step 2: 2-(piperidin-1-yl)-5-(tetrazol-5-yl)aniline: 5% Pd/C (50% w/w water) Type 87L (107 mg, 0.025 mmol) in EtOH (1 ml) was added to a filtered solution of the product from step 1 above (394 mg, 1.44 mmol) in EtOH (6.4 ml) at RT. The reaction mixture was stirred at RT under H.sub.2 (4 bar pressure) for 19 h. The catalyst was removed by filtration through Celite and washed with MeOH (20 ml). The filtrate was concentrated in vacuo and the residue was dissolved in DCM (5 ml) and dried by passage through a phase separator. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (206 mg, 0.801 mmol, 56% yield, 95% purity) as a cream solid. UPLC-MS (Method 2) m/z 243.1 (MH).sup. at 0.78 min.

(442) Step 3: methyl 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(tetrazol-5-yl)phenyl)sulfamoyl)benzoate: The product from step 2 above (61.5 mg, 0.252 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (81 l, 1.01 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 3 days. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (37.4 mg, 0.078 mmol, 31% yield, 99% purity) as a sticky cream solid. UPLC-MS (Method 1) m/z 473.4 (M+H).sup.+, 471.3 (MH).sup. at 1.45 min.

(443) Step 4: 4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(tetrazol-5-yl)phenyl)sulfamoyl)benzoic acid: The product from step 3 above (35 mg, 0.074 mmol) was dissolved in THF (2 ml) and treated with 1 M LiOH(aq) (296 l, 0.296 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 50 C. to afford the title compound (29.1 mg, 0.060 mmol, 81% yield, 95% purity) as a pale yellow solid. UPLC-MS (Method 1) m/z 459.2 (M+H).sup.+, 457.2 (MH).sup. at 1.31 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 16.79 (br s, 1H), 13.10 (br s, 1H), 8.74 (s, 1H), 8.42 (d, J=2.2 Hz, 1H), 8.12 (dd, J=8.7, 2.2 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.67 (dd, J=8.3, 2.0 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 3.95 (s, 3H), 2.83-2.71 (m, 4H), 1.71-1.63 (m, 4H), 1.58-1.50 (m, 2H).

Example 260: I-3-(N-(5-cyano-2-(3-hydroxypiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(444) ##STR00594##

(445) Step 1: I-methyl 3-(N-(5-cyano-2-(3-hydroxypiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoate: The product from Example 258 step 2 (55.1 mg, 0.254 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (82 l, 1.02 mmol) and treated with a solution of the product from Example 203 step 2 (80 mg, 0.305 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (62.7 mg, 0.141 mmol, 56% yield, 100% purity) as a white solid. UPLC-MS (Method 1) m/z 444.4 (M+H).sup.+, 442.3 (MH).sup. at 1.50 min.

(446) Step 2: I-3-(N-(5-cyano-2-(3-hydroxypiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid: The product from step 1 above (60 mg, 0.135 mmol) was dissolved in THF (2 ml) and treated with 1 M LiOH(aq) (541 l, 0.541 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 50 C. to afford the title compound (57.8 mg, 0.125 mmol, 93% yield, 93% purity) as a white solid. UPLC-MS (Method 1) m/z 430.2 (M+H).sup.+, 428.2 (MH).sup. at 1.33 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.34 (br s, 1H), 9.77 (br s, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.10 (dd, J=8.0, 1.8 Hz, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.48 (br d, J=8.2 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 5.16 (br s, 1H), 3.71 (br s, 1H), 3.15-2.85 (m, 4H), 2.72-2.62 (m, 2H), 1.86-1.76 (m, 1H), 1.73-1.63 (m, 1H), 1.51-1.41 (m, 2H), 1.21 (t, J=7.4 Hz, 3H).

Example 261: 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(tetrazol-5-yl)phenyl)sulfamoyl)benzoic acid

(447) ##STR00595##

(448) Step 1: methyl 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(tetrazol-5-yl)phenyl)sulfamoyl)benzoate: The product from Example 259 step 2 (62.0 mg, 0.254 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (82 l, 1.02 mmol) and treated with a solution of the product from Example 203 step 2 (80 mg, 0.305 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 3 days. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (37.6 mg, 0.076 mmol, 30% yield, 95% purity) as a light yellow solid. UPLC-MS (Method 1) m/z 471.3 (M+H).sup.+, 469.3 (MH).sup. at 1.65 min.

(449) Step 2: 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(tetrazol-5-yl)phenyl)sulfamoyl)benzoic acid: The product from step 1 above (35 mg, 0.074 mmol) was dissolved in THF (2 ml) and treated with 1 M LiOH(aq) (298 l, 0.298 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 50 C. to afford the title compound (30.9 mg, 0.068 mmol, 91% yield, 95% purity) as a pale brown solid. UPLC-MS (Method 1) m/z 457.3 (M+H).sup.+, 455.2 (MH).sup. at 1.51 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 16.75 (br s, 1H), 13.22 (br s, 1H), 9.33 (br s, 1H), 8.36 (d, J=1.9 Hz, 1H), 8.07 (dd, J=8.0, 1.9 Hz, 1H), 7.86 (d, J=2.1 Hz, 1H), 7.75 (dd, J=8.4, 2.1 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 3.05 (q, J=7.4 Hz, 2H), 2.77-2.67 (m, 4H), 1.56-1.49 (m, 4H), 1.48-1.41 (m, 2H), 1.21 (t, J=7.4 Hz, 3H).

Example 262: I-4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl) sulfamoyl)benzoic acid

(450) ##STR00596##

(451) Step 1: I-3-fluoro-1-(4-(methylsulfonyl)-2-nitrophenyl)piperidine: Et.sub.3N (449 l, 3.22 mmol) was added to a solution of 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (196 mg, 0.895 mmol) and I-3-fluoropiperidine hydrochloride (125 mg, 0.895 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 20 h. 1 M HCl(aq) (2 ml) was added and the organic phase was dried by passage through a phase separator. The filtrate was concentrated in vacuo to afford the title compound (273 mg, 0.895 mmol, 100% yield, 99% purity) as a dark yellow solid. UPLC-MS (Method 2) m/z no ionisation at 1.15 min.

(452) Step 2: I-2-(3-fluoropiperidin-1-yl)-5-(methylsulfonyl)aniline: 5% Pd/C (50% w/w water) Type 87L (107 mg, 0.025 mmol) in EtOH (1 ml) was added to a suspension of the product from step 1 above (273 mg, 0.895 mmol, 99% purity) in EtOH (19 ml) at RT. The reaction mixture was stirred at RT under H.sub.2 (4 bar pressure) for 3 days. The catalyst was removed by filtration through Celite and washed with MeOH (20 ml). The filtrate was concentrated in vacuo to afford the title compound (239 mg, 0.867 mmol, 96% yield, 99% purity) as a cream solid. UPLC-MS (Method 2) m/z 273.1 (M+H).sup.+ at 1.37 min.

(453) Step 3: I-methyl 4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoate: The product from step 2 above (69.1 mg, 0.254 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (82 l, 1.02 mmol) and treated with a solution of the product from Example 203 step 2 (80 mg, 0.305 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 2 days. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (55.7 mg, 0.112 mmol, 44% yield) as a white solid. UPLC-MS (Method 1) m/z 499.3 (M+H).sup.+, 497.2 (MH).sup. at 1.54 min.

(454) Step 4: I-4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoic acid: The product from step 3 above (53 mg, 0.106 mmol) was dissolved in THF (5 ml) and treated with 1 M LiOH(aq) (425 l, 0.425 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. More 1 M LiOH(aq) (425 l, 0.425 mmol) was added and the reaction mixture was stirred at 40 C. for 1 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 50 C. to afford the title compound (21.3 mg, 0.043 mmol, 40% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m/z 485.3 (M+H).sup.+, 483.1 (MH).sup. at 1.39 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.32 (br s, 1H), 9.45 (br s, 1H), 8.35 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.0, 1.9 Hz, 1H), 7.64-7.57 (m, 2H), 7.49 (d, J=2.2 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 4.86-4.64 (m, 1H), 3.21-3.11 (m, 1H), 3.07-2.98 (m, 5H), 2.95-2.85 (m, 2H), 2.81-2.74 (m, 1H), 2.00-1.86 (m, 1H), 1.82-1.72 (m, 1H), 1.71-1.53 (m, 2H), 1.20 (t, J=7.4 Hz, 3H).

Example 263: (S)-3-(N-(5-cyano-2-(3-hydroxypiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(455) ##STR00597##

(456) Step 1: (S)-4-(3-hydroxypiperidin-1-yl)-3-nitrobenzonitrile: Et.sub.3N (906 l, 6.50 mmol) was added to a solution of 4-fluoro-3-nitrobenzonitrile (300 mg, 1.81 mmol) and(S)-piperidin-3-ol hydrochloride (249 mg, 1.81 mmol) in DCM (20 ml) and the resultant solution was stirred at RT overnight. 1 M HCl(aq) (2 ml) was added and the organic phase was concentrated in vacuo to afford the title compound (465 mg, 1.81 mmol, 100% yield, 96% purity) as a dark orange viscous oil. UPLC-MS (Method 2) m/z 248.3 (M+H).sup.+, 246.2 (MH).sup. at 1.02 min.

(457) Step 2: (S)-3-amino-4-(3-hydroxypiperidin-1-yl)benzonitrile: A mixture of the product from step 1 above (447 mg, 1.81 mmol), iron powder (2.48 g, 44.4 mmol), ammonium chloride (116 mg, 2.17 mmol), IPA (15 ml) and water (7.6 ml) was stirred at 90 C. for 20 h. The mixture was filtered through Celite, rinsing with MeOH (25 ml) and the filtrate was concentrated in vacuo. The residue was diluted with DCM (20 ml), dried by passage through a phase separator and the crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (190 mg, 0.875 mmol, 48% yield, 100% purity) as a dark orange solid. UPLC-MS (Method 2) m/z 218.3 (M+H).sup.+ at 0.95 min.

(458) Step 3: (S)-methyl 3-(N-(5-cyano-2-(3-hydroxypiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoate: The product from step 2 above (55.1 mg, 0.254 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (82 l, 1.02 mmol) and treated with a solution of the product from Example 203 step 2 (80 mg, 0.305 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (42.7 mg, 0.094 mmol, 37% yield, 98% purity) as a white solid. UPLC-MS (Method 1) m/z 444.4 (M+H).sup.+, 442.3 (MH).sup. at 1.50 min.

(459) Step 4: (S)-3-(N-(5-cyano-2-(3-hydroxypiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid: The product from step 3 above (40 mg, 0.090 mmol) was dissolved in THF (2 ml) and treated with 1 M LiOH(aq) (361 l, 0.361 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 50 C. to afford the title compound (34.7 mg, 0.078 mmol, 87% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m/z 430.3 (M+H).sup.+, 428.2 (MH).sup. at 1.33 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.34 (br s, 1H), 9.76 (br s, 1H), 8.35 (d, J=1.8 Hz, 1H), 8.10 (dd, J=8.0, 1.8 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.48 (dd, J=8.3, 1.9 Hz, 1H), 7.31 (d, J=1.9 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 5.16 (s, 1H), 3.70 (br s, 1H), 3.13-2.82 (m, 4H), 2.71-2.61 (m, 2H), 1.85-1.75 (m, 1H), 1.73-1.62 (m, 1H), 1.51-1.41 (m, 2H), 1.20 (t, J=7.4 Hz, 3H).

Example 264: (S)-3-(N-(5-cyano-2-(3-hydroxypiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(460) ##STR00598##

(461) Step 1: (S)-methyl 3-(N-(5-cyano-2-(3-hydroxypiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from Example 263 step 2 (54.7 mg, 0.252 mmol) was suspended in a mixture of DCM (1 ml) and pyridine (81 l, 1.01 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (91.9 mg, 0.206 mmol, 82% yield, 100% purity) as a cream solid. UPLC-MS (Method 1) m/z 446.3 (M+H).sup.+, 444.3 (MH).sup. at 1.31 min.

(462) Step 2: (S)-3-(N-(5-cyano-2-(3-hydroxypiperidin-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 2 above (89 mg, 0.200 mmol) was dissolved in THF (5 ml) and treated with 1 M LiOH(aq) (799 l, 0.799 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 50 C. to afford the title compound (79.6 mg, 0.179 mmol, 90% yield, 97% purity) as a cream solid. UPLC-MS (Method 1) m/z 432.2 (M+H).sup.+, 430.1 (MH).sup. at 1.14 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.19 (br s, 1H), 9.24 (br s, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.16 (dd, J=8.7, 2.2 Hz, 1H), 7.45 (dd, J=8.3, 1.9 Hz, 1H), 7.41 (d, J=1.9 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 5.10 (s, 1H), 3.89 (s, 3H), 3.77-3.69 (m, 1H), 2.95-2.85 (m, 2H), 2.79-2.71 (m, 1H), 2.70-2.62 (m, 1H), 1.90-1.81 (m, 1H), 1.76-1.67 (m, 1H), 1.58-1.37 (m, 2H).

Example 265: I-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(463) ##STR00599##

(464) Step 1: I-3-fluoro-1-(2-nitro-4-(tetrazol-1-yl)phenyl)piperidine: Et.sub.3N (449 l, 3.22 mmol) was added to a solution of the product from Example 214 step 1 (187 mg, 0.895 mmol) and I-3-fluoropiperidine hydrochloride (125 mg, 0.895 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 20 h. 1 M HCl(aq) (2 ml) was added and the organic phase was dried by passage through a phase separator and concentrated in vacuo to afford the title compound (281 mg, 0.895 mmol, 100% yield, 93% purity) as a dark orange viscous oil. UPLC-MS (Method 2) m/z no ionisation at 1.20 min.

(465) Step 2: I-2-(3-fluoropiperidin-1-yl)-5-(tetrazol-1-yl)aniline: 5% Pd/C (50% w/w water) Type 87L (107 mg, 0.025 mmol) in EtOH (1 ml) was added to a suspension of the product from step 1 above (281 mg, 0.895 mmol, 93% purity) in EtOH (19 ml) at RT. The reaction mixture was stirred at RT under H.sub.2 (4 bar pressure) for 3 days. The catalyst was removed by filtration through Celite and washed with MeOH (20 ml). The filtrate was concentrated in vacuo to afford the title compound (241 mg, 0.863 mmol, 96% yield, 96% purity) as a light yellow viscous oil. UPLC-MS (Method 2) m/z no ionisation at 1.14 min.

(466) Step 3: I-methyl 3-(N-(2-(3-fluoropiperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from step 2 above (66.1 mg, 0.237 mmol, 96% purity) was dissolved in a mixture of DCM (1 ml) and pyridine (81 l, 1.01 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (73.0 mg, 0.144 mmol, 61% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m/z 491.3 (M+H).sup.+, 489.2 (MH).sup. at 1.31 min.

(467) Step 4: I-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 3 above (71 mg, 0.141 mmol, 97% purity) was dissolved in THF (2 ml) and treated with 1 M LiOH(aq) (579 l, 0.579 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 50 C. to afford the title compound (55.8 mg, 0.111 mmol, 77% yield, 95% purity) as a cream solid. UPLC-MS (Method 1) m/z 477.2 (M+H).sup.+, 475.2 (MH).sup. at 1.25 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.16 (br s, 1H), 9.95 (s, 1H), 8.81 (br s, 1H), 8.42 (d, J=2.2 Hz, 1H), 8.14 (dd, J=8.7, 2.2 Hz, 1H), 7.79 (d, J=2.4 Hz, 1H), 7.54 (dd, J=8.6, 2.5 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 4.95-4.79 (m, 1H), 3.93 (s, 3H), 3.07-2.70 (m, 4H), 1.97-1.74 (m, 3H), 1.74-1.64 (m, 1H).

Example 266: I-4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(tetrazol-1-yl)phenyl) sulfamoyl)benzoic acid

(468) ##STR00600##

(469) Step 1: I-methyl 4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoate: The product from Example 265 step 2 (66.6 mg, 0.254 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (82 l, 1.02 mmol) and treated with a solution of the product from Example 203 step 2 (80 mg, 0.302 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (35.6 mg, 0.071 mmol, 28% yield, 97% purity) as a sticky cream solid. UPLC-MS (Method 1) m/z 489.3 (M+H).sup.+, 487.3 (MH).sup. at 1.58 min.

(470) Step 2: I-4-ethyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid: The product from step 2 above (33 mg, 0.068 mmol) was dissolved in THF (2 ml) and treated with 1 M LiOH(aq) (270 l, 0.270 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 50 C. to afford the title compound (29.4 mg, 0.061 mmol, 90% yield, 98% purity) as a cream solid. UPLC-MS (Method 1) m/z 473.2 (MH).sup. at 1.43 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.31 (br s, 1H), 9.97 (s, 1H), 9.38 (br s, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.0, 1.8 Hz, 1H), 7.72 (d, J=2.5 Hz, 1H), 7.62 (app. D, J=8.0 Hz, 2H), 7.44 (d, J=8.6 Hz, 1H), 4.84-4.67 (m, 1H), 3.13-2.94 (m, 3H), 2.83-2.74 (m, 2H), 2.69-2.61 (m, 1H), 2.00-1.85 (m, 1H), 1.82-1.70 (m, 1H), 1.70-1.55 (m, 2H), 1.22 (t, J=7.4 Hz, 3H).

Example 267:4-cyclopropyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

(471) ##STR00601##

(472) Step 1: methyl 4-bromo-3-(chlorosulfonyl)benzoate: A mixture of 4-bromo-3-(chlorosulfonyl)benzoic acid (500 mg, 1.67 mmol) and SOCl.sub.2 (5 ml) was heated under reflux for 4 h. Upon cooling to RT mixture was concentrated in vacuo and the residue was added slowly to MeOH (10 ml) at 0 C. The mixture was concentrated in vacuo to provide the title compound (758 mg, 1.45 mmol, 87% yield, 60% purity), contaminated with 4-bromo-3-(chlorosulfonyl)benzoic acid, as a beige solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.50-8.46 (m, 1H), 7.78-7.68 (m, 2H), 3.86 (s, 3H).

(473) Step 2: methyl 4-bromo-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: A mixture of 2-(piperidin-1-yl)-5-(trifluoromethyl)aniline (240 mg, 0.653 mmol, 60% purity), the product from step 1 above (341 mg, 1.09 mmol) and pyridine (0.25 ml, 3.09 mmol) in DCM (6.5 ml) was stirred at RT for 2 days. The mixture was concentrated onto silica and purified by chromatography on silica gel (12 g cartridge, 0-30% EtOAc/isohexane) to afford the title compound (325 mg, 0.605 mmol, 93% yield, 97% purity) as a beige solid. UPLC-MS (Method 1) m/z 521.1 (M+H).sup.+, 519.0 (MH).sup. at 2.00 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6).Math. 9.49 (s, 1H), 8.46 (br s, 1H), 8.04 (br s, 2H), 7.47-7.41 (m, 1H), 7.38-7.34 (m, 1H), 7.34-7.28 (m, 1H), 3.88 (s, 3H), 2.77 (t, J=5.2 Hz, 4H), 1.62-1.54 (m, 4H), 1.51-1.44 (m, 2H).

(474) Step 3: methyl 4-bromo-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)-N-((2-(trimethylsilyl) ethoxy)methyl)sulfamoyl)benzoate: A suspension of NaH (36 mg, 0.900 mmol, 60% w/w in mineral oil) in THF (5 ml) was cooled to 0 C. and slowly treated with the product from step 2 above (325 mg, 0.605 mmol) in THF (5 ml). The mixture was warmed to RT and stirred for 1 h, then treated with SEM-CI (0.150 ml, 0.847 mmol). The resultant mixture was stirred at RT overnight. The mixture was carefully quenched with water (15 ml) and extracted with EtOAc (340 ml). The combined organic phases were washed with brine (15 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (24 g cartridge, 0-20% EtOAc/isohexane) to afford the title compound (275 mg, 0.418 mmol, 69% yield, 99% purity) as a clear colourless oil. UPLC-MS (Method 1) m/z 651.7 (M+H).sup.+ at 2.30 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.44-8.40 (m, 1H), 8.11-8.04 (m, 2H), 7.69-7.63 (m, 1H), 7.34-7.28 (m, 2H), 5.45 (br s, 1H), 5.00 (br s, 1H), 3.86 (s, 3H), 3.38 (br s, 2H), 2.90-2.79 (m, 4H), 1.55 (br s, 4H), 1.53-1.48 (m, 2H), 0.67 (t, J=8.0 Hz, 2H), 0.16 (s, 9H).

(475) Step 4: methyl 4-cyclopropyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: Two reactions were set up. A mixture of the product from step 3 above (20 mg, 0.030 mmol) and tributyl(cyclopropyl) stannane (20 mg, 0.060 mmol) in dioxane (0.5 ml) was purged with N.sub.2 for 10 min before .sup.tBuXPhos Pd G3 (2.5 mg, 3.15 mol) was added. The mixture was purged with N.sub.2 for 5 min and then heated to reflux and stirred overnight. The same reaction was set up using the product from step 3 above (80 mg, 0.122 mmol). The two reaction mixtures were combined, concentrated onto silica and purified by chromatography on silica gel (4 g cartridge, 0-50% EtOAc/isohexane) to provide the title compound (80 mg, 0.078 mmol, 51% yield, 47% purity) as a mixture with methyl 4-butyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate (29% impurity). UPLC-MS (Method 1) m/z 483.3 (M+H).sup.+, 481.3 (MH).sup. at 2.03 min.

(476) Step 5: 4-cyclopropyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: A mixture of the product from step 4 above (80 mg, 0.078 mmol, 47% purity) and LiOH (30 mg, 0.702 mmol) in THF/MeOH/water (4:1:1, 2.4 ml) was stirred at 40 C. overnight. The mixture was diluted with water (5 ml) and the pH was adjusted to pH 4 using 1 M HCl(aq). The aqueous phase was extracted with EtOAc (320 ml). The combined organic phases were washed with brine (10 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The crude product was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 60-90% MeCN in Water) to afford the title compound (17.4 mg, 0.037 mmol, 47% yield, 99% purity) as a white solid. UPLC-MS (Method 1) m/z 469.3 (M+H).sup.+, 467.2 (MH).sup. at 1.88 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.44 (d, J=1.9 Hz, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.35-7.26 (m, 2H), 7.25-7.17 (m, 1H), 7.12 (d, J=8.2 Hz, 1H), 2.88-2.77 (m, 5H), 1.63-1.55 (m, 4H), 1.52-1.45 (m, 2H), 1.11-1.04 (m, 2H), 0.86-0.79 (m, 2H). Two exchangeable protons not observed.

Example 268: 4-butyl-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid

(477) ##STR00602##

(478) The title compound (11.7 mg, 0.023 mmol, 53% yield, 95% purity) was obtained as a white solid by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 60-90% MeCN in Water) as a by-product from the reaction in Example 267 step 5. UPLC-MS (Method 1) m/z 485.3 (M+H).sup.+, 483.2 (MH).sup. at 2.05 min. 1H NMR (500 MHz, DMSO-d.sub.6) 8.39 (d, J=1.8 Hz, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.43-7.28 (m, 2H), 7.26-7.15 (m, 1H), 2.92 (t, J=7.9 Hz, 2H), 2.81-2.66 (m, 4H), 1.61-1.41 (m, 8H), 1.39-1.29 (m, 2H), 0.87 (t, J=7.3 Hz, 3H). Two exchangeable protons not observed.

Example 269: I-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)-4-methoxybenzoic acid

(479) ##STR00603##

(480) Step 1: I-methyl 3-(N-(2-(3-fluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)-4-methoxybenzoate: The product from Example 262 step 2 (68.6 mg, 0.252 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (81 l, 1.01 mmol) and treated with a solution of methyl 3-(chlorosulfonyl)-4-methoxybenzoate (80 mg, 0.302 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 2 days. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (95.6 mg, 0.191 mmol, 76% yield) as a white solid. UPLC-MS (Method 1) m/z 501.3 (M+H).sup.+, 499.2 (MH).sup. at 1.37 min.

(481) Step 2: I-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)-4-methoxybenzoic acid: The product from step 2 above (93 mg, 0.186 mmol) was dissolved in THF (5 ml) and treated with 1 M LiOH(aq) (743 l, 0.743 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 20 h. Additional 1 M LiOH(aq) (743 l, 0.743 mmol) was added and the reaction was stirred at 40 C. for a further 3 days. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 50 C. to afford the title compound (69.4 mg, 0.134 mmol, 72% yield, 94% purity) as a white solid. UPLC-MS (Method 1) m/z 487.2 (M+H).sup.+, 485.1 (MH).sup. at 1.22 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.18 (br s, 1H), 8.82 (br s, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.15 (dd, J=8.7, 2.2 Hz, 1H), 7.65 (d, J=2.2 Hz, 1H), 7.54 (dd, J=8.4, 2.2 Hz, 1H), 7.41-7.27 (m, 2H), 4.94-4.78 (m, 1H), 3.92 (s, 3H), 3.15-2.91 (m, 3H), 2.89-2.81 (m, 1H), 1.98-1.74 (m, 3H), 1.73-1.61 (m, 1H). Three protons obscured by solvent.

Example 270: 4-ethyl-3-(N-(2-(3-hydroxy-3-methylazetidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(482) ##STR00604##

(483) Step 1: 3-methyl-1-(2-nitro-4-(trifluoromethyl)phenyl) azetidin-3-ol: Et.sub.3N (720 l, 5.18 mmol) was added to a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (201 l, 1.44 mmol) and 3-methylazetidin-3-ol hydrochloride (230 mg, 1.87 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 20 h. 1 M HCl(aq) (2 ml) was added and the organic phase was dried by passage through a phase separator and concentrated in vacuo to afford the title compound (396 mg, 1.44 mmol, 100% yield) as a light orange viscous oil. UPLC-MS (Method 2) m/z no ionisation at 1.34 min.

(484) Step 2: 1-(2-amino-4-(trifluoromethyl)phenyl)-3-methylazetidin-3-ol: 5% Pd/C (50% w/w water) Type 87L (107 mg, 0.025 mmol) in EtOH (1 ml) was added to a suspension of the product from step 1 above (396 mg, 1.44 mmol) in EtOH (6.4 ml) at RT. The reaction mixture was stirred at RT under H.sub.2 (4 bar pressure) for 19 h. The catalyst was removed by filtration through Celite and washed with MeOH (20 ml). The filtrate was concentrated in vacuo and the residue was suspended in DCM (5 ml) and dried by passage through a phase separator. The crude product was purified directly by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (326 mg, 1.32 mmol, 92% yield) as a light orange solid. UPLC-MS (Method 2) m/z 247.3 (M+H).sup.+ at 1.11 min.

(485) Step 3: methyl 4-ethyl-3-(N-(2-(3-hydroxy-3-methylazetidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: The product from step 2 above (62.5 mg, 0.254 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (82 l, 1.02 mmol) and treated with a solution of the product from Example 203 step 2 (80 mg, 0.305 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 20 h. The crude product was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (12.7 mg, 0.026 mmol, 10% yield, 95% purity) as a light pink viscous oil. UPLC-MS (Method 1) m/z 473.4 (M+H).sup.+, 471.3 (MH).sup. at 1.52 min.

(486) Step 4: 4-ethyl-3-(N-(2-(3-hydroxy-3-methylazetidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: The product from step 3 above (12.7 mg, 0.027 mmol) was dissolved in THF (2 ml) and treated with 1 M LiOH(aq) (108 l, 0.108 mmol). MeOH was added dropwise until the mixture was a solution and the reaction was stirred at 30 C. for 2 days. Additional 1 M LiOH(aq) (108 l, 0.108 mmol) was added and the reaction was stirred at 40 C. for 5 h. Additional 1 M LiOH(aq) (108 l, 0.108 mmol) was added and the reaction was stirred at 40 C. for 3 days. Additional 1 M LiOH(aq) (108 l, 0.108 mmol) was added and the reaction was stirred at 40 C. for 24 h. Additional 1 M LiOH(aq) (500 l, 0.500 mmol) was added and the reaction was stirred at 40 C. for 24 h. The reaction mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and neutralised to pH 6 using 1 M HCl(aq). The resultant lumpy suspension was sonicated to afford a cloudy suspension which was concentrated in vacuo to 2 ml. The precipitate was collected by filtration, washing with water (22 ml). The solid was suspended in MeCN (4 ml), concentrated in vacuo and dried at 50 C. The crude product was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 35-65% MeCN in Water) to afford the title compound (4 mg, 8.46 mol, 32% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m/z 459.3 (M+H).sup.+, 457.2 (MH).sup. at 1.37 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.03 (br s, 1H), 9.60 (br s, 1H), 8.26 (d, J=1.8 Hz, 1H), 8.09 (d, J=7.7 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H), 7.28 (br s, 1H), 6.49 (d, J=8.6 Hz, 1H), 6.33 (br s, 1H), 5.50 (s, 1H), 4.00 (d, J=8.1 Hz, 2H), 3.89 (d, J=8.1 Hz, 2H), 2.94 (q, J=7.4 Hz, 2H), 1.42 (s, 3H), 1.17 (t, J=7.4 Hz, 3H).

Example 271: 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-(pyrazol-1-yl)benzoic acid

(487) ##STR00605##

(488) Step 1: methyl 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-(pyrazol-1-yl)benzoate: To a degassed solution of Example 267 Step 3 (100 mg, 0.152 mmol) in DMSO (0.75 ml) was added pyrazole (25.0 mg, 0.367 mmol), CuI (10 mg, 0.053 mmol), L-proline (8.0 mg, 0.069 mmol) and K.sub.2CO.sub.3 (75.0 mg, 0.543 mmol). The mixture was heated to 90 C. overnight. The mixture was diluted with water (10 ml) and EtOAc (10 ml) and the solid was removed by filtration. The filtrate was extracted with EtOAc (315 mL), the organic phases were then combined, washed with brine (10 ml) and dried by passage through a phase separator. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.30 g, 0.047 mmol, 31% yield, 80% purity) as a pale yellow solid. UPLC-MS (Method 1) m/z 509.2 (M+H).sup.+, 507.2 (MH).sup. at 1.98 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.68 (s, 1H), 10.00 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.45-8.35 (m, 1H), 8.31-8.25 (m, 1H), 8.02-7.96 (m, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.81-7.77 (m, 1H), 7.46-7.40 (m, 1H), 7.38-7.33 (m, 1H), 6.69 (s, 1H), 2.74-2.66 (m, 4H), 1.63-1.55 (m, 4H), 1.52-1.46 (m, 2H).

(489) Step 2: 3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-(pyrazol-1-yl)benzoic acid: A mixture of the product from step 1 above (30 mg, 0.047 mmol) and LiOH (5.6 mg, 0.23 mmol) in THF/MeOH/water (4:1:1, 1 ml) was stirred at 40 C. overnight. The mixture was diluted with water (5 ml), acidified to pH 4 using 1 M HCl(aq) and extracted with EtOAc (320 ml). The combined organic extracts were washed with brine (10 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (9.0 mg, 0.018 mmol, 37% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m/z 495.2 (M+H).sup.+, 493.1 (MH).sup. at 1.33 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.68 (s, 1H), 10.00 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.45-8.35 (m, 1H), 8.31-8.25 (m, 1H), 8.02-7.96 (m, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.81-7.77 (m, 1H), 7.46-7.40 (m, 1H), 7.38-7.33 (m, 1H), 6.69 (s, 1H), 2.74-2.66 (m, 4H), 1.63-1.55 (m, 4H), 1.52-1.46 (m, 2H).

Example 272: 4-(oxetan-2-yl)-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(490) ##STR00606##

(491) Step 1: methyl 4-bromo-2-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)-N-((2-(trimethylsilyl) ethoxy)methyl)sulfamoyl)benzoate: A solution of the product from Example 228 Step 1 (1.20 g, 2.30 mmol) in THF (10 ml, 122 mmol) was cooled to 0 C., then treated with sodium hydride (0.138 g, 3.45 mmol, 60% w/w in mineral oil). The mixture was warmed to RT and stirred for 1 h, then treated with SEM-CI (0.572 ml, 3.22 mmol). The resultant mixture was stirred at RT overnight, then diluted with water (50 ml) and extracted with EtOAc (50 ml). The organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-50% TBME/isohexane) to afford the title compound (1.33 g, 1.8 mmol, 80% yield, 90% purity) as a colourless oil. UPLC-MS (Method 1) m/z 651.3 (M+H).sup.+ at 2.30 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.11 (d, J=1.9 Hz, 1H), 8.04 (dd, J=8.2, 1.9 Hz, 1H), 7.71-7.64 (m, 1H), 7.62 (dd, J=8.3, 1.8 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 7.27-7.21 (m, 1H), 5.76 (s, 2H), 3.61 (s, 3H), 3.52-3.42 (m, 2H), 3.00-2.75 (m, 4H), 1.54-1.48 (m, 6H), 0.84-0.76 (m, 2H), 0.13 (s, 9H).

(492) Step 2: 5-bromo-2-(hydroxymethyl)-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)-N-((2-(trimethylsilyl) ethoxy)methyl)benzenesulfonamide: A solution of the product from Step 1 above (1.20 g, 1.66 mmol, 90% purity) in THF (20 ml, 244 mmol) was cooled to 0 C., then treated with 2.0 M LiAlH.sub.4 in THF (0.921 ml, 1.8 mmol, 90% purity). The mixture was stirred at 0 C. for 1 h. The mixture was carefully quenched with water (20 ml) and extracted with EtOAc (100 ml). The organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-20% TBME/isohexane) to afford the title compound (0.685 g, 1.00 mmol, 60% yield, 90% purity) as a colourless oil. UPLC-MS (Method 1) m/z 622.9 (M+H).sup.+ at 2.25 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6).Math. 7.98-7.88 (m, 2H), 7.80 (d, J=8.3 Hz, 1H), 7.70-7.61 (m, 1H), 7.29 (d, J=8.6 Hz, 1H), 7.19 (d, J=2.3 Hz, 1H), 5.48 (t, J=5.3 Hz, 1H), 4.64 (d, J=45.8 Hz, 2H), 3.32 (s, 2H), 2.97-2.92 (m, 4H), 1.62-1.45 (m, 6H), 0.90-0.80 (m, 2H), 0.77-0.68 (m, 2H), 0.15 (s, 9H).

(493) Step 3: 5-bromo-2-formyl-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)-N-((2-(trimethylsilyl) ethoxy)methyl)benzenesulfonamide: The product from Step 2 above (0.685 g, 1.00 mmol, 90% purity) in DCM (20 ml, 311 mmol) was treated with MnO2 (0.955 g, 10.9 mmol). The mixture was stirred at RT for 2 h, then filtered through Celite, and concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-20% TBME/isohexane) to afford the title compound (0.410 g, 0.60 mmol, 61% yield, 92% purity) as a colourless oil. UPLC-MS (Method 1) m/z 621.3 (M+H).sup.+ at 2.35 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 10.10 (d, J=0.8 Hz, 1H), 8.23-8.07 (m, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.65 (dd, J=8.8, 2.3 Hz, 1H), 7.28 (d, J=8.6 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 5.48 (d, J=10.7 Hz, 1H), 4.87 (d, J=10.8 Hz, 1H), 3.08-3.02 (br m, 4H), 1.65-1.52 (m, 6H), 0.93-0.78 (m, 2H), 0.73-0.62 (m, 2H), 0.15 (s, 9H).

