Aryl sulfonohydrazides

Abstract

Compound of formula I: ##STR00001##
wherein: A is selected from: (i) ##STR00002##
where R.sup.F1 is H or F; (ii) ##STR00003## (iii) a N-containing C.sub.6 heteroaryl group; and B is ##STR00004##
where X.sup.1 is either CR.sup.F2 or N, where R.sup.F2 is H or F; X.sup.2 is either CR.sup.3 or N, where R.sup.3 is selected from H, Me, Cl, F OMe; X.sup.3 is either CH or N; X.sup.4 is either CR.sup.F3 or N, where R.sup.F3 is H or F; where only one or two of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 may be N; and R.sup.4 is selected from I, optionally substituted phenyl, optionally substituted C.sub.5-6 heteroaryl; optionally substituted C.sub.1-6 alkyl and optionally substituted C.sub.1-6 alkoxy, which are useful in the treatment of a condition ameliorated by the inhibition of MOZ.

Claims

1. A compound of formula I: ##STR00325## wherein: A is selected from the group consisting of: (i) ##STR00326## wherein R.sup.F1 is H or F; (ii) ##STR00327## wherein R.sup.F1 is H or F; and (iii) a N-containing C.sub.6 heteroaryl group; and B is ##STR00328## wherein X.sup.1 is either CR.sup.F2 or N, wherein R.sup.F2 is H or F; X.sup.2 is either CR.sup.3 or N, wherein R.sup.3 is selected from the group consisting of H, Me, Cl, F, and OMe; X.sup.3 is CH; X.sup.4 is either CR.sup.F3 or N, wherein R.sup.F3 is H or F; wherein only one or two of X.sup.1, X.sup.2, and X.sup.4 may be N; and R.sup.4 is selected from the group consisting of optionally substituted phenyl, optionally substituted C.sub.5-6 heteroaryl; optionally substituted C.sub.1-6 alkyl and optionally substituted C.sub.2-6 alkoxy and OCF.sub.3, with the proviso that the compound is not P1 or P2: ##STR00329##

2. The compound according to claim 1, wherein A is: ##STR00330##

3. The compound according to claim 1, wherein R.sup.F1 is H.

4. The compound according to claim 1, wherein R.sup.F1 is F.

5. The compound according to claim 1, wherein none of X.sup.1, X.sup.2, and X.sup.4 are N.

6. The compound according to claim 2, wherein none of X.sup.1, X.sup.2, and X.sup.4 are N, and R.sup.F1, R.sup.F2, R.sup.3 and R.sup.F3 are selected from one of the combinations below: TABLE-US-00032 R.sup.F1 R.sup.F2 R.sup.3 R.sup.F3 (i) H H H H (ii) F H H H (iii) H H H F (iv) H H Cl H (v) H F Cl H (vi) F H Cl H (vii) H H Me H (viii) H F Me H (ix) F H Me H (x) H H OMe H (xi) F H OMe H (xii) H H F H (xiii) F H F H

7. The compound according to claim 1, wherein one of X.sup.1, X.sup.2, and X.sup.4 is N.

8. The compound according to claim 1, wherein R.sup.4 is unsubstituted phenyl.

9. The compound according to claim 1, wherein R.sup.4 is phenyl substituted by a single substituent selected from the group consisting of halo, cyano and C.sub.1-4 alkoxy.

10. The compound according to claim 9, wherein the substituent is halo and is selected from F and Cl.

11. The compound according to claim 9, wherein the substituent is cyano.

12. The compound according to claim 9, wherein the substituent is methoxy.

13. The compound according to claim 1, wherein R.sup.4 is optionally substituted C.sub.5-6 heteroaryl, and is selected from the group consisting of: (a) C.sub.6 (N.sub.1): ##STR00331## (b) C.sub.6 (N.sub.2): ##STR00332## (c) C.sub.5 (O.sub.1 or S.sub.1): ##STR00333## (d) C.sub.5 (N.sub.2): ##STR00334## (e) C.sub.5 (N.sub.3): ##STR00335## (f) C.sub.5 (N.sub.1S.sub.1) ##STR00336## and (g) C.sub.5 (N.sub.2O.sub.1) ##STR00337##

14. The compound according to claim 1, wherein R.sup.4 is selected from methyl, ethyl, iso-propyl and CF.sub.3.

15. The compound according to claim 1, wherein R.sup.4 is selected from the group consisting of: ##STR00338##

16. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable excipient.

17. A method of treatment of cancer associated with aberrant proliferation of B cells, comprising administering to a patient in need of treatment, a compound according to claim 1.

18. A method of treatment of a condition ameliorated by the inhibition of MOZ, comprising administering to a patient in need of treatment, a compound according to claim 1.

Description

EXAMPLES

(1) The following are examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.