(494) Step 4: 5-bromo-2-(oxetan-2-yl)-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)-N-((2-(trimethylsilyl) ethoxy)methyl)benzenesulfonamide: Trimethylsulphoxonium iodide (0.581 g, 2.64 mmol) in tert-butanol (10 ml, 105 mmol) was treated with KOtBu (0.296 g, 2.64 mmol). The mixture was stirred at 50 C. for 30 min, then treated with the product from Step 3 above (0.410 g, 0.607 mmol, 92% purity). The resultant mixture was stirred at 50 C. overnight, then filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-20% TBME/isohexane) to afford the title compound (0.165 g, 0.24 mmol, 40% yield, 95% purity) as a colourless oil. UPLC-MS (Method 1) m/z 649.3 at 2.40 min.

(495) Step 5: methyl 4-(oxetan-2-yl)-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)-N-((2-(trimethylsilyl) ethoxy)methyl)sulfamoyl)benzoate: A solution of the product from Step 4 above (0.160 g, 0.234 mmol), triethylamine (0.069 ml, 0.494 mmol) and PdCl2 (dppf).Math. DCM (0.040 g, 0.049 mmol) in MeOH (10 ml) was stirred at 100 C. under a CO atmosphere (4 bar). After 24 h, the reaction was cooled, filtered through Celite and concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-20% EtOAc/isohexane) to afford the title compound (0.085 g, 0.134 mmol, 57% yield, 99% purity) as a colourless oil. UPLC-MS (Method 1) m/z 629.4 (M+H).sup.+ at 2.28 min.

(496) Step 6: 4-(oxetan-2-yl)-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: A solution of the product from Step 5 above (0.085 g, 0.134 mmol, 99% purity) in THF (5 ml, 0.13 mmol) was treated with 1.0 M TBAF in THF (0.135 ml, 0.135 mmol) and stirred at RT for 16 h. Additional 1.0 M TBAF in THF (0.135 ml, 0.135 mmol) added and the resultant mixture heated at 40 C. for 80 h. The mixture was then treated with a solution of LiOH (9.71 mg, 0.40 mmol) in water (2 ml) and stirred at RT for 3 h. The mixture was acidified using 1.0 M citric acid (aq) and extracted with EtOAc (50 ml). The organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane, followed by 0-10% MeOH/EtOAc) to afford the title compound (10.3 mg, 0.020 mmol, 15% yield, 98% purity) as a colourless solid. UPLC-MS (Method 1) m/z 485.3 (M+H).sup.+ at 1.73 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.37 (s, 1H), 9.61 (s, 1H), 8.31-8.21 (m, 2H), 8.16 (d, J=8.0 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.31 (d, J=2.2 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 6.34 (t, J=7.5 Hz, 1H), 4.69 (td, J=7.9, 5.9 Hz, 1H), 4.57 (dt, J=9.1, 6.1 Hz, 1H), 3.19-3.09 (m, 1H), 2.79-2.67 (m, 2H), 2.60-2.53 (m, 2H), 2.42-2.32 (m, 1H), 1.54-1.46 (m, 4H), 1.45-1.38 (m, 2H).

Example 273: 4-ethyl-3-(N-(5-(1-methyl-1,2,3-triazol-4-yl)-2-(piperidin-1-yl)phenyl) sulfamoyl)benzoic acid

(497) ##STR00607##

(498) Step 1: 1-(4-bromo-2-nitrophenyl)piperidine: Piperidine (9.88 ml, 45.5 mmol) was added to a solution of 4-bromo-1-fluoro-2-nitrobenzene (5.60 ml, 45.5 mmol) in MeCN (50 ml) and then the resulting solution was stirred at RT for 2 h. The solution was concentrated in vacuo. The residue was purified by chromatography on silica gel (220 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (13.4 g, 44.7 mmol, 97% yield, 94% purity) as a red oil. UPLC-MS (Method 1) m/z 285.1 (M+H).sup.+ at 1.82 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.99 (d, J=2.4 Hz, 1H), 7.71 (dd, J=8.9, 2.5 Hz, 1H), 7.24 (d, J=8.9 Hz, 1H), 3.01-2.86 (m, 4H), 1.63-1.55 (m, 4H), 1.55-1.49 (m, 2H).

(499) Step 2: 1-(2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine: A mixture of the product from Step 1 above (12.30 g, 43.1 mmol, 94% purity), Bis(pinacolato)diboron (13.2 g, 51.8 mmol), KOAc (12.7 g, 129 mmol) and PdCl.sub.2 (dppf).Math. DCM (3.16 g, 4.31 mmol) in dioxane (10 ml) was degassed with N.sub.2 for 15 min and then heated at 80 C. for 16 h. The mixture was diluted with water (250 ml) and extracted with EtOAc (250 ml). The organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (220 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (15.6 g, 44.7 mmol, 97% yield, 85% purity) as a brown oil. UPLC-MS (Method 1) m/z 333.3 (M+H).sup.+ at 1.99 min.

(500) .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.95 (d, J=1.6 Hz, 1H), 7.73 (dd, J=8.4, 1.6 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 3.10-2.99 (m, 4H), 1.67-1.49 (m, 6H), 1.29 (s, 12H).

(501) Step 3: 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline: A solution of the product from Step 2 above (15.6 g, 35.2 mmol, 85% purity) in MeOH (20 ml, 494 mmol) was treated with 10% Pd/C (3.75 g, 3.52 mmol). The resultant mixture was hydrogenated (2 bar) for 16 h, and then filtered through Celite and concentrated in vacuo. The residue was purified by chromatography on silica gel (220 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (5.20 g, 12.0 mmol, 41% yield, 95% purity) as a brown solid. UPLC-MS (Method 1) m/z 303.3 (M+H).sup.+ at 1.41 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.04 (d, J=1.4 Hz, 1H), 6.90 (dd, J=7.7, 1.5 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 4.63 (s, 2H), 2.80-2.70 (m, 4H), 1.65 (p, J=5.6 Hz, 4H), 1.55-1.49 (m, 2H), 1.26 (s, 12H).

(502) Step 4: methyl 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfamoyl)benzoate: A solution of product from Step 3 above (3.53 g, 11.1 mmol, 95% purity), methyl 3-(chlorosulfonyl)-4-ethylbenzoate (3.20 g, 12.18 mmol) and pyridine (3.60 ml, 44.5 mmol) in DCM (20 ml) was vigorously stirred at RT for 41 h. The reaction mixture was loaded onto Celite and purified by chromatography on silica gel (80 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (4.89 g, 9.16 mmol, 83% yield, 99% purity) as an off-white solid. UPLC-MS (Method 1) m/z 529.4 (M+H).sup.+ at 2.12 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.04 (br s, 1H), 8.38 (d, J=1.9 Hz, 1H), 8.11 (dd, J=8.0, 1.9 Hz, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.34 (dd, J=7.9, 1.5 Hz, 1H), 7.31 (d, J=1.4 Hz, 1H), 7.07 (d, J=7.9 Hz, 1H), 3.85 (s, 3H), 3.05 (q, J=7.4 Hz, 2H), 2.68 (app. T, J=5.2 Hz, 4H), 1.59-1.49 (m, 4H), 1.49-1.41 (m, 2H), 1.24-1.18 (m, 15H).

(503) Step 5: methyl 4-ethyl-3-(N-(5-(1-methyl-1,2,3-triazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: To the reaction vessel containing product from Step 4 above (0.150 g, 0.28 mmol, 99% purity), 4-bromo-1-methyl-1,2,3-triazole (0.055 g, 0.34 mmol), K.sub.3PO.sub.4 (0.078 g, 0.37 mmol) in dioxane (5 ml, 0.28 mmol) and water (1 ml) was added Xphos Pd G3 (0.024 g, 0.03 mmol). The resultant mixture was degassed with N.sub.2 for 15 min and then heated at 80 C. for 2 h. The reaction mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.106 g, 0.22 mmol, 77% yield) as a white solid. UPLC-MS (Method 1) m/z 484.4 (M+H).sup.+ at 1.67 min.

(504) Step 6: 4-ethyl-3-(N-(5-(1-methyl-1,2,3-triazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (0.658 ml, 0.658 mmol) was added to a solution of the product from Step 5 above (0.106 g, 0.219 mmol) in THF (5 ml, 61.0 mmol) and stirred at RT overnight. The mixture was then acidified to pH 6 using 10% w/v citric acid (aq) and the resultant precipitate was collected by filtration to afford the title compound (67.2 mg, 0.136 mmol, 65% yield, 99% purity) as a white solid. UPLC-MS (Method 1) m/z 470.4 (M+H).sup.+ at 1.58 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.37 (br s, 1H), 9.26 (br s, 1H), 8.38 (d, J=1.9 Hz, 1H), 8.09 (dd, J=8.0, 1.9 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.32 (dd, J=8.2, 2.1 Hz, 1H), 7.29-7.24 (m, 2H), 3.95 (s, 3H), 3.07 (q, J=7.4 Hz, 2H), 2.66 (t, J=5.3 Hz, 4H), 1.62-1.55 (m, 4H), 1.51-1.44 (m, 2H), 1.23 (t, J=7.4 Hz, 3H).

Example 274:4-ethyl-3-(N-(5-(1-methyl-1,2,3-triazol-5-yl)-2-(piperidin-1-yl)phenyl) sulfamoyl)benzoic acid

(505) ##STR00608##

(506) Step 1: methyl 4-ethyl-3-(N-(5-(1-methyl-1,2,3-triazol-5-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: To the reaction vessel containing the product from Example 273 Step 4 (0.150 g, 0.28 mmol, 99% purity), 5-bromo-1-methyl-1,2,3-triazole (0.055 g, 0.34 mmol), K.sub.3PO.sub.4 (0.078 g, 0.36 mmol) in dioxane (5 ml, 0.28 mmol) and water (1 ml) was added Xphos Pd G3 (0.024 g, 0.03 mmol). The resultant mixture was degassed with N.sub.2 for 15 min and then heated at 80 C. for 2 h. The reaction mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.115 g, 0.238 mmol, 85% yield) as a light brown oil. UPLC-MS (Method 1) m/z 484.4 (M+H).sup.+ at 1.65 min.

(507) Step 2: 4-ethyl-3-(N-(5-(1-methyl-1,2,3-triazol-5-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (0.713 ml, 0.71 mmol) was added to a solution of the product from Step 1 above (0.115 g, 0.238 mmol) in THF (5 ml) and stirred at RT overnight. The mixture was then acidified to pH 6 using 10% w/v citric acid (aq) and the resultant precipitate was collected by filtration to afford the title compound (76.1 mg, 0.154 mmol, 67% yield, 99% purity) as a white solid. UPLC-MS (Method 1) m/z 470.4 (M+H).sup.+ at 1.55 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.99 (br s, 1H), 8.42 (d, J=1.8 Hz, 1H), 8.36 (s, 1H), 8.05 (dd, J=7.9, 1.8 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.49 (dd, J=8.2, 2.0 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 4.06 (s, 3H), 3.06 (q, J=7.4 Hz, 2H), 2.61 (t, J=5.2 Hz, 4H), 1.57 (p, J=5.4 Hz, 4H), 1.50-1.45 (m, 2H), 1.21 (t, J=7.4 Hz, 3H).

Example 275:4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(thiazol-5-yl)phenyl)sulfamoyl)benzoic acid

(508) ##STR00609##

(509) Step 1: methyl 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(thiazol-5-yl)phenyl)sulfamoyl)benzoate: To the reaction vessel containing the product from Example 273 Step 4 (0.150 g, 0.28 mmol, 99% purity), 5-bromothiazole (0.056 g, 0.34 mmol), K.sub.3PO.sub.4 (0.078 g, 0.37 mmol) in dioxane (5 ml) and water (1 ml) was added Xphos Pd G3 (0.024 g, 0.03 mmol). The resultant mixture was degassed with N.sub.2 for 15 min and then heated at 80 C. for 6 h. The reaction mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.100 g, 0.19 mmol, 69% yield, 95% purity) as a brown oil. UPLC-MS (Method 1) m/z 486.3 (M+H).sup.+ at 1.80 min.

(510) Step 2: 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(thiazol-5-yl)phenyl)sulfamoyl)benzoic acid: 1.0 M LiOH(aq) (0.587 ml, 0.587 mmol) was added to a solution of the product from Step 1 above (0.100 g, 0.196 mmol, 95% purity) in THF (5 ml) and stirred at RT overnight. The mixture was then acidified to pH 6 with 10% w/v citric acid (aq) and the resultant precipitate was collected by filtration to afford the title compound (71.2 mg, 0.143 mmol, 75% yield, 97% purity) as a white solid. UPLC-MS (Method 1) m/z 472.3 (M+H).sup.+ at 1.75 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.36 (br s, 1H), 9.16 (br s, 1H), 9.03 (s, 1H), 8.44 (d, J=1.8 Hz, 1H), 8.10 (dd, J=8.0, 1.8 Hz, 1H), 8.05 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.42 (dd, J=8.3, 2.2 Hz, 1H), 7.28 (d, J=2.2 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 3.07 (q, J=7.4 Hz, 2H), 2.67 (t, J=5.2 Hz, 4H), 1.59 (p, J=5.7 Hz, 4H), 1.48 (m, 2H), 1.22 (t, J=7.4 Hz, 3H).

Example 276: 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(pyrazol-3-yl)phenyl)sulfamoyl)benzoic acid

(511) ##STR00610##

(512) To the reaction vessel containing the product from Example 273 Step 4 (0.150 g, 0.28 mmol, 99% purity), 3-bromopyrazole (0.050 g, 0.34 mmol), K.sub.3PO.sub.4 (0.078 g, 0.37 mmol) in dioxane (5 ml) and water (1 ml) was added Xphos Pd G3 (0.024 g, 0.03 mmol). The resultant mixture was degassed with N.sub.2 for 15 min and then heated at 80 C. for 10 h. The mixture was treated with 1 M NaOH (aq) (2 ml) and stirred for 1 h at RT and then extracted with TBME (50 ml). The aqueous phase was neutralised with saturated NH.sub.4Cl (aq) (1 ml) and extracted with EtOAc (20 ml). The organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 10-80% MeCN in Water) to afford the title compound to afford the title compound (18.2 mg, 0.04 mmol, 14% yield, 99% purity) as a brown solid. UPLC-MS (Method 1) m/z 455.4 (M+H).sup.+ at 1.54 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.13 (br s, 1H), 8.99 (s, 1H), 8.42 (d, J=1.8 Hz, 1H), 8.07 (dd, J=8.0, 1.8 Hz, 1H), 7.67 (s, 1H), 7.62-7.52 (m, 2H), 7.48 (dd, J=8.2, 2.0 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 6.43 (d, J=2.2 Hz, 1H), 3.07 (q, J=7.4 Hz, 2H), 2.68-2.58 (m, 4H), 1.57 (p, J=5.4 Hz, 4H), 1.50-1.44 (m, 2H), 1.22 (t, J=7.4 Hz, 3H).

Example 277:4-ethyl-3-(N-(5-(1-methylpyrazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid

(513) ##STR00611##

(514) Step 1: methyl 4-ethyl-3-(N-(5-(1-methylpyrazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: To the reaction vessel containing the product from Example 273 Step 4 (0.150 g, 0.28 mmol, 99% purity), 4-bromo-1-methylpyrazole (0.054 g, 0.34 mmol), K.sub.3PO.sub.4 (0.078 g, 0.37 mmol) in dioxane (5 ml) and water (1 ml) was added Xphos Pd G3 (0.024 g, 0.03 mmol). The resultant mixture was degassed with N.sub.2 for 15 min and then heated at 80 C. for 2 h. The reaction mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-60% EtOAc/isohexane) to afford the title compound (0.105 g, 0.214 mmol, 76% yield, 98% purity) as a light brown oil. UPLC-MS (Method 1) m/z 483.4 (M+H).sup.+ at 1.76 min.

(515) Step 2: 4-ethyl-3-(N-(5-(1-methylpyrazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 1.0 M LiOH(aq) (0.640 ml, 0.640 mmol) was added to a solution of the product from Step 1 above (0.105 g, 0.21 mmol, 98% purity) in THF (5 ml) and the resultant mixture stirred at RT overnight. The mixture was then acidified to pH 6 with 10% w/v citric acid (aq) and the resultant precipitate was collected by filtration to afford the title compound (41.9 mg, 0.085 mmol, 41% yield, 98% purity) as a tan solid. UPLC-MS (Method 1) m/z 469.4 (M+H).sup.+ at 1.64 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.40 (s, 1H), 8.92 (s, 1H), 8.48 (d, J=1.8 Hz, 1H), 8.08 (dd, J=8.0, 1.8 Hz, 1H), 7.91 (s, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.58 (d, J=0.8 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.21 (dd, J=8.2, 2.1 Hz, 1H), 7.14 (d, J=8.3 Hz, 1H), 3.84 (s, 3H), 3.06 (q, J=7.4 Hz, 2H), 2.59 (t, J=5.2 Hz, 4H), 1.59 (p, J=5.5 Hz, 4H), 1.52-1.45 (m, 2H), 1.22 (t, J=7.4 Hz, 3H).

Example 278: 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(1,3,4-thiadiazol-2-yl)phenyl)sulfamoyl)benzoic acid

(516) ##STR00612##

(517) Step 1: methyl 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(1,3,4-thiadiazol-2-yl)phenyl)sulfamoyl)benzoate: To the reaction vessel containing the product from Example 273 Step 4 (0.150 g, 0.28 mmol, 99% purity), 2-bromo-1,3,4-thiadiazole (0.056 g, 0.34 mmol), K.sub.3PO.sub.4 (0.078 g, 0.36 mmol) in dioxane (4 ml, 0.28 mmol) and water (1 ml) was added Xphos Pd G3 (0.024 g, 0.03 mmol). The resultant mixture was degassed with N.sub.2 for 15 min and then heated at 80 C. for 16 h. The reaction mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (0.021 g, 0.04 mmol, 13% yield, 86% purity) as colourless oil. UPLC-MS (Method 1) m/z 487.3 (M+H).sup.+ at 1.78 min.

(518) Step 2: 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(1,3,4-thiadiazol-2-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (0.111 ml, 0.11 mmol) was added to a solution of the product from Step 1 above (0.021 g, 0.04 mmol, 86% purity) in THF (5 ml) and the resultant mixture stirred at RT overnight. The mixture was then acidified to pH 6 using 10% w/v citric acid (aq) and the resultant precipitate was collected by filtration to afford the title compound (1.8 mg, 3.62 mol, 10% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 473.3 (M+H).sup.+ at 1.63 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.55 (br s, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.07 (d, J=8.1 Hz, 1H), 7.66 (d, J=2.0 Hz, 2H), 7.59 (d, J=8.0 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 3.08 (q, J=7.4 Hz, 2H), 2.77 (t, J=5.8 Hz, 4H), 1.60-1.54 (m, 4H), 1.51-1.45 (m, 2H), 1.20 (t, J=7.4 Hz, 3H).

Example 279: 4-ethyl-3-(N-(5-(5-methylisoxazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid

(519) ##STR00613##

(520) Step 1: methyl 4-ethyl-3-(N-(5-(5-methylisoxazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: To the reaction vessel containing the product from Example 273 Step 4 (0.150 g, 0.28 mmol, 99% purity), 4-bromo-5-methylisoxazole (0.055 g, 0.34 mmol), K.sub.3PO.sub.4 (0.078 g, 0.36 mmol) in dioxane (4 ml, 0.28 mmol) and water (1 ml) was added Xphos Pd G3 (0.024 g, 0.03 mmol). The resultant mixture was degassed with N.sub.2 for 15 min and then heated at 80 C. for 16 h. The reaction mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-30% EtOAc/isohexane) to afford the title compound (0.110 g, 0.22 mmol, 76% yield, 95% purity) as yellow oil. UPLC-MS (Method 1) m/z 484.4 (M+H).sup.+ at 1.90 min.

(521) Step 2: 4-ethyl-3-(N-(5-(5-methylisoxazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (0.682 ml, 0.682 mmol) was added to a solution of the product from Step 1 above (0.110 g, 0.23 mmol, 95% purity) in THF (5 ml) and stirred at RT overnight. The mixture was then acidified to pH 6 using 10% w/v citric acid (aq) and the resultant precipitate was collected by filtration to afford crude mixture of products. The crude product was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 10-80% MeCN in Water) to afford the title compound (13.3 mg, 0.03 mmol, 12% yield, 96% purity) as a white solid. UPLC-MS (Method 1) m/z 470.4 (M+H).sup.+ at 1.79 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.69 (s, 1H), 8.43 (d, J=1.8 Hz, 1H), 8.08 (dd, J=7.9, 1.8 Hz, 1H), 7.64 (dd, J=7.8 Hz, 1H), 7.34-7.13 (m, 3H), 3.07 (q, J=7.4 Hz, 2H), 2.63 (t, J=5.2 Hz, 4H), 2.42 (s, 3H), 1.59 (p, J=5.4 Hz, 4H), 1.48 (m, 2H), 1.22 (t, J=7.4 Hz, 3H).

Example 280:4-ethyl-3-(N-(5-(1-methylpyrazol-3-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid

(522) ##STR00614##

(523) Step 1: methyl 4-ethyl-3-(N-(5-(1-methylpyrazol-3-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: To the reaction vessel containing the product from Example 273 Step 4 (0.150 g, 0.28 mmol, 99% purity), 3-bromo-1-methylpyrazole (0.035 ml, 0.34 mmol), K.sub.3PO.sub.4 (0.078 g, 0.34 mmol) in dioxane (5 ml) and water (1 ml) was added Xphos Pd G3 (0.024 g, 0.04 mmol). The resultant mixture was degassed with N.sub.2 for 15 min and then heated at 80 C. for 2 h. The reaction mixture was allowed to cool to RT, filtered and then concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.085 g, 0.16 mmol, 57% yield) as a pale brown solid. UPLC-MS (Method 1) m/z 483.3 (M+H).sup.+ at 1.82 min.

(524) Step 2: 4-ethyl-3-(N-(5-(1-methylpyrazol-3-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (2.82 ml, 0.582 mmol) was added to a solution of the product from Step 1 above (0.085 g, 0.176 mmol, 92% purity) in THF (3.5 ml) and the resultant mixture stirred at RT for 72 h. The mixture was then acidified to pH 6 using 1 M citric acid (aq) and the resultant precipitate was collected by filtration to afford the title compound (44 mg, 0.089 mmol, 51% yield) as a white solid. UPLC-MS (Method 1) m/z 469.2 (M+H).sup.+ at 1.66 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.4 (s br, 1H), 8.91 (s, 1H), 8.45 (d, J=1.8 Hz, 1H), 8.07 (dd, J=8.0, 1.8 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.60-7.53 (m, 2H), 7.43 (dd, J=8.2, 2.0 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.43 (d, J=2.2 Hz, 1H), 3.84 (s, 3H), 3.06 (q, J=7.4 Hz, 2H), 2.63 (t, J=5.2 Hz, 4H), 1.63-1.55 (m, 4H), 1.51-1.44 (m, 2H), 1.21 (t, J=7.4 Hz, 3H).

Example 281: 4-ethyl-3-(N-(5-(1-methylpyrazol-5-yl)-2-(piperidin-1-yl)phenyl

(525) ##STR00615##

(526) Step 1: methyl 4-ethyl-3-(N-(5-(1-methylpyrazol-5-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: To the reaction vessel containing the product from Example 273 Step 4 (0.140 g, 0.26 mmol, 99% purity), 5-bromo-1-methylpyrazole (51.2 mg, 0.32 mmol), K.sub.3PO.sub.4 (0.073 g, 0.34 mmol) in dioxane (5 ml) and water (1 ml) was added Xphos Pd G3 (0.022 g, 0.03 mmol). The resultant mixture was degassed with N.sub.2 for 15 min and then heated at 80 C. for 2 h. The reaction mixture was allowed to cool to RT, filtered and then concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.105 g, 0.22 mmol, 82% yield) as a brown oil. UPLC-MS (Method 1) m/z 483.6 (M+H).sup.+ at 1.79 min.

(527) Step 2: 4-ethyl-3-(N-(5-(1-methylpyrazol-3-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (3.45 ml, 3.49 mmol) was added to a solution of the product from Step 1 above (0.105 g, 0.22 mmol) in THF (4 ml) and stirred at RT overnight. The mixture was then acidified to pH 6 using 1 M citric acid (aq) and the resultant precipitate was collected by filtration to afford the title compound (71 mg, 0.144 mmol, 66% yield) as a pale brown solid. UPLC-MS (Method 1) m/z 469.6 (M+H).sup.+ at 1.60 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.37 (br s, 1H), 9.18 (s, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.0, 1.8 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.42 (d, J=1.9 Hz, 1H), 7.26-7.19 (m, 3H), 6.22 (d, J=1.9 Hz, 1H), 3.71 (s, 3H), 3.07 (q, J=7.4 Hz, 2H), 2.66 (t, J=5.3 Hz, 4H), 1.65-1.55 (m, 4H), 1.53-1.44 (m, 2H), 1.23 (t, J=7.4 Hz, 3H).

Example 282: 4-ethyl-3-(N-(5-(2-methylthiazol-5-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid

(528) ##STR00616##

(529) Step 1: methyl 4-ethyl-3-(N-(5-(2-methylthiazol-5-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: To the reaction vessel containing the product from Example 273 Step 4 (0.140 g, 0.27 mmol, 99% purity), 5-bromo-2-methylthiazole (56.6 mg, 0.318 mmol), K.sub.3PO.sub.4 (0.073 g, 0.36 mmol) in dioxane (5 ml) and water (1 ml) was added Xphos Pd G3 (0.023 g, 0.03 mmol). The resultant mixture was degassed with N.sub.2 for 15 min and then heated at 80 C. for 3 h. The reaction mixture was allowed to cool to RT, filtered and then concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.096 g, 0.19 mmol, 71% yield) as a brown oil. UPLC-MS (Method 1) m/z 500.2 (M+H).sup.+ at 1.92 min.

(530) Step 2: 4-ethyl-3-(N-(5-(2-methylthiazol-5-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (2.88 ml, 2.88 mmol) was added to a solution of the product from Step 1 above (0.096 g, 0.19 mmol) in THF (4 ml) and stirred at RT overnight. The mixture was then acidified to pH 6 using 1 M citric acid (aq) and the resultant precipitate was collected by filtration to give material which was azeotroped with MeCN (5 ml) to afford the title compound (68 mg, 0.133 mmol, 69% yield) as a pale brown solid. UPLC-MS (Method 1) m/z 486.5 (M+H).sup.+ at 1.82 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.37 (br s, 1H), .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.36 (s br, 1H), 9.12 (s, 1H), 8.45 (d, J=1.8 Hz, 1H), 8.10 (dd, J=7.9, 1.9 Hz, 1H), 7.75 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.34 (dd, J=8.3, 2.2 Hz, 1H), 7.21 (d, J=2.2 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 3.07 (q, J=7.4 Hz, 2H), 2.69-2.62 (m, 7H), 1.64-1.55 (m, 4H), 1.51-1.44 (m, 2H), 1.22 (t, J=7.4 Hz, 3H).

Example 283:4-ethyl-3-(N-(2-(3-hydroxyazetidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid

(531) ##STR00617##

(532) Step 1: 1-(2-nitro-4-(tetrazol-1-yl)phenyl) azetidin-3-ol: Et.sub.3N (720 l, 5.16 mmol) was added to a solution of the product from Example 214 Step 1 (300 mg, 1.434 mmol) and azetidin-3-ol hydrochloride (204 mg, 1.86 mmol) in DCM (6 ml) and the resultant solution was stirred at RT for 3 days. The reaction mixture was concentrated in vacuo and the residue triturated with water (10 ml), filtered and washed with water (210 ml). The solid was dried at 50 C. for 4 h to afford the title compound (368 mg, 1.40 mmol, 98% yield) as a dark orange solid. UPLC-MS (Method 2) m/z no ionisation at 0.77 min.

(533) Step 2: 1-(2-amino-4-(tetrazol-1-yl)phenyl) azetidin-3-ol: The product from step 1 above (368 mg, 1.40 mmol) was dissolved in MeOH (500 ml) and divided into three portions. To each portion was added 5% Pd/C (50% w/w water) Type 87L (140 mg, 0.033 mmol) in MeOH (1 ml). Each reaction mixture was hydrogenated at 4 bar at 40 C. for 6-20 h. The reaction mixtures were combined, filtered through Celite and concentrated in vacuo to afford the title compound (316 mg, 1.32 mmol, 94% yield, 97% purity) as a light brown solid. UPLC-MS (Method 2) m/z 233.3 (M+H).sup.+ at 0.56 min.

(534) Step 3: methyl 4-ethyl-3-(N-(2-(3-hydroxyazetidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoate: The product from step 2 above (58.9 mg, 0.246 mmol, 97% purity) was suspended in a mixture of DCM (1 ml) and pyridine (82 l, 1.02 mmol) then treated with a solution of the product from Example 183 Step 1 (80 mg, 0.305 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 4 days. The reaction mixture was purified directly by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (37 mg, 0.081 mmol, 33% yield) as an off-white solid.

(535) Step 4: 4-ethyl-3-(N-(2-(3-hydroxyazetidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid: The product from step 3 above (37 mg, 0.081 mmol) was dissolved in THF (2 ml) and treated with 1 M LiOH(aq) (323 l, 0.323 mmol). MeOH was added dropwise until the mixture was a solution. The reaction mixture was stirred at 30 C. for 20 h. The mixture was diluted with water (3 ml), concentrated in vacuo and the resultant aqueous solution diluted with water (to 5 ml). The aqueous phase was washed with EtOAc (25 ml) and then neutralised to pH 6 using 10% w/v citric acid (aq). The resultant precipitate was filtered and washed with water (22 ml), then dried in vacuo at 50 C. to afford the title compound (7.1 mg, 0.015 mmol, 19% yield, 97% purity) as a light brown solid. UPLC-MS (Method 1) m/z 443.2 (MH).sup. at 0.98 min. 1H NMR (500 MHz, DMSO-d.sub.6) 13.18 (br s, 1H), 9.72 (s, 1H), 8.32 (d, J=1.8 Hz, 1H), 8.10 (dd, J=8.0, 1.9 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.59-7.49 (m, 1H), 6.76 (d, J=2.5 Hz, 1H), 6.63 (d, J=8.9 Hz, 1H), 5.61 (d, J=6.0 Hz, 1H), 4.53-4.46 (m, 1H), 4.33-4.28 (m, 2H), 3.75 (dd, J=8.6, 5.0 Hz, 2H), 2.98 (q, J=7.4 Hz, 2H), 1.19 (t, J=7.4 Hz, 3H). One exchangeable proton not observed.

Example 286: 4-ethyl-3-(N-(5-(isothiazol-5-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid

(536) ##STR00618##

(537) Step 1: Methyl 4-ethyl-3-(N-(5-(isothiazol-5-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: A mixture of the product from Example 273 Step 4 (140 mg, 0.265 mmol), 5-bromoisothiazole (52.1 mg, 0.318 mmol) and K.sub.3PO.sub.4 (73.1 mg, 0.344 mmol) in dioxane (5 ml) and water (1 ml) was treated with Xphos Pd G3 (22.4 mg, 0.026 mmol). The reaction mixture was degassed with N.sub.2 for 15 min, then heated at 80 C. for 3 h. The mixture was allowed to cool to RT, then was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (121 mg, 0.239 mmol, 90% yield, 96% purity) as a brown oil. UPLC-MS (Method 2) m/z 486.3 (M+H).sup.+ at 1.94 min.

(538) Step 2: 4-ethyl-3-(N-(5-(isothiazol-5-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (2.5 ml, 2.50 mmol) was added to a solution of the product from Step 1 above (121 mg, 0.239 mmol, 96% purity) in THF (5 ml) and the solution was stirred at RT overnight. Additional 1 M LiOH(aq) (1.75 ml, 1.75 mmol) was added and the solution was stirred overnight. The mixture was adjusted to pH 6 using 1 M citric acid (aq), the precipitate was collected by filtration and dried in vacuo to afford the title compound (37.8 mg, 0.076 mmol, 32% yield, 95% purity) as a pale brown solid. UPLC-MS (Method 1) m/z 472.5 (M+H).sup.+, 470.2 (MH).sup. at 1.85 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.3 (br s, 1H), 9.26 (br s, 1H), 8.53 (d, J=1.8 Hz, 1H), 8.45 (d, J=1.8 Hz, 1H), 8.11 (dd, J=8.0, 1.8 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.48 (dd, J=8.3, 2.2 Hz, 1H), 7.29 (d, J=2.2 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 3.08 (q, J=7.4 Hz, 2H), 2.71 (t, J=5.3 Hz, 4H), 1.64-1.55 (m, 4H), 1.53-1.44 (m, 2H), 1.22 (t, J=7.4 Hz, 3H).

Example 287:4-ethyl-3-(N-(5-(1-methylimidazol-5-yl)-2-(piperidin-1-yl)phenyl) sulfamoyl)benzoic acid

(539) ##STR00619##

(540) Step 1: 1-(4-bromo-2-nitrophenyl)piperidine: Piperidine (9.88 ml, 100 mmol) was added to a solution of 4-bromo-1-fluoro-2-nitrobenzene (5.60 ml, 45.5 mmol) in MeCN (50 ml) and the resultant solution was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (220 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (13.4 g, 44.2 mmol, 97% yield, 94% purity) as a red oil. UPLC-MS (Method 1): m/z 285.1 (M+H).sup.+, at 1.82 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.99 (d, J=2.4 Hz, 1H), 7.71 (dd, J=8.9, 2.5 Hz, 1H), 7.24 (d, J=8.9 Hz, 1H), 3.01-2.86 (m, 4H), 1.63-1.55 (m, 4H), 1.55-1.49 (m, 2H).

(541) Step 2: 1-(2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine: A mixture of the product from Step 1 above (1 g, 3.33 mmol, 94% purity), bis(pinacolato)diboron (1.27 g, 5.00 mmol), KOAc (0.981 g, 10.0 mmol), PdCl.sub.2 (dppf) (0.244 g, 0.333 mmol) in dioxane (10 ml) was degassed with N.sub.2 for 5 min. The reaction was heated at 80 C. for 12 h. The mixture was then diluted with water (50 ml) and extracted with EtOAc (50 ml). The organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (1.40 g, 3.16 mmol, 95% yield, 75% purity) as a brown oil. UPLC-MS (Method 1): m/z 333.3 (M+H).sup.+, at 1.99 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.95 (d, J=1.6 Hz, 1H), 7.73 (dd, J=8.4, 1.6 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 3.04 (t, J=5.1 Hz, 4H), 1.67-1.52 (m, 6H), 1.29 (s, 12H).

(542) Step 3: 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline: A solution of the product from Step 2 above (15.6 g, 39.9 mmol, 75% purity) in MeOH (20 ml, 494 mmol) was treated with 10% Pd/C (4.25 g, 3.99 mmol). The solution was hydrogenated at a pressure of 2 bar for 16 h. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (220 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (5.20 g, 16.4 mmol, 41% yield, 95% purity) as a brown solid. UPLC-MS (Method 1): m/z 303.3 (M+H).sup.+, at 1.41 min, 95% purity (254 nm). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.04 (d, J=1.4 Hz, 1H), 6.90 (dd, J=7.7, 1.5 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 4.63 (s, 2H), 2.80-2.70 (m, 4H), 1.65 (p, J=5.6 Hz, 4H), 1.55-1.49 (m, 2H), 1.26 (s, 12H).

(543) Step 4: Methyl 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfamoyl)benzoate: A solution of the product from Step 3 above (3.53 g, 11.1 mmol, 95% purity), the product from Example 203 Step 2 (3.20 g, 12.2 mmol) and pyridine (3.60 ml, 44.5 mmol) in DCM (20 ml) was vigorously stirred at RT for 41 h. The reaction mixture was concentrated in vacuo onto Celite. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-30% then 100% EtOAc/isohexane) to afford the title compound (4.89 g, 9.16 mmol, 83% yield, 99% purity) as an off-white solid. UPLC-MS (Method 2): m/z 529.4 (M+H).sup.+, 527.3 (MH).sup. at 2.12 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.04 (br s, 1H), 8.38 (d, J=1.9 Hz, 1H), 8.11 (dd, J=8.0, 1.9 Hz, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.34 (dd, J=7.9, 1.5 Hz, 1H), 7.31 (d, J=1.4 Hz, 1H), 7.07 (d, J=7.9 Hz, 1H), 3.85 (s, 3H), 3.05 (q, J=7.4 Hz, 2H), 2.68 (t, J=5.2 Hz, 4H), 1.59-1.49 (m, 4H), 1.49-1.41 (m, 2H), 1.24-1.18 (m, 15H).

(544) Step 5: methyl 4-ethyl-3-(N-(5-(1-methylimidazol-5-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: To the reaction vessel containing the product from Step 4 above (0.150 g, 0.284 mmol, 99% purity), 5-bromo-1-methylimidazole (0.055 g, 0.341 mmol), K.sub.3PO.sub.4 (0.078 g, 0.369 mmol) and dioxane (5 ml, 0.284 mmol) and water (1 ml) was added Xphos Pd G3 (0.024 g, 0.028 mmol). The resultant reaction mixture was degassed with N.sub.2 for 15 min and then heated to 80 C. for 6 h. The reaction mixture was allowed to cool to RT, filtered and then concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% 10% (MeOH/DCM) in DCM) to afford the title compound (0.100 g, 0.204 mmol, 72% yield, 99% purity) as a yellow oil. UPLC-MS (Method 1): m/z 483.4 (M+H).sup.+, 481.3 (MH).sup. at 1.15 min.

(545) Step 6: 4-ethyl-3-(N-(5-(1-methylimidazol-5-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (0.622 ml, 0.622 mmol) was added to a solution the product from Step 5 above (0.100 g, 0.207 mmol, 99% purity) in THF (5 ml, 61.0 mmol) and the solution was stirred at RT overnight. The mixture was then adjusted to pH 6 with citric acid to form a precipitate which was filtered under suction to afford the crude product. The crude product was purified by preparative HPLC (Waters, Basic (0.1% Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 m, 1950 mm column, 20-50% MeCN in Water) to afford the title compound (4.4 mg, 9.30 mol, 5% yield, 99% purity) as a white solid. UPLC-MS (Method 1): m/z 469.4 (M+H).sup.+, 467.3 (MH).sup. at 1.08 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.08 (br s, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.08 (dd, J=8.0, 1.8 Hz, 1H), 7.65 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.26-7.13 (m, 3H), 6.86 (s, 1H), 3.54 (s, 3H), 3.06 (q, J=7.4 Hz, 2H), 2.71-2.59 (m, 4H), 1.60 (p, J=5.6 Hz, 4H), 1.52-1.45 (m, 2H), 1.23 (t, J=7.4 Hz, 3H). 1 exchangeable proton not observed.

Example 288: 4-ethyl-3-(N-(5-(1-methyl-1,2,4-triazol-5-yl)-2-(piperidin-1-yl)phenyl) sulfamoyl)benzoic acid

(546) ##STR00620##

(547) Step 1: 1-(4-bromo-2-nitrophenyl)piperidine: Piperidine (4.95 ml, 50.0 mmol) was added to a solution of 4-bromo-1-fluoro-2-nitrobenzene (2.79 ml, 22.7 mmol) in MeCN (25 ml) and the resultant solution was stirred at RT overnight. The reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (120 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (6.8 g, 22.7 mmol, 100% yield, >95% purity) as a red liquid. UPLC-MS (Method 2): m/z 285.1 (M+H).sup.+, at 1.82 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.00 (d, J=2.5 Hz, 1H), 7.71 (dd, J=8.9, 2.5 Hz, 1H), 7.25 (d, J=8.8 Hz, 1H), 2.98-2.92 (m, 4H), 1.63-1.50 (m, 6H).

(548) Step 2: 1-(2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine: A mixture of the product from Step 1 above (6.8 g, 22.7 mmol, >95% purity), bis(pinacolato)diboron (9.08 g, 35.8 mmol), KOAc (7.02 g, 71.5 mmol), Pd (dppf) Cl2.Math.DCM (1.95 g, 2.39 mmol) in 1dioxane (70 ml) was degassed with nitrogen for 15 min. The reaction was heated at 80 C. for 12 h. The mixture was diluted with brine (350 ml) and extracted with EtOAc (350 ml). The organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (220 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (7.7 g, 16.2 mmol, 72% yield, 70% purity) as an orange oil. UPLC-MS (Method 2): m/z 333.6 (M+H).sup.+, at 1.98 min.

(549) Step 3: 1-(4-(1-methyl-1,2,4-triazol-5-yl)-2-nitrophenyl)piperidine: To the reaction vessel containing 5-bromo-1-methyl-1,2,4-triazole (0.102 g, 0.632 mmol), the product from Step 2 above (0.250 g, 0.527 mmol, 70% purity), K.sub.3PO.sub.4 (0.145 g, 0.685 mmol) and 5:1 dioxane: water (12 ml) was added Xphos Pd G3 (0.045 g, 0.053 mmol). The resultant reaction mixture was degassed with N.sub.2 for 15 min and then heated to 80 C. for 2 h. The mixture was diluted with EtOAc (50 ml) and washed with water (50 ml). The organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.150 g, 0.517 mmol, 98% yield, 99% purity) as an orange solid. UPLC-MS (Method 1): m/z 288.2 (M+H).sup.+, at 1.29 min.

(550) Step 4: 5-(1-methyl-1,2,4-triazol-5-yl)-2-(piperidin-1-yl)aniline: The product from Step 3 above (0.150 g, 0.522 mmol) was dissolved in MeOH (10 ml) and 10% Pd/C (50% w/w water) Type 39 (0.013 g, 6.11 mol) was added and the reaction was placed under hydrogen (2 bar) and stirred at room temperature for 16 h. The mixture was filtered through Celite, washed with MeOH (20 ml) and the filtrate concentrated in vacuo to afford the title compound (0.121 g, 0.353 mmol, 68% yield, 75% purity) as a brown oil. UPLC-MS (Method 1): m/z 258.3 (M+H).sup.+ at 0.88 min.

(551) Step 5: Methyl 4-ethyl-3-(N-(5-(1-methyl-1,2,4-triazol-5-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: A solution of the product from Step 4 above (0.121 g, 0.353 mmol, 75% purity) in DCM (3 ml) and pyridine (0.171 ml, 2.12 mmol) were added to a solution of the product from Example 203 Step 2 (0.093 g, 0.353 mmol) in DCM (3 ml) and the solution was stirred at RT for 48 h. The mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (0.095 g, 0.187 mmol, 53% yield, 95% purity) as a white solid. UPLC-MS (Method 1): m/z 484.4 (M+H).sup.+, 482.3 (MH).sup. at 1.64 min.

(552) Step 6: 4-ethyl-3-(N-(5-(1-methyl-1,2,4-triazol-5-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (0.560 ml, 0.560 mmol) was added to a solution of the product from Step 5 above (0.095 g, 0.187 mmol, 95% purity) in THF (5 ml, 61.0 mmol) and the solution was stirred at RT for 16 h. The mixture was then adjusted to pH 6 with citric acid to form a precipitate which was filtered under suction to afford the title compound (46.8 mg, 0.098 mmol, 52% yield, 98% purity) as a white solid. UPLC-MS (Method 1): m/z 470.3 (M+H).sup.+, 468.3 (MH).sup. at 1.49 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.37 (d, J=1.8 Hz, 1H), 8.06 (dd, J=8.0, 1.8 Hz, 1H), 7.92 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.53-7.43 (m, 2H), 7.24 (d, J=8.2 Hz, 1H), 3.84 (s, 3H), 3.07 (q, J=7.4 Hz, 2H), 2.71 (t, J=5.2 Hz, 4H), 1.58 (p, J=5.5 Hz, 4H), 1.52-1.45 (m, 2H), 1.22 (t, J=7.4 Hz, 3H). 2 exchangeable protons not observed.

Example 289: 4-ethyl-3-(N-(5-(oxazol-2-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid

(553) ##STR00621##

(554) Step 1: 2-(3-nitro-4-(piperidin-1-yl)phenyl) oxazole: To the reaction vessel containing 2-bromooxazole (0.094 g, 0.632 mmol), the product from Example 287 Step 2 (0.250 g, 0.527 mmol), K.sub.3PO.sub.4 (0.145 g, 0.685 mmol) and 5:1 dioxane:water (12 ml) was added Xphos Pd G3 (0.045 g, 0.053 mmol). The resultant reaction mixture was degassed with N.sub.2 for 15 min and then heated to 80 C. for 2 h. The mixture was diluted with EtOAc (50 ml) and washed with water (50 ml). The organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (0.137 g, 0.481 mmol, 91% yield, 96% purity) as an orange oil. UPLC-MS (Method 1): m/z 274.2 (M+H).sup.+, at 1.60 min.

(555) Step 2: 5-(oxazol-2-yl)-2-(piperidin-1-yl)aniline: The product from Step 1 above (0.137 g, 0.501 mmol) was dissolved in MeOH (10 ml), 10% Pd/C (50% w/w water) Type 39 (0.013 g, 5.64 mol) was added and the reaction was stirred under hydrogen (2 bar) at room temperature for 16 h. The mixture was filtered through Celite, washed with MeOH (20 ml) and concentrated in vacuo to afford the title compound (0.119 g, 0.489 mmol, 98% yield) as a brown oil. UPLC-MS (Method 1): m/z 244.3 (M+H).sup.+ at 1.18 min.

(556) Step 3: Methyl 4-ethyl-3-(N-(5-(oxazol-2-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: A solution of the product from Step 2 above (0.119 g, 0.489 mmol) in DCM (3 ml) and pyridine (0.237 ml, 2.93 mmol) was added to a solution of the product from Example 203 Step 2 (0.128 g, 0.489 mmol) in DCM (3 ml, 46.6 mmol) and the resultant solution was stirred at RT for 48 h. The mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (0.140 g, 0.298 mmol, 61% yield) as a brown oil. UPLC-MS (Method 1): m/z 470.4 (M+H).sup.+, 468.3 (MH).sup. at 1.86 min.

(557) Step 4: 4-ethyl-3-(N-(5-(oxazol-2-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (0.894 ml, 0.894 mmol) was added to a solution of the product from Step 3 above (0.140 g, 0.298 mmol) in THF (5 ml) and the solution was stirred at RT for 16 h. The mixture was then adjusted to pH 6 with citric acid to form a precipitate which was filtered under suction to afford the title compound (95 mg, 0.207 mmol, 70% yield, 99% purity) as an off-white solid. UPLC-MS (Method 1): m/z 456.4 (M+H).sup.+, 454.3 (MH).sup. at 1.72 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.28 (br s, 1H), 9.27 (br s, 1H), 8.38 (d, J=1.8 Hz, 1H), 8.13 (s, 1H), 8.08 (dd, J=8.0, 1.8 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.69 (dd, J=8.3, 2.1 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.31 (s, 1H), 7.23 (d, J=8.4 Hz, 1H), 3.07 (q, J=7.4 Hz, 2H), 2.70 (t, J=5.2 Hz, 4H), 1.56 (p, J=5.6 Hz, 4H), 1.50-1.44 (m, 2H), 1.22 (t, J=7.4 Hz, 3H).

Example 290:4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(pyrazin-2-yl)phenyl)sulfamoyl)benzoic acid

(558) ##STR00622##

(559) Step 1: 2-(3-nitro-4-(piperidin-1-yl)phenyl) pyrazine: To the reaction vessel the product from Example 287 Step 2 (0.250 g, 0.527 mmol), 2-bromopyrazine (0.084 g, 0.527 mmol), K.sub.3PO.sub.4 (0.145 g, 0.685 mmol) and 5:1 dioxane:water (12 ml) was added Xphos Pd G3 (0.045 g, 0.053 mmol). The resultant reaction mixture was degassed with N.sub.2 for 15 min and then heated to 80 C. for 16 h. The mixture was diluted with EtOAc (50 ml) and washed with water (50 ml). The organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (0.145 g, 0.500 mmol, 95% yield, 98% purity) as an orange oil. UPLC-MS (Method 1): m/z 285.2 (M+H).sup.+, at 1.57 min.

(560) Step 2: 2-(piperidin-1-yl)-5-(pyrazin-2-yl)aniline: The product from Step 1 above (0.145 g, 0.510 mmol, 98% purity) was dissolved in MeOH (10 ml) and 10% Pd/C (50% w/w water) Type 39 (0.013 g, 6.11 mol) was added and the reaction was stirred under hydrogen (3 bar) at room temperature for 1 h. The mixture was filtered through Celite, washed with MeOH (20 ml) and concentrated in vacuo to afford the crude product. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (0.051 g, 0.201 mmol, 39% yield) as a yellow oil. UPLC-MS (Method 1): m/z 255.3 (M+H).sup.+ at 0.95 min.

(561) Step 3: Methyl 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(pyrazin-2-yl)phenyl)sulfamoyl)benzoate: A solution of the product from Step 2 above (0.051 g, 0.201 mmol) in DCM (3 ml) and pyridine (0.097 ml, 1.20 mmol) was added to a solution of the product from Example 203 Step 2 (0.063 g, 0.241 mmol) in DCM (3 ml) and the resultant solution was stirred at RT for 72 h. The mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (0.090 g, 0.176 mmol, 88% yield, 94% purity) as a white solid. UPLC-MS (Method 1): m/z 481.4 (M+H).sup.+, 479.3 (MH).sup. at 1.86 min.

(562) Step 4: 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(pyrazin-2-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (0.562 ml, 0.562 mmol) was added to a solution of the product from Step 3 above (0.090 g, 0.187 mmol, 94% purity) in THF (5 ml) and the solution was stirred at RT for 16 h. The mixture was then adjusted to pH 6 with citric acid to form a precipitate which was filtered under suction and washed with water (10 ml) to afford the title compound (67 mg, 0.141 mmol, 75% yield, 98% purity) as a pale yellow solid. UPLC-MS (Method 1): m/z 467.3 (M+H).sup.+, 465.3 (MH).sup. at 1.70 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.28 (br s, 1H), 9.18 (br s, 1H), 9.04 (d, J=1.5 Hz, 1H), 8.62 (dd, J=2.5, 1.5 Hz, 1H), 8.55 (d, J=2.5 Hz, 1H), 8.44 (d, J=1.8 Hz, 1H), 8.08 (dd, J=8.0, 1.8 Hz, 1H), 7.91 (d, J=2.1 Hz, 1H), 7.85 (dd, J=8.4, 2.1 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 3.08 (q, J=7.4 Hz, 2H), 2.71 (t, J=5.2 Hz, 4H), 1.58 (q, J=5.6 Hz, 4H), 1.52-1.44 (m, 2H), 1.22 (t, J=7.4 Hz, 3H).

Example 291:3-(N-(5-(3,5-dimethylisoxazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(563) ##STR00623##

(564) Step 1: 1-(4-bromo-2-nitrophenyl)piperidine: Piperidine (9.88 ml, 100 mmol) was added to a solution of 4-bromo-1-fluoro-2-nitrobenzene (5.60 ml, 45.5 mmol) in MeCN (50 ml) and the resultant solution was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (220 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (13.4 g, 44.2 mmol, 97% yield, 94% purity) as a red oil. UPLC-MS (Method 1): m/z 285.1 (M+H).sup.+, at 1.82 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.99 (d, J=2.4 Hz, 1H), 7.71 (dd, J=8.9, 2.5 Hz, 1H), 7.24 (d, J=8.9 Hz, 1H), 3.01-2.86 (m, 4H), 1.63-1.55 (m, 4H), 1.55-1.49 (m, 2H).

(565) Step 2: 1-(2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine: A mixture of the product from Step 1 above (1 g, 3.33 mmol, 94% purity), bis(pinacolato)diboron (1.27 g, 5.00 mmol), KOAc (0.981 g, 10.0 mmol), and PdCl.sub.2 (dppf) (0.244 g, 0.333 mmol) in dioxane (10 ml) was degassed with N.sub.2 for 5 min. The reaction was heated at 80 C. for 12 h. The mixture was diluted with water (50 ml) and extracted with EtOAc (50 ml). The organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (1.40 g, 3.16 mmol, 95% yield, 75% purity) as a brown oil. UPLC-MS (Method 1): m/z 333.3 (M+H).sup.+ at 1.99 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.95 (d, J=1.6 Hz, 1H), 7.73 (dd, J=8.4, 1.6 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 3.04 (t, J=5.1 Hz, 4H), 1.67-1.52 (m, 6H), 1.29 (s, 12H).

(566) Step 3: 2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline: A solution of the product from Step 2 above (1.40 g, 3.16 mmol, 75% purity) in MeOH (20 ml) was treated with 10% Pd/C (0.336 g, 0.316 mmol). The solution was hydrogenated (2 bar) for 2 h. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (0.695 g, 2.21 mmol, 70% yield, 96% purity) as a waxy white solid. UPLC-MS (Method 1): m/z 303.3 (M+H).sup.+, at 1.41 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.04 (d, J=1.4 Hz, 1H), 6.90 (dd, J=7.7, 1.5 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 4.63 (s, 2H), 2.80-2.70 (m, 4H), 1.55-1.49 (m, 2H), 1.55-1.49 (m, 2H), 1.26 (s, 12H).

(567) Step 4: 5-(3,5-dimethylisoxazol-4-yl)-2-(piperidin-1-yl)aniline: A mixture of the product from Step 3 above (0.150 g, 0.496 mmol, 96% purity), 4-bromo-3,5-dimethylisoxazole (0.105 g, 0.596 mmol) and K.sub.3PO.sub.4 (0.137 g, 0.645 mmol) in dioxane (5 ml) and water (1 ml) was treated with Xphos Pd G3 (0.042 g, 0.050 mmol). The resultant mixture was degassed with N.sub.2 for 15 min and then heated to 80 C. for 2 h. The reaction mixture was allowed to cool to RT and then concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (0.100 g, 0.276 mmol, 56% yield, 75% purity) as a brown oil. UPLC-MS (Method 1): m/z 272.3 (M+H).sup.+, at 1.11 min.

(568) Step 5: Methyl 3-(N-(5-(3,5-dimethylisoxazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoate: A solution of the product from Step 4 above (0.10 g, 0.276 mmol, 75% purity) in DCM (3 ml) and pyridine (0.134 ml, 1.66 mmol) was added to a solution of the product from Example 203 Step 2 (0.087 g, 0.332 mmol) in DCM (3 ml) and the resultant solution was stirred at RT for 72 h. The mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-40% EtOAc/isohexane) to afford the title compound (0.110 g, 0.206 mmol, 74% yield, 93% purity) as a white solid. UPLC-MS (Method 1): m/z 498.4 (M+H).sup.+, 496.3 (MH).sup. at 1.94 min.

(569) Step 6: 3-(N-(5-(3,5-dimethylisoxazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid: 4 M HCl(aq) (0.276 ml, 1.11 mmol) was added to a solution of the product from Step 5 above (0.110 g, 0.221 mmol, 93%) in dioxane (5 ml) and the solution was stirred at 60 C. for 16 h. Conc. HCl(aq) (2 ml) was added and the mixture heated to 70 C. for 16 h. The mixture was concentrated in vacuo to afford crude product. The crude product was purified by purified by chromatography (40 g reverse phase C18 cartridge, 15-70% MeCN/0.1% formic acid (aq)) to afford the title compound (23 mg, 0.045 mmol, 20% yield, 97% purity) as a cream solid. UPLC-MS (Method 1): m/z 484.4 (M+H).sup.+, 482.3 (MH).sup. at 1.80 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.39 (d, J=1.8 Hz, 1H), 8.09 (dd, J=7.9, 1.9 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 7.09 (dd, J=8.1, 2.1 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 3.10-3.02 (q, J=7.4 Hz, 2H), 2.64 (t, J=5.1 Hz, 4H), 2.27 (s, 3H), 2.09 (s, 3H), 1.60 (p, J=5.4 Hz, 4H), 1.53-1.44 (m, 2H), 1.22 (t, J=7.4 Hz, 3H). 2 exchangeable protons not observed.

Example 292:4-ethyl-3-(N-(5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(piperidin-1-yl)phenyl) sulfamoyl)benzoic acid

(570) ##STR00624##

(571) Step 1: 1-(4-bromo-2-nitrophenyl)piperidine: Piperidine (4.95 ml, 50 mmol) was added to a solution of 4-bromo-1-fluoro-2-nitrobenzene (2.79 ml, 22.7 mmol) in MeCN (25 ml). The reaction mixture was stirred at RT overnight then concentrated in vacuo. The residue was purified by chromatography on silica gel (120 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (6.8 g, 22.7 mmol, 100% yield, 95% purity) as a red liquid. UPLC-MS (Method 2) m/z 285.1 (M+H).sup.+ at 1.82 min.

(572) Step 2: 1-(2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine: A mixture of the product from Step 1 above (6.8 g, 22.7 mmol, 95% purity), bis(pinacolato)diboron (9.08 g, 35.8 mmol), KOAc (7.02 g, 71.5 mmol) and PdCl.sub.2 (dppf).Math. DCM (1.95 g, 2.39 mmol) in dioxane (70 ml) was degassed using N.sub.2 for 15 min. The resultant mixture was heated at 80 C. for 12 h. The mixture was allowed to cool to RT and was then diluted with brine (350 ml) and extracted with EtOAc (350 ml). The phases were separated and the organic phase dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (220 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (7.7 g, 16.2 mmol, 72% yield, 70% purity) as an orange oil. UPLC-MS (Method 2) m/z 333.6 (M+H).sup.+ at 1.98 min.

(573) Step 3: 2-methyl-5-(3-nitro-4-(piperidin-1-yl)phenyl)-1,3,4-oxadiazole: A mixture of the product from Step 2 above (360 mg, 0.759 mmol, 70% purity), 2-bromo-5-methyl-1,3,4-oxadiazole (212 mg, 1.3 mmol), and K.sub.3PO.sub.4 (299 mg, 1.41 mmol) in dioxane (10 ml) and water (2 ml) was treated with Xphos Pd G3 (92 mg, 0.108 mmol). The resultant mixture was degassed with N.sub.2 for 15 min, then heated at 80 C. for 2 h. The mixture was allowed to cool to RT, then was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (115 mg, 0.279 mmol, 37% yield, 70% purity) as a brown oil. UPLC-MS (Method 2) m/z 289.5 (M+H).sup.+ at 1.39 min.

(574) Step 4: 5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(piperidin-1-yl)aniline: A solution of the product from Step 3 above (115 mg, 0.279 mmol, 70% purity) in EtOH (3 ml) was treated with 5% Pd/C (50% w/w water) Type 87L (42.4 mg, 0.029 mmol). The resultant mixture was hydrogenated (1 bar) for 1 h, filtered through Celite and the filtrate concentrated in vacuo to afford the crude product (75 mg). UPLC-MS (Method 2) m/z 259.6 (M+H).sup.+ at 1.33 min.

(575) Step 5: methyl 4-ethyl-3-(N-(5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: A solution of the product from Step 4 above (75 mg) in DCM (1 ml) and pyridine (73.3 l, 0.906 mmol) was added to a solution of the product from Example 203 Step 2 (43.6 mg, 0.166 mmol, 95% purity) in DCM (1 ml) and the resultant solution was stirred at RT for 2 days. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (20 mg, 0.039 mmol, 14% yield over two steps, 95% purity) as a colourless oil. UPLC-MS (Method 2) m/z 485.3 (M+H).sup.+ at 1.69 min.

(576) Step 6: 4-ethyl-3-(N-(5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (413 l, 0.413 mmol) was added to a solution of the product from Step 5 above (20 mg, 0.039 mmol, 95% purity) in THF (1 ml) and the resultant mixture was stirred at RT overnight. The reaction mixture was concentrated in vacuo to remove THE, acidified to pH 6 using 1 M citric acid (aq) and the resultant precipitate was collected by filtration and dried in vacuo to afford the title compound (6 mg, 0.012 mmol, 31% yield, 95% purity) as a pale brown solid. UPLC-MS (Method 1) m/z 471.4 (M+H).sup.+, 469.3 (MH).sup. at 1.61 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.3 (br s, 1H), 9.37 (br s, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.10 (dd, J=8.0, 1.8 Hz, 1H), 7.68 (dd, J=8.4, 2.1 Hz, 1H), 7.64-7.61 (m, 2H), 7.26 (d, J=8.4 Hz, 1H), 3.07 (q, J=7.4 Hz, 2H), 2.75 (t, J=5.2 Hz, 4H), 2.53 (s, 3H), 1.57 (m, J=6.5 Hz, 4H), 1.52-1.43 (m, 2H), 1.22 (t, J=7.4 Hz, 3H).

Example 293: 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(pyridazin-3-yl)phenyl)sulfamoyl)benzoic

(577) ##STR00625##

(578) Step 1: 3-(3-nitro-4-(piperidin-1-yl)phenyl)pyridazine: A mixture of the product from Example 287 Step 2 (360 mg, 0.759 mmol, 70% purity), 3-bromopyridazine (258 mg, 1.63 mmol) and K.sub.3PO.sub.4 (299 mg, 1.41 mmol) in dioxane (10 ml) and water (2 ml) was treated with Xphos Pd G3 (92 mg, 0.108 mmol). The reaction mixture was degassed with N.sub.2 for 15 min and then heated at 80 C. overnight. Additional 3-bromopyridazine (129 mg, 0.813 mmol), Xphos Pd G3 (56 mg, 0.054 mmol) and K.sub.3PO.sub.4 (150 mg, 0.75 mmol) was added and the mixture heated at 80 C. for 4 days. The mixture was allowed to cool to RT, then was filtered through Celite and concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (53 mg, 0.186 mmol, 19% yield, 80% purity) as a brown oil. UPLC-MS (Method 2) m/z 285.2 (M+H).sup.+ at 1.33 min. Two batches of product were combined to afford the title compound (95 mg, 0.294 mmol, 19% yield, 88% purity).

(579) Step 2: 2-(piperidin-1-yl)-5-(pyridazin-3-yl)aniline: A solution of the product from Step 1 above (95 mg, 0.294 mmol, 88% purity) in EtOH (3 ml) was treated with 10% Pd/C (50% w/w water) Type 87L (35.6 mg, 0.023 mmol). The resultant mixture was hydrogenated (1 bar) for 1.5 h, filtered through Celite and the filtrate removed in vacuo to afford the crude product (83 mg). UPLC-MS (Method 2) m/z 255.6 (M+H).sup.+ at 1.21 min.

(580) Step 3: methyl 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(pyridazin-3-yl)phenyl)sulfamoyl)benzoate: A solution of the product from Step 2 above (83 mg) in DCM (1 ml) and pyridine (60.2 l, 0.744 mmol) was added to a solution of the product from Example 203 Step 2 (35.8 mg, 0.129 mmol, 95% purity) in DCM (1 ml) and the resultant solution was stirred at RT for 72 h. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (4 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (22 mg, 0.043 mmol, 15% yield over two steps, 95% purity) as a colourless oil. UPLC-MS (Method 2) m/z 481.1 (M+H).sup.+ at 2.59 min.

(581) Step 4: 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(pyridazin-3-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (458 l, 0.458 mmol) was added to a solution of the product from Step 3 above (22 mg, 0.043 mmol, 95% purity) in THF (1 ml) and the resultant mixture was stirred at RT overnight. The reaction mixture was concentrated in vacuo to remove THE, acidified to pH 6 using 1 M citric acid (aq) and the precipitate collected by filtration and dried in vacuo to afford the title compound (11 mg, 0.022 mmol, 52% yield, 95% purity) as a pale yellow solid. UPLC-MS (Method 1) m/z 467.3 (M+H).sup.+, 465.3 (MH).sup. at 1.56 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.3 (br s, 1H), 9.16 (dd, J=4.9, 1.5 Hz, 2H), 8.40 (d, J=1.8 Hz, 1H), 8.07 (dd, J=8.0, 1.8 Hz, 1H), 8.03-7.98 (m, 2H), 7.85 (dd, J=8.4, 2.2 Hz, 1H), 7.72 (dd, J=8.7, 4.9 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 3.08 (q, J=7.5 Hz, 2H), 2.70 (t, J=5.2 Hz, 4H), 1.60-1.53 (m, 4H), 1.51-1.44 (m, 2H), 1.22 (t, J=7.4 Hz, 3H).

Example 294: 3-(N-(4-bromo-2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(582) ##STR00626##

(583) Step 1: 1-(5-bromo-2-nitro-4-(trifluoromethyl)phenyl)piperidine: A solution of 1-bromo-5-fluoro-4-nitro-2-(trifluoromethyl)benzene (300 mg, 1.04 mmol) and piperidine (250 l, 2.53 mmol) in DCM (6 ml) was allowed to stand at RT for 1 h. The reaction mixture was washed with 1 M HCl(aq) (22 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo, azeotroping with toluene (3 ml), to afford the title compound (353 mg, 1.00 mmol, 96% yield) as a bright orange oil, which crystallised upon standing. UPLC-MS (Method 1) m/z 352.9 (M+H).sup.+ at 1.96 min.

(584) Step 2: 4-bromo-2-(piperidin-1-yl)-5-(trifluoromethyl)aniline: The product from Step 1 above (353 mg, 1.00 mmol) was combined with zinc dust (500 mg, 7.65 mmol) and NH.sub.4Cl(s) (410 mg, 7.66 mmol) in THF (9 ml) and water (3 ml). The resultant mixture was stirred at RT for 4 days, then allowed to stand for 1 day. The mixture was filtered through Celite, washing with EtOAc (35 ml). The phases were separated, the organic phase dried over MgSO.sub.4, filtered and concentrated in vacuo to afford the title compound (315 mg, 0.799 mmol, 80% yield, 82% purity) as a dark orange oil. UPLC-MS (Method 1) m/z 323.2 (M+H).sup.+ at 1.96 min.

(585) Step 3: Methyl 3-(N-(4-bromo-2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoate: The product from Step 2 above (315 mg, 0.799 mmol, 82% purity) was dissolved in a mixture of DCM (1 ml) and pyridine (150 l, 1.86 mmol) and treated with the product from Example 203 Step 2 (250 mg, 0.952 mmol). The resultant solution was allowed to stand at RT for 18 h, then heated at 35 C. for 4 days. The mixture was concentrated in vacuo and the residue dissolved in EtOAc (4 ml) and sequentially washed with water (3 ml), saturated NaHCO.sub.3(aq) (3 ml) and brine (2 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (363 mg, 0.614 mmol, 77% yield, 93% purity) as a brown oil. UPLC-MS (Method 1): m/z 549.2 (M+H).sup.+, 547.1 (MH).sup. at 2.13 min.

(586) Step 4: 3-(N-(4-bromo-2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-ethylbenzoic acid: The product from Step 3 above (63 mg, 0.107 mmol, 93% purity) was dissolved in THF (1 ml) and treated with 1 M LiOH(aq) (427 l, 0.427 mmol). The resultant solution was allowed to stand at RT for 18 h. The mixture was diluted with water (2 ml) and concentrated in vacuo. The resultant aqueous solution was diluted with water (1 ml) and acidified to PH 5 using 1 M HCl(aq). The resultant precipitate was filtered, washing with water (31 ml) and dried in vacuo to afford a tan solid (50 mg). The crude product was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 50-80% MeCN in Water) to afford the title compound (32 mg, 0.057 mmol, 53% yield, 95% purity) as a tan solid. UPLC-MS (Method 2): m/z 535.2 (M+H).sup.+, 533.1 (MH).sup. at 1.34 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.27 (br s, 1H), 9.68 (br s, 1H), 8.32 (d, J=1.8 Hz, 1H), 8.10 (dd, J=8.0, 1.8 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.36 (s, 1H), 7.24 (s, 1H), 3.04 (q, J=7.4 Hz, 2H), 2.88-2.77 (m, 4H), 1.59-1.40 (m, 6H), 1.21 (t, J=7.4 Hz, 3H).

Example 295:3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid

(587) ##STR00627##

(588) Step 1: Methyl 4-bromo-3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: A mixture of the product from Example 182 Step 2 (250 mg, 1.24 mmol), the product from Example 316 Step 1 (433 mg, 1.37 mmol) and pyridine (300 l, 3.71 mmol) in DCM (7 ml) was stirred at 35 C. for 3 days. The mixture was concentrated in vacuo onto silica and purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (403 mg, 0.834 mmol, 67% yield, 99% purity) as a white solid. UPLC-MS (Method 1) m/z 478.2 (M+H).sup.+, 476.0 (MH).sup. at 1.79 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.65 (s, 1H), 8.45-8.41 (m, 1H), 8.07-8.01 (m, 2H), 7.57 (dd, J=8.4, 2.0 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 3.88 (s, 3H), 2.85-2.79 (m, 4H), 1.54-1.47 (m, 4H), 1.47-1.42 (m, 2H).

(589) Step 2: Methyl 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoate: The product from Step 1 above (403 mg, 0.834 mmol, 99% purity) and Pd-174 (61 mg, 85.0 mol) in THF (17 ml) was treated with cyclopropylzinc (II) bromide (0.5 M in THF) (6.7 ml, 3.35 mmol) and the mixture was stirred at RT for 2 h and then at 55 C. for 3 h. Upon cooling to RT the mixture was quenched with MeOH (5 ml). The mixture was concentrated in vacuo onto silica and purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexane to afford the title compound (267 mg, 0.565 mmol, 67% yield, 93% purity) as a pale yellow solid. UPLC-MS (Method 1) m/z 440.3 (M+H).sup.+, 438.2 (MH).sup. at 1.81 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.53 (s, 1H), 8.37 (d, J=1.9 Hz, 1H), 8.04 (dd, J=8.3, 1.9 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 7.17 (d, J=8.5 Hz, 1H), 3.86 (s, 3H), 2.86-2.81 (m, 4H), 2.75-2.70 (m, 1H), 1.53-1.48 (m, 4H), 1.47-1.42 (m, 2H), 1.13-1.06 (m, 2H), 0.92-0.85 (m, 2H).