Acronyms

(2) For convenience, many chemical moieties are represented using well known abbreviations, including but not limited to, methyl (Me), ethyl (Et), n-propyl (nPr), isopropyl (iPr), n-butyl (nBu), tert-butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex), phenyl (Ph), biphenyl (biPh), benzyl (Bn), naphthyl (naph), methoxy (MeO), ethoxy (EtO), benzoyl (Bz), and acetyl (Ac).

(3) For convenience, many chemical compounds are represented using well known abbreviations, including but not limited to, methanol (MeOH), ethanol (EtOH), isopropanol (i-PrOH), ether or diethyl ether (Et.sub.2O), acetic acid (AcOH), acetonitrile (MeCN), dichloromethane (methylene chloride, DCM), trifluoroacetic acid (TFA), dimethylformamide (DMF), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), meta-chloroperoxybenzoic acid (mCPBA), 1,1-bis(diphenylphosphino)ferrocene (dppf), 2-dicyclohexylphosphino-2,6-diisopropoxybiphenyl (Ruphos), tert-butyloxycarbonyl (Boc), 2-(trimethylsilyl)ethoxymethyl (SEM), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI), 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIPEA), lithium bis(trimethylsilyl)amide (LiHMDS) and 1-hydroxybenzotriazole (HOBt), Tetrabutylammonium bromide (TBAB), Chloro-(2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)[2-(2-aminoethyl)phenyl]palladium(I)-methyl-t-butyl ether adduct (RuPhos palladacycle precatalyst), Lithium bis(trimethylsilyl)amide (LiHMDS), Bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct (DABAL-AlMe.sub.3), 2-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (XPhos), dimethoxyethane (DME).

General Experimental Details

(4) .sup.1H NMR

(5) .sup.1H Nuclear Magnetic Resonance spectra were recorded at 400.13 Hz, on an Avance III Nanobay 400 MHz Bruker spectrometer coupled to the BACS 60 automatic sample changer. Results are recorded as follows: chemical shifts () in ppm acquired in either CDCl.sub.3 (7.26 ppm for .sup.1H) or DMSO-d.sub.6 (2.50 ppm for .sup.1H) as a reference. Solvents used for NMR studies are from Cambridge Isotope Laboratories. Each proton resonance was assigned according to the following convention: chemical shift (), multiplicity, coupling constant (J Hz) and number of protons. In reporting of the spectral data, the following abbreviations are utilised: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet.

(6) LCMS A

(7) Low resolution mass spectrometry analyses were performed on an Agilent 6100 Series Single Quad LC/MS coupled with an Agilent 1200 Series HPLC, 1200 Series G1311A quaternary pump, 1200 series G1329A thermostatted autosampler and 1200 series G1314B variable wavelength detector. The conditions for liquid chromatography were: reverse phase HPLC analysis fitted with a Phenomenex Luna C8(2) 5 m (504.6 mm) 100 column; column temperature: 30 C.; injection volume: 5 L; solvent: 99.9% acetonitrile, 0.1% formic acid; gradient: 5-100% of solvent over 10 min; detection: 254 nm. The conditions for mass spectrometry were: quadrupole ion source; ion mode: multimode-ES; drying gas temp: 300 C.; vaporizer temperature: 200 C.; capillary voltage: 2000 V (positive), 4000 (negative); scan range: 100-1000 m/z; step size: 0.1 sec; acquisition time: 10 min.

(8) LCMS B

(9) All analyses were done on an Agilent 6224 TOF LC/MS Mass Spectrometer coupled to an Agilent 1290 Infinity (Agilent, Palo Alto, Calif.). All data were acquired and reference mass corrected via a dual-spray electrospray ionisation (ESI) source. Each scan or data point on the Total Ion Chromatogram (TIC) is an average of 13,700 transients, producing a spectrum every second. Mass spectra were created by averaging the scans across each peak and background subtracted against the first 10 seconds of the TIC. Acquisition was performed using the Agilent Mass Hunter Data Acquisition software version B.05.00 Build 5.0.5042.2 and analysis was performed using Mass Hunter Qualitative Analysis version B.05.00 Build 5.0.519.13.

(10) Chromatographic separation was performed using an Agilent Zorbax SB-C18 Rapid Resolution HT 2.150 mm, 1.8 m column (Agilent Technologies, Palo Alto, Calif.) using an acetonitrile gradient (5% to 100%) over 3.5 min at 0.5 mL/min.