(590) Step 3: 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: A mixture of the product from Step 2 above (267 mg, 0.565 mmol, 93% purity) and LiOH (97 mg, 2.26 mmol) in THF/MeOH/water (4:1:1, 10.8 ml) was stirred at 40 C. for 4 days. The mixture was diluted with water (10 ml), acidified to pH 4 using 1 M HCl(aq) and extracted with EtOAc (320 ml). The combined organic extracts were washed with brine (20 ml), dried by passage through a phase separator and the solvent removed in vacuo. The residue was dissolved in DCM, concentrated in vacuo onto silica and purified by chromatography on silica gel (12 g cartridge, 0-10% MeOH/DCM). The residue was triturated with TBME to afford the title compound (138 mg, 0.311 mmol, 55% yield, 96% purity) as a white solid. UPLC-MS (Method 1) m/z 426.3 (M+H).sup.+, 424.3 (MH).sup. at 1.65 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.27 (s, 1H), 9.48 (s, 1H), 8.37 (d, J=1.9 Hz, 1H), 8.02 (dd, J=8.2, 1.9 Hz, 1H), 7.54 (dd, J=8.4, 2.0 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.17 (dd, J=8.4, 1.9 Hz, 2H), 2.86-2.80 (m, 4H), 2.77-2.68 (m, 1H), 1.55-1.41 (m, 6H), 1.12-1.05 (m, 2H), 0.90-0.82 (m, 2H).

Example 296: 4-cyclopropyl-3-(N-(5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid

(591) ##STR00628##

(592) Step 1: Methyl 4-bromo-3-(N-(5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: A mixture of the product from Example 207 Step 2 (250 mg, 0.983 mmol), the product of Example 316 Step 1 (342 mg, 1.08 mmol) and pyridine (240 l, 2.97 mmol) in DCM (6 ml) was stirred at 35 C. for 4 days. The mixture was concentrated in vacuo onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (326 mg, 0.583 mmol, 59% yield, 95% purity) as a light tan solid. UPLC-MS (Method 1) m/z 531.1 (M+H).sup.+, 529.0 (MH).sup. at 1.63 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.57 (s, 1H), 8.48-8.44 (m, 1H), 8.08-8.01 (m, 2H), 7.62 (dd, J=8.6, 2.2 Hz, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H), 3.87 (s, 3H), 3.04 (s, 3H), 2.86-2.81 (m, 4H), 1.60-1.53 (m, 4H), 1.51-1.46 (m, 2H).

(593) Step 2: Methyl 4-cyclopropyl-3-(N-(5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: The product from Step 1 above (326 mg, 0.583 mmol, 95% purity) and Pd-174 (42 mg, 58.0 mol) in THF (12 ml) was treated with cyclopropylzinc (II) bromide (0.5 M in THF) (4.7 ml, 2.35 mmol) and the mixture was stirred at RT for 2 h and then at 55 C. for 3 h. Upon cooling to RT, the mixture was quenched with MeOH (5 ml). The mixture was concentrated in vacuo onto silica and purified by chromatography on silica gel (12 g cartridge, 0-5% MeOH/DCM) to afford the title compound (284 mg, 0.461 mmol, 79% yield, 80% purity) as a yellow solid. UPLC-MS (Method 1) m/z 493.3 (M+H).sup.+, 491.2 (MH).sup. at 1.66 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.46 (s, 1H), 8.39 (d, J=1.9 Hz, 1H), 8.03 (dd, J=8.3, 1.9 Hz, 1H), 7.62-7.57 (m, 1H), 7.46 (d, J=2.2 Hz, 1H), 7.26 (d, J=8.5 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 3.85 (s, 3H), 3.00 (s, 3H), 2.87-2.82 (m, 4H), 2.80-2.72 (m, 1H), 1.58-1.52 (m, 4H), 1.50-1.45 (m, 2H), 1.12-1.08 (m, 2H), 0.91-0.85 (m, 2H).

(594) Step 3: 4-cyclopropyl-3-(N-(5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: A mixture of the product from Step 2 above (284 mg, 0.461 mmol, 80% purity) and LiOH (79 mg, 1.85 mmol) in THF/MeOH/water (4:1:1, 9 ml) was stirred at 40 C. for 4 days. The mixture was diluted with water (10 ml), acidified to pH 4 using 1 M HCl(aq) and extracted with EtOAc (320 ml). The combined organic extracts were washed with brine (20 ml), dried by passage through a phase separator and the solvent removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (12 g cartridge, 0-10% MeOH/DCM) to afford the title compound (121 mg, 0.245 mmol, 53% yield, 97% purity) as a white solid after trituration with TBME. UPLC-MS (Method 1) m/z 479.2 (M+H).sup.+, 477.2 (MH).sup. at 1.50 min. 1H NMR (500 MHz, DMSO-d.sub.6) 13.26 (s, 1H), 9.41 (s, 1H), 8.39 (d, J=1.9 Hz, 1H), 8.01 (dd, J=8.3, 1.9 Hz, 1H), 7.59 (dd, J=8.4, 2.2 Hz, 1H), 7.47 (d, J=2.2 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 2.99 (s, 3H), 2.88-2.81 (m, 4H), 2.79-2.71 (m, 1H), 1.60-1.52 (m, 4H), 1.50-1.44 (m, 2H), 1.14-1.06 (m, 2H), 0.90-0.83 (m, 2H).

Example 297:4-ethyl-3-(N-(5-(isoxazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid

(595) ##STR00629##

(596) Step 1: 5-(isoxazol-4-yl)-2-(piperidin-1-yl)aniline: A mixture of the product from Example 273 Step 3 (250 mg, 0.827 mmol), 4-bromoisoxazole (147 mg, 0.993 mmol), K.sub.3PO.sub.4 (228 mg, 1.08 mmol) in dioxane (10 ml) and water (2 ml) was treated with Xphos Pd G3 (70 mg, 0.083 mmol). The reaction mixture was degassed with N.sub.2 for 15 min, then heated at 80 C. overnight. Additional 4-bromoisoxazole (74 mg, 0.50 mmol), K.sub.3PO.sub.4 (114 mg, 0.540 mmol) and Xphos Pd G3 (35 mg, 0.042 mmol) was added. The mixture was heated at 80 C. overnight. The mixture was allowed to cool to RT, then was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (90 mg, 0.277 mmol, 34% yield, 75% purity) as a brown oil. UPLC-MS (Method 2) m/z 244.2 (M+H).sup.+ at 1.51 min.

(597) Step 2: Methyl 4-ethyl-3-(N-(5-(isoxazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: A solution of the product from Step 1 above (90 mg, 0.277 mmol, 75% purity) in DCM (1 ml) and pyridine (180 l, 2.22 mmol) was added to a solution of the product from Example 203 Step 2 (107 mg, 0.407 mmol, 95% purity) in DCM (1 ml) and the resultant solution was stirred at RT for 2 days. The mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (139 mg, 0.237 mmol, 85% yield, 80% purity) as a light brown solid. UPLC-MS (Method 2) m/z 470.6 (M+H).sup.+ at 1.85 min.

(598) Step 3: 4-ethyl-3-(N-(5-(isoxazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 4 M HCl in dioxane (370 l, 1.48 mmol) was added to a solution of the product from Step 2 above (139 mg, 0.237 mmol, 80% purity) in dioxane (3 ml) and the resultant solution was stirred at 60 C. overnight. Water (1 ml) was added and the solution was heated at 60 C. overnight. Additional 4 M HCl in dioxane (370 L, 1.48 mmol) and water (1 ml) was added and the solution was heated at 60 C. for 2 days. The reaction mixture was concentrated in vacuo and purified by chromatography (13 g reverse phase C18 cartridge, 5-90% MeCN/0.1% formic acid (aq)) to afford the title compound (33 mg, 0.069 mmol, 29% yield, 95% purity) as an off white solid. UPLC-MS (Method 1) m/z 456.3 (M+H).sup.+, 454.2 (MH).sup. at 1.76 min. .sup.1H NMR (500 MHz, DMSO-d6) 13.3 (br s, 1H), 9.27 (s, 1H), 9.08 (br s, 1H), 8.93 (s, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.06 (dd, J=8.0, 1.9 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.39 (dd, J=8.2, 2.1 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 3.05 (q, J=7.4 Hz, 2H), 2.57 (t, J=5.2 Hz, 4H), 1.57-1.49 (m, 4H), 1.48-1.40 (m, 2H), 1.21 (t, J=7.4 Hz, 3H).

Example 298:4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(1,2,3-triazol-4-yl)phenyl)sulfamoyl)benzoic acid

(599) ##STR00630##

(600) Step 1: 1-(2-nitro-4-((trimethylsilyl) ethynyl)phenyl)piperidine: The product from Example 273 Step 1 (0.680 g, 2.39 mmol) in dry THF (5 ml) was treated with Et.sub.3N (0.499 ml, 3.58 mmol), Pd(PPh.sub.3).sub.4 (0.055 g, 0.048 mmol) and Cul(s) (0.018 g, 0.095 mmol) followed by ethynyltrimethylsilane (0.219 ml, 3.10 mmol). The resultant dark mixture was stirred at RT for 16 h, then heated at 70 C. for 16 h and then at 100 C. for 16 h. The mixture was cooled, diluted with water (50 ml) and extracted with DCM (250 ml). The organic phases were combined and dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-10% TBME in isohexane) to afford the title compound (0.520 g, 1.31 mmol, 55% yield, 76% purity) as a brown oil. UPLC-MS (Method 1): m/z 303.3 (M+H).sup.+, at 2.17 min.

(601) Step 2: 1-(4-ethynyl-2-nitrophenyl)piperidine: The product from Step 1 above (0.520 g, 1.31 mmol, 76% purity) in dry THF (5 ml) was treated with 1.0 M TBAF (1.57 ml, 1.57 mmol). The resultant mixture was stirred at RT for 16 h, then concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (0.240 g, 0.907 mmol, 69% yield, 87% purity) as a brown oil. UPLC-MS (Method 1): m/z 231.3 (M+H).sup.+ at 1.72 min.

(602) Step 3: 1-(2-nitro-4-(1,2,3-triazol-4-yl)phenyl)piperidine: The product from Step 2 above (0.240 g, 0.907 mmol, 87% purity) in dry MeOH (1 ml) and DMF (9 ml) was treated with Cul(s) (8.6 mg, 0.045 mmol) followed by trimethylsilylazide (0.169 ml, 1.27 mmol). The resultant mixture was heated at 100 C. for 16 h, then concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (0.090 g, 0.319 mmol, 35% yield, 97% purity) as a red oil. UPLC-MS (Method 1): m/z 274.3 (M+H).sup.+, 272.2 (MH).sup., at 1.39 min.

(603) Step 4: 2-(piperidin-1-yl)-5-(1,2,3-triazol-4-yl)aniline: The product from Step 3 above (0.090 g, 0.319 mmol, 97% purity) was dissolved in MeOH (10 ml) and treated with 10% Pd/C (50% w/w water) Type 39 (8.1 mg, 3.80 mol). The resultant mixture was hydrogenated (2 bar) at RT for 16 h. The mixture was filtered through Celite, washing with MeOH (20 ml). The filtrate was concentrated in vacuo to afford the title compound (70 mg, 0.282 mmol, 88% yield, 98% purity) as a colourless oil. UPLC-MS (Method 1): m/z 244.3 (M+H).sup.+ at 0.72 min.

(604) Step 5: methyl 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(1,2,3-triazol-4-yl)phenyl)sulfamoyl)benzoate: A solution of the product from Step 4 above (70 mg, 0.282 mmol, 98% purity) in DCM (3 ml) and pyridine (0.047 ml, 0.575 mmol) was added to a solution of the product from Example 203 Step 2 (0.076 g, 0.288 mmol) in DCM (3 ml) and the resultant solution was stirred at RT for 16 h, then concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (75 mg, 0.152 mmol, 54% yield, 95% purity) as a white solid. UPLC-MS (Method 1): m/z 470.4 (M+H).sup.+, 468.3 (MH).sup., at 1.69 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.12 (br s, 1H), 8.41 (d, J=1.9 Hz, 1H), 8.09 (dd, J=8.0, 1.9 Hz, 1H), 7.75-7.58 (m, 2H), 7.54 (d, J=8.1 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 3.83 (s, 3H), 3.13-2.97 (q, J=7.4 Hz, 2H), 2.66-2.58 (m, 4H), 1.60-1.53 (m, 4H), 1.50-1.43 (m, 2H), 1.22 (t, J=7.4 Hz, 3H). Two exchangeable protons not observed.

(605) Step 6: 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(1,2,3-triazol-4-yl)phenyl)sulfamoyl)benzoic acid: A solution of the product from Step 5 above (75 mg, 0.152 mmol, 95% purity) in THF (5 ml) was treated with 1 M LiOH(aq) (0.479 ml, 0.479 mmol) and the resultant mixture stirred at RT over the weekend. The mixture was then acidified to pH 7 using 10% w/v citric acid (aq) and then concentrated in vacuo. The residue was purified by chromatography (12 g reverse phase C18 cartridge, 10-45% MeCN/0.1% formic acid (aq)) to afford the title compound (40.2 mg, 0.086 mmol, 57% yield, 98% purity) as a pale yellow solid. UPLC-MS (Method 1): m/z 456.4 (M+H).sup.+, 454.3 (MH).sup. at 1.54 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.02 (br s, 1H), 8.42 (d, J=1.8 Hz, 1H), 8.12 (br s, 1H), 8.05 (dd, J=7.9, 1.8 Hz, 1H), 7.67 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.53 (dd, J=8.3, 2.0 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 3.06 (q, J=7.4 Hz, 2H), 2.66-2.60 (m, 4H), 1.60-1.53 (m, 4H), 1.50-1.43 (m, 2H), 1.22 (t, J=7.4 Hz, 3H).

Example 299:3-(N-(5-(1,3,4-oxadiazol-2-yl)-2-(piperidin-1-yl)phenylsulfamoyl)-4-ethylbenzoic acid

(606) ##STR00631##

(607) Step 1: methyl 3-nitro-4-(piperidin-1-yl)benzoate: methyl 4-fluoro-3-nitrobenzoate (500 mg, 2.51 mmol) in dry DMF (5 ml) was treated with piperidine (744 l, 7.53 mmol) and stirred at RT for 2 h. The mixture was diluted with water (50 ml) and extracted with EtOAc (100 ml). The organic phase was washed with brine (50 ml), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford the title compound (650 mg, 2.31 mmol, 92% yield, 94% purity) as a red oil. UPLC-MS (Method 1) m/z 265.2 (M+H).sup.+ at 1.62 min.

(608) Step 2: 3-nitro-4-(piperid-1-yl)benzohydrazide: The product from Step 1 above (650 mg, 2.31 mmol, 94% purity) in dry EtOH (5 ml) was treated with hydrazine hydrate (1.04 ml, 11.5 mmol) and heated at 80 C. for 16 h. The mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-5% MeOH/DCM) to afford the title compound (530 mg, 2.00 mmol, 86% yield, 99% purity) as an orange oil. UPLC-MS (Method 1) m/z 265.2 (M+H).sup.+ at 0.99 min.

(609) Step 3: 2-(3-nitro-4-(piperidin-1-yl)phenyl)-1,3,4-oxadiazole: The product from Step 2 above (530 mg, 2.00 mmol, 99% purity) was treated with triethyl orthoformate (5 ml) and the mixture was heated at 100 C. for 16 h. The mixture was allowed to cool to RT and was then concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-5% MeOH/DCM) to afford the title compound (486 mg, 1.75 mmol, 87% yield, 99% purity) as a red solid. UPLC-MS (Method 1) m/z 275.3 (M+H).sup.+ at 1.38 min.

(610) Step 4: 5-(1,3,4-oxadiazol-2-yl)-2-(piperidin-1-yl)aniline: The product from Step 3 above (486 mg, 1.75 mmol, 99% purity) in MeOH (10 ml) was treated with 10% Pd/C (50% w/w water) Type 39 (45.0 mg, 0.180 mmol). The reaction mixture was hydrogenated (2 bar) at RT for 16 h. The mixture was filtered through Celite, washing with MeOH (20 ml) and then concentrated in vacuo to afford the title compound (302 mg, 1.17 mmol, 66% yield, 95% purity) as a red oil. UPLC-MS (Method 1) m/z 245.3 (M+H).sup.+ at 1.15 min.

(611) Step 5: methyl 3-(N-(5-(1,3,4-oxadiazol-2-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoate: A solution of the product from Step 4 above (100 mg, 0.409 mmol, 95% purity) in DCM (3 ml) and pyridine (199 l, 2.45 mmol) were added to a solution of the product from Example 203 Step 2 (108 mg, 0.409 mmol) in DCM (1 ml) and the solution was stirred at RT for 4 days. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (133 mg, 0.257 mmol, 63% yield, 91% purity) as a white solid. UPLC-MS (Method 1) m/z 471.4 (M+H).sup.+, 469.3 (MH).sup. at 1.72 min.

(612) Step 6: 3-(N-(5-(1,3,4-oxadiazol-2-yl)-2-(piperidin-1-yl)phenylsulfamoyl)-4-ethylbenzoic acid: 1 M LiOH(aq) (772 l, 0.772 mmol) was added to a solution of the product from Step 5 above (133 mg, 0.257 mmol, 91% purity) in THF (5 ml) and the mixture was stirred at RT overnight. The mixture was acidified to pH 6 using 10% w/v citric acid (aq) and the resultant mixture was concentrated in vacuo. The residue was purified by chromatography (12 g reverse phase C18 cartridge, 10-45% MeCN/0.1% formic acid (aq)) to afford the title compound (55.8 mg, 0.12 mmol, 47% yield, 98% purity) as a white solid. UPLC-MS (Method 1) m/z 457.3 (M+H).sup.+, 455.3 (MH).sup. at 1.58 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.24 (br s, 1H), 9.43 (br s, 1H), 9.24 (s, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.0, 1.9 Hz, 1H), 7.80-7.68 (m, 2H), 7.62 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.3 Hz, 1H), 3.07 (q, J=7.4 Hz, 2H), 2.76 (t, J=5.2 Hz, 4H), 1.58-1.52 (m, 4H), 1.47 (m, 2H), 1.23 (t, J=7.4 Hz, 3H).

Example 300:4-ethyl-3-(N-(5-(isoxazol-5-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid

(613) ##STR00632##

(614) Step 1: 1-(3-nitro-4-(piperidin-1-yl)phenyl) ethanone: Piperidine (539 l, 5.46 mmol) was added to a solution of 1-(4-fluoro-3-nitrophenyl) ethanone (1 g, 5.46 mmol) and Et.sub.3N (2.28 ml, 16.4 mmol) in MeCN (10 ml) and the resultant solution was stirred at RT overnight. The reaction mixture was concentrated in vacuo to afford the title compound (1.2 g, 4.64 mmol, 85% yield, 96% purity) as a red oil. UPLC-MS (Method 1) m/z 249.3 (M+H).sup.+ at 1.48 min.

(615) Step 2: I-3-(dimethylamino)-1-(3-nitro-4-(piperidin-1-yl)phenyl) prop-2-en-1-one: The product from Step 1 above (1.2 g, 4.64 mmol, 96% purity) was treated with N,N-dimethylformamide dimethyl acetal (10.0 ml, 4.64 mmol) and the mixture was heated at 120 C. for 16 h. The mixture was allowed to cool to RT and then concentrated in vacuo to afford the title compound (1.3 g, 4.07 mmol, 88% yield, 95% purity) as a red oil. UPLC-MS (Method 1) m/z 304.3 (M+H).sup.+ at 1.39 min.

(616) Step 3: 5-(3-nitro-4-(piperidin-1-yl)phenyl) isoxazole: The product from Step 2 above (1.3 g, 4.07 mmol, 95% purity) was combined with hydroxylamine hydrochloride (339 mg, 4.89 mmol) in MeOH (10 ml) and the mixture was heated at 70 C. for 3 h. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (937 mg, 3.26 mmol, 80% yield, 95% purity) as a red oil. UPLC-MS (Method 1) m/z 274.2 (M+H).sup.+ at 1.62 min.

(617) Step 4: 5-(isoxazol-5-yl)-2-(piperidin-1-yl)aniline: A mixture of the product from Step 3 above (200 mg, 0.730 mmol, 95% purity) in THF (9 ml) and water (3 ml) was treated with zinc dust (287 mg, 4.39 mmol) and NH.sub.4Cl(s) (235 mg, 4.39 mmol). The resultant mixture was stirred at RT for 1 h. The mixture was filtered through Celite, washing with EtOAc, and then concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-50% TBME/isohexane) to afford the title compound (102 mg, 0.419 mmol, 57% yield) as a cream solid. UPLC-MS (Method 1) m/z 244.3 (M+H).sup.+ at 1.27 min.

(618) Step 5: methyl 4-ethyl-3-(N-(5-(isoxazol-5-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: A solution of the product from Step 4 above (102 mg, 0.419 mmol) in DCM (3 ml) and pyridine (203 l, 2.52 mmol) were added to a solution of the product from Example 203 Step 2 (110 mg, 0.419 mmol) in DCM (5 ml) and the solution was stirred at RT for 2 days. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (150 mg, 0.319 mmol, 76% yield) as a white solid. UPLC-MS (Method 1) m/z 470.4 (M+H).sup.+, 468.3 (MH).sup. at 1.85 min.

(619) Step 6: 4-ethyl-3-(N-(5-(isoxazol-5-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 4 M HCl in dioxane (399 l, 1.59 mmol) was added to a solution of the product from Step 5 above (150 mg, 0.319 mmol) in dioxane (5 ml) and the mixture was heated at 60 C. for 16 h. Concentrated HCl(aq) (2 ml) was added and the mixture was heated at 70 C. for a further 16 h. The mixture was concentrated in vacuo and the solid slurried with TBME (20 ml) for 30 min. The solid was collected to afford the title compound (145 mg, 0.309 mmol, 97% yield, 97% purity) as a cream solid. UPLC-MS (Method 1) m/z 456.4 (M+H).sup.+, 454.3 (MH).sup. at 1.74 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.32 (br s, 1H), 8.59 (d, J=1.9 Hz, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.0, 1.8 Hz, 1H), 7.61 (dd, J=8.2, 1.9 Hz, 2H), 7.54 (d, J=2.1 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.79 (d, J=1.9 Hz, 1H), 3.06 (q, J=7.4 Hz, 2H), 2.75-2.68 (m, 4H), 1.60-1.53 (m, 4H), 1.50-1.43 (m, 2H), 1.22 (t, J=7.4 Hz, 3H). One exchangeable proton not observed.

Example 301: 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(pyrazol-4-yl)phenyl)sulfamoyl)benzoic acid

(620) ##STR00633##

(621) Step 1: tert-butyl 4-(3-nitro-4-(piperidin-1-yl)phenyl)-pyrazole-1-carboxylate: A mixture of the product from Example 287 Step 2 (291 mg, 0.714 mmol, 70% purity), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole-1-carboxylate (250 mg, 0.85 mmol) and K.sub.3PO.sub.4 (235 mg, 1.11 mmol) in dioxane (10 ml) and water (2 ml) was treated with Xphos Pd G3 (71.9 mg, 0.085 mmol). The reaction mixture was degassed with N.sub.2 for 15 min and then heated at 80 C. for 1 h. The mixture was allowed to cool to RT, then was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (201 mg, 0.497 mmol, 83% yield, 92% purity) as a red oil. UPLC-MS (Method 2) m/z 373.3 (M+H).sup.+ at 1.85 min.

(622) Step 2: tert-butyl 4-(3-amino-4-(piperidin-1-yl)phenyl)-pyrazole-1-carboxylate: A solution of the product from Step 1 above (201 mg, 0.497 mmol, 92% purity) in MeOH (10 ml) was treated with 10% Pd/C (57.4 mg, 0.027 mmol). The solution was hydrogenated at a pressure of 1 bar for 1 h. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to afford the title compound (160 mg, 0.439 mmol, 88% yield, 94% purity) as a clear oil. UPLC-MS (Method 2) m/z 343.3 (M+H).sup.+ at 1.77 min.

(623) Step 3: tert-butyl 4-(3-(2-ethyl-5-(methoxycarbonyl)phenylsulfonamido)-4-(piperidin-1-yl)phenyl)-pyrazole-1-carboxylate: A solution of the product from Step 2 above (160 mg, 0.439 mmol, 94% purity) in DCM (5 ml) and pyridine (227 l, 2.80 mmol) was treated with the product from Example 203 Step 2 (135 mg, 0.488 mmol, 95% purity) and the solution was stirred at RT for 2 days. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (112 mg, 0.158 mmol, 36% yield, 80% purity) as a yellow solid. UPLC-MS (Method 2) m/z 569.4 (M+H).sup.+ at 2.06 min.

(624) Step 4: 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(pyrazol-4-yl)phenyl)sulfamoyl)benzoic acid: The product from Step 3 above (112 mg, 0.158 mmol, 80% purity) was treated with 4 M HCl in dioxane (59.8 l, 1.97 mmol) and water (0.5 ml). The solution was heated at 60 C. for 6 h. Concentrated HCl(aq) (1 ml) and water (1 ml) was added and reaction mixture heated at 60 C. overnight. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography using a (13 g reverse phase C18 cartridge, 15-80% MeCN/0.1% formic acid (aq)) to afford the title compound (35.5 mg, 0.074 mmol, 47% yield, 95% purity) as a pale yellow solid. UPLC-MS (Method 1) m/z 455.4 (M+H).sup.+, 453.3 (MH).sup. at 1.54 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.1 (br s, 1H), 8.94 (br s, 1H), 8.47 (d, J=1.8 Hz, 1H), 8.08 (dd, J=8.0, 1.9 Hz, 1H), 7.79 (s, 2H), 7.59 (d, J=8.0 Hz, 1H), 7.33-7.22 (m, 2H), 7.14 (d, J=8.2 Hz, 1H), 3.06 (q, J=7.4 Hz, 2H), 2.59 (t, J=5.2 Hz, 4H), 1.62-1.54 (m, 4H), 1.51-1.43 (m, 2H), 1.22 (t, J=7.4 Hz, 3H). One exchangeable proton not observed.

Example 302: 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(pyridazin-4-yl)phenyl)sulfamoyl)benzoic acid

(625) ##STR00634##

(626) Step 1: methyl 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(pyridazin-4-yl)phenyl)sulfamoyl)benzoate: A mixture of the product from Example 273 Step 4 (150 mg, 0.281 mmol, 99% purity), 4-chloropyridazine hydrochloride (51.4 mg, 0.341 mmol) and K.sub.3PO.sub.4 (139 mg, 0.653 mmol) in dioxane (5 ml) and water (1 ml) was treated with Xphos Pd G3 (24 mg, 0.028 mmol). The reaction mixture was degassed with N.sub.2 for 15 min, then heated at 80 C. for 2 h. The mixture was allowed to cool to RT and was then diluted with water (50 ml) and extracted with EtOAc (2 50 ml). The combined organic extracts were dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (82 mg, 0.171 mmol, 61% yield) as a yellow oil. UPLC-MS (Method 2) m/z 481.4 (M+H).sup.+ at 1.64 min.

(627) Step 2: 4-ethyl-3-(N-(2-(piperidin-1-yl)-5-(pyridazin-4-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (1.71 ml, 1.71 mmol) was added to a solution of the product from Step 1 above (82 mg, 0.171 mmol) in THF (2 ml) and the solution was stirred at RT overnight. The reaction mixture was concentrated in vacuo to remove THE, acidified to pH 6 using 1 M HCl(aq) and the resultant precipitate collected by filtration and dried in vacuo to afford the title compound (60 mg, 0.122 mmol, 72% yield, 95% purity) as a yellow solid. UPLC-MS (Method 1) m/z 467.4 (M+H).sup.+, 465.3 (MH).sup. at 1.56 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.4 (br s, 1H), 9.38 (dd, J=2.5, 1.2 Hz, 1H), 9.30 (br s, 1H), 9.21 (dd, J=5.5, 1.2 Hz, 1H), 8.43 (d, J=1.8 Hz, 1H), 8.09 (dd, J=8.0, 1.9 Hz, 1H), 7.74 (dd, J=5.5, 2.6 Hz, 1H), 7.65 (dd, J=8.3, 2.2 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 3.07 (q, J=7.4 Hz, 2H), 2.70 (t, J=5.2 Hz, 4H), 1.63-1.53 (m, 4H), 1.51-1.42 (m, 2H), 1.22 (t, J=7.4 Hz, 3H).

Example 303: 4-ethyl-3-(N-(4-methyl-5-(5-methylisoxazol-4-yl)-2-(piperidin-1-yl)phenyl) sulfamoyl)benzoic acid

(628) ##STR00635##

(629) Step 1: 1-(4-bromo-5-methyl-2-nitrophenyl)piperidine: 1-bromo-4-fluoro-2-methyl-5-nitrobenzene (1.1 g, 4.70 mmol) in dry DMF (5 ml) was treated with piperidine (1.39 ml, 14.1 mmol) and the resultant mixture stirred at RT for 72 h. The mixture was diluted with water (50 ml) and extracted with EtOAc (100 ml). The organic phase was washed with brine (50 ml), dried over MgSO.sub.4, filtered, and concentrated in vacuo to afford the title compound (1.4 g, 4.63 mmol, 99% yield, 99% purity) as a red oil. UPLC-MS (Method 1) m/z 299.1 (M+H).sup.+ at 1.95 min.

(630) Step 2: 1-(5-methyl-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine: A mixture of the product from Step 1 above (1.4 g, 4.63 mmol, 99% purity), bis(pinacolato)diboron (1.76 g, 6.95 mmol), KOAc (1.36 g, 13.9 mmol) and PdCl.sub.2 (dppf).Math.DCM (339 mg, 0.463 mmol) in dioxane (10 ml) was degassed with N.sub.2 for 15 min and then heated at 80 C. for 16 h. The mixture was diluted with water (50 ml) and extracted with EtOAc (50 ml). The organic phase was dried over MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (1.6 g, 3.23 mmol, 70% yield, 70% purity) as an orange solid. UPLC-MS (Method 1) m/z 347.4 (M+H).sup.+ at 2.15 min.

(631) .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.01 (s, 1H), 7.02 (s, 1H), 3.02 (t, J=5.1 Hz, 4H), 2.48 (s, 3H), 1.67-1.50 (m, 6H), 1.29 (s, 12H).

(632) Step 3: 4-methyl-2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline: The product from Step 2 above (500 mg, 1.01 mmol, 70% purity) in MeOH (5 ml) was treated with 10% Pd/C (108 mg, 0.101 mmol). The reaction mixture was hydrogenated (2 bar) at RT for 2 h. The mixture was filtered through Celite, washing with MeOH (20 ml), and then concentrated in vacuo to afford the title compound (340 mg, 1.00 mmol, 99% yield, 93% purity) as a light brown solid. UPLC-MS (Method 1) m/z 317.7 (M+H).sup.+ at 1.44 min.

(633) Step 4: 4-methyl-5-(5-methylisoxazol-4-yl)-2-(piperidin-1-yl)aniline: A mixture of the product from Step 3 above (200 mg, 0.588 mmol, 93% purity), 4-iodo-5-methylisoxazole (135 mg, 0.647 mmol), K.sub.3PO.sub.4 (162 mg, 0.765 mmol), dioxane (4 ml) and water (1 ml) was treated with Xphos Pd G3 (50 mg, 0.059 mmol). The resultant mixture was degassed with N.sub.2 for 15 min and then heated at 80 C. for 2 h. The mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-30% EtOAc/isohexane) to afford the title compound (150 mg, 0.531 mmol, 90% yield, 96% purity) as a waxy tan solid. UPLC-MS (Method 1) m/z 272.3 (M+H).sup.+ at 1.07 min. 1H NMR (500 MHz, DMSO-d.sub.6) 8.53 (s, 1H), 6.79 (s, 1H), 6.52 (s, 1H), 4.58 (s, 2H), 2.82-2.70 (m, 4H), 2.33 (s, 3H), 2.04 (s, 3H), 1.70-1.63 (m, 4H), 1.57-1.47 (m, 2H).

(634) Step 5: methyl 4-ethyl-3-(N-(4-methyl-5-(5-methylisoxazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: A solution of the product from Step 4 above (150 mg, 0.531 mmol, 96% purity) in DCM (3 ml) and pyridine (258 l, 3.18 mmol) was added to a solution of the product from Example 203 Step 2 (139 mg, 0.531 mmol) in DCM (3 ml) and the resultant solution was stirred at RT for 2 days. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-40% EtOAc/isohexane) to afford the title compound (220 mg, 0.438 mmol, 82% yield, 99% purity) as a light brown oil. UPLC-MS (Method 1) m/z 498.4 (M+H).sup.+, 496.2 (MH).sup. at 1.95 min.

(635) Step 6: 4-ethyl-3-(N-(4-methyl-5-(5-methylisoxazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 4 M HCl in dioxane (553 l, 2.21 mmol) was added to a solution of the product from Step 5 above (220 mg, 0.438 mmol, 99% purity) in dioxane (5 ml) and the mixture was heated at 60 C. for 16 h. The mixture was concentrated in vacuo and the solid slurried with MeCN (5 ml) for 30 min. The solid was collected by filtration to afford the title compound (195 mg, 0.390 mmol, 89% yield, 98% purity) as a cream solid. UPLC-MS (Method 1) m/z 484.4 (M+H).sup.+, 482.3 (MH).sup. at 1.80 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.89 (br s, 1H), 8.57 (s, 1H), 8.35 (d, J=1.8 Hz, 1H), 8.08 (dd, J=7.9, 1.8 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.13 (br s, 1H), 6.92 (br s, 1H), 3.06 (q, J=7.4 Hz, 2H), 2.82-2.55 (m, 4H), 2.20 (s, 3H), 2.12 (s, 3H), 1.73-1.55 (m, 4H), 1.54-1.40 (m, 2H), 1.22 (t, J=7.4 Hz, 3H). One exchangeable proton not observed.

Example 304: 4-ethyl-3-(N-(4-fluoro-5-(5-methylisoxazol-4-yl)-2-(piperidin-1-yl)phenyl) sulfamoyl)benzoic acid

(636) ##STR00636##

(637) Step 1: 1-(4-bromo-5-fluoro-2-nitrophenyl)piperidine: 1-bromo-2,4-difluoro-2-methyl-5-nitrobenzene (1 g, 4.20 mmol) in dry DMF (5 ml) was treated with Et.sub.3N (586 l, 4.20 mmol) followed by piperidine (415 l, 4.20 mmol) and the mixture was stirred at RT for 3 days. The mixture was diluted with water (50 ml) and extracted with EtOAc (100 ml). The organic phase was washed with brine (50 ml), dried over MgSO.sub.4, filtered, and concentrated in vacuo to afford the title compound (1.27 g, 3.02 mmol, 72% yield, 72% purity) as a red oil. UPLC-MS (Method 1) m/z 303.2 (M+H).sup.+ at 1.84 min.