(11) LCMS C:

(12) Liquid Chromatography-Mass spectrometry (LCMS) was performed on two different instruments, a Finnigan LCQ Advantage MAX carried out on a Phenomenex column (Gemini, 3 m, 110 , 204 mm) and a Waters Auto Purification System 3100 carried out with a Waters column (XBridge, 4 m, 100 , 4.6100 mm). High Performance Liquid Chromatography (HPLC) was also carried out on two different instruments, the Waters Auto Purification System 3100 with a Waters column (XBridgePrep C18, 5 m, OBD, 19100 mm) and the Waters Alliance HT 2795 with a Phenomenex column (Luna, 5 m, C18, 100 , 15010 mm)

(13) Standard Methods

(14) Sulfonamide Coupling

(15) To a solution of the benzoic acid hydrazide in pyridine, cooled to 100 C. with an ice bath, was added dropwise 1 mL of the benzenesulfonyl chloride. The reaction mixture was stir for 4 hours at room temperature. Then, the mixture was poured into a solution of 2 M HCl with ice. A precipitate formed and was filtered on a sintered funnel. The solid was slurried in hot isopropanol and allowed to cool down in the freezer overnight. The solvent was filtered off and the solid dried to give the desired product.

(16) Carboxylation

(17) To a solution of the biphenyl (1 eq.) in THF (1 M) was added n-butyllithium (2.5 M in hexanes, 1.1 eq). The reaction mixture was allowed to stir at 78 C. for 40 minutes before being poured onto a vast excess of dry ice. After the majority of dry ice evaporated, the reaction mixture was concentrated in vacuo. The resulting solid was suspended with a small amount of water, acidified with 1 M HCl and filtered. The solid was washed with 1 M HCl and petroleum benzine (PB) to yield the desired product.

(18) Suzuki Coupling Method A

(19) To a degassed solution of 9:1 1,4-dioxane:H.sub.2O (0.2 M), under an atmosphere of nitrogen, was added the benzoic acid (1 eq.), the boronic acid (3 eq.), K.sub.2CO.sub.3 (1.5 eq.) and the palladium catalyst (0.05 eq.). The reaction was irradiated in a CEM microwave at 80 C. for 30 minutes, then cooled and passed through a pad of Celite. The Celite was washed with EtOAc (20 mL). The mixture was acidified using 2 M HCl (1 mL) and the organics removed in vacuo. The solid precipitate was collected via filtration to give the title compound.

(20) Suzuki Coupling Method B

(21) To a degassed solution of 3:1 1,4-dioxane:H.sub.2O (0.3 M), under an atmosphere of nitrogen, was added the benzoic acid (1 eq.), the boronic acid (2 eq.), 2 M aq. soln of K.sub.3PO.sub.4 (3 eq.) and the palladium catalyst (0.05 eq.). The reaction was irradiated in a CEM microwave at 150 C. for 30 minutes, then cooled and passed through a pad of Celite. The Celite was washed with EtOAc (20 mL). The mixture was acidified using 2 M HCl (1 mL) and the organics removed in vacuo. The solid precipitate was collected via filtration to give the title compound.

(22) Suzuki Coupling Method C

(23) The boronate (1 eq.), aryl bromide hydrobromide salt (1.1 eq.) and PdCl.sub.2(dppf) (0.05 eq.), under an atmosphere of nitrogen, were suspended in dioxane (0.2 M). A solution of K.sub.2CO.sub.3 (1.5 eq.) in water (0.3 M) was added and the mixture degassed. The reaction was irradiated in a CEM microwave at 120 C. for 30 minutes. The mixture was cooled, and the volatile solvents removed in vacuo. The aqueous residue was diluted with water and shaken with DCM. The mixture was filtered through Celite, the aqueous layer separated and washed with a further portion of DCM. The organic extracts were discarded. The aqueous phase was diluted with water and treated with 5% w/v citric acid. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give the title compound.

(24) Suzuki Coupling Method D

(25) The aryl bromide (1.0 eq), arylboronic acid (1.1 eq), K.sub.2CO.sub.3 (1.5 eq) and PdCl.sub.2(PPh.sub.3).sub.2(5 mol %), under an atmosphere of nitrogen, were suspended in a 1:1 THF:H.sub.2O mixture (4 mL per mmol). The reaction was heated to reflux and allowed to stir overnight. The mixture was then cooled to room temperature and partitioned between EtOAc and water. The organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered, dry loaded onto silica and purified by column chromatography using silica as the stationary phase and a mixture of petroleum benzine/EtOAc as the eluent.

(26) Suzuki Coupling Method E

(27) To a degassed solution of 1,4-dioxane (0.1 M), under an atmosphere of nitrogen, was added the benzoic acid (1 eq.), bis(pinacolato)diboron (1.5 eq.), and KOAc (4.4 eq.) sequentially. The mixture was degassed once again and then PdCl.sub.2(dppf) (5 mol %) was added. The resulting solution was heated to 110 C. overnight. The solvent was removed in vacuo to give a dark gummy residue, which was taken up into EtOAc and H.sub.2O. The organic layer was separated and the aqueous was further extracted with EtOAc (2). The combined organic layers were washed with 2 M HCl, dried over MgSO.sub.4 and concentrated in vacuo to give a dark brown solid. The resulting solid was triturated with petroleum benzine to afford the title compound.

(28) Suzuki Coupling Method F

(29) To a degassed solution of DMF:H.sub.2O (10:1 ratio) (0.3 M), under an atmosphere of nitrogen, was added the pinacol ester (1 mmol), 2-bromopyridine or 2-chloropyrimidine (1.5 eq.), and Cs.sub.2CO.sub.3 (4.4 eq.). The whole mixture was degassed once again and then Pd(PPh.sub.3).sub.4(5 mol %) was added. The resulting solution was heated to 110 C. overnight. The solvent was removed in vacuo to give a dark gummy residue, which was taken up into EtOAc and H.sub.2O, then acidified with 2 M HCl to pH 2. The organic layer was separated and the aqueous layer was further extracted with EtOAc (2). The combined organic layers were dried over MgSO.sub.4 and concentrated in vacuo to give a black oily residue. The residue was dry loaded onto silica gel in vacuo then purified by flash column chromatography, eluting with 10-30% EtOAc/petroleum benzine and 1% acetic acid to afford the title compound.

(30) Ullmann Transformation Method A

(31) Na.sub.2CO.sub.3 (1 eq.) was added to a degassed solution of water (0.35 M) and the appropriate bromobenzoic acid (1 eq.) and was refluxed for 30 minutes. A further portion of Na.sub.2CO.sub.3 (1.5 eq.) was added to the reaction and refluxed for a further 30 minutes. Separately CuBr.sub.2 (0.1 eq.) and trans-N, N-dimethylcyclohexane-1,2-diamine (0.2 eq.) were added to degassed water (0.04 M) and an intense blue colour was observed. This mixture was added to the refluxing aqueous solution and allowed to stir at this temperature overnight. The resulting solution was allowed to cool to room temperature and was acidified with conc. HCl and extracted into EtOAc. The organics were dried with MgSO.sub.4, filtered, and the solvent removed in vacuo to give the desired product.

(32) Ullmann Coupling Method B

(33) The benzoic acid (1 eq.), substituted N-heterocycle (1.5 eq.), K.sub.2CO.sub.3 (4.5 eq.), and CuI (0.24 eq.) were suspended in dry, degassed DMF (0.1 M), under an atmosphere of nitrogen, and to this was added trans-N, N-dimethyl-1,2-cyclohexanediamine (0.2 eq.). The resulting solution was heated to 110 C. overnight. The solvent was removed in vacuo, and the resulting material taken up into EtOAc and H.sub.2O and acidified with 2 M HCl (pH 2). The organic layer was separated and the aqueous layer was further extracted with EtOAc (2). The combined organic layers were washed with H.sub.2O and brine, then dried over MgSO.sub.4 and concentrated in vacuo to give a brown oily residue. The residue was dry loaded onto silica gel in vacuo before being purified by flash column chromatography, eluting with 10-30% EtOAc/petroleum benzine and 1% acetic acid to afford the title compound.

(34) Alkylation of Aryl Hydroxyl Method

(35) To a solution of the hydroxyl benzoic acid (1 eq.) and the bromoalkyl derivative (3.5 eq.) in DMF (0.33 M) was added K.sub.2CO.sub.3 (2.5 eq.). This solution was heated to 110 C. for 4 hours, upon which time the reaction was cooled to room temperature and acidified with conc. HCl, then extracted with EtOAc. The organics were collected and dried with MgSO.sub.4, filtered and the solvent removed in vacuo to give a yellow slurry. This was then dissolved in EtOH (0.1 M) and NaOH (2.5 eq.) was added to the mixture and allowed to stir at room temperature overnight. The solvent was then removed in vacuo. To the resulting solid was added water, and this was then acidified with conc. HCl. The resulting precipitate was collected by filtration to give the desired product.

(36) Amide Coupling Method A

(37) The benzoic acid (1 eq.), sulfonyl hydrazide (1.25 eq.), HOAt (1.25 eq.) and EDCI.HCl (1.25 eq.) were dissolved in MeCN (0.8 M), under an atmosphere of nitrogen. The solution was heated to 40 C. and allowed to stir for 17 hours, upon which time the reaction was cooled, concentrated in vacuo, then loaded directly onto silica for purification. The crude material was purified by silica gel chromatography (Isolera Biotage, 0-100% EtOAc in petroleum benzine 40-60 C.). Product-containing fractions were combined and concentrated in vacuo to give the title compound.

(38) Amide Coupling Method B

(39) The benzoic acid (1 eq.), sulfonyl hydrazide (1.25 eq.), HOAt (1.25 eq.) and EDCI.HCl (1.25 eq.) were dissolved in MeCN (0.8 M), under an atmosphere of nitrogen. The solution was heated to 40 C. and allowed to stir for 17 hours, upon which time the reaction was cooled, concentrated in vacuo. The residue was partitioned between water and EtOAc, and the layers separated. The aqueous layer was further washed with two portions of EtOAc. The combined organic layers were dried (Na.sub.2SO.sub.4) then loaded directly onto silica for purification. The crude material was purified by silica gel chromatography (Isolera Biotage, 0-100% EtOAc in petroleum benzine 40-60 C.). Product-containing fractions were combined and concentrated in vacuo to give the title compound.