(638) Step 2: 1-(5-fluoro-2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine: A mixture of the product from Step 1 above (1.27 g, 3.02 mmol, 72% purity), bis(pinacolato)diboron (1.15 g, 4.52 mmol), KOAc (888 mg, 9.05 mmol) and PdCl.sub.2 (dppf).Math.DCM (221 mg, 0.302 mmol) in dioxane (10 ml) was degassed with N.sub.2 for 15 min and then heated at 80 C. for 16 h. The mixture was diluted with water (50 ml) and extracted with EtOAc (50 ml). The organic phase was dried over MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-100% TBME/isohexane) to afford the title compound (1.05 g, 1.80 mmol, 59% yield, 60% purity) as an orange solid. UPLC-MS (Method 1) m/z 347.4 (M+H).sup.+ at 2.15 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.03 (d, J=6.4 Hz, 1H), 6.97 (d, J=12.1 Hz, 1H), 3.07 (t, J=5.0 Hz, 4H), 1.68-1.49 (m, 6H), 1.29 (s, 12H).

(639) Step 3: 4-fluoro-2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline: The product from Step 2 above (500 mg, 0.857 mmol, 60% purity) in MeOH (5 ml) was treated with 10% Pd/C (50% w/w water) Type 39 (91 mg, 0.086 mmol). The reaction mixture was hydrogenated at 2 bar at RT for 2 h. The mixture was filtered through Celite, washing with MeOH (20 ml), and then concentrated in vacuo to afford the title compound (373 mg, 0.559 mmol, 65% yield, 48% purity) as a dark blue oil. UPLC-MS (Method 1) m/z 321.4 (M+H).sup.+ at 1.62 min.

(640) Step 4: 4-fluoro-5-(5-methylisoxazol-4-yl)-2-(piperidin-1-yl)aniline: A mixture of the product from Step 3 above (373 mg, 0.559 mmol, 48% purity), 4-iodo-5-methylisoxazole (128 mg, 0.610 mmol), K.sub.3PO.sub.4 (153 mg, 0.721 mmol), dioxane (4 ml) and water (1 ml) was treated with Xphos Pd G3 (47 mg, 0.060 mmol). The resultant mixture was degassed with N.sub.2 for 15 min and then heated at 80 C. for 2 h. The mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-30% EtOAc/isohexane) to afford the title compound (180 mg, 0.458 mmol, 83% yield, 70% purity) as a dark brown solid. UPLC-MS (Method 1) m/z 276.3 (M+H).sup.+ at 1.50 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.60 (d, J=1.6 Hz, 1H), 6.81 (d, J=12.0 Hz, 1H), 6.72 (d, J=7.8 Hz, 1H), 4.66 (br s, 2H), 2.82-2.75 (m, 4H), 2.46 (s, 3H), 1.70-1.57 (m, 6H).

(641) Step 5: methyl 4-ethyl-3-(N-(4-fluoro-5-(5-methylisoxazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: A solution of the product from Step 4 above (180 mg, 0.458 mmol, 70% purity) in DCM (3 ml) and pyridine (222 l, 2.75 mmol) was added to a solution of the product from Example 203 Step 2 (120 mg, 0.458 mmol) in DCM (3 ml) and the resultant solution stirred at RT for 72 h. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-30% EtOAc/isohexane) to afford the title compound (120 mg, 0.167 mmol, 37% yield, 70% purity) as a white solid. UPLC-MS (Method 1) m/z 502.4 (M+H).sup.+, 500.3 (MH).sup. at 1.96 min.

(642) Step 6: 4-ethyl-3-(N-(4-fluoro-5-(5-methylisoxazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 4 M HCl in dioxane (210 l, 0.840 mmol) was added to a solution of the product from Step 5 above (120 mg, 0.167 mmol, 70% purity) in dioxane (5 ml) and the mixture was heated at 60 C. for 16 h. The mixture was concentrated in vacuo. The residue was purified by chromatography (12 g reverse phase C18 cartridge, 15-85% MeCN/0.1% formic acid (aq)) to afford the title compound (30.5 mg, 0.061 mmol, 36% yield, 98% purity) as an off-white solid. UPLC-MS (Method 1) m/z 488.3 (M+H).sup.+, 486.2 (MH).sup. at 1.83 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.30 (br s, 1H), 9.48-9.07 (s, 1H), 8.59 (d, J=1.8 Hz, 1H), 8.32 (d, J=1.8 Hz, 1H), 8.08 (dd, J=8.0, 1.8 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 7.06 (d, J=12.0 Hz, 1H), 3.04 (q, J=7.4 Hz, 2H), 2.64 (t, J=5.1 Hz, 4H), 2.35 (s, 3H), 1.48 (d, J=9.7 Hz, 4H), 1.43 (d, J=8.6 Hz, 2H), 1.22 (t, J=7.4 Hz, 3H).

Example 305: 4-ethyl-3-(N-(2-fluoro-3-(5-methylisoxazol-4-yl)-6-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid

(643) ##STR00637##

(644) Step 1: 1-(4-bromo-3-fluoro-2-nitrophenyl)piperidine: 1-bromo-2,4-fluoro-3-nitrobenzene (1 g, 4.20 mmol) in dry DMF (5 ml) was cooled to 0 C. Et.sub.3N (1.17 ml, 8.40 mmol) followed by piperidine (415 l, 4.20 mmol) were added and the mixture was stirred at RT for 24 h. The mixture was diluted with water (50 ml) and extracted with EtOAc (100 ml). The organic phase was washed with brine (50 ml), dried over MgSO.sub.4, filtered, and concentrated in vacuo to afford the title compound (1.2 g, 3.76 mmol, 90% yield, 95% purity) as a red oil. UPLC-MS (Method 1) m/z 303.4 (M+H).sup.+ at 1.88 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.82 (t, J=8.5 Hz, 1H), 7.13 (dd, J=9.1 Hz, 1H), 2.97 (t, J=5.1 Hz, 4H), 1.62-1.48 (m, 6H).

(645) Step 2: 3-bromo-2-fluoro-6-(piperidin-1-yl)aniline: A solution of the product from Step 1 above (500 mg, 1.56 mmol, 95% purity) in THF (9 ml) and water (3 ml) was treated with zinc dust (615 mg, 9.40 mmol) and NH.sub.4Cl(s) (503 mg, 9.40 mmol). The resultant mixture was stirred at RT for 2 h. The mixture was filtered through Celite, washing with EtOAc (35 ml), and then concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-20% EtOAc/isohexane) to afford the title compound (320 mg, 1.14 mmol, 72% yield, 97% purity) as a light brown oil. UPLC-MS (Method 1) m/z 273.1 (M+H).sup.+ at 1.79 min.

(646) Step 3: 2-fluoro-6-(piperidin-1-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline: A mixture of the product from Step 2 above (320 mg, 1.14 mmol, 97% purity), bis(pinacolato)diboron (433 mg, 1.70 mmol), KOAc (335 mg, 3.41 mmol) and PdCl.sub.2 (dppf).Math. DCM (83 mg, 0.114 mmol) in dioxane (10 ml) was degassed with N.sub.2 for 15 min and then heated at 80 C. for 16 h. The mixture was diluted with water (50 ml) and extracted with EtOAc (50 ml). The organic phase was dried over MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (379 mg, 1.11 mmol, 98% yield, 94% purity) as a light green solid. UPLC-MS (Method 1) m/z 321.4 (M+H).sup.+ at 1.83 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.01 (s, 1H), 7.02 (s, 1H), 3.02 (t, J=5.1 Hz, 4H), 2.48 (s, 3H), 1.67-1.50 (m, 6H), 1.29 (s, 12H).

(647) Step 4: 2-fluoro-3-(5-methylisoxazol-4-yl)-6-(piperidin-1-yl)aniline: A mixture of the product from Step 3 above (200 mg, 0.587 mmol, 94% purity), 4-iodo-5-methylisoxazole (135 mg, 0.646 mmol), K.sub.3PO.sub.4 (162 mg, 0.763 mmol), dioxane (4 ml) and water (1 ml) was treated with Xphos Pd G3 (50.0 mg, 0.059 mmol). The resultant mixture was degassed with N.sub.2 for 15 min and then heated at 80 C. for 2 h. The mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (140 mg, 0.386 mmol, 66% yield, 76% purity) as waxy tan solid. UPLC-MS (Method 1) m/z 276.3 (M+H).sup.+ at 1.58 min.

(648) Step 5: Methyl 4-ethyl-3-(N-(2-fluoro-3-(5-methylisoxazol-4-yl)-6-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: A solution of the product from Step 4 above (140 mg, 0.386 mmol, 76% purity) in DCM (3 ml) and pyridine (188 l, 2.32 mmol) was added to a solution of the product from Example 203 Step 2 (102 mg, 0.386 mmol) in DCM (3 ml) and the resultant solution was stirred at RT for 48 h. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-40% EtOAc/isohexane) to afford the title compound (64 mg, 0.089 mmol, 23% yield, 70% purity) as a light brown oil. UPLC-MS (Method 1) m/z 502.4 (M+H).sup.+, 500.3 (MH).sup. at 1.81 min.

(649) Step 6: 4-ethyl-3-(N-(2-fluoro-3-(5-methylisoxazol-4-yl)-6-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: 4 M HCl in dioxane (110 l, 0.440 mmol) was added to a solution of the product from Step 5 above (64 mg, 0.089 mmol, 70% purity) in dioxane (5 ml) and the mixture was heated at 60 C. for 72 h. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 50-80% MeCN in Water) to afford the title compound (4 mg, 7.88 mol, 9% yield, 96% purity) as a white solid. UPLC-MS (Method 1) m/z 488.4 (M+H).sup.+, 486.3 (MH).sup. at 1.68 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.21 (br s, 1H), 9.52 (s, 1H), 8.58 (s, 1H), 8.30 (d, J=1.8 Hz, 1H), 8.08 (dd, J=8.0, 1.9 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.32 (t, J=8.4 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 3.08 (d, J=7.1 Hz, 2H), 2.80-2.69 (m, 4H), 2.38 (s, 3H), 1.35-1.18 (m, 9H).

Example 306: 4-ethyl-3-(N-(4-Chloro-5-(5-methylisoxazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid

(650) ##STR00638##

(651) Step 1: 1-(4-bromo-5-chloro-2-nitrophenyl)piperidine: 1-bromo-2-chloro-4-fluoro-5-nitrobenzene (1 g, 3.93 mmol) in dry DMF (5 ml) was cooled to 0 C. Et.sub.3N (1.09 ml, 7.86 mmol) and piperidine (388 l, 3.93 mmol) were sequentially added and the mixture was stirred at RT for 24 h. The mixture was diluted with water (50 ml) and extracted with EtOAc (100 ml). The organic phase was washed with brine (50 ml), dried over MgSO.sub.4, filtered, and concentrated in vacuo to afford the title compound (1.2 g, 3.68 mmol, 94% yield, 98% purity) as a red oil. UPLC-MS (Method 1) m/z 319.2 (M+H).sup.+ at 1.97 min.

(652) Step 2: 5-bromo-4-chloro-2-(piperidin-1-yl)aniline: A solution of the product from Step 1 above (1.20 g, 3.68 mmol, 98% purity) in THF (9 ml) and water (3 ml) was treated with zinc dust (1.44 g, 22.1 mmol) and NH.sub.4Cl(s) (1.18 g, 22.1 mmol). The resultant mixture was stirred at RT for 2 h. The mixture was filtered through Celite, washing with EtOAc (35 ml), and then concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-20% EtOAc/isohexane) to afford the title compound (880 mg, 2.92 mmol, 79% yield, 96% purity) as a light brown oil. UPLC-MS (Method 1) m/z 289.1 (M+H).sup.+ at 1.87 min.

(653) Step 3: 4-chloro-2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline: A mixture of the product from Step 2 above (880 mg, 2.92 mmol, 96% purity), bis(pinacolato)diboron (1.11 g, 4.38 mmol), KOAc (859 mg, 8.75 mmol) and PdCl.sub.2 (dppf).Math. DCM (213 mg, 0.292 mmol) in dioxane (10 ml) was degassed with N.sub.2 for 15 min and then heated at 80 C. for 16 h. The mixture was diluted with water (50 ml) and extracted with EtOAc (50 ml). The organic phase was dried over MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (980 mg, 2.38 mmol, 82% yield, 82% purity) as a brown oil. UPLC-MS (Method 1) m/z 337.3 (M+H).sup.+ at 1.89 min.

(654) Step 4: 4-chloro-5-(5-methylisoxazol-4-yl)-2-(piperidin-1-yl)aniline: A mixture of the product from Step 3 above (300 mg, 0.731 mmol, 82% purity), 4-iodo-5-methylisoxazole (168 mg, 0.804 mmol), K.sub.3PO.sub.4 (202 mg, 0.950 mmol), dioxane (4 ml) and water (1 ml) was treated with Xphos Pd G3 (62.0 mg, 0.073 mmol). The resultant mixture was degassed with N.sub.2 for 15 min and then heated at 80 C. for 2 h. The mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (225 mg, 0.717 mmol, 98% yield, 93% purity) as waxy tan solid. UPLC-MS (Method 1) m/z 292.2 (M+H).sup.+ at 1.69 min.

(655) Step 5: methyl 3-(N-(4-chloro-5-(5-methylisoxazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoate: A solution of the product from Step 4 above (225 mg, 0.717 mmol, 93% purity) in DCM (3 ml) and pyridine (348 l, 4.30 mmol) was added to a solution of the product from Example 203 Step 2 (188 mg, 0.717 mmol) in DCM (3 ml) and the resultant solution was stirred at RT for 3 days. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (40 g cartridge, 0-40% EtOAc/isohexane) to afford the title compound (320 mg, 0.525 mmol, 73% yield, 85% purity) as a light brown oil. UPLC-MS (Method 1) m/z 518.3 (M+H).sup.+, 516.1 (MH).sup. at 2.02 min.

(656) Step 6: 3-(N-(4-chloro-5-(5-methylisoxazol-4-yl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid: 4 M HCl in dioxane (656 l, 2.63 mmol) was added to a solution of the product from Step 5 above (320 mg, 0.525 mmol, 85% purity) in dioxane (5 ml) and the mixture was heated at 60 C. for 24 h. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 50-80% MeCN in Water) to afford the title compound (42.6 mg, 0.083 mmol, 16% yield, 98% purity) as a white solid. UPLC-MS (Method 1) m/z 504.3 (M+H).sup.+, 502.2 (MH).sup. at 1.90 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.59 (br s, 1H), 8.35 (d, J=1.8 Hz, 1H), 8.08 (dd, J=7.9, 1.8 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.24 (s, 1H), 7.09 (s, 1H), 3.12-2.97 (m, 2H), 2.67 (t, J=7.4 Hz, 4H), 2.26 (s, 3H), 1.55 (q, J=5.6 Hz, 4H), 1.45 (q, J=5.8 Hz, 2H), 1.22 (t, J=7.4 Hz, 3H). Two exchangeable protons not observed.

Example 308: 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(657) ##STR00639##

(658) Step 1: 4,4-difluoro-1-(4-(methylsulfonyl)-2-nitrophenyl)piperidine: A mixture of 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (500 mg, 2.28 mmol) and 4,4-difluoropiperidine (276 mg, 2.28 mmol) and Et.sub.3N (400 l, 2.87 mmol) was sonicated in DCM (6 ml) until a clear solution was formed. The resultant solution was allowed to stand at RT for 2 h. The reaction mixture was sequentially washed with 1 M HCl(aq) (4 ml), water (4 ml) and brine (2 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to afford the title compound (717 mg, 1.90 mmol, 83% yield, 85% purity) as a bright yellow solid. UPLC-MS (Method 1) m/z 321.3 (M+H).sup.+ at 1.28 min.

(659) Step 2: 2-(4,4-difluoropiperidin-1-yl)-5-(methylsulfonyl)aniline: The product from Step 1 above (717 mg, 2.24 mmol, 85% purity) was dissolved in 1:1 EtOH/THF (100 ml) and hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm, full hydrogen mode, RT, 1 ml/min, then 20 bar, 40 C., recirculating for 2 h, then 40 bar, 50 C. recirculating for 2 h, then 40 bar, 50 C.). The mixture was concentrated in vacuo. The residue was dissolved in a mixture of AcOH (50 ml), THF (50 ml) and water (10 ml) and filtered. The filtrate was concentrated in vacuo and dissolved in AcOH (50 ml) and hydrogenated in a ThalesNano H-cube flow reactor (10% Pd/C, 304 mm, Full hydrogen, RT, 1 ml/min, recirculating for 1.5 h). The mixture was concentrated in vacuo, azeotroping with toluene (50 ml). The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (162 mg, 0.469 mmol, 21% yield, 84% purity) as a pale yellow foam. UPLC-MS (Method 1) m/z 291.2 (M+H).sup.+ at 1.18 min.

(660) Step 3: Methyl 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)-4-ethylbenzoate: The product from Step 2 above (62 mg, 0.179 mmol, 84% purity) was dissolved in a mixture of DCM (1 ml) and pyridine (50 l, 0.618 mmol) and treated with the product from Example 203 Step 2 (50 mg, 0.188 mmol). The resultant solution was allowed to stand at RT for 3 days. Additional product from Example 203 Step 2 (53 mg, 0.200 mmol) was added and the resultant solution allowed to stand at RT for 4 days. The mixture was concentrated in vacuo onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (104 mg, 0.167 mmol, 93% yield, 83% purity) as a light beige foam. UPLC-MS (Method 1) m/z 517.2 (M+H).sup.+, 515.3 (MH).sup. at 1.55 min.

(661) Step 4: 3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)-4-ethylbenzoic acid: A mixture of the product from Step 3 above (104 mg, 0.167 mmol, 83% purity) and LiOH (28 mg, 0.655 mmol) in THF/MeOH/water (4:1:1, 6 ml) was stirred at 40 C. for 18 h. The mixture was diluted with water (5 ml), acidified to pH 4 using 1 M HCl(aq) and extracted with EtOAc (310 ml). The organic extracts were combined and washed with brine (10 ml), dried by passage through a phase separator and the solvent removed in vacuo. The crude product was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 35-65% MeCN in Water) to afford the title compound (36.3 mg, 72 mol, 42% yield, 99% purity) as a white solid. UPLC-MS (Method 1) m/z 503.2 (M+H).sup.+, 501.1 (MH).sup. at 1.41 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.33 (s, 1H), 9.89 (s, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.10 (dd, J=8.0, 1.8 Hz, 1H), 7.65-7.59 (m, 2H), 7.55 (d, J=2.2 Hz, 1H), 7.35 (d, J=8.5 Hz, 1H), 3.05 (s, 3H), 3.02 (q, J=7.4 Hz, 2H), 2.94-2.88 (m, 4H), 2.12-2.01 (m, 4H), 1.20 (t, J=7.4 Hz, 3H).

Example 309:4-cyclopropyl-3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl) sulfamoyl)benzoic acid

(662) ##STR00640##

(663) Step 1: Methyl 4-bromo-3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoate: The product from Example 308 Step 2 (102 mg, 0.313 mmol, 84% purity) was dissolved in a mixture of DCM (1 ml) and pyridine (50 l, 0.618 mmol) and treated with the product from Example 316 Step 1 (103 mg, 0.325 mmol). The resultant suspension was sonicated, and then diluted with DCM (1 ml) to afford a clear solution. The mixture was allowed to stand at RT for 4 days. The mixture was concentrated in vacuo onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (108 mg, 0.101 mmol, 32% yield, 53% purity) as a beige foam. UPLC-MS (Method 1) m/z 567.2 (M+H).sup.+, 565.0 (MH).sup. at 1.52 min.

(664) Step 2: Methyl 4-bromo-3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoate: A degassed mixture of the product from Step 1 above (108 mg, 0.101 mmol, 53% purity) and Pd-174 (7.00 mg, 9.71 mol) in THF (2 ml) was treated with cyclopropylzinc (II) bromide (0.5 M in THF) (800 l, 0.400 mmol). The mixture was heated at 60 C. for 18 h. Upon cooling to RT the mixture was concentrated onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (54 mg, 62.0 mol, 61% yield, 61% purity) as a light brown oil. UPLC-MS (Method 1) m/z 529.2 (M+H).sup.+, 527.1 (MH).sup. at 1.55 min.

(665) Step 3: 4-cyclopropyl-3-(N-(2-(4,4-difluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoic acid: A mixture of the product from Step 2 above (54 mg, 62.0 mol, 61% purity) and LiOH (11 mg, 0.257 mmol) in THF/MeOH/water (4:1:1, 2.4 ml) was stirred at 40 C. for 18 h. The mixture was diluted with water (5 ml), acidified to pH 4 with 1 M HCl(aq) and extracted with EtOAc (310 ml). The organic extracts were combined and washed with brine (10 ml), dried by passage through a phase separator and the solvent removed in vacuo. The crude product was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 35-65% MeCN in Water) to afford the title compound (13.8 mg, 27.0 mol, 42% yield, 99% purity) as a white solid. UPLC-MS (Method 1) m/z 515.2 (M+H).sup.+, 513.0 (MH).sup. at 1.40 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.27 (s, 1H), 9.80 (s, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.01 (dd, J=8.2, 1.8 Hz, 1H), 7.65-7.58 (m, 1H), 7.55 (d, J=2.2 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.2 Hz, 1H), 3.02 (s, 3H), 2.98-2.93 (m, 4H), 2.84-2.75 (m, 1H), 2.10-2.01 (m, 4H), 1.11-1.03 (m, 2H), 0.90-0.83 (m, 2H).

Example 310: 3-(N-(5-cyano-2-(4,4-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid

(666) ##STR00641##

(667) Step 1: methyl 4-bromo-3-(N-(5-cyano-2-(4,4-difluoropiperidin-1-yl)phenyl)sulfamoyl)benzoate: The product from Example 221 Step 2 (100 mg, 0.400 mmol) was dissolved in a mixture of DCM (1 ml) and pyridine (100 l, 1.23 mmol) and treated with the product from Example 316 Step 1 (130 mg, 0.410 mmol). The resultant solution was allowed to stand at RT for 4 days. The mixture was concentrated in vacuo onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (123 mg, 0.234 mmol, 58% yield, 98% purity) as a light orange solid. UPLC-MS (Method 1) m/z 514.2 (M+H).sup.+, 512.0 (MH).sup. at 1.65 min.

(668) Step 2: methyl 4-bromo-3-(N-(5-cyano-2-(4,4-difluoropiperidin-1-yl)phenyl)sulfamoyl)benzoate: A degassed mixture of the product from Step 1 above (123 mg, 0.234 mmol, 98% purity) and Pd-174 (17 mg, 24 mol) in THF (4.5 ml) was treated with cyclopropylzinc (II) bromide (0.5 M in THF) (1.8 ml, 0.900 mmol). The mixture was heated at 60 C. for 18 h. Upon cooling to RT the mixture was concentrated in vacuo onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (99.4 mg, 0.192 mmol, 82% yield, 92% purity) as a yellow solid. UPLC-MS (Method 1) m/z 476.3 (M+H).sup.+, 474.2 (MH).sup. at 1.69 min.

(669) Step 3: 3-(N-(5-cyano-2-(4,4-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: A mixture of the product from Step 2 above (99.4 mg, 0.192 mmol, 92% purity) and LiOH (33 mg, 0.772 mmol) in THF/MeOH/water (4:1:1, 6.6 ml) was stirred at 40 C. for 18 h. The mixture was diluted with water (10 ml), acidified to pH 4 using 1 M HCl(aq) and extracted with EtOAc (320 ml). The combined organic extracts were washed with brine (20 ml), dried by passage through a phase separator and the solvent removed in vacuo. The crude product was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 35-65% MeCN in Water) to afford the title compound (55.8 mg, 0.120 mmol, 62% yield, 99% purity) as a white solid. UPLC-MS (Method 1) m/z 462.2 (M+H).sup.+, 460.2 (MH).sup. at 1.54 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.29 (s, 1H), 9.81 (s, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.02 (dd, J=8.2, 2.0 Hz, 1H), 7.56 (dd, J=8.4, 1.8 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.16 (d, J=8.2 Hz, 1H), 2.97-2.91 (m, 4H), 2.80-2.71 (m, 1H), 2.07-1.95 (m, 4H), 1.10-1.03 (m, 2H), 0.90-0.83 (m, 2H).

Example 311: I-3-(N-(5-cyano-2-(3-fluoropiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic

(670) ##STR00642##

(671) Step 1: I-4-(3-fluoropiperidin-1-yl)-3-nitrobenzonitrile: A mixture of 4-fluoro-3-nitrobenzonitrile (400 mg, 2.41 mmol) and I-3-fluoropiperidine hydrochloride (336 mg, 2.41 mmol) and Et.sub.3N (700 l, 5.02 mmol) was sonicated in DCM (6 ml) for 5 min. The resultant suspension was stirred at RT for 18 h. The reaction mixture was sequentially washed with 1 M HCl(aq) (4 ml), water (4 ml) and brine (2 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to afford the title compound (596 mg, 2.37 mmol, 98% yield, 99% purity) as a bright yellow solid. UPLC-MS (Method 1): m/z 250.3 (M+H).sup.+ at 1.35 min.

(672) Step 2: I-3-amino-4-(3-fluoropiperidin-1-yl)benzonitrile: The product from Step 1 above (596 mg, 2.37 mmol, 99% purity) was combined with iron powder (2.5 g, 44.8 mmol) and NH.sub.4Cl(s) (150 mg, 2.80 mmol) in IPA (20 ml) and water (10 ml), then heated at 80 C. and stirred overnight. The mixture was cooled and allowed to stand for 24 h. The mixture was filtered through Celite, rinsing with EtOAc (210 ml) and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (304 mg, 1.36 mmol, 62% yield, 98% purity). UPLC-MS (Method 1): m/z 220.3 (M+H).sup.+ at 1.32 min.

(673) Step 3: I-methyl 3-(N-(5-cyano-2-(3-fluoropiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoate: The product from Example 203 Step 2 (300 mg, 1.13 mmol) was added to a solution of pyridine (0.1 ml, 1.24 mmol) and the product from Step 2 above (152 mg, 0.679 mmol, 98% purity) in DCM (1 ml). The resultant solution was allowed to stand at RT for 3 days. The mixture was treated with PhMe (1 ml) and concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (254 mg, 0.570 mmol, 84% yield) as a white foamy solid. UPLC-MS (Method 1): m/z 446.4 (M+H).sup.+, 444.3 (MH).sup., at 1.70 min.

(674) Step 4: I-3-(N-(5-cyano-2-(3-fluoropiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid: The product from Step 3 above (254 mg, 0.570 mmol) was dissolved in THF (10 ml) and treated with 1 M LiOH(aq) (2 ml, 2.00 mmol). MeOH was added to afford a clear solution. The resultant solution was allowed to stand at RT for 1 week. The mixture was diluted with water (4 ml) and concentrated in vacuo. The resultant aqueous solution was diluted with water (2 ml) and washed with TBME (8 ml), then concentrated in vacuo to remove residual TBME. The solution was diluted with water (4 ml) and acidified with 1 M HCl(aq) to pH 4 and the resultant white precipitate collected by filtration, washing with water (24 ml). The resultant solid was dried in vacuo to afford the title compound (214 mg, 0.471 mmol, 83% yield, 95% purity) as a white solid. UPLC-MS (Method 2): m/z 432.4 (M+H).sup.+, 430.3 (MH).sup. at 0.99 min. 1H NMR (500 MHz, DMSO-d.sub.6) 13.33 (s, 1H), 9.52 (s, 1H), 8.32 (d, J=1.8 Hz, 1H), 8.11 (dd, J=8.0, 1.8 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.31-7.14 (m, 2H), 4.69 (dtt, J=48.2, 7.3, 3.6 Hz, 1H), 3.25-3.09 (m, 1H), 3.02 (q, J=7.4 Hz, 2H), 2.95-2.84 (m, 2H), 2.83-2.70 (m, 1H), 2.05-1.84 (m, 1H), 1.82-1.69 (m, 1H), 1.69-1.45 (m, 2H), 1.21 (t, J=7.4 Hz, 3H).

Example 312: I-3-(N-(5-cyano-2-(3-fluoropiperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid

(675) ##STR00643##

(676) Step 1: I-methyl 4-bromo-3-(N-(5-cyano-2-(3-fluoropiperidin-1-yl)phenyl)sulfamoyl)benzoate: The product from Example 316 Step 1 (350 mg, 1.11 mmol) was added to a solution of pyridine (100 l, 1.24 mmol) and the product from Example 311 Step 2 (152 mg, 0.679 mmol, 98% purity) in DCM (1 ml). The resultant solution was allowed to stand at RT for 3 days. The mixture was treated with PhMe (1 ml) and concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (313 mg, 0.618 mmol, 91% yield, 98% purity) as a white foamy solid. UPLC-MS (Method 1): m/z 496.2 (M+H).sup.+, 494.1 (MH).sup., at 1.66 min.

(677) Step 2: I-methyl 3-(N-(5-cyano-2-(3-fluoropiperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoate: A mixture of the product from Step 1 above (313 mg, 0.618 mmol, 98% purity) and Pd-174 (45 mg, 0.062 mmol) in THF (10 ml) was treated with cyclopropylzinc (II) bromide (0.5 M in THF) (5 ml, 2.50 mmol) and then heated at 60 C. for 45 min. The mixture was cooled in an ice bath, quenched with saturated NH.sub.4Cl (aq) (1 ml) and the THF removed in vacuo. The residue was extracted with DCM (4 ml, then 21 ml). The combined organic extracts were directly purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexane) to afford two batches of the title compound:

(678) Batch 1 (50 mg, 0.105 mmol, 17% yield, 96% purity) as a clear colourless oil, which partially crystallised on standing. UPLC-MS (Method 1): m/z 458.4 (M+H).sup.+, 456.3 (MH).sup., at 1.70 min. Batch 2 (192 mg, 0.386 mmol, 63% yield, 92% purity) as a clear colourless oil, which partially crystallised on standing.

(679) Step 3: I-3-(N-(5-cyano-2-(3-fluoropiperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: The products from Step 2 above: Batch 1 (50 mg, 0.105 mmol, 17% yield, 96% purity) and Batch 2 (192 mg, 0.386 mmol, 63% yield, 92% purity) were each dissolved in THF (2 ml or 8 ml respectively) and treated with 1 M LiOH(aq) (400 l, 0.400 mmol; or 1.6 ml, 1.60 mmol respectively). MeOH was added to the reaction mixtures to form clear solutions, which were allowed to stand at RT for 30 h. The mixtures were neutralised with AcOH and concentrated in vacuo. The residues were combined and purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 50-85% MeCN in Water) to afford the title compound (127 mg, 0.281 mmol, 57% yield, 98% purity) as a white solid. UPLC-MS (Method 2): m/z 444.4 (M+H).sup.+, 442.3 (MH).sup., at 1.01 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.30 (s, 1H), 9.43 (s, 1H), 8.38 (d, J=1.8 Hz, 1H), 8.03 (dd, J=8.2, 1.9 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.32-7.09 (m, 3H), 4.71 (dtt, J=48.0, 7.3, 3.5 Hz, 1H), 3.26-3.13 (m, 1H), 3.01-2.88 (m, 2H), 2.86-2.77 (m, 1H), 2.76-2.66 (m, 1H), 1.97-1.84 (m, 1H), 1.79-1.70 (m, 1H), 1.69-1.50 (m, 2H), 1.21-1.03 (m, 2H), 0.97-0.73 (m, 2H).

Example 313: 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(680) ##STR00644##

(681) Step 1: 3,3-difluoro-1-(4-(methylsulfonyl)-2-nitrophenyl)piperidine: A mixture of 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (500 mg, 2.28 mmol) and 3,3-difluoropiperidine hydrochloride (359 mg, 2.28 mmol) and triethylamine (700 l, 5.02 mmol) was sonicated in DCM (6 ml) for 5 min. The resultant suspension was stirred at RT for 18 h. The reaction mixture was sequentially washed with 1 M HCl (4 ml), water (4 ml) and brine (2 ml), diluted with EtOAc (175 ml), washed with brine (10 ml), dried over MgSO.sub.4, filtered and concentrated in vacuo to afford the title compound (709 mg, 2.19 mmol, 96% yield, 99% purity) as a bright yellow solid. UPLC-MS (Method 1): m/z 321.1 (M+H).sup.+, at 1.24 min.

(682) Step 2: 2-(3,3-difluoropiperidin-1-yl)-5-(methylsulfonyl)aniline: The product from Step 1 above (709 mg, 2.19 mmol, 99% purity) was combined with iron powder (2.5 g, 44.8 mmol) and NH.sub.4Cl(s) (150 mg, 2.80 mmol) in IPA (20 ml) and water (10 ml), heated at 80 C. and stirred overnight. The mixture was cooled and allowed to stand for 24 h. The mixture was filtered through Celite, rinsing with EtOAc (210 ml) and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (505 mg, 1.74 mmol, 79% yield) as a white solid. UPLC-MS (Method 1): m/z 291.1 (M+H).sup.+ at 1.16 min.

(683) Step 3: methyl 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)-4-ethylbenzoate: The product from Example 203 Step 2 (300 mg, 1.13 mmol) was added to a solution of pyridine (100 l, 1.24 mmol) and the product from Step 2 above (252 mg, 0.868 mmol) in DCM (2 ml). The resultant solution was allowed to stand at RT for 11 days. The mixture was treated with PhMe (1 ml) and concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-60% EtOAc/isohexane) to afford the title compound (319 mg, 0.618 mmol, 71% yield) as a white foamy solid. UPLC-MS (Method 1): m/z 517.4 (M+H).sup.+, 515.2 (MH).sup. at 1.57 min.

(684) Step 4: 3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)-4-ethylbenzoic acid: The product from Step 3 above (319 mg, 0.618 mmol) was dissolved in THF (9 ml) and treated with 1 M LiOH(aq) (3 ml, 3.00 mmol). The resultant biphasic mixture was stirred at RT for 18 h. The mixture was concentrated in vacuo. The resultant aqueous solution was diluted with water (6 ml) and acidified with 1 M HCl(aq) to pH 4 and the resultant white precipitated collected by filtration, washing with water (24 ml). The resultant solid was suspended in MeCN (5 ml), the suspension concentrated and dried in vacuo to afford the title compound (292 mg, 0.569 mmol, 92% yield, 98% purity) as a white solid. UPLC-MS (Method 2): m/z 503.2 (M+H).sup.+, 501.2 (MH).sup. at 0.99 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6).Math. 12.81 (s, 1H), 8.60-8.35 (m, 1H), 7.96-7.74 (m, 1H), 7.73-7.51 (m, 1H), 7.42-7.20 (m, 1H), 7.12-6.51 (m, 2H), 3.54-3.41 (m, 2H), 3.24-3.11 (m, 4H), 2.84 (s, 3H), 2.05-1.92 (m, 2H), 1.82-1.71 (m, 2H), 1.15 (t, J=7.4 Hz, 3H).

Example 314: I-4-cyclopropyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl) sulfamoyl)benzoic acid

(685) ##STR00645##

(686) Step 1: I-methyl 4-bromo-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: The product from Example 316 Step 1 (300 mg, 0.947 mmol) was added to a solution of pyridine (0.1 ml, 1.24 mmol) and the product from Example 243 Step 2 (191 mg, 0.735 mmol) in DCM (2 ml). The resultant solution was allowed to stand at RT for 24 h. The mixture was treated with PhMe (1 ml) and concentrated in vacuo.