(40) Amide Coupling Method C

(41) To a stirred solution of the carboxylic acid in acetonitrile (0.1 M) was added HBTU (1.0 eq) and the resulting reaction mixture was cooled to 0 C. N-Ethyldiisopropylamine (1 eq) was added and the reaction mixture was allowed to stir at 0 C. for 1 hour. The sulfonylhydrazide (1.2 eq.) was then added and the reaction mixture was heated to reflux overnight. The reaction mixture was then cooled to room temperature and was dry loaded onto silica in vacuo before being purified by column chromatography using silica gel as the stationary phase and a mixture of petroleum benzine/EtOAc as the eluent.

Synthesis of Key Intermediates

(a) 5-Chloro-4-fluoro-[1,1-biphenyl]-3-carboxylic acid (I1)

(42) ##STR00044##

(43) (i) 3-Chloro-4-fluoro-1,1-biphenyl was obtained by the Suzuki coupling method D from 1-bromo-3-chloro-4-fluorobenzene as a pale yellow oil that crystallized as an off-white solid upon standing (43% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.60 (dd, J=7.0, 2.3 Hz, 1H), 7.53-7.46 (m, 2H), 7.44-7.41 (m, 3H), 7.38-7.35 (m, 1H), 7.19 (t, J=8.7 Hz, 1H).

(44) (ii) 5-Chloro-4-fluoro-[1,1-biphenyl]-3-carboxylic acid was obtained by the carboxylation method from 3-chloro-4-fluoro-1,1-biphenyl as a colourless solid (84% yield). .sup.1H NMR (400 MHz, DMSO) 13.76 (s, 1H), 8.09 (dd, J=6.4, 2.4 Hz, 1H), 8.01 (dd, J=6.1, 2.4 Hz, 1H), 7.78-7.64 (m, 2H), 7.49 (m, 2H), 7.45-7.36 (m, 1H). LCMS A rt 6.62 min, m/z 249.1[MH].sup.

(b) 4-Fluoro-5-methyl-[1,1-biphenyl]-3-carboxylic acid (I2)

(45) ##STR00045##

(46) (i) 4-Fluoro-3-methyl-1,1-biphenyl was obtained by the Suzuki coupling method D from 5-bromo-2-fluorotoluene as a colourless oil (5.90 g, 100%). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.46-7.38 (m, 2H), 7.35-7.27 (m, 3H), 7.27-7.21 (m, 2H), 6.99-6.90 (m, 1H), 2.23 (d, J=1.9 Hz, 3H).

(47) (ii) 4-Fluoro-5-methyl-[1,1-biphenyl]-3-carboxylic acid was obtained by the carboxylation method from 4-fluoro-3-methyl-1,1-biphenyl as a pale yellow solid (2.09 g, 33% yield). .sup.1H NMR (400 MHz, DMSO) 13.29 (s, 1H), 7.88 (dd, J=6.4, 2.4 Hz, 1H), 7.83 (dd, J=6.4, 2.0 Hz, 1H), 7.72-7.61 (m, 2H), 7.49-7.45 (m, 2H), 7.40-7.37 (m, 1H), 2.34 (d, J=2.0 Hz, 3H). LCMS A rt 6.41 min, m/z 229.1[MH].sup..

(c) 3-Chloro-2-fluoro-5-(thiophen-2-yl)benzoic acid (I3)

(48) ##STR00046##

(49) (i) 2-(3-Chloro-4-fluorophenyl)thiophene was obtained by the Suzuki coupling method D from 1-bromo-3-chloro-4-fluorobenzene as a colourless solid (347 mg, 28% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.61 (dd, J=6.9, 2.3 Hz, 1H), 7.43 (ddd, J=8.6, 4.5, 2.3 Hz, 1H), 7.28 (dd, J=5.1, 1.1 Hz, 1H), 7.23 (dd, J=3.6, 1.1 Hz, 1H), 7.13 (t, J=8.7 Hz, 1H), 7.06 (dd, J=5.1, 3.6 Hz, 1H).

(50) (ii) 3-Chloro-2-fluoro-5-(thiophen-2-yl)benzoic acid was obtained by the carboxylation method from 2-(3-chloro-4-fluorophenyl)thiophene as an off white solid (64 mg, 39% yield). .sup.1H NMR (400 MHz, DMSO) 13.25 (s, 1H), 8.02 (dd, J=7.0, 2.3 Hz, 1H), 7.80-7.67 (m, 2H), 7.65 (d, J=3.9 Hz, 1H), 7.51 (t, J=8.9 Hz, 1H).

(d) 3-(Pyridazin-4-yl)benzoic acid (I4)

(51) ##STR00047##

(52) Following the Suzuki coupling method C, 3-(pyridazin-4-yl)benzoic acid was obtained as a pale brown solid (78% yield). .sup.1H NMR (400 MHz, DMSO): 9.70-9.65 (m, 1H), 9.33-9.28 (m, 1H), 8.38 (s, 1H), 8.17 (d, J=7.8 Hz, 1H), 8.12-8.05 (m, 2H), 7.71 (t, J=7.8 Hz, 1H). Acid proton not observed. LCMS B rt 3.15 min, m/z 201.1 [M+H].sup.+.

(e) 3-Fluoro-5-(furan-2-yl)benzoic acid (I5)

(53) ##STR00048##

(54) Following the Suzuki coupling method A, 3-fluoro-5-(furan-2-yl)benzoic acid (I5I5) was obtained as a light brown solid (39% yield). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.18 (t, J=1.4 Hz, 1H), 7.66 (ddd, J=8.8, 2.5, 1.4 Hz, 1H), 7.61 (ddd, J=9.4, 2.5, 1.5 Hz, 1H), 7.53-7.51 (m, 1H), 6.79 (dd, J=3.4, 0.8 Hz, 1H), 6.52 (dd, J=3.4, 1.8 Hz, 1H). LCMS B rt 3.65 min, m/z 205.1 [MH].sup..

(f) 3-(Furan-2-yl)-5-methoxybenzoic acid (I6)

(55) ##STR00049##

(56) Following Suzuki coupling method A, 3-(furan-2-yl)-5-methoxybenzoic acid (I6A) was obtained as a light brown solid (71% yield). 25% of the material was starting acid. The material was used as is for the next step. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.01 (t, J=1.5, 1.5 Hz, 1H), 7.52 (dd, J=2.5, 1.4 Hz, 1H), 7.50 (dd, J=1.8, 0.7 Hz, 1H), 7.46 (dd, J=2.5, 1.5 Hz, 1H), 6.75 (dd, J=3.4, 0.8 Hz, 1H), 6.50 (dd, J=3.4, 1.8 Hz, 1H), 3.91 (s, 3H).

(g) 3-Chloro-5-(furan-2-yl)benzoic acid (I7)

(57) ##STR00050##

(58) Following Suzuki coupling method A, using Pd(dppf)Cl.sub.2, 3-chloro-5-(furan-2-yl)benzoic acid was obtained as a light brown solid (39% yield). .sup.1H NMR (400 MHz, DMSO): 8.15 (t, J=1.5, 1.5 Hz, 1H), 8.02 (t, J=1.9 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.78 (t, J=1.9 Hz, 1H), 7.23 (d, J=3.4 Hz, 1H), 6.65 (dd, J=3.4, 1.8 Hz, 1H).

(h) 2-Phenylisonicotinic acid (I8)

(59) ##STR00051##

(60) Following the Suzuki coupling method B, using Pd(PPh.sub.3).sub.4, 2-phenylisonicotinic acid was isolated as a crude mixture with 30% of the starting acid present. Due to poor solubility, this was unable to be purified further, and the material was used as is for the next step.

(i) 2-Fluoro-5-(pyridazin-4-yl)benzoic acid (I9)

(61) ##STR00052##

(62) Following the Suzuki coupling method C, 2-fluoro-5-(pyridazin-4-yl)benzoic acid was obtained as a tan solid (21% yield). .sup.1H NMR (400 MHz, DMSO): 9.72 (dd, J=2.5, 1.2 Hz, 1H), 9.36 (dd, J=5.4, 1.2 Hz, 1H), 8.12 (dd, J=5.5, 2.5 Hz, 1H), 8.05-7.96 (m, 2H), 7.89 (dd, J=8.1, 1.8 Hz, 1H). LCMS B rt 3.12 min, m/z 219.1 [M+H].sup.+.

(j) 5-Phenylnicotinic acid (I10)

(63) ##STR00053##

(64) Following the Suzuki coupling method B, using Pd(dppf)Cl.sub.2, 5-phenylnicotinic acid was obtained as a white solid (63% yield). .sup.1H NMR (400 MHz, DMSO): 9.10 (d, J=18.2 Hz, 2H), 8.45 (t, J=1.8, 1.8 Hz, 1H), 7.80-7.76 (m, 2H), 7.55-7.29 (m, 3H). LCMS B rt 3.37 min, m/z 200.1 [M+H].sup.+.