(687) The residue was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (379 mg, 0.698 mmol, 95% yield, 99% purity) as a white foamy solid. UPLC (Method 1): m/z 537.2 (M+H).sup.+, 535.1 (MH).sup. at 1.67 min.

(688) Step 2: I-methyl 4-cyclopropyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: A mixture of the product from Step 1 above (379 mg, 0.698 mmol, 99% purity) and Pd-174 (50 mg, 0.069 mmol) in THF (10 ml) was treated with cyclopropylzinc (II) bromide (0.5 M in THF) (5 ml, 2.50 mmol) and then heated to 60 C. and stirred for 18 h. Additional cyclopropylzinc (II) bromide (0.5 M in THF) (1 ml, 0.500 mmol) was added and heating continued for 1 h. The mixture was neutralised using saturated NH.sub.4Cl (aq) (1 ml) and concentrated in vacuo. The residue was extracted with DCM (24 ml). The extracts were combined and concentrated in vacuo. The residue was partially purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (184 mg, 0.343 mmol, 49% yield, 93% purity) as a clear white foam. UPLC (Method 1): m/z 499.3 (M+H).sup.+, 497.3 (MH).sup. at 1.73 min.

(689) Step 3: I-4-cyclopropyl-3-(N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid: The product from Step 2 above (184 mg, 0.343 mmol, 93% purity) was dissolved in THF (5 ml) and treated with 1 M LiOH(aq) (2.5 ml, 2.50 mmol). The resultant biphasic mixture was stirred at RT for 3 days. The mixture was concentrated in vacuo to remove the THF, then diluted with water (5 ml) and acidified to pH 4 using 1 M HCl(aq). The resultant white precipitate was collected by filtration, washing with water, and dried in vacuo to afford a white solid. The solid was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 35-65% MeCN in Water) to afford the title compound (106 mg, 0.214 mmol, 63% yield, 98% purity). UPLC (Method 2): m/z 485.3 (M+H).sup.+, 483.3 (MH).sup. at 1.09 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.29 (s, 1H), 9.61 (s, 1H), 8.49 (d, J=1.9 Hz, 1H), 8.02 (dd, J=8.2, 1.9 Hz, 1H), 7.38-7.29 (m, 2H), 7.22 (d, J=8.7 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 5.42-4.92 (m, 1H), 3.84-3.71 (m, 1H), 3.37-3.22 (m, 1H), 2.94-2.82 (m, 2H), 2.82-2.65 (m, 2H), 1.91-1.74 (m, 1H), 1.74-1.61 (m, 1H), 1.61-1.40 (m, 2H), 1.23-1.03 (m, 2H), 0.92-0.83 (m, 1H), 0.83-0.73 (m, 1H).

Example 315: 3-(N-(2-(4-cyanopiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid

(690) ##STR00646##

(691) Step 1: Methyl 4-bromo-3-(N-(2-(4-cyanopiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoate: The product from Example 316 Step 1 (300 mg, 0.947 mmol) was added to a solution of pyridine (100 l, 1.24 mmol) and the product from Example 237 Step 2 (200 mg, 0.735 mmol) in DCM (1 ml). The resultant solution was allowed to stand at RT for 24 h. The mixture was treated with PhMe (1 ml) and concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (388 mg, 0.710 mmol, 97% yield) as a pale yellow foamy solid. UPLC-MS (Method 1): m/z 546.2 (M+H).sup.+, 544.1 (MH).sup. at 1.74 min.

(692) Step 2: Methyl 3-(N-(2-(4-cyanopiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-cyclopropylbenzoate: A mixture of the product from Step 1 above (388 mg, 0.710 mmol) and Pd-174 (50 mg, 0.069 mmol) in THF (10 ml) was treated with cyclopropylzinc (II) bromide (0.5 M in THF) (5 ml, 2.50 mmol) and then heated at 60 C. for 1.5 h. The mixture was cooled and allowed to stand at RT overnight. The mixture was neutralised using saturated NH.sub.4Cl (aq) (1 ml) and concentrated in vacuo. The residue was extracted with DCM (24 ml). The extracts were combined and concentrated in vacuo. The residue was partially purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (263 mg, 0.430 mmol, 61% yield, 83% purity) as a white solid. UPLC-MS (Method 1): m/z 508.3 (M+H).sup.+, 506.2 (MH).sup. at 1.77 min.

(693) Step 3: 3-(N-(2-(4-cyanopiperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: The product from Step 2 above (263 mg, 0.430 mmol, 83% purity) was dissolved in THF (5 ml) and treated with 1 M LiOH(aq) (2.5 ml, 2.50 mmol). The resultant biphasic mixture was stirred at RT for 3 days. The mixture was concentrated in vacuo to remove the THF. The resultant aqueous mixture was acidified using AcOH and concentrated in vacuo. The residue was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 35-65% MeCN in Water) to afford the title compound (125 mg, 0.248 mmol, 58% yield, 98% purity). UPLC-MS (Method 2): m/z 494.3 (M+H).sup.+, 492.2 (MH).sup. at 1.13 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.26 (s, 1H), 9.59 (s, 1H), 8.42 (d, J=1.9 Hz, 1H), 8.01 (dd, J=8.2, 1.9 Hz, 1H), 7.45-7.35 (m, 1H), 7.35-7.22 (m, 2H), 7.16 (d, J=8.3 Hz, 1H), 3.03-2.85 (m, 3H), 2.85-2.78 (m, 1H), 2.78-2.67 (m, 2H), 2.01-1.89 (m, 2H), 1.89-1.78 (m, 2H), 1.13-0.99 (m, 2H), 0.92-0.75 (m, 2H).

Example 316: 3-(N-(5-cyano-2-(3,3-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid

(694) ##STR00647##

(695) Step 1: Methyl 4-bromo-3-(chlorosulfonyl)benzoate: A mixture of 4-bromo-3-(chlorosulfonyl)benzoic acid (23.9 g, 76 mmol) and SOCl.sub.2 (160 ml) was heated under reflux for 4 h. Upon cooling to RT the volatiles were removed in vacuo and the residue was added slowly to MeOH (500 ml) at 0 C. The precipitate was collected and washed with small amounts of cold MeOH to afford the title compound (17.3 g, 54.7 mmol, 72% yield, 99% purity) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.47 (d, J=2.0 Hz, 1H), 7.78-7.71 (m, 2H), 3.86 (s, 3H).

(696) Step 2: Methyl 4-bromo-3-(N-(5-cyano-2-(3,3-difluoropiperidin-1-yl)phenyl)sulfamoyl)benzoate: A mixture of the product from Example 233 Step 2 (150 mg, 0.632 mmol, 99% purity), the product from Step 1 above (218 mg, 0.695 mmol, 99% purity) and pyridine (153 l, 1.9 mmol) in DCM (4 ml) was stirred at 35 C. for 6 days. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (327 mg, 0.547 mmol, 86% yield, 86% purity) as a brown oil. UPLC-MS (Method 2) m/z 514.1 (M+H).sup.+ at 1.50 min.

(697) Step 3: methyl 3-(N-(5-cyano-2-(3,3-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoate: A degassed mixture of the product from Step 2 above (180 mg, 0.301 mmol, 86% purity) and Pd-174 (25.2 mg, 0.035 mmol) in THF (4 ml) was treated with cyclopropylzinc (II) bromide (0.5 M in THF) (2.80 ml, 1.40 mmol). The reaction mixture was stirred at 40 C. for 1 h then concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (84 mg, 0.139 mmol, 46% yield, 79% purity) as a brown oil. UPLC-MS (Method 2) m/z 476.3 (M+H).sup.+ at 1.56 min.

(698) Step 4: 3-(N-(5-cyano-2-(3,3-difluoropiperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: 1 M LiOH(aq) (1.39 ml, 1.39 mmol) was added to a solution of the product from Step 3 above (84 mg, 0.139 mmol, 79% purity) in THF (2 ml) and the resultant mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc (50 ml) and washed with water (2 50 ml). The organic phase was dried by passage through a phase separator and concentrated in vacuo. The residue was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 35-65% MeCN in Water) to afford the title compound (5 mg, 10.3 mol, 7% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 462.1 (M+H).sup.+, 460.2 (MH).sup. at 1.56 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.63 (d, J=1.8 Hz, 1H), 8.13 (dd, J=8.2, 1.9 Hz, 1H), 7.49 (d, J=1.9 Hz, 1H), 7.40 (dd, J=8.3, 1.9 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H), 3.13 (t, J=10.9 Hz, 2H), 3.00 (t, J=5.4 Hz, 2H), 2.71 (tt, J=8.5, 5.2 Hz, 1H), 2.06 (tt, J=13.6, 6.4 Hz, 2H), 1.90 (h, J=6.0, 5.4 Hz, 2H), 1.19-1.14 (m, 2H), 0.87 (dt, J=6.8, 4.7 Hz, 2H). Two exchangeable protons not observed.

Example 317: 4-ethyl-3-(N-(2-(4-fluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl) sulfamoyl)benzoic acid

(699) ##STR00648##

(700) Step 1: 4-fluoro-1-(4-(methylsulfonyl)-2-nitrophenyl)piperidine: A mixture of 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (500 mg, 2.28 mmol), 4-fluoropiperidine hydrochloride (318 mg, 2.28 mmol) and triethylamine (699 l, 5.02 mmol) was sonicated in DCM (6 ml) until a clear solution was formed. The reaction solution was stirred at RT for 2 h then diluted with DCM (10 ml) and sequentially washed with 1 M HCl(aq) (15 ml), water (15 ml) and brine (15 ml). The organic phase was dried by passage through a phase separator and concentrated in vacuo to afford the title compound (651 mg, 2.09 mmol, 92% yield, 97% purity) as a bright orange solid. UPLC-MS (Method 2) m/z 303.2 (M+H).sup.+ at 1.15 min.

(701) Step 2: 2-(4-fluoropiperidin-1-yl)-5-(methylsulfonyl)aniline: The product from Step 1 above (651 mg, 2.09 mmol, 97% purity) was dissolved in acetic acid (20 ml) and 5% Pd/C (50% w/w water) Type 87L (130 mg, 2.09 mmol) was added. The solution was hydrogenated (5 bar) for 3 days. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (482 mg, 1.65 mmol, 79% yield, 93% purity) as a red oil which solidified on standing. UPLC-MS (Method 2) m/z 273.2 (M+H).sup.+ at 1.04 min.

(702) Step 3: methyl 4-ethyl-3-(N-(2-(4-fluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoate: The product from Example 203 Step 2 (159 mg, 0.575 mmol, 95% purity) was added to a solution of pyridine (134 l, 1.65 mmol) and the product from Step 2 above (150 mg, 0.512 mmol, 93% purity) in DCM (1 ml). The resultant solution was stirred at RT overnight. The reaction mixture was concentrated in vacuo then partially purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) and then purified by chromatography (24 g reverse phase C18 cartridge, 15-65% MeCN/0.1% formic acid (aq)) to afford the title compound (175 mg, 0.351 mmol, 69% yield) as a white solid. UPLC-MS (Method 2) m/z 499.3 (M+H).sup.+ at 1.40 min.

(703) Step 4: 4-ethyl-3-(N-(2-(4-fluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (1.4 ml, 1.4 mmol) was added to a solution of the product from Step 3 above (175 mg, 0.351 mmol) in THF (3 ml). The reaction mixture was stirred at RT overnight then concentrated in vacuo. The residue was dissolved in water (12 ml) and washed with EtOAc (12 ml). The aqueous phase was acidified using 1 M HCl until pH 4-5 and the product was extracted with EtOAc (212 ml). The combined organic extracts were dried over MgSO.sub.4 and concentrated in vacuo to afford the title compound (106 mg, 0.208 mmol, 59% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 485.3 (M+H).sup.+, 483.3 (MH).sup. at 1.39 min. 1H NMR (500 MHz, DMSO-d.sub.6) 13.3 (br s, 1H), 9.77 (br s, 1H), 8.31 (d, J=1.8 Hz, 1H), 8.11 (dd, J=8.0, 1.9 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 4.88-4.67 (m, 1H), 3.32 (s, 3H), 3.02 (q, J=7.4 Hz, 2H), 2.99-2.92 (m, 2H), 2.83-2.73 (m, 2H), 1.98-1.79 (m, 2H), 1.80-1.68 (m, 2H), 1.21 (t, J=7.4 Hz, 3H).

Example 318:3-(N-(5-cyano-2-(4-fluoropiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid

(704) ##STR00649##

(705) Step 1: 4-(4-fluoropiperidin-1-yl)-3-nitrobenzonitrile: A mixture of 4-fluoro-3-nitrobenzonitrile (500 mg, 3.01 mmol), 4-fluoropiperidine hydrochloride (420 mg, 3.01 mmol) and triethylamine (923 l, 6.62 mmol) was sonicated in DCM (6 ml) until a clear solution was formed. The reaction mixture was stirred at RT overnight, diluted with DCM (40 ml) and sequentially washed with water (50 ml) and brine (50 ml). The organic phase was dried by passage through a phase separator and concentrated in vacuo to afford the title compound (735 mg, 2.80 mmol, 93% yield, 95% purity) as a bright orange solid. UPLC-MS (Method 2) m/z 250.5 (M+H).sup.+ at 1.31 min.

(706) Step 2: 3-amino-4-(4-fluoropiperidin-1-yl)benzonitrile: The product from Step 1 above (735 mg, 2.80 mmol, 95% purity) was combined with iron powder (3.29 g, 59 mmol) and NH.sub.4Cl(s) (205 mg, 3.83 mmol) in 2:1 IPA/water (30 ml), heated at 70 C. overnight. The reaction mixture was allowed to cool then filtered through Celite, rinsing with EtOAc (200 ml) and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (350 mg, 1.56 mmol, 56% yield, 98% purity) as a red oil. UPLC-MS (Method 2) m/z 220.6 (M+H).sup.+ at 1.27 min.

(707) Step 3: methyl 3-(N-(5-cyano-2-(4-fluoropiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoate: The product from Example 203 Step 2 (198 mg, 0.753 mmol) was added to a solution of pyridine (166 l, 2.05 mmol) and the product from Step 3 above (150 mg, 0.670 mmol, 98% purity) in DCM (1 ml). The reaction mixture was stirred at RT for 4 days then concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (322 mg) as a red oil. UPLC-MS (Method 2) m/z 446.3 (M+H).sup.+ at 1.57 min.

(708) Step 4: 3-(N-(5-cyano-2-(4-fluoropiperidin-1-yl)phenyl)sulfamoyl)-4-ethylbenzoic acid: 1 M LiOH(aq) (2.89 ml, 2.89 mmol) was added to a solution of the product from Step 3 above (322 mg) in THF (6 ml). The reaction mixture was stirred at RT overnight then concentrated in vacuo. The residue was dissolved in water (12 ml) and washed with EtOAc (12 ml). The aqueous phase was acidified using 1 M HCl until pH 4-5 and the product extracted with EtOAc (215 ml). The combined organic extracts were dried by passage through a phase separator and concentrated in vacuo to afford the title compound (234 mg, 0.515 mmol, 77% yield over 2 steps, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 432.4 (M+H).sup.+, 430.3 (MH).sup. at 1.53 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.3 (br s, 1H), 9.77 (br s, 1H), 8.31 (d, J=1.8 Hz, 1H), 8.11 (dd, J=8.0, 1.8 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 4.77 (ddt, J=48.6, 7.0, 3.5 Hz, 1H), 3.02 (q, J=7.4 Hz, 2H), 2.96 (t, J=9.9 Hz, 2H), 2.83-2.71 (m, 2H), 1.95-1.83 (m, 2H), 1.80-1.67 (m, 2H), 1.21 (t, J=7.4 Hz, 3H).

Example 319: 4-cyclopropyl-3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl) sulfamoyl)benzoic acid

(709) ##STR00650##

(710) Step 1: methyl 4-bromo-3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoate: The product from Example 316 Step 1 (350 mg, 1.11 mmol) was added to a solution of pyridine (100 l, 1.24 mmol) and the product from Example 313 Step 2 (252 mg, 0.868 mmol) in DCM (2 ml). The resultant solution was allowed to stand at RT for 11 days. The mixture was treated with PhMe (1 ml) and concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-60% EtOAc/isohexane) to afford the title compound (276 mg, 0.482 mmol, 56% yield, 99% purity) as a white foamy solid. UPLC-MS (Method 1): m/z 567.3 (M+H).sup.+, 565.5 (MH).sup. at 1.54 min.

(711) Step 2: methyl 4-cyclopropyl-3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoate: A mixture of the product from Step 1 above (276 mg, 0.482 mmol, 99% purity) and Pd-174 (50 mg, 0.069 mmol) in THF (10 ml) was treated with cyclopropylzinc (II) bromide (0.5 M in THF) (5 ml, 2.50 mmol) and then heated at 60 C. for 1.5 h. The mixture was cooled and allowed to stand at RT overnight. The mixture was neutralised using saturated NH.sub.4Cl (aq) (1 ml) and concentrated in vacuo. The residue was extracted with DCM (24 ml). The extracts were combined and concentrated in vacuo. The residue was partially purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/DCM), then by chromatography on silica gel (24 g cartridge, 10-60% EtOAc/isohexane) to afford the title compound (160 mg, 0.275 mmol, 57% yield, 91% purity) as a white solid. UPLC-MS (Method 1): m/z 529.3 (M+H).sup.+, 527.3 (MH).sup., at 1.58 min.

(712) Step 3: 4-cyclopropyl-3-(N-(2-(3,3-difluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoic acid: The product from Step 2 above (160 mg, 0.275 mmol, 91% purity) was dissolved in THF (5 ml) and treated with 1 M LiOH(aq) (2.5 ml, 2.50 mmol). The resultant biphasic mixture was stirred at RT for 3 days. The mixture was concentrated in vacuo to remove the THF. The resultant aqueous mixture was acidified using AcOH and concentrated in vacuo. The residue was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 35-65% MeCN in Water) to afford the title compound (86 mg, 0.164 mmol, 60% yield, 98% purity). UPLC-MS (Method 2): m/z 515.3 (M+H).sup.+, 513.2 (MH).sup. at 1.00 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.27 (s, 1H), 9.38 (s, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.61 (s, 1H), 7.42-7.27 (m, 2H), 7.19 (d, J=8.2 Hz, 1H), 3.40-3.24 (m, 2H), 3.17-3.04 (m, 2H), 2.97 (s, 3H), 2.81-2.66 (m, 1H), 2.09-1.94 (m, 2H), 1.87-1.68 (m, 2H), 1.20-1.00 (m, 2H), 0.96-0.79 (m, 2H). Two protons partially obscured by water.

Example 320: 4-cyclopropyl-3-(N-(2-(4-fluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl) sulfamoyl)benzoic acid

(713) ##STR00651##

(714) Step 1: Methyl 4-bromo-3-(N-(2-(4-fluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoate: The product from Example 316 Step 1 (420 mg, 1.33 mmol, 99% purity) was added to a solution of pyridine (296 l, 3.66 mmol) and the product from Example 317 Step 2 (332 mg, 1.13 mmol, 93% purity) in DCM (2 ml). The reaction mixture was stirred at RT for 6 days then concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (395 mg, 0.623 mmol, 55% yield, 87% purity) as a pale red solid. UPLC-MS (Method 2) m/z 549.1 (M+H).sup.+ at 1.40 min.

(715) Step 2: methyl 4-cyclopropyl-3-(N-(2-(4-fluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoate: A degassed mixture of the product from Step 1 above (395 mg, 0.623 mmol, 87% purity) and Pd-174 (51.8 mg, 0.072 mmol) in THF (10 ml) was treated with cyclopropylzinc (II) bromide (0.5 M in THF) (5.75 ml, 2.88 mmol). The reaction mixture was heated at 70 C. for 1 h. Additional Pd-174 (51.8 mg, 0.072 mmol) and cyclopropylzinc (II) bromide (0.5 M in THF) (5.75 ml, 2.88 mmol) was added and the mixture was stirred at 70 C. for 3 h. The mixture was allowed to cool to RT and was concentrated in vacuo. The residue was partitioned between brine (75 ml) and DCM (75 ml) and the phases separated. The aqueous phase was extracted with DCM (75 ml) and the organic phases were combined and filtered through Celite. The filtrate was dried over MgSO.sub.4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (226 mg, 0.398 mmol, 64% yield, 90% purity) as a pale yellow solid. UPLC-MS (Method 2) m/z 511.3 (M+H).sup.+ at 1.48 min.

(716) Step 3: 4-cyclopropyl-3-(N-(2-(4-fluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (1.77 ml, 1.77 mmol) was added to a solution of the product from Step 2 above (226 mg, 0.398 mmol, 90% purity) in THF (3.5 ml). The reaction mixture was stirred at RT overnight then concentrated in vacuo. The residue was dissolved in water (12 ml) and washed with EtOAc (12 ml). The aqueous phase was acidified to pH 4-5 using 1 M HCl(aq) and the precipitate was collected by filtration and dried in vacuo. The crude product was purified by chromatography on a 24 g reverse phase cartridge (0-100% MeCN/Water 0.1% Formic Acid) to afford the title compound (93 mg, 0.178 mmol, 45% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 497.3 (M+H).sup.+, 495.2 (MH).sup. at 1.38 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.2 (br s, 1H), 9.65 (br s, 1H), 8.40 (d, J=1.9 Hz, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.59 (s, 1H), 7.51 (d, J=2.2 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 7.16 (d, J=8.2 Hz, 1H), 4.87-4.71 (m, 1H), 3.02-2.99 (m, 5H), 2.87-2.74 (m, 3H), 2.01-1.88 (m, 2H), 1.85-1.74 (m, 2H), 1.13-1.05 (m, 2H), 0.89-0.85 (m, 2H).

Example 321: I-4-cyclopropyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl) sulfamoyl)benzoic acid

(717) ##STR00652##

(718) Step 1: -methyl 4-bromo-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoate: The product from Example 316 Step 1 (198 mg, 0.63 mmol, 99% purity) was added to a solution of the product from Example 262 Step 2 (156 mg, 0.567 mmol, 99% purity) and pyridine (139 l, 1.72 mmol) in DCM (1 ml). The resultant solution was stirred at RT for 6 days. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (207 mg, 0.377 mmol, 66% yield) as a pale yellow solid. UPLC-MS (Method 2) m/z 550.1 (M+H).sup.+ at 1.46 min.

(719) Step 2: -methyl 4-cyclopropyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoate: A degassed mixture of the product from Step 1 above (207 mg, 0.377 mmol) and Pd-174 (27.2 mg, 0.038 mmol) in THF (6 ml) was treated with cyclopropylzinc (II) bromide (0.5 M in THF) (3.01 ml, 1.51 mmol). The resultant mixture was heated at 70 C. for 1 h. Additional Pd-174 (27.2 mg, 0.038 mmol) and cyclopropylzinc (II) bromide (0.5 M in THF) (3.01 ml, 1.51 mmol) was added and the reaction was stirred at 70 C. for 3 h. The mixture was allowed to cool to RT, then was filtered through Celite and concentrated in vacuo. The residue was partitioned between brine (75 ml) and DCM (75 ml) and the phases separated. The organic phase was dried by passage through a phase separator and concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (128 mg, 0.248 mmol, 66% yield, 99% purity) as a pale yellow solid. UPLC-MS (Method 2) m/z 511.3 (M+H).sup.+ at 1.49 min.

(720) Step 3: -4-cyclopropyl-3-(N-(2-(3-fluoropiperidin-1-yl)-5-(methylsulfonyl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (1 ml, 1.00 mmol) was added to a solution of the product from Step 2 above (128 mg, 0.248 mmol, 99% purity) in THF (2 ml). The resultant mixture was stirred at RT overnight. The reaction mixture was concentrated in vacuo, dissolved in water (12 ml) and washed with EtOAc (12 ml). The aqueous phase was acidified to pH 4-5 using 1 M HCl(aq) and extracted with EtOAc (212 ml). The product precipitated as a white solid in the organic phase and was dissolved in THF (20 ml). The organic phase was dried by passage through a phase separator and concentrated in vacuo. To remove residual THF, the residue was dissolved in 1 M LiOH(aq) (5 ml) and acidified using 1 M HCl(aq) until pH 4-5. The product precipitated as a white solid and was collected by filtration to afford the title compound (63 mg, 0.121 mmol, 49% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 497.6 (M+H).sup.+, 495.2 (MH).sup. at 1.40 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.3 (br s, 1H), 9.37 (br s, 1H), 8.41 (d, J=1.9 Hz, 1H), 8.01 (dd, J=8.2, 1.9 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.49 (d, J=2.2 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 4.84-4.68 (m, 1H), 3.26-3.13 (m, 1H), 3.02-2.88 (m, 5H), 2.89-2.79 (m, 1H), 2.79-2.67 (m, 1H), 2.01-1.85 (m, 1H), 1.77 (d, J=6.7 Hz, 1H), 1.71-1.51 (m, 2H), 1.14-1.04 (m, 2H), 0.95-0.88 (m, 1H), 0.87-0.80 (m, 1H).

Example 322: 3-(N-(5-cyano-2-(4-fluoropiperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid

(721) ##STR00653##

(722) Step 1: Methyl 4-bromo-3-(N-(5-cyano-2-(4-fluoropiperidin-1-yl)phenyl)sulfamoyl)benzoate: The product from Example 316 Step 1 (393 mg, 1.24 mmol, 99% purity) was added to a solution of pyridine (277 l, 3.42 mmol) and the product from Example 318 Step 2 (250 mg, 1.12 mmol, 98% purity) in DCM (2 ml). The resultant solution was stirred at RT for 6 days. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (372 mg, 0.749 mmol, 67% yield) as a pink solid. UPLC-MS (Method 2) m/z 497.2 (M+H).sup.+ at 1.46 min.

(723) Step 2: Methyl 3-(N-(5-cyano-2-(4-fluoropiperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoate: A degassed mixture of the product from Step 1 above (372 mg, 0.749 mmol) and Pd-174 (54.1 mg, 0.075 mmol) in THF (10 ml) was treated with cyclopropylzinc (II) bromide (0.5 M in THF) (6 ml, 3.00 mmol). The resultant mixture was heated at 70 C. for 1 h. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (276 mg, 0.57 mmol, 76% yield, 95% purity) as a pale yellow solid. UPLC-MS (Method 2) m/z 458.4 (M+H).sup.+ at 1.53 min.

(724) Step 3: 3-(N-(5-cyano-2-(4-fluoropiperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: 1 M LiOH(aq) (2.41 ml, 2.41 mmol) was added to a solution of the product from Step 2 above (276 mg, 0.573 mmol, 95% purity) in THF (5 ml). The reaction mixture was stirred at RT overnight then concentrated in vacuo. The reaction mixture was acidified to pH 4-5 using 1 M HCl(aq). The precipitate was collected by filtration and dried in vacuo. The crude product was purified by chromatography (24 g reverse phase C18 cartridge, 0-100% MeCN/0.1% formic acid (aq)) to afford the title compound (169 mg, 0.362 mmol, 63% yield, 95% purity) as a white solid. UPLC-MS (Method 1) m/z 444.3 (M+H).sup.+, 442.3 (MH).sup. at 1.53 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.3 (br s, 1H), 9.69 (br s, 1H), 8.37 (d, J=1.9 Hz, 1H), 8.03 (dd, J=8.2, 1.9 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 4.86-4.69 (m, 1H), 3.04-2.96 (m, 2H), 2.87-2.71 (m, 3H), 1.97-1.83 (m, 2H), 1.82-1.69 (m, 2H), 1.13-1.04 (m, 2H), 0.91-0.84 (m, 2H).

Example 323: 4-cyclopropyl-3-(N-(2-(piperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid

(725) ##STR00654##

(726) Step 1: Methyl 3-(benzylthio)-4-cyclopropylbenzoate: To a degassed mixture of methyl 3-bromo-4-cyclopropylbenzoate (850 mg, 3.33 mmol), DIPEA (1.2 ml, 6.87 mmol) and XantPhos Pd G3 (300 mg, 0.316 mmol) in dioxane (13 ml) was added phenylmethanethiol (425 l, 3.62 mmol) and the mixture was stirred at 100 C. overnight. The mixture was cooled to RT, concentrated in vacuo onto silica and purified by chromatography on silica gel (40 g cartridge, 20-70% DCM/isohexane) to afford the title compound (600 mg, 1.91 mmol, 58% yield, 95% purity) as an orange oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.86 (d, J=1.8 Hz, 1H), 7.67 (dd, J=8.1, 1.8 Hz, 1H), 7.40-7.35 (m, 2H), 7.35-7.29 (m, 2H), 7.28-7.22 (m, 1H), 7.04 (d, J=8.1 Hz, 1H), 4.27 (s, 2H), 3.83 (s, 3H), 2.21-2.12 (m, 1H), 1.06-0.99 (m, 2H), 0.75-0.68 (m, 2H).

(727) Step 2: Methyl 3-(chlorosulfonyl)-4-cyclopropylbenzoate: A mixture of the product from Step 1 above (600 mg, 1.91 mmol, 95% purity), AcOH (110 l, 1.92 mmol) and water (250 l) in MeCN (9 ml) at 10 C. was treated with 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (565 mg, 2.87 mmol). The mixture was stirred at 10 C. for 3 h. The mixture was diluted with water (50 ml) and extracted with DCM (250 ml). The organic phases were combined, dried over MgSO.sub.4, filtered and concentrated in vacuo onto silica, then purified by chromatography on silica gel (40 g cartridge, 0-50% DCM/isohexane) to afford the title compound (440 mg, 1.52 mmol, 80% yield, 95% purity) as a pale yellow oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.36 (d, J=2.0 Hz, 1H), 7.77 (dd, J=8.2, 2.1 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 3.84 (s, 3H), 3.22-3.01 (m, 1H), 1.08-0.98 (m, 2H), 0.79-0.70 (m, 2H).

(728) Step 3: Methyl 4-cyclopropyl-3-(N-(2-(piperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoate: The product from Step 2 above (50 mg, 0.182 mmol) was added to a solution of pyridine (40 l, 0.495 mmol) and the product from Example 214 Step 3 (40 mg, 0.164 mmol, 99% purity) in DCM (300 l). The resultant solution was stirred at RT overnight. Additional pyridine (40 l, 0.495 mmol) was added and the reaction was stirred for 3 days. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (76 mg, 0.157 mmol, 96% yield) as a white solid. UPLC-MS (Method 2) m/z 483.4 (M+H).sup.+ at 1.66 min.

(729) Step 4: 4-cyclopropyl-3-(N-(2-(piperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid: 1 M LiOH(aq) (630 l, 0.63 mmol) was added to a solution of the product from Step 3 above (76 mg, 0.157 mmol) in THF (1.3 ml). The reaction mixture was stirred at RT overnight then concentrated in vacuo. The reaction mixture was adjusted to pH 6 with 1 M HCl(aq). The precipitate collected by filtration and dried in vacuo. The crude product was purified by chromatography on a 24 g reverse phase cartridge (0-100% MeCN/Water 0.1% Formic Acid) to afford the title compound (52 mg, 0.105 mmol, 67% yield, 95% purity) as a white solid.

(730) UPLC-MS (Method 1) m/z 469.4 (M+H).sup.+, 467.3 (MH).sup. at 1.57 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.94 (s, 1H), 8.48 (d, J=1.9 Hz, 1H), 8.00 (dd, J=8.2, 1.9 Hz, 1H), 7.67 (d, J=2.5 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 7.16 (d, J=8.2 Hz, 1H), 2.86-2.76 (m, 1H), 2.73 (t, J=5.2 Hz, 4H), 1.62-1.53 (m, 4H), 1.52-1.43 (m, 2H), 1.13-1.06 (m, 2H), 0.88-0.79 (m, 2H). Two exchangeable protons not observed.

Example 324: 3-(N-(5-cyano-4-fluoro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid

(731) ##STR00655##

(732) Step 1: 2-fluoro-5-nitro-4-(piperidin-1-yl)benzonitrile: Piperidine (269 l, 2.72 mmol) was added to a suspension of 2,4-difluoro-5-nitrobenzonitrile (500 mg, 2.72 mmol) in DCM (5 ml) at 0 C. The resultant solution was allowed to warm to RT and stirred for 2 h. Additional DCM (50 ml) was added and the reaction mixture was washed with water (260 ml). The organic phase was dried by passage through a phase separator and concentrated in vacuo to afford the title compound (660 mg, 2.44 mmol, 90% yield, 92% purity) as a yellow solid. UPLC-MS (Method 2) m/z 250.6 (M+H).sup.+ at 1.50 min.

(733) Step 2: 5-amino-2-fluoro-4-(piperidin-1-yl)benzonitrile: The product from Step 1 above (660 mg, 2.44 mmol, 92% purity) was combined with Zinc dust (1.04 g, 15.9 mmol) and NH.sub.4Cl(s) (850 mg, 15.9 mmol) in THF (11 ml) and water (4 ml). The resultant solution was stirred at RT overnight. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was dissolved in EtOAc (60 ml) and washed with water (60 ml). The organic phase was dried by passage through a phase separator and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (533 mg, 2.19 mmol, 90% yield, 90% purity) as a dark brown solid. UPLC-MS (Method 2) m/z 220.3 (M+H).sup.+ at 1.51 min.

(734) Step 3: methyl 4-bromo-3-(N-(5-cyano-4-fluoro-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: The product from Example 316 Step 1 (393 mg, 1.21 mmol, 99% purity) was added to a solution of pyridine (277 l, 3.42 mmol) and the product from Step 2 above (250 mg, 1.03 mmol, 90% purity) in DCM (2 ml). The resultant solution was stirred at RT for 5 days. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (357 mg, 0.712 mmol, 69% yield, 99% purity) as a brown oil. UPLC-MS (Method 2) m/z 497.3 (M+H).sup.+ at 1.63 min.

(735) Step 4: methyl 3-(N-(5-cyano-4-fluoro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoate: To a degassed mixture of the product from Step 3 above (357 mg, 0.712 mmol, 99% purity) and Pd-174 (52 mg, 0.072 mmol) in THF (10 ml) was added cyclopropylzinc (II) bromide (0.5 M in THF) (5.8 ml, 2.9 mmol). The resultant solution was heated at 70 C. for 1 h. The mixture was allowed to cool to RT, concentrated in vacuo and purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (273 mg, 0.489 mmol, 68% yield, 82% purity) as a brown oil. UPLC-MS (Method 2) m/z 458.4 (M+H).sup.+ at 1.69 min.