(k) 3-Fluoro-5-propoxybenzoic acid (I11)

(65) ##STR00054##

(66) Following the Alkylation of Aryl Hydroxyl method, 3-fluoro-5-propoxybenzoic acid was obtained as a white solid (77% yield). .sup.1H NMR (400 MHz, DMSO) 13.31 (s, 1H), 7.27 (dd, J=2.4, 1.3 Hz, 1H), 7.22 (ddd, J=8.9, 2.4, 1.3 Hz, 1H), 7.10 (dt, J=10.8, 2.4, 2.4 Hz, 1H), 3.99 (t, J=6.5, 6.5 Hz, 2H), 1.73 (h, J=7.4, 7.4, 7.4, 7.4, 7.4 Hz, 2H), 0.97 (t, J=7.4, 7.4 Hz, 3H). LCMS B rt 3.67 min, m/z 197.1 [MH].sup..

(l) 2-Fluoro-3-methyl-5-propoxybenzoic acid (I12)

(67) ##STR00055##

(68) Following the Alkylation of Aryl Hydroxyl method, 3-fluoro-5-propoxybenzoic acid was obtained as a white solid (65% yield). .sup.1H NMR (400 MHz, DMSO) 13.17 (s, 1H), 7.18-6.98 (m, 2H), 3.91 (t, J=6.5, 6.5 Hz, 2H), 2.23 (d, J=2.3 Hz, 3H), 1.70 (h, J=7.4, 7.4, 7.4, 7.4, 7.4 Hz, 2H), 0.96 (t, J=7.4, 7.4 Hz, 3H). LCMS B rt 3.68 min, m/z 213.1 [M+H].sup.+.

(m) 2-Fluoro-5-isopropoxy-3-methylbenzoic acid (I13)

(69) ##STR00056##

(70) Following the Alkylation of Aryl Hydroxyl method, 3-fluoro-5-propoxybenzoic acid was obtained as a white solid (59% yield). .sup.1H NMR (400 MHz, DMSO): 13.16 (s, 1H), 7.19-6.91 (m, 2H), 4.56 (hept, J=6.0 Hz, 1H), 2.22 (d, J=2.1 Hz, 3H), 1.24 (d, J=6.0 Hz, 6H). LCMS B r.t. 3.63, m/z 213.1 [M+H].sup.+.

(n) Substituted Benzoic Acids I

(71) The following compounds were made by the Ullmann transformation method A:

(72) TABLE-US-00002 Structure Starting material Product details A1 5-bromo-2- fluorobenzoic acid (3.5 g, 15.98 mmol) Off white solid (2.16 g, 87% yield). .sup.1H NMR (400 MHz, DMSO) 7.18 (dd, J = 6.0, 3.2 Hz, 1H), 7.09 (dd, J = 10.5, 8.9 Hz, 1H), 6.98- 6.93 (m, 1H). LCMS B rt 3.19 min, m/z 157.1 [M + H].sup.+. A2 3-bromo-5- methylbenzoic acid (0.2, 5.82 mmol) White solid (0.141, 100% yield). .sup.1H NMR (400 MHz, DMSO) 7.82 (s, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 2.36 (s, 3H). LCMS B rt 3.63 min, m/z 151.0 [M H].sup.. A3 5-bromo-2-fluoro- 3-methylbenzoic acid (0.47, 2.01 mmol) White solid (0.301 g, 83% yield). .sup.1H NMR (400 MHz, DMSO) 7.75 (d, J = 5.8 Hz, 2H), 2.26 (d, J = 1.8 Hz, 3H). LCMS A rt 6.09 min, m/z 171.1 [M + H].sup.+. A4 0 3-bromo-5- methoxybenzoic acid (0.65 g, 2.8 mmol) White solid (0.457 g, 97% yield). .sup.1H NMR (400 MHz, DMSO) 6.96 (s, 1H), 6.91 (s, 1H), 6.54 (t, J = 2.2 Hz, 1H), 3.73 (s, 3H). LCMS B, rt 3.25 min, m/z 167.1 [M H].sup.. A5 Off white solid (0.540 g, 85% yield). .sup.1H NMR (400 MHz, DMSO) 7.20 (dd, J = 2.1, 1.4 Hz, 1H), 7.09 (ddd, J = 9.2, 2.4, 1.3 Hz, 1H), 6.81 (dt, J = 10.6, 2.4 Hz, 1H). LCMS B rt 3.29 min, m/z 155.1 [M + H].sup.+.