(736) Step 5: 3-(N-(5-cyano-4-fluoro-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: 1 M LiOH(aq) (2.4 ml, 2.4 mmol) was added to a solution of the product from Step 4 above (273 mg, 0.489 mmol, 82% purity) in THF (5 ml). The reaction mixture was stirred at RT overnight, concentrated in vacuo for the removal of THF and adjusted to pH 6 with 1 M HCl(aq). The precipitate was collected by filtration and dried in vacuo. The crude product was purified by chromatography on a 24 g reverse phase cartridge (0-100% MeCN/Water 0.1% Formic Acid) to afford the title compound (80 mg, 0.177 mmol, 36% yield, 98% purity) as a white solid. UPLC-MS (Method 1) m/z 444.4 (M+H).sup.+, 442.4 (MH).sup. at 1.57 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.3 (br s, 1H), 9.65 (br s, 1H), 8.30 (d, J=1.9 Hz, 1H), 8.02 (dd, J=8.2, 1.9 Hz, 1H), 7.16 (d, J=8.2 Hz, 1H), 7.13 (d, J=7.2 Hz, 1H), 7.03 (d, J=12.0 Hz, 1H), 3.02-2.92 (m, 4H), 2.74-2.65 (m, 1H), 1.49-1.39 (m, 6H), 1.13-1.04 (m, 2H), 0.95-0.84 (m, 2H).

Example 325:4-cyclopropyl-3-(N-(2-(3-hydroxyazetidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid

(737) ##STR00656##

(738) The product from Example 323 Step 2 (42.9 mg, 0.148 mmol) was added to a solution of pyridine (34.5 l, 0.426 mmol) and the product from Example 283 Step 2 (33 mg, 0.134 mmol) in DCM (0.2 ml). The resultant solution was stirred at RT for 3 days, then concentrated in vacuo. The residue was dissolved in THF (0.5 ml) and treated with 1 M LiOH(aq) (240 l, 0.240 mmol). The resultant mixture was stirred at RT overnight. Additional 1 M LiOH(aq) (240 l, 0.240 mmol) was added and the mixture was stirred for 24 h. The reaction mixture was concentrated in vacuo and the residue dissolved in water (12 ml) and washed with TBME (12 ml). The aqueous phase was acidified using 1 M HCl(aq) to pH 4-5 and the product was extracted into EtOAc (212 ml). The organic phases were combined and passed through a phase separator, then concentrated in vacuo. The residue was purified by chromatography (24 g reverse phase C18 cartridge, 15-40% MeCN/0.1% formic acid (aq)) to afford the title compound (6 mg, 0.013 mmol, 10% yield, 96% purity) as a white solid. UPLC-MS (Method 2): m/z 457.4 (M+H).sup.+, 455.3 (MH).sup., at 0.61 min. .sup.1H NMR (500 MHz, Methanol-d.sub.4) 9.33 (s, 1H), 8.51 (d, J=1.8 Hz, 1H), 8.35 (s, 1H), 8.11 (dd, J=8.2, 1.8 Hz, 1H), 7.50 (dd, J=8.8, 2.5 Hz, 1H), 7.11 (d, J=8.2 Hz, 1H), 6.97 (d, J=2.5 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 4.69-4.60 (m, 1H), 4.47-4.41 (m, 2H), 3.87 (dd, J=8.6, 4.9 Hz, 2H), 2.86-2.77 (m, 1H), 1.18-1.10 (m, 2H), 0.96-0.89 (m, 2H).

Example 326: 3-(N-(5-cyano-2-(4-cyanopiperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid

(739) ##STR00657##

(740) Step 1: 1-(4-cyano-2-nitrophenyl)piperidine-4-carbonitrile: A mixture of 4-fluoro-3-nitrobenzonitrile (300 mg, 1.81 mmol), piperidine-4-carbonitrile (220 l, 1.97 mmol) and Et.sub.3N (800 l, 5.74 mmol) in DCM (9 ml) was stirred at RT overnight. The mixture was diluted with DCM (15 ml), washed with saturated NH.sub.4Cl (aq) (15 ml), dried by passage through a phase separator, and the solvent was removed in vacuo to afford the title compound (449 mg, 1.73 mmol, 96% yield, 99% purity) as a yellow solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.33 (d, J=2.1 Hz, 1H), 7.90 (dd, J=8.8, 2.1 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 3.31-3.23 (m, 2H), 3.18-3.09 (m, 3H), 2.03-1.93 (m, 2H), 1.86-1.76 (m, 2H).

(741) Step 2: 1-(2-amino-4-cyanophenyl)piperidine-4-carbonitrile: A mixture the product from Step 1 above (449 mg, 1.73 mmol, 99% purity), iron powder (2 g, 35.8 mmol) and NH.sub.4Cl(s) (111 mg, 2.08 mmol) in IPA (15 ml) and water (7.5 ml) was heated at 90 C. overnight. Upon cooling to RT, the mixture was filtered through Celite, rinsing with EtOAc and then concentrated in vacuo. The residue was extracted with DCM (230 ml) and the combined organic phases were dried by passage through a phase separator, and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (196 mg, 0.840 mmol, 48% yield, 97% purity) as a light tan solid after trituration with TBME. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.00-6.92 (m, 3H), 5.19 (s, 2H), 3.07-2.92 (m, 3H), 2.80-2.70 (m, 2H), 2.07-1.97 (m, 2H), 1.97-1.86 (m, 2H).

(742) Step 3: methyl 3-(N-(5-cyano-2-(4-cyanopiperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoate: A mixture of the product from Step 2 above (50 mg, 0.214 mmol, 97% purity), the product from Example 323 Step 2 (62 mg, 0.214 mmol,) and pyridine (52.0 l, 0.643 mmol) in DCM (1 ml) was stirred at 35 C. for 3 days. The mixture was concentrated in vacuo onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (77 mg, 0.157 mmol, 73% yield, 95% purity) as a light purple solid. UPLC-MS (Method 1) m/z 465.4 (M+H).sup.+, 463.3 (MH).sup. at 1.57 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 8.37 (d, J=1.9 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.62-7.52 (m, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.23-7.16 (m, 2H), 3.86 (s, 3H), 2.99-2.89 (m, 3H), 2.79-2.71 (m, 3H), 1.90-1.84 (m, 2H), 1.76-1.66 (m, 2H), 1.11-1.04 (m, 2H), 0.91-0.84 (m, 2H).

(743) Step 4: 3-(N-(5-cyano-2-(4-cyanopiperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: A mixture of the product from Step 3 above (77 mg, 0.157 mmol, 95% purity) and LiOH (27 mg, 0.631 mmol) in THF/MeOH/water (4:1:1, 2.7 ml) was stirred at 40 C. overnight. The mixture was diluted with water (5 ml), acidified to pH 4 using 1 M HCl(aq) and extracted with EtOAc (310 ml). The organic phases were combined and washed with brine (5 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (12.1 mg, 0.026 mmol, 16% yield, 98% purity) as a white solid. UPLC-MS (Method 1) m/z 451.8 (M+H).sup.+, 449.3 (MH).sup. at 1.39 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.28 (s, 1H), 9.68 (s, 1H), 8.36 (d, J=1.9 Hz, 1H), 8.02 (dd, J=8.2, 1.9 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 3.01-2.89 (m, 3H), 2.81-2.71 (m, 3H), 1.93-1.85 (m, 2H), 1.80-1.70 (m, 2H), 1.12-1.04 (m, 2H), 0.91-0.84 (m, 2H).

Example 327: 3-(N-(4-chloro-5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid

(744) ##STR00658##

(745) Step 1: 2-chloro-4-fluoro-5-nitrobenzonitrile: 2-chloro-4-fluoro-benzonitrile (1.00 g, 6.43 mmol) was dissolved in conc H.sub.2SO.sub.4 (aq) (6.85 ml, 129 mmol) and cooled to 0 C. before adding nitric acid (8.45 ml, 129 mmol). The mixture was kept at 0 C. for 30 min before stirring at RT overnight. The reaction mixture was diluted with water (50 ml) and extracted with DCM (50 ml). The organic phase was dried (MgSO.sub.4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-50% TBME/isohexane) to afford the title compound (0.240 g, 1.15 mmol, 18% yield, 96% purity) as a white solid. UPLC-MS (Method 1) m/z no ionisation at 1.17 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.97 (d, J=7.7 Hz, 1H), 8.30 (d, J=10.9 Hz, 1H).

(746) Step 2: 2-chloro-5-nitro-4-(piperidin-1-yl)benzonitrile: The product from Step 1 above (0.240 g, 1.15 mmol, 96% purity) in dry DCM (10 ml) was treated with triethylamine (0.160 ml, 1.15 mmol) and piperidine (0.113 ml, 1.15 mmol) and the mixture was stirred at RT for 24 h. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (100 ml). The organic phase was washed with brine (50 ml), dried (MgSO.sub.4), filtered and concentrated in vacuo to afford the title compound (0.298 g, 1.10 mmol, 96% yield, 98% purity) as a bright orange solid. UPLC-MS (Method 1) m/z 266.5 (M+H).sup.+, at 1.63 min.

(747) Step 3: 5-amino-2-chloro-4-(piperidin-1-yl)benzonitrile: The product from Step 2 above (0.298 g, 1.10 mmol, 98% purity) was combined with zinc dust (0.431 g, 6.59 mmol) and NH.sub.4Cl(s) (0.353 g, 6.59 mmol) in THF (9 ml) and water (3 ml). The resultant mixture was stirred at RT for 16 h, filtered through Celite and then concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-20% EtOAc/isohexane) to afford the title compound (0.243 g, 0.897 mmol, 82% yield, 87% purity) as a brown solid. UPLC-MS (Method 1) m/z 236.3 (M+H).sup.+, at 1.66 min.

(748) Step 4: Methyl 3-(N-(4-chloro-5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoate: To a solution of the product from Step 3 above (0.050 g, 0.212 mmol, 87% purity) in DCM (3 ml) and pyridine (0.103 ml, 1.27 mmol) was added the product from Example 323 Step 2 (0.058 g, 0.212 mmol) and the reaction mixture was stirred at RT for 72 h and then concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (0.039 g, 0.081 mmol, 38% yield, 98% purity) as a brown solid. UPLC-MS (Method 1) m/z 474.3 (M+H).sup.+, 472.2 (MH).sup. at 1.91 min.

(749) Step 5: 3-(N-(4-chloro-5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: 1 M LiOH(aq) (0.242 ml, 0.242 mmol) was added to a solution of the product from Step 4 above (39 mg, 0.081 mmol, 98% purity) in THF (5 ml) and the resultant solution was stirred at RT for 16 h. The reaction mixture was then adjusted to pH 6 with 10% w/v citric acid (aq) and the resultant precipitate was collected under suction and washed with water (5 ml) to afford the title compound (21.6 mg, 0.046 mmol, 57% yield, 98% purity) as a tan solid. UPLC-MS (Method 1): m/z 460.3 (M+H).sup.+, 458.3 (MH).sup. at 1.77 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.20 (br s, 1H), 9.70 (br s, 1H), 8.35 (d, J=1.9 Hz, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.24 (s, 1H), 7.13 (d, J=8.7 Hz, 2H), 3.00-2.87 (m, 4H), 2.85-2.70 (m, 1H), 1.55-1.40 (m, 6H), 1.07 (dd, J=8.2, 2.5 Hz, 2H), 0.87 (d, J=5.5 Hz, 2H).

Example 328: 3-(N-(5-cyano-2-(cis-3,5-dimethylpiperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid

(750) ##STR00659##

(751) Step 1: 4-(cis-3,5-dimethylpiperidin-1-yl)-3-nitrobenzonitrile: Triethylamine (520 l, 3.73 mmol) was added to a solution of 4-fluoro-3-nitrobenzonitrile (250 mg, 1.51 mmol) and cis-3,5-dimethylpiperidine (190 mg, 1.68 mmol) in DCM (2 ml) and the resultant solution was stirred at RT overnight. The reaction mixture was diluted with DCM (10 ml), washed with water (212 ml) and brine (12 ml). The organic phase was dried by passage through a phase separator and concentrated in vacuo to afford the title compound (370 mg, 1.41 mmol, 94% yield, 99% purity) as a bright yellow solid. UPLC-MS (Method 2): m/z 260.3 (M+H).sup.+ at 1.71 min.

(752) Step 2: 3-amino-4-(cis-3,5-dimethylpiperidin-1-yl)benzonitrile: The product from Step 1 above (370 mg, 1.43 mmol) was combined with Zinc dust (560 mg, 8.56 mmol) and Ammonium chloride (458 mg, 8.56 mmol) in THF (6 ml) and water (2 ml). The resultant mixture was stirred at RT overnight. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was dissolved in EtOAc (20 ml) and washed with water (20 ml). The organic phase was dried over MgSO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (300 mg, 1.24 mmol, 87% yield, 95% purity) as a dark red solid. UPLC-MS (Method 2): m/z 230.4 (M+H).sup.+ at 1.72 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 6.99-6.93 (m, 3H), 5.07 (s, 2H), 3.11-3.05 (m, 2H), 2.03 (t, J=11.1 Hz, 2H), 1.88-1.75 (m, 3H), 0.87 (d, J=6.5 Hz, 6H), 0.66 (q, J=11.8 Hz, 1H).

(753) Step 3: Methyl 3-(N-(5-cyano-2-(cis-3,5-dimethylpiperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoate: To a mixture the product from Step 2 above (70 mg, 0.290 mmol) and the product from Example 323 Step 2 (88 mg, 0.319 mmol) in DCM (600 l) at RT was added pyridine (152 l, 1.89 mmol). The resultant solution was stirred at RT for 72 h and then concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-60% EtOAc/isohexane) to afford the title compound (108 mg, 0.224 mmol, 77% yield, 97% purity) as a pale yellow solid. UPLC-MS (Method 2): m/z 468.5 (M+H).sup.+, at 1.94 min.

(754) Step 4: 3-(N-(5-cyano-2-(cis-3,5-dimethylpiperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: A mixture of methyl of the product from Step 3 above (108 mg, 0.231 mmol) and 1 M LiOH(aq) (23 mg, 0.924 mmol) in THF/MeOH/water (4:1:1, 4 ml) was heated to 40 C. and stirred for 3 days. The reaction mixture was concentrated in vacuo and the residue was adjusted to pH 4 with 1 M HCl(aq). The resultant precipitate was filtered, washed with water and dried to afford the crude product. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-10% MeOH/DCM) to afford the title compound (37 mg, 0.080 mmol, 35% yield, 98% purity) as a clear colourless oil. UPLC-MS (Method 1): m/z 454.4 (M+H).sup.+, 452.3 (MH).sup. at 1.82 min. .sup.1H NMR (500 MHz, Methanol-d.sub.4) 8.60 (d, J=1.9 Hz, 1H), 8.13 (dd, J=8.2, 1.8 Hz, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.41 (dd, J=8.3, 1.9 Hz, 1H), 7.27 (d, J=8.3 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H), 2.99-2.93 (m, 2H), 2.80-2.71 (m, 1H), 2.18 (t, J=11.2 Hz, 2H), 1.86-1.74 (m, 3H), 1.17-1.08 (m, 2H), 0.93-0.83 (m, 8H), 0.69 (q, J=12.2 Hz, 1H).

Example 329: 4-cyclopropyl-3-(N-(2-(piperidin-1-yl)-5-sulfamoylphenyl)sulfamoyl)benzoic acid

(755) ##STR00660##

(756) Step 1: Methyl 4-cyclopropyl-3-(N-(2-(piperidin-1-yl)-5-sulfamoylphenyl)sulfamoyl)benzoate: A mixture of 3-amino-4-(piperidin-1-yl)benzenesulfonamide (100 mg, 0.392 mmol), the product from Example 323 Step 2 (129 mg, 0.470 mmol) and pyridine (100 l, 1.24 mmol) in DCM (2 ml) was stirred at RT for 2 days. The mixture was concentrated in vacuo onto silica and purified by chromatography on silica gel (12 g cartridge, 0-10% MeOH/DCM) to afford the title compound (174 mg, 0.296 mmol, 76% yield, 84% purity) as a white solid. UPLC-MS (Method 1): m/z 494.4 (M+H).sup.+, 492.1 (MH).sup. at 1.58 min.

(757) Step 2: 4-cyclopropyl-3-(N-(2-(piperidin-1-yl)-5-sulfamoylphenyl)sulfamoyl)benzoic acid: A mixture of the product from Step 1 above (174 mg, 0.296 mmol, 84% purity) and LiOH (50 mg, 1.17 mmol) in THF/MeOH/water (4:1:1, 5.4 ml) was stirred at 40 C. overnight. The mixture was diluted with water (5 ml), acidified to pH 4 with 1 M HCl(aq) and extracted with EtOAc (320 ml). The combined organic phases were washed with brine (15 ml), dried by passage through a phase separator and then concentrated in vacuo. The crude product was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 35-65% MeCN in Water) to afford the title compound (93.9 mg, 0.194 mmol, 66% yield, 99% purity) as a white solid. UPLC-MS (Method 1): m/z 480.4 (M+H).sup.+, 478.3 (MH).sup. at 1.44 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.22 (s, 1H), 9.23 (s, 1H), 8.44 (d, J=1.9 Hz, 1H), 8.00 (dd, J=8.2, 1.9 Hz, 1H), 7.59 (d, J=2.2 Hz, 1H), 7.52 (dd, J=8.4, 2.2 Hz, 1H), 7.29-7.23 (m, 3H), 7.15 (d, J=8.4 Hz, 1H), 2.77-2.67 (m, 5H), 1.54-1.46 (m, 4H), 1.46-1.38 (m, 2H), 1.10-1.02 (m, 2H), 0.86-0.79 (m, 2H).

Example 330: 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-cyclobutylbenzoic acid

(758) ##STR00661##

(759) Step 1: Methyl 4-bromo-3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: A mixture of the product from Example 182 Step 2 (250 mg, 1.23 mmol), the product from Example 316 Step 1 (409 mg, 1.29 mmol) and pyridine (300 l, 3.71 mmol) in DCM (6 ml) was stirred at RT for 5 days. The mixture was concentrated in vacuo onto silica and purified by chromatography on silica gel (24 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (360 mg, 0.753 mmol, 61% yield) as a light tan solid. UPLC-MS (Method 1): m/z 478.3 (M+H).sup.+, 476.1 (MH).sup. at 1.80 min.

(760) Step 2: Methyl 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-cyclobutylbenzoate: To a flame-dried flask was added Mg turnings (137 mg, 5.64 mmol) and iodine (10 mg, 0.039 mmol). A small aliquot of bromocyclobutane (0.35 ml, 3.72 mmol) in THF (4 ml) was added and the mixture was heated to reflux with a heat gun. Once the brown colour disappeared the remaining solution was added at a rate that reflux was maintained. Upon complete addition the mixture was stirred at RT for 2 h. The mixture was slowly added to 2 M zinc chloride in 2-methyltetrahydrofuran (2.8 ml, 5.60 mmol) at 0 C. and then warmed to RT and stirred for 1 h. A solution of the product from Step 1 above (180 mg, 0.376 mmol) In THF (2 ml) and PdCl.sub.2 (dppf). DCM (62 mg, 0.076 mmol) were added and the mixture was heated at 70 C. for 4 h and then stirred at RT overnight. The mixture was quenched with saturated NH.sub.4Cl (aq) (20 ml) and extracted with EtOAc (320 ml). The organic extracts were combined, washed with brine (20 ml), dried by passage through a phase separator and concentrated in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (12 g cartridge, 0-75% EtOAc/isohexane) to afford the title compound (118 mg, 0.250 mmol, 66% yield, 96% purity) as a light brown oil. UPLC-MS (Method 1): m/z 454.4 (M+H).sup.+, 452.4 (MH).sup. at 1.95 min.

(761) Step 3: 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-cyclobutylbenzoic acid: A mixture of the product from Step 2 above (118 mg, 0.250 mmol, 96% purity) and LiOH (43 mg, 1.01 mmol) in THF/MeOH/water (4:1:1, 4 ml) was stirred at 40 C. overnight. The mixture was diluted with water (5 ml), acidified to pH 4 with 1 M HCl(aq) and extracted with EtOAc (320 ml). The combined organic phases were washed with brine (15 ml), dried by passage through a phase separator and concentrated in vacuo. The crude product was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 m, 1950 mm column, 50-80% MeCN in Water) to afford the title compound (60 mg, 0.134 mmol, 54% yield, 99% purity) as a white solid. UPLC-MS (Method1): m/z 440.4 (M+H).sup.+, 438.3 (MH).sup. at 1.80 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.30 (s, 1H), 9.57 (s, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.16 (d, J=8.2 Hz, 1H), 7.93 (d, J=8.2 Hz, 1H), 7.59-7.48 (m, 1H), 7.21 (d, J=2.0 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 4.34-4.23 (m, 1H), 2.84-2.73 (m, 4H), 2.28-2.12 (m, 4H), 1.98-1.82 (m, 2H), 1.51-1.41 (m, 6H).

Example 331: 4-cyclopropyl-3-(N-(4-fluoro-5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid

(762) ##STR00662##

PART A; Preparation of INTERMEDIATE 1; 4-fluoro-5-(methylsulfonyl)-2-(pyridin-2-yl)aniline

(763) ##STR00663##

Step-1: Synthesis of (2,4-difluorophenyl)(methyl)sulfane

(764) To a stirred solution of 2,4-difluorobenzenethiol (CAS No. 1996-44-7; 5 g, 0.03421 mol, 1 eq) in THF (50 ml, 10 Vol) was added K.sub.2CO.sub.3 (23.60 g, 0.17105 mol, 5 eq) at 0 C. followed by methyl iodide (14.5 g, 0.102 mol, 3 eq). The reaction mixture was stirred at room temperature for 16 hr, then poured into water (500 mL) and extracted with ethyl acetate (2200 ml). The combined organic layer was washed with brine solution (200 ml), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to give title sulfane (4.3 g, 78.47%).

Step-2: Synthesis of 2,4-difluoro-1-(methylsulfonyl)benzene

(765) A mixture of Step-1 sulfane (2.5 g, 0.0141 mole, 1 eq) in 30% H.sub.2O.sub.2 (1 g (3.5 mL), 0.0312 mole, 2.2 eq) was stirred at 80 C. for 16 h, cooled and diluted with water (250 mL) then extracted with EtOAc (2200 ml). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure to get crude. The crude was purified by flash column chromatography (230-400 silica) using 13% EtOAc in hexane to give title methylsulphone as brown liquid (1.9 g, 63.35%). UPLC-MS (Method 1) m/z 193.1 (M+H).sup.+ at 1.54 min.

Step-3: Synthesis of 1,5-difluoro-2-(methylsulfonyl)-4-nitrobenzene

(766) To a stirred solution of Step-2 methylsulphone (1.4 g, 0.00728 mole, 1 eq) in conc. H.sub.2SO.sub.4 (14 ml, 10 V) was added KNO.sub.3 (2.2 g, 0.0218 mol, 3 eq) portion wise. After completion of reaction as indicated by TLC (30% EtOAc in hexane), the reaction mixture was poured into ice cold water (250 mL) and extracted with DCM (2150 ml). The combined organic layer was washed with sat NaHCO.sub.3 solution (250 ml), dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure to give title nitrobenzene as yellow solid (1.5 g, 86.82%).

Step-4: Synthesis of 1-(5-fluoro-4-(methylsulfonyl)-2-nitrophenyl)piperidine

(767) To a stirred solution of Step-3 nitrobenzene (1.5 g, 0.00632 mole, 1 eq) in THF (30 mL) was added DIPEA (2.447 g, 0.01897 mole, 3 eq) and piperidine (0.538 g, 0.00632 mole, 1 eq). The reaction mixture was stirred at 80 C. for 1 h, cooled and diluted with water (250 mL) then extracted with EtOAc (2100 ml). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced pressure to give title piperidine as a yellow solid (1.2 g, 62.76%). UPLC-MS (Method 1) m/z 303.3 (M+H).sup.+ at 2.14 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6).Math. 8.17 (d, 1H), 7.34 (d, 1H), 3.34 (s, 3H), 3.10 (bs, 4H), 1.66 (m, 6H).

Step-5: Synthesis of 4-fluoro-5-(methylsulfonyl)-2-(piperidin-1-yl)aniline

(768) To a solution of Step-4 piperidine (1.2 g, 0.00396 mol, 1 eq) in EtOAc (10 ml) was added SnCl.sub.2 2H.sub.2O (4.48 g, 0.01984 mol, 5 eq). The reaction mixture was stirred at room temperature for 30 min, diluted with water (200 ml) and pH was set 12 using 1 N NaOH solution. The aqueous layer was extracted with ethyl acetate (2100 ml). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude was dissolved in DCM (10 mL) and followed by addition of n-pentane (20 mL). The precipitated solid was filtered to give title aniline as off white solid (0.9 g, 92.51%). UPLC-MS (Method 1) m/z 273.3 (M+H).sup.+ at 2.08 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.12 (d, 1H), 6.89 (d, 1H), 4.99 (s, 2H), 3.20 (s, 3H), 2.83 (bs, 4H), 1.67 (bs, 4H), 1.54 (bs, 2H).

(769) PART B; Step 1: Methyl 4-cyclopropyl-3-(N-(4-fluoro-5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: A solution of 4-fluoro-5-(methylsulfonyl)-2-(piperidin-1-yl)aniline (INTERMEDIATE 1) (0.10 g, 0.367 mmol) in pyridine (1.04 ml, 12.9 mmol) was treated with the product from Example 323 Step 2 (0.131 g, 0.477 mmol) and the resultant solution was stirred at RT for 24 h then at 50 C. for 96 h. The mixture was concentrated in vacuo and the residue purified by chromatography on silica gel (24 g cartridge, 0-60% EtOAc/isohexane) to afford the title compound (73 mg, 0.143 mmol, 39% yield) as a brown solid. UPLC-MS (Method 1): m/z 511.3 (M+H).sup.+, 509.2 (MH).sup. at 1.64 min.

(770) Step 2: 4-cyclopropyl-3-(N-(4-fluoro-5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: LiOH (10.3 mg, 0.429 mmol) was added to a mixture of the product from Step 1 above (0.073 g, 0.143 mmol) in THF (3 ml) and water (1 ml) at RT. The resultant mixture was stirred at RT for 24 h. The reaction mixture was concentrated in vacuo. The residue was acidified with 10% w/v citric acid (aq) and the precipitate collected by filtration to afford the title compound (32 mg, 0.064 mmol, 45% yield, 99% purity) as a white solid. UPLC-MS (Method 1): m/z 497.3 (M+H).sup.+, 495.2 (MH).sup. at 1.50 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.17 (br s, 1H), 9.60 (br s, 1H), 8.30 (d, J=1.9 Hz, 1H), 8.01 (d, J=8.2 Hz, 1H), 7.21 (d, J=7.7 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.02 (d, J=12.6 Hz, 1H), 3.11 (s, 3H), 3.06-2.98 (m, 4H), 2.80-2.72 (m, 1H), 1.55-1.45 (m, 6H), 1.17-1.04 (m, 2H), 0.93-0.87 (m, 2H).

Example 332:3-(N-(4-chloro-5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid

(771) ##STR00664##

PART A; Preparation of INTERMEDIATE 4; 4-chloro-5-(methylsulfonyl)-2-(pyridin-2-yl)aniline

(772) ##STR00665##

Step-1: Synthesis of 1-(5-chloro-4-(methylsulfonyl)-2-nitrophenyl)piperidine

(773) To a mixture of 1-bromo-5-chloro-4-(methylsulfonyl)-2-nitrobenzene (1 g, 0.00319 mol, 1 eq) and piperidine (0.273 g, 0.00319 mole, 1 eq) in 1,4-dioxane (10 mL) was added K.sub.3PO.sub.4 (1.01 g, 0.00478 mol, 1.5 eq). The reaction mixture was purged with N.sub.2 for 30 min at room temperature, then Pd.sub.2 (dba) 3 (0.145 g, 0.00015 mole, 0.05 eq) and Xanthphos (0.184 g, 0.000319) were added. The resulting reaction mixture was stirred at 50 C. for 1 h, cooled, diluted with water (100 mL) and extracted with ethyl acetate (250 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and reduced in vacuo to give title piperidine as a brown liquid (1 g, 73.78%). This crude material was used directly for the next step.

Step-2: Synthesis of 4-chloro-5-(methylsulfonyl)-2-(piperidin-1-yl)aniline

(774) To a solution of Step-1 piperidine (1.5 g, 0.0047 mol, 1 eq) in EtOAc (50 ml) was added SnCl.sub.2 2H.sub.2O (5.32 g, 0.0235 mol, 5 eq). The reaction mixture was stirred at room temperature for 2 h, diluted with water (100 ml) and pH was set 12 using 1 N NaOH solution. The aqueous layer was extracted with ethyl acetate (2100 ml). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography using neutral alumina using 20% EtOAc in Hexane as eluent. The resulting material was dissolved in DCM (10 mL) and followed by addition of n-pentane (20 mL). The precipitated solid was filtered to give title aniline as off white solid (0.41 g, 30.18%). UPLC-MS (Method 1) m/z 289.2/291.2 (M+H).sup.+ at 2.27 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.37 (d, 1H), 6.99 (d, 1H), 5.31 (s, 2H), 3.24 (s, 3H), 2.82 (bs, 4H), 1.67 (bs, 4H), 1.52 (bs, 2H).

(775) PART B; Step 1: Methyl 3-(N-(4-chloro-5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoate: A solution of 4-chloro-5-(methylsulfonyl)-2-(piperidin-1-yl)aniline (0.10 g, 0.346 mmol) in pyridine (0.980 ml, 12.1 mmol) was treated with the product from Example 323 Step 2 (0.124 g, 0.450 mmol) and the resultant solution was stirred at RT for 24 h then at 50 C. for 96 h. The mixture was concentrated in vacuo and the residue purified by chromatography on silica gel (24 g cartridge, 0-10% EtOAc/DCM followed by 0-50% EtOAc/Isohexane) to afford the title compound (84 mg, 0.159 mmol, 46% yield, 100% purity) as a cream solid. UPLC-MS (Method 1): m/z 527.3 (M+H).sup.+, 525.1 (MH).sup. at 1.72 min.

(776) Step 2: 3-(N-(4-chloro-5-(methylsulfonyl)-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: LiOH (0.011 g, 0.478 mmol) was added to a mixture of the product from Step 1 above (0.084 g, 0.159 mmol, 100% purity) in THF (3 ml) and water (1 ml) at RT. The resultant mixture was stirred at RT for 24 h. The reaction mixture was concentrated in vacuo. The residue was acidified with 10% w/v citric acid (aq) and the precipitate collected by filtration to afford the title compound (65 mg, 0.126 mmol, 79% yield, 99% purity) as a pale yellow solid. UPLC-MS (Method 1): m/z 513.3 (M+H).sup.+, 511.2 (MH).sup. at 1.58 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.20 (br s, 1H), 9.50 (br s, 1H), 8.34 (d, J=1.9 Hz, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.51 (s, 1H), 7.20 (s, 1H), 7.16 (d, J=8.3 Hz, 1H), 3.16 (s, 3H), 3.02-2.96 (m, 4H), 2.80-2.72 (m, 1H), 1.54-1.50 (m, 4H), 1.49-1.43 (m, 2H), 1.13-1.04 (m, 2H), 0.92-0.86 (m, 2H).

Example 333: 4-cyclopropyl-3-(N-(4-fluoro-2-(piperidin-1-yl)-5-(tetrazol-1-yl)phenyl) sulfamoyl)benzoic acid

(777) ##STR00666##

PART A; Preparation of INTERMEDIATE 3; 4-fluoro-2-(piperidin-1-yl)-5-(1H-tetrazol-1-yl) aniline

(778) ##STR00667##

Step-1: Synthesis of 2-fluoro-5-nitro-4-(piperidin-1-yl)aniline

(779) To a stirred solution of 2,4-difluoro-5-nitroaniline (7 g, 0.0287 mol, 1 eq) in THF (70 ml, 10 Vol) was added DIPEA (11.1 g, 0.0861 mol, 3 eq) at room temperature under N.sub.2, followed by piperidine (2.44 g, 0.0287 mol, 1 eq) at 0 C. The reaction mixture was then stirred at 70 C. for 16 h, cooled and poured into water (500 mL) then extracted with ethyl acetate (3250 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give title aniline as a brown oil and a mixture of regioisomers (10 g, quantitative). UPLC-MS (Method 1) m/z 240.3 (M+H).sup.+ at 2.14 and 2.44 min. This material was used directly in the next step.

Step-2: Synthesis of 1-(5-fluoro-2-nitro-4-(1H-tetrazol-1-yl)phenyl)piperidine

(780) A solution of Step-1 aniline (10 g, 0.042 mol, 1 eq) in acetic acid (200 ml, 20 Vol) was stirred for 5 min, then triethylorthoformate (31.08 g, 0.21 mol, 5 eq) was added followed by TMS-N.sub.3 (24.15 g, 0.21 mol, 5 eq) at 0 C. The resulting reaction mixture was stirred at 70 C. for 4 h, cooled and poured into water (500 mL) then extracted with ethyl acetate (3250 mL). The combined organic layer was washed with NaHCO.sub.3 solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure to give title tetrazole as a brown oil and a mixture of regioisomers (15 g, Quantitative). UPLC-MS (Method 1) m/z 293.3 (M+H).sup.+ at 2.19 and 2.24 min. This material was used directly in the next step.

Step-3: Synthesis of 4-fluoro-2-(piperidin-1-yl)-5-(1H-tetrazol-1-yl)aniline

(781) To a stirred solution of Step-2 tetrazole (15 g, 0.051 mol, 1 eq) in ethyl acetate (100 ml) was added SnCl.sub.2. 2H.sub.2O (38.9 g, 0.205 mol, 4 eq). The reaction mixture was stirred at room temperature for 2 h then poured into water (700 mL) and ethyl acetate (250 mL). The precipitate of stannous hydroxide was filtered through a cellite bed and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography using neutral alumina using 20-100% EtOAc in hexane eluent to give a mixture of regioisomers. The desired regioisomer was isolated by reverse phase column chromatography (A) 0.1% FA in water, (B) acetonitrile (40:60) and identified by .sup.1H NMR NOE experiments to give title aniline as pale yellow solid (0.560 g, 14.18%). UPLC-MS (Method 1) m/z 263.3 (M+H).sup.+ at 2.19 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.93 (s, 1H), 7.06 (d, 1H), 7.02 (d, 1H), 5.04 (s, 2H), 2.82 (bs, 4H), 1.69 (m, 4H), 1.54 (m, 2H).

(782) PART B; Step 1: Methyl 4-cyclopropyl-3-(N-(4-fluoro-2-(piperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)benzoate: A solution of 4-fluoro-2-(piperidin-1-yl)-5-(tetrazol-1-yl)aniline (INTERMEDIATE 3) (0.30 g, 1.14 mmol) in pyridine (3.24 ml, 40.0 mmol) was treated with the product from Example 323 Step 2 (0.408 g, 1.49 mmol) and the resultant solution was stirred at RT for 24 h then at 50 C. for 96 h. The mixture was concentrated in vacuo and the residue purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane followed by 0-10% EtOAc/DCM) to afford (0.277 g, 0.548 mmol, 48% yield, 99% purity) as a white solid. UPLC-MS (Method 1): m/z 523.4 (M+Na).sup.+, 499.2 (MH).sup. at 1.72 min.

(783) Step 2: 4-cyclopropyl-3-(N-(4-fluoro-2-(piperidin-1-yl)-5-(1H-tetrazol-1-yl)phenyl)sulfamoyl)benzoic acid: LiOH (0.039 g, 1.644 mmol) was added to a solution of the product from Step 1 above (0.277 g, 0.548 mmol, 99% purity) in THF (3 ml, 0.548 mmol) and water (1 ml) at RT. The resultant mixture was stirred at RT for 24 h. The reaction mixture was concentrated in vacuo. The residue was acidified with 10% w/v citric acid (aq) and the precipitate collected by filtration to give (220 mg, 0.447 mmol, 82% yield, 99% purity) as a cream solid. UPLC-MS (Method 1): m/z 509.3 (M+Na)+, 485.2 (MH).sup. at 1.57 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.21 (br s, 1H), 9.80 (d, J=1.6 Hz, 1H), 9.55 (br s, 1H), 8.39 (d, J=1.9 Hz, 1H), 8.01 (dd, J=8.2, 1.9 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.29 (d, J=12.3 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 2.79 (m, 5H), 1.48 (d, J=6.4 Hz, 4H), 1.43 (q, J=9.4, 7.3 Hz, 2H), 1.13-1.04 (m, 2H), 0.90-0.81 (m, 2H).

Example 334: 3-(N-(4-chloro-2-(piperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid

(784) ##STR00668##

PART A; Preparation of INTERMEDIATE 4; 4-chloro-2-(piperidin-1-yl)-5-(1H-tetrazol-1-yl) aniline

(785) ##STR00669##

Step-1: Synthesis of 2-chloro-4-fluoro-5-nitroaniline

(786) To a solution of 2-chloro-4-fluoroaniline (5.00 g, 0.0343 mole, 1 eq) in H.sub.2SO.sub.4 (15 mL) was added guanidine nitrite (4.19 g, 0.0343 mole, 1 eq) at 0 C. The reaction mixture was stirred for 2 h at room temperature, then basified using 20% NaOH solution (100 ml) and poured in cold water (500 mL). The precipitated solid was filtered and dried in vacuo to give title nitroaniline brown solid (3.7 g, 56.92%).

Step-2: Synthesis of 2-chloro-5-nitro-4-(piperidin-1-yl)aniline

(787) To a solution of Step-1 nitroaniline (3.56 g, 0.0191 mole, 1 eq) and piperidine (3.56 g, 0.038 mole, 2 eq) in THF (35 mL) was added DIPEA (7.5 mL, 0.057 mole, 2 eq). The resulting reaction mixture was stirred at 70 C. for 16 h, cooled and diluted with water (100 mL) then extracted with ethyl acetate (3100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4 concentrated under reduced pressure to give title aniline as orange solid (4.20 g, 89.36%). UPLC-MS (Method 1) m/z 256.3/258.3 (M+H).sup.+ at 2.43 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.28 (s, 1H), 7.17 (s, 1H), 5.65 (s, 2H), 2.77 (m, 4H), 1.36 (m, 4H), 1.54 (m, 2H).

Step-3: Synthesis of 1-(5-chloro-2-nitro-4-(1H-tetrazol-1-yl)phenyl)piperidine

(788) To a solution of Step-2 aniline (4.2 g, 0.0164 mol, 1 eq) in acetic acid (40 mL) was added triethyl orthoformate (12.15 g, 0.0821 mole, 5 eq) and TMS-azide (9.4 g, 0.0821 mole, 5 eq) at 0 C. The reaction mixture was stirred at 70 C. for 2 h, cooled and basified in sat NaHCO.sub.3 solution (400 mL) and extracted with ethyl acetate (3100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure and the resulting crude material was purified by trituration in pentane (50 mL) and (diethyl ether (20 mL) to give title piperidine as a brown solid (3.20 g, 63.11%). UPLC-MS (Method 1) m/z 309.3/311.3 (M+H).sup.+ at 2.31 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.84 (s, 1H), 8.39 (s, 1H), 7.63 (s, 1H), 3.14 (bs, 4H), 1.62 (bs, 6H).

Step-4: Synthesis of 4-chloro-2-(piperidin-1-yl)-5-(1H-tetrazol-1-yl)aniline

(789) To a solution of Step-3 piperidine (1.0 g, 0.0032 mol, 1.0 eq) in EtOAC was stirred and SnCl.sub.2 was added (3.06 g, 0.0161 mol, 3 eq.) The reaction mixture was stirred at room temperature for 4 h, filtered through a celite bed, diluted with water (100 mL) and extracted with ethyl acetate (3100 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure and the crude product was purify by combi flash chromatography neutral silica using (5% ethyl acetate in hexane) to give title aniline as a light brown solid (0.587 g, 56.72%). UPLC-MS (Method 1) m/z 279.3/281.3 (M+H).sup.+ at 2.36 min. 1H NMR (500 MHz, DMSO-d.sub.6) 9.84 (s, 1H), 7.11 (s, 1H), 6.91 (s, 1H), 5.33 (s, 2H), 2.82 (bs, 4H), 1.69 (m, 4H), 1.54 (m, 2H).

(790) PART B; Step 1: Methyl 3-(N-(4-chloro-2-(piperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoate: A solution of 4-chloro-2-(piperidin-1-yl)-5-(tetrazol-1-yl)aniline (INTERMEDIATE 4) (0.30 g, 1.08 mmol) in pyridine (3.05 ml, 37.7 mmol) was treated with the product from Example 323 Step 2 (0.384 g, 1.40 mmol) and the solution was stirred at RT for 24 h then at 70 C. for 96 h. The mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel (24 g cartridge, 0-50% EtOAc/isohexane followed by 0-10% EtOAc/DCM) to afford the title compound (52 mg, 0.099 mmol, 9% yield, 99% purity) as a colourless solid. UPLC-MS (Method 1): m/z 539.3 (M+Na)+, 515.2 (MH).sup. at 1.74 min.

(791) Step 2: 3-(N-(4-chloro-2-(piperidin-1-yl)-5-(tetrazol-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: LiOH (7.08 mg, 0.296 mmol) was added to a mixture of the product from Step 1 above (0.052 g, 0.099 mmol, 99% purity) in THF (3 ml) and water (1 ml) at RT. The resultant mixture was stirred at RT for 24 h. The reaction mixture was concentrated in vacuo and the residue acidified with 10% w/v citric acid (aq). The resultant precipitate was collected by filtration to afford the title compound (33 mg, 0.062 mmol, 63% yield, 95% purity) as a cream solid. UPLC-MS (Method 1): m/z 525.3 (M+Na).sup.+, 501.2 (MH).sup. at 1.63 min. 1H NMR (500 MHz, DMSO-d.sub.6) 13.20 (br s, 1H), 9.80 (s, 1H), 8.40 (d, J=1.9 Hz, 1H), 8.00 (dd, J=8.2, 1.8 Hz, 1H), 7.40 (d, J=7.2 Hz, 2H), 7.17-7.11 (m, 1H), 2.80 (t, J=5.2 Hz, 5H), 1.52 (q, J=5.6 Hz, 4H), 1.48-1.42 (m, 2H), 1.13-0.99 (m, 2H), 0.89-0.77 (m, 2H). 1 exchangeable proton not observed.

Example 335: 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-(cyclopropyl-d.SUB.5.)benzoic acid

(792) ##STR00670##

(793) Step 1: Methyl 4-bromo-3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: A mixture of the product from Example 182 step 2 (1.00 g, 4.92 mmol), the product from Example 316 Step 1 (1.64 g, 5.18 mmol) and pyridine (1.2 ml, 14.8 mmol) in DCM (25 ml) was stirred at RT overnight. The mixture was loaded onto silica and purified by chromatography on silica gel (40 g cartridge, 0-100% EtOAc/isohexane) and then triturated with TBME to afford the title compound (1.44 g, 3.01 mmol, 61% yield) as a white solid. UPLC-MS (Method 1): m/z 478.3 (M+H).sup.+, 476.3 (MH).sup. at 1.80 min.

(794) Step 2: Methyl 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-(cyclopropyl-d.sub.5)benzoate: A flame-dried flask was charged with Mg turnings (72 mg, 2.96 mmol) and iodine (5 mg, 0.020 mmol). A small portion (0.25 ml) of a solution of cyclopropyl-d.sub.5 bromide (250 mg, 1.98 mmol) in THF (2 ml) was added and the mixture was heated to reflux with a heat gun. Once the brown colour disappeared the remaining solution was added at a rate that reflux was maintained. Upon complete addition the mixture was stirred at RT for 30 min. The mixture was slowly added to 2 M ZnCl in 2-methyltetrahydrofuran (1.5 ml, 3.00 mmol) at 0 C. and then warmed to RT and stirred for 20 min. A solution of the product from Step 1 above (95 mg, 0.198 mmol) in THF (1 ml) and PdCl.sub.2 (dppf).Math.DCM (30 mg, 0.037 mmol) were added and the mixture was heated to 70 C. for 2 h. The mixture was quenched with saturated NH.sub.4Cl (aq) (10 ml) and extracted with EtOAc (320 ml). The combined organic phase was washed with brine (10 ml), dried by passage through a phase separator and then concentrated in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (82 mg, 0.179 mmol, 90% yield, 97% purity) as a pale yellow oil. UPLC-MS (Method 1): m/z 445.5 (M+H).sup.+, 443.4 (MH).sup. at 1.82 min.

(795) Step 3: 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-(cyclopropyl-d.sub.5)benzoic acid: A mixture of the product from step 2 above (82 mg, 0.179 mmol, 97% purity) and LiOH.Math.H.sub.2O (30.0 mg, 0.716 mmol) in THF/MeOH/water (4:1:1, 3 ml) was stirred at 40 C. over the weekend. The mixture was diluted with water (5 ml), acidified to pH 4 using 1 M HCl(aq) and extracted with EtOAc (315 ml). The organic phases were combined and washed with brine (10 ml), dried by passage through a phase separator and concentrated in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (4 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (27 mg, 0.060 mmol, 33% yield, 96% purity) as a white solid. UPLC-MS (Method 1): m/z 431.6 (M+H).sup.+, 429.4 (MH).sup. at 1.66 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.25 (s, 1H), 9.48 (s, 1H), 8.37 (d, J=1.9 Hz, 1H), 8.02 (dd, J=8.3, 1.9 Hz, 1H), 7.54 (dd, J=8.4, 2.0 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.20-7.14 (m, 2H), 2.87-2.80 (m, 4H), 1.53-1.47 (m, 4H), 1.47-1.43 (m, 2H).

Example 336:3-(N-(5-cyano-3-methyl-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid

(796) ##STR00671##

(797) Step 1: 1-(4-bromo-2-methyl-6-nitrophenyl)piperidine: To a solution of 5-bromo-2-fluoro-1-methyl-3-nitrobenzene (1.01 g, 4.32 mmol) in DCM (10 ml) at RT was added piperidine (0.64 ml, 6.4 mmol) and then triethylamine (1.2 ml, 8.6 mmol). The resultant solution was stirred at RT for 17 h. Additional piperidine (1.3 ml, 13 mmol) was added and the mixture heated at 40 C. for 6 h. Additional piperidine (3.5 ml, 35 mmol) was added and the mixture heated at 40 C. for 17 h and then at 50 C. for 3 h. Additional piperidine (7.0 ml, 70 mmol) was added and the mixture was heated at 50 C. for 4 h. The reaction mixture was allowed to cool to RT and then washed with water (320 ml). The aqueous phase was extracted with DCM (10 ml) and the organic phase was dried by passage through a phase separator and concentrated in vacuo. The residue was diluted with DCM (100 ml) and washed with 0.5 M HCl(aq) (350 ml). The organic phase was dried over MgSO.sub.4 and concentrated in vacuo to afford the title compound (1.17 g, 3.84 mmol, 89% yield, 98% purity) as an orange solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.80 (s, 1H), 7.71 (s, 1H), 2.90-2.77 (m, 4H), 2.33 (s, 3H), 1.61-1.51 (m, 6H).

(798) Step 2: 3-methyl-5-nitro-4-(piperidin-1-yl)benzonitrile: A solution of the product from step 1 above (1.17 g, 3.84 mmol, 98% purity) and dicyanozinc (0.483 g, 4.12 mmol) in DMA (5 ml) was degassed with N.sub.2 for 10 min, then Pd(PPh.sub.3).sub.4 (0.453 g, 0.392 mmol) was added in 4 portions. The reaction mixture was heated to 100 C. under N.sub.2 for 2 h. The reaction mixture was allowed to cool to RT and then filtered through Celite with EtOAc (50 ml). The filtrate was washed with saturated NaHCO.sub.3(aq) (220 ml), water (220 ml) and brine (220 ml). The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g column, 0-40% EtOAc/isohexane) to afford the title compound (720 mg, 2.88 mmol, 73% yield, 98% purity) as a bright yellow colourless solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.17 (d, J=2.0 Hz, 1H), 7.93 (d, J=2.1 Hz, 1H), 2.95-2.85 (m, 4H), 2.36 (s, 3H), 1.65-1.50 (m, 6H).

(799) Step 3: 3-amino-5-methyl-4-(piperidin-1-yl)benzonitrile: To a mixture of the product from step 2 above (720 mg, 2.88 mmol, 98% purity) and NH.sub.4Cl (188 mg, 3.52 mmol) in IPA (10 ml) and water (3 mL) was added iron powder (1.64 g, 29.4 mmol) and the reaction mixture was heated at 90 C. for 4 h. The suspension was cooled to RT and filtered through Celite, washing with MeOH (10 ml) and the solvent were removed in vacuo. 0.1 M HCl(aq) (100 ml) was added and the solution washed with EtOAc (50 ml). The aqueous solution was neutralised with sat. NaHCO.sub.3(aq) (50 ml) and then extracted with ethyl acetate (550 ml). The combined organic phases were dried over MgSO.sub.4, filtered and concentrated in vacuo to afford the title compound (220 mg) as a light brown oil and was used without further purification.

(800) Step 4: Methyl 3-(N-(5-cyano-3-methyl-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoate: To a solution of the product from step 3 above (110 mg) and pyridine (0.204 ml, 2.52 mmol) in DCM (5 ml) was added the product from Example 323 step 2 (177 mg, 0.613 mmol, 95% purity) at 0 C. and the mixture was stirred at RT for 19 h. The reaction mixture was diluted with DCM (50 ml) and sequentially washed with 0.5 M HCl(aq) (250 ml), water (50 ml) and brine (50 ml). The combined organic phases were dried over MgSO.sub.4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound (104 mg, 0.225 mmol, 16% yield over 2 steps, 98% purity) as a cream solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 9.52 (s, 1H), 8.33 (s, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.45 (s, 1H), 7.21 (d, J=8.4 Hz, 1H), 6.88 (s, 1H), 3.86 (s, 3H), 3.07-2.96 (m, 4H), 2.77-2.66 (m, 1H), 2.29 (s, 3H), 1.65-1.52 (m, 6H), 1.16-1.10 (m, 2H), 0.98-0.87 (m, 2H).

(801) Step 5: 3-(N-(5-cyano-3-methyl-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-cyclopropylbenzoic acid: LiOH (16.5 mg, 0.688 mmol) was added to a solution of the product from step 4 above (104 mg, 0.225 mmol, 98% purity) in THF (1 ml) and water (0.5 ml) at RT. The resultant mixture was stirred at RT for 24 h. The reaction mixture was concentrated in vacuo and the residue was acidified with 10% w/v citric acid (aq). The resultant precipitate was collected under filtration and washed with water (50 ml) to afford the title compound (57.5 mg, 0.125 mmol, 55% yield, 96% purity) as a white solid. UPLC-MS (Method 2): m/z 440.7 (M+H).sup.+, 438.3 (MH).sup. at 1.29 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.30 (s, 1H), 9.46 (s, 1H), 8.33 (d, J=1.8 Hz, 1H), 8.04 (dd, J=8.2, 1.8 Hz, 1H), 7.44 (s, 1H), 7.18 (d, J=8.3 Hz, 1H), 6.90 (d, J=2.1 Hz, 1H), 3.03-2.95 (m, 4H), 2.75-2.67 (m, 1H), 2.29 (s, 3H), 1.66-1.49 (m, 6H), 1.14-1.09 (m, 2H), 0.94-0.89 (m, 2H).

Example 337:4-(tert-butyl)-3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid

(802) ##STR00672##

(803) Step 1: 3-bromo-4-(tert-butyl)benzoic acid: To a mixture of 4-(tert-butyl)benzoic acid (10 g, 56.1 mmol), nitric acid (37 ml), water (28 ml), AcOH (170 ml) and Br.sub.2 (5.20 ml, 101 mmol) was added silver nitrate (9.63 g, 56.7 mmol) in water (28.5 ml) via dropping funnel over 30 min. Upon complete addition the mixture was stirred at RT overnight. The mixture was poured onto ice/water and stirred until all the ice melted. The precipitate was collected by filtration, dissolved in EtOAc (600 ml) and sequentially washed with water (200 ml) and brine (200 ml). The organic phase was dried by passage through a phase separator and concentrated in vacuo to afford the title compound (13.4 g, 21.9 mmol, 39% yield, 42% purity) as a yellow solid and was used without further purification. UPLC-MS (Method 1): 255.1 (MH).sup. at 1.73 min.

(804) Step 2: Methyl 3-bromo-4-(tert-butyl)benzoate: A mixture of the product from step 1 above (13.4 g, 21.9 mmol, 42% purity), iodomethane (2.7 ml, 43.4 mmol) and K.sub.2CO.sub.3 (6.06 g, 43.8 mmol) in DMF (20 ml) was stirred at RT for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in DCM (100 ml), washed with 1 M HCl(aq) (100 ml) and brine (3100 ml). The organic phase was dried by passage through a phase separator and the solvent was concentrated in vacuo onto silica and partially purified by chromatography on silica gel (80 g cartridge, 0-10% EtOAc/isohexane) and then further purified by chromatography (40 g reverse phase C18 cartridge, 35-95% MeCN/0.1% formic acid (aq) to afford the title compound (4.19 g, 15.0 mmol, 68% yield, 97% purity) as a pale yellow oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.09 (d, J=1.9 Hz, 1H), 7.88 (dd, J=8.3, 1.9 Hz, 1H), 7.63 (d, J=8.3 Hz, 1H), 3.85 (s, 3H), 1.48 (s, 9H).

(805) Step 3: Methyl 3-(benzylthio)-4-(tert-butyl)benzoate: A mixture of the product from step 2 above (4.19 g, 15.0 mmol, 97% purity), DIPEA (5.50 ml, 31.5 mmol), Pd.sub.2 (dba) 3 (1.38 g, 1.51 mmol) and Xantphos (1.30 g, 2.25 mmol) in dioxane (70 ml) was sparged with N.sub.2 for 15 min. benzyl mercaptan (1.90 ml, 16.1 mmol) was added and the mixture was stirred at 100 C. for 18 h and then at RT for 3 days. Additional benzyl mercaptan (1.90 ml, 16.1 mmol) was added and the mixture was stirred at 100 C. for 5 h. Additional Pd.sub.2 (dba) 3 (1.38 g, 1.51 mmol) and xantphos (1.30 g, 2.25 mmol) were added and stirring at 100 C. was continued overnight. Additional DIPEA (5.50 ml, 31.5 mmol) was added and stirring at 100 C. was continued overnight. Upon cooling to RT the mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (120 g cartridge, 0-100% DCM/isohexane) to afford the title compound (1.18 g, 2.85 mmol, 19% yield, 76% purity) as a pale yellow oil. UPLC-MS (Method 1): m/z 315.2 (M+H).sup.+, 313.2 (MH).sup. (ES.sup.) at 2.06 min.

(806) Step 4: Methyl 4-(tert-butyl)-3-(chlorosulfonyl)benzoate: To a solution of the product from step 3 above (1.18 g, 2.85 mmol, 76% purity) in AcOH (0.21 ml), water (1.5 ml), and MeCN (20 ml) at 10 C. was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (843 mg, 4.28 mmol) and the mixture was stirred at 10 C. for 2 h. The mixture was concentrated in vacuo to 5 ml, extracted with DCM (240 ml), and the combined organic phase was dried by passage through a phase separator and concentrated in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (40 g cartridge, 0-100% DCM/isohexane) to afford the title compound (697 mg, 2.28 mmol, 80% yield, 95% purity) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.76 (d, J=2.2 Hz, 1H), 7.79 (dd, J=8.3, 2.2 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 3.84 (s, 3H), 1.53 (s, 9H).

(807) Step 5: Methyl 4-(tert-butyl)-3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoate: A mixture of the product from Example 182 step 2 (100 mg, 492 mol, 93% purity), the product from step 4 above (226 mg, 738 mol, 95% purity) and pyridine (0.12 ml, 1.52 mmol) in DCM (2 ml) was stirred at 35 C. for 3 days. The mixture was concentrated in vacuo onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% DCM/isohexane) to afford the title compound (111 mg, 135 mol, 27% yield, 55% purity) as a light brown oil. UPLC-MS (Method 1): m/z 456.6 (M+H).sup.+, 454.3 (MH).sup. at 1.98 min.

(808) Step 6: 4-(tert-butyl)-3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)benzoic acid: A mixture of the product from step 5 above (111 mg, 135 mol, 55% purity) and LiOH.Math.H.sub.2O (23.0 mg, 548 mol) THF/MeOH/water (4:1:1, 2.1 ml) was stirred at 40 C. overnight. The mixture was diluted with water (5 ml), acidified to pH 4 with 1 M HCl(aq) and extracted with EtOAc (315 ml). The combined organic extracts were washed with brine (10 ml), dried by passage through a phase separator and the solvent was removed in vacuo. The residue was loaded onto silica and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to afford the title compound as a white solid. UPLC-MS (Method 1): m/z 442.6 (M+H).sup.+, 440.3 (MH).sup., at 1.98 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.09 (d, J=1.9 Hz, 1H), 7.88 (dd, J=8.3, 1.9 Hz, 1H), 7.63 (d, J=8.3 Hz, 1H), 3.85 (s, 3H), 1.48 (s, 9H).

Example 338: 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethynylbenzoic acid

(809) ##STR00673##

(810) Step 1: methyl 3-bromo-4-((trimethylsilyl) ethynyl)benzoate: A mixture of methyl 3-bromo-4-iodobenzoate (1.00 g, 2.93 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (51 mg, 0.073 mmol) and CuI(s) (14 mg, 0.073 mmol) in THF (10 ml) was prepared under a N.sub.2 atmosphere. Et.sub.3N (2.04 ml, 14.7 mmol) and ethynyltrimethylsilane (488 l, 3.52 mmol) were added and the mixture was stirred at RT overnight. The reaction mixture was filtered through Celite and concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g cartridge, 0-20% EtOAc/isohexane) to afford the title compound (870 mg, 2.52 mmol, 86% yield, 90% purity) as a yellow liquid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.17-8.14 (m, 1H), 7.94-7.90 (m, 1H), 7.70 (d, J=8.1 Hz, 1H), 3.87 (s, 3H), 0.27 (s, 9H).

(811) Step 2: methyl 3-(benzylthio)-4-((trimethylsilyl) ethynyl)benzoate: A mixture of the product from step 1 above (870 mg, 2.52 mmol, 90% purity), Pd.sub.2 (dba) 3 (140 mg, 0.598 mmol), DIPEA (780 l, 4.47 mmol) and dioxane (6.5 ml) was sparged with N.sub.2 for 15 min before benzyl mercaptan (280 l, 2.37 mmol) was added. The mixture was heated to 100 C. and stirred overnight. Upon cooling to RT the mixture was filtered through Celite. The filtrate was loaded onto silica and purified by chromatography on silica gel (330 g cartridge, 0-50% DCM/isohexane) to afford the title compound (880 mg, 2.36 mmol, 94% yield, 95% purity) as an orange solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.91-7.86 (m, 1H), 7.70-7.66 (m, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.46-7.42 (m, 2H), 7.37-7.31 (m, 2H), 7.29-7.24 (m, 1H), 4.36 (s, 2H), 3.85 (s, 3H), 0.25 (s, 9H).

(812) Step 3: methyl 3-(chlorosulfonyl)-4-((trimethylsilyl) ethynyl)benzoate: To a solution of the product from step 2 above (880 mg, 2.36 mmol, 95% purity), AcOH (150 l, 2.62 mmol) and water (300 l) in MeCN (12 ml) at 10 C. was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (700 mg, 3.55 mmol) in 4 portions and the mixture was stirred at 10 C. for 2 h. The mixture was concentrated in vacuo, dissolved in water (30 ml) and extracted with DCM (330 ml). The combined organic phases were dried by passage through a phase separator and concentrated onto silica in vacuo. The crude product was purified by chromatography on silica gel (40 g cartridge, 0-100% DCM/isohexane) to afford the title compound (637 mg, 1.35 mmol, 57% yield, 70% purity) as a clear colourless oil. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.38 (d, J=1.9 Hz, 1H), 7.84 (dd, J=8.0, 1.9 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 3.87 (s, 3H), 0.22 (s, 9H).

(813) Step 4: methyl 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-((trimethylsilyl) ethynyl)benzoate: The product from step 3 above (256 mg, 0.541 mmol, 70% purity) was added to a solution of pyridine (0.12 mL, 1.5 mmol) and the product from Example 182, step 2 (100 mg, 0.492 mmol, 93% purity) in DCM (1 mL). The resultant solution was stirred at RT for 3 days. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc/isohexane) to the title compound (285 mg, 0.492 mmol, 100% yield, 85% purity) as a pale yellow oil. UPLC-MS (Method 1): m/z 496.3 (M+H).sup.+, 494.2 (MH).sup., at 2.08 min.

(814) Step 5: 3-(N-(5-cyano-2-(piperidin-1-yl)phenyl)sulfamoyl)-4-ethynylbenzoic acid: To a solution of the product from step 4 above (285 mg, 492 mol, 85% purity) in THF (3 ml) was added 1 M LiOH(aq) (1.50 mL, 1.50 mmol). The reaction mixture was heated to 40 C. and stirred for 3 h. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was acidified to pH 4 using 1 M HCl(aq). The precipitate was collected by filtration and purified by chromatography purified by chromatography (24 g reverse phase C18 cartridge, 15-80% MeCN/0.1% formic acid (aq)) to afford the title compound (100 mg, 0.230 mmol, 47% yield, 94% purity) as a white solid. UPLC-MS (Method 1): m/z 410.5 (M+H).sup.+, 408.3 (MH).sup., at 1.66 min. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 13.75 (br s, 1H), 8.47 (s, 1H), 8.37-8.31 (m, 2H), 7.83 (dd, J=8.7, 2.1 Hz, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.27 (d, J=8.7 Hz, 1H), 5.65 (d, J=2.9 Hz, 1H), 4.41 (d, J=2.9 Hz, 1H), 3.23-3.10 (m, 4H), 1.50-1.38 (m, 6H).

(815) Biological Investigations

(816) The following assays can be used to illustrate the commercial utilities of the compounds according to the present invention.

(817) Biological Assay 1: ERAP1 Mediated Hydrolysis of an Amide Substrate Measured in a Biochemical System

(818) Materials and Solutions

(819) 1 Assay buffer (AB): 25 mM Bis-tris propane, 0.05% w/v Hydroxypropylmethylcellulose pH 7.75 made with Optima grade water

(820) Decapeptide WRVYEKC(Dnp)ALK-acid (where Dnp is Dinitrophenyl maleimide) (10-mer) L-Leucine 7-amido-4-methylcoumarin (L-AMC)

(821) Purified ERAP1 (37-941)-10His (ERAP1)

(822) Assay Procedure:

(823) 12.5 L ERAP1 enzyme in 1AB was combined with 250 nL test compound in DMSO. 12.5 L of either 240 UM L-AMC in 1AB or 100 UM 10-mer in 1AB was added to the reaction and incubated at 23 C. for 1 h. For detection, plates were read at excitation 365 nm and emission 442 nm (L-AMC) or excitation 279 nm and emission 355 nm (10-mer). Compound IC.sub.50 was determined using a 4 parameter equation. The results for selected compounds according to the invention are shown in Table 1.

(824) OVA Antigen Presentation Assay

(825) The cellular effect of representative compounds according to the invention on antigen presentation was measured by assessing their effect on the presentation of an ovalbumin-specific peptide (SIINFEKL) to T-cells, as previously described [Reeves et al, (2014) Proc. Natl. Acad. Sci. USA 111; 17594-17599]. Briefly, SiHa cells were transiently transfected with plasmids encoding mouse H2Kb and an ER-targeted N-terminally extended precursor peptide derived from ovalbumin (MRYMILGLLALAAVCSAAIVMKSIINFEHL) using Lipofectamine 3000. The cells were harvested 6 h post-transfection and transfected SiHa cells were plated compounds across a 12-point concentration response curve to quantify ERAP1 inhibitor IC.sub.50. SiHa cells were cultured in the presence of compound for 48 h. Subsequently, B3Z cells [Karttunen et al, (1992) Proc. Natl. Acad. Sci. USA 89; 6020-6024] were added to the cell culture for 4 h; the B3Z T-cell hybridoma encodes a TCR recognizing specifically the SIINFEHL/H2Kb complex at the cell surface, which upon activation, triggers a signalling cascade leading to the transcription of the LacZ gene that is under the control of the IL-2 promoter. Intracellular -galactosidase activity as a readout of T-cell activation was measured by quantifying the conversion of chlorophenored--D-galacto-pyrannoside (CPRG) to chlorophenol red by measuring absorbance at 570 nm.

(826) Representative IC.sub.50 curve for exemplar compounds according to the invention are shown in FIG. 1. Data was normalized to the signal obtained in the absence of compound (high) and absence of antigen (low) and presented as the meanSTD (n=2). FIG. 2 shows a summary of the IC.sub.50 data generated for exemplar compounds according to the invention. The data is presented as the meanSEM (n=6).

(827) Immunopeptidomics

(828) The effect of representative compounds according to the invention on global antigen processing was determined using an unbiased proteomics pipeline as described by Purcell and colleagues [Purcell et al, (2019) Nat Protoc. 14; 1687-1707]. Briefly, 500 million SiHa cells were treated with compound for 24 h or siRNA for 72 hours and then harvested, lysed and MHC-bound peptides isolated by immunoaffinity capture. The peptides were eluted using 10% (v/v) acetic acid and separated from the MHC-1 and B2-microglobulin proteins by HPLC before analysis by LC-MS/MS. Representative results are shown in FIG. 3, which demonstrates the comparable effects of ERAP1 siRNA and compound inhibition on the immunopeptidome (and hence antigen presentation) of SiHa cells. ERAP1 knockdown impacts the length of antigens presented on MHC Class I, reducing the total proportion of 8 and 9 amino acid peptides but increasing the number of 10, 11, 12 and 13 amino acid peptides. 10 M of compound led to greater effects on antigen peptide length compared with 1 M.

(829) Various modifications and variations of the described aspects of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes of carrying out the invention which are obvious to those skilled in the relevant fields are intended to be within the scope of the following claims.

(830) TABLE-US-00015 TABLE 1 Activity of selected compounds according to the invention 1 High 3 High 4 High 6 High 7 Medium 8 Low 9 High 10 High 11 Medium 12 High 13 High 14 High 15 High 16 High 17 Low 18 Medium 19 Medium 20 Medium 21 Low 22 Low 23 Low 24 High 25 Medium 26 High 27 Medium 28 High 29 High 30 High 31 High 32 High 33 High 34 Low 35 High 36 Medium 37 Medium 39 Medium 40 Medium 41 High 42 Low 43 High 46 Medium 49 High 51 High 52 Medium 54 High 55 High 59 High 61 Low 62 High 63 Medium 64 High 65 High 66 High 67 High 68 High 69 High 70 Medium 71 High 72 High 73 High 74 High 75 Medium 77 Medium 78 Medium 80 Medium 83 Medium 84 Medium 86 High 161 High 165 Medium 171 Medium 177 High 178 Medium 179 High 180 High 181 High 182 High 183 Low 184 High 185 High 186 High 187 Medium 188 Medium 189 Low 190 Medium 200 Medium 201 High 202 High 203 High 204 High 205 High 206 High 207 High 208 High 209 High 210 High 211 High 212 High 213 High 214 High 215 High 216 High 217 High 218 High 219 High 220 High 221 High 222 High 223 High 224 High 225 Low 227 Medium 228 High 229 High 230 High 231 High 232 High 233 High 234 High 235 High 236 High 237 High 238 High 239 High 240 High 241 High 242 High 243 High 244 High 245 High 246 High 247 High 248 High 249 High 250 High 251 High 252 High 253 High 254 High 255 Medium 257 High 258 High 259 High 260 High 261 High 262 High 263 High 264 High 265 High 266 High 267 High 268 High 269 High 270 Medium 271 Medium 272 High 273 High 274 High 275 High 276 High 277 High 278 High 279 High 280 High 281 High 282 High 283 High 286 High 287 High 288 High 289 High 290 High 291 High 292 High 293 High 294 High 295 High 296 High 297 High 298 High 299 High 300 High 301 High 302 High 303 High 304 High 305 High 306 High 308 High 309 High 310 High 311 High 312 High 313 High 314 High 315 High 316 High 317 High 318 High 319 High 320 High 321 High 322 High 323 High 324 High 325 High 326 High 327 High 328 High 329 High 330 High 331 High 332 High 333 High 334 High 335 High 336 High 337 Medium 338 Low IC.sub.50 vs Decapeptide WRVYEKC(Dnp)ALK-acid (where Dnp is Dinitrophenyl maleimide) (10-mer); High (<500 nM), Medium (<5 M), Low (>5 M).

(831) TABLE-US-00016 TABLE 2 Structures of compounds according to the invention (1) (3) (4) (6) (7) (8) 0 (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) 0 (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) 00 (29) 01 (30) 02 (31) 03 (32) 04 (33) 05 (34) 06 (35) 07 (36) 08 (37) 09 (39) 0 (40) (41) (42) (43) (46) (49) (51) (52) (54) (55) 0 (59) (61) (62) (63) (64) (65) (66) (67) (68) (69) 0 (70) (71) (72) (73) (74) (75) (77) (78) (80) (83) 0 (84) (86) (161) (165) (171) (177) (178) (179) (180) (181) 0 (182) (183) (184) (185) (186) (187) (188) (189) (190) (200) 0 (201) (202) (203) (204) (205) (206) (207) (208) (209) (210) 0 (211) (212) (213) (214) (215) (216) (217) (218) (219) (220) 0 (221) (222) (223) (224) (225) (227) (228) (229) (230) (231) 0 (232) (233) (234) (235) (236) (237) (238) (239) (240) (241) 00 (242) 01 (243) 02 (244) 03 (245) 04 (246) 05 (247) 06 (248) 07 (249) 08 (250) 09 (251) 0 (252) (253) (254) (255) (257) (258) (259) (260) (261) (262) 0 (263) (264) (265) (266) (267) (268) (269) (270) (271) (272) 0 (273) (274) (275) (276) (277) (278) (279) (280) (281) (282) 0 (283) (286) (287) (288) (289) (290) (291) (292) (293) (294) 0 (295) (296) (297) (298) (299) (300) (301) (302) (303) (304) 0 (305) (306) (308) (309) (310) (311) (312) (313) (314) (315) 0 (316) (317) (318) (319) (320) (321) (322) (323) (324) (325) 0 (326) (327) (328) (329) (330) (331) (332) (333) (334) (335) 0 (336) (337) (338)

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