(o) Substituted Benzoic Acids II

(73) The following compounds were made by the Alkylation of Aryl Hydroxyl method:

(74) TABLE-US-00003 Structure Starting material Product details A5 A1 (0.2 g, 1.28 mmol) Off white solid (0.212, 84% yield). .sup.1H NMR (400 MHz, DMSO) 7.27 (dd, J = 5.9, 3.1 Hz, 1H), 7.23-7.12 (m, 2H), 4.71-4.47 (m, 1H), 1.24 (d, J = 6.0 Hz, 6H). LCMS B rt 3.53 min, m/z 199.1 [M + H].sup.+. A6 A1 (0.350 g, 2.24 mmol) White solid (0.271 g, 62% yield). .sup.1H NMR (400 MHz, DMSO) 7.32 (dd, J = 5.6, 3.0 Hz, 1H), 7.26-7.16 (m, 2H), 6.02 (ddt, J = 17.3, 10.4, 5.2 Hz, 1H), 5.39 (dq, J = 17.3, 1.7 Hz, 1H), 5.26 (ddd, J = 10.5, 3.1, 1.5 Hz, 1H), 4.59 (dt, J = 5.2, 1.5 Hz, 2H). LCMS A rt 5.84 min, m/z 197.0 [M + H].sup.+. A7 A2 (0.2 g, 5.82 mmol) White solid (0.141, 100% yield). .sup.1H NMR (400 MHz, DMSO) 7.34 (s, 1H), 7.22 (s, 1H), 6.98 (s, 1H), 4.04 (q, J = 7.0 Hz, 2H), 2.31 (s, 3H), 1.32 (t, J = 7.0 Hz, 3H). LCMS A rt 6.01 min, m/z 181.1 [M + H].sup.+. A8 A3 (0.18 g, 1.06 mmol) White solid (0.301 g, 83% yield). .sup.1H NMR (400 MHz, DMSO) 7.19-6.93 (m, 2H), 4.01 (q, J = 7.0 Hz, 2H), 2.22 (d, J = 2.3 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H). LCMS A, rt 5.97 min, m/z 199.07 [M + H].sup.+. A9 A2 (0.15 g, 0.99 mmol) White solid (0.185 g, 97% yield). .sup.1H NMR (400 MHz, DMSO) 7.32 (s, 1H), 7.20 (s, 1H), 6.97 (s, 1H), 4.62 (dt, J = 12.0, 6.0 Hz, 1H), 2.31 (s, 3H), 1.26 (d, J = 6.0 Hz, 6H. LCMS B rt 3.56 min, m/z 193.1 [M H].sup.. A10 A1 (0.150 g, 0.96 mmol) White solid (0.091 g, 49% yield). .sup.1H NMR (400 MHz, DMSO) 7.39 (dd, J = 5.5, 3.0 Hz, 1H), 7.33-7.18 (m, 2H), 4.84 (d, J = 2.4 Hz, 2H), 3.60 (t, J = 2.4 Hz, 1H). LCMS B rt 3.42 min, m/z 195.1 [M + H].sup.+. A11 A4 (0.150 g, 2.2 mmol) White solid (0.178 g, 39% yield). .sup.1H NMR (400 MHz, DMSO) 7.02 (d, J = 2.2 Hz, 1H), 6.69 (t, J = 2.2 Hz, 2H), 4.73-4.56 (m, 1H), 3.77 (s, 3H), 1.26 (d, J = 6.0 Hz, 6H). LCMS A rt 6.06 min, m/z 211.2 [M + H].sup.+. A12 0 A4 (0.15 g, 0.82 mmol) White solid (0.161 g, 92% yield). .sup.1H NMR (400 MHz, DMSO) 7.06-7.02 (m, 2H), 6.71 (d, J = 2.3 Hz, 1H), 4.04 (q, J = 7.0 Hz, 2H), 3.77 (s, 3H), 1.32 (t, J = 7.0 Hz, 3H). LCMS A rt 5.83 min, m/z 197.1 [M + H].sup.+. A13 A1 (0.125 g, 0.9 mmol) White solid (0.142 g, 86% yield). .sup.1H NMR (400 MHz, DMSO) 7.28 (dd, J = 5.8, 3.2 Hz, 1H), 7.25-7.13 (m, 2H), 4.03 (q, J = 6.9 Hz, 2H), 1.31 (t, J = 6.9 Hz, 3H). LCMS B rt 3.46 min, m/z 185.0 [M + H].sup.+. A14 3-hydroxybenzoic acid Colourless solid (75% yield). .sup.1H NMR (400 MHz, DMSO) 7.53 (d, J = 7.7 Hz, 1H), 7.45 (dd, J = 2.4, 1.5 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.22-7.18 (m, 1H), 6.04 (ddt, J = 17.2, 10.4, 5.1 Hz, 1H), 5.40 (ddd, J = 17.3, 3.3, 1.6 Hz, 1H), 5.27 (dd, J = 10.6, 1.5 Hz, 1H), 4.62 (dt, J = 5.1, 1.4 Hz, 2H). LCMS B rt 3.41 min, m/z 177.1 [M H].sup.. A15 A2 Colourless solid (24% yield). .sup.1H NMR (400 MHz, DMSO) 7.83 (s, 1H), 7.75 (s, 1H), 7.68 (s, 1H), 3.88 (dq, J = 8.9, 2.9 Hz, 1H), 2.33 (s, 3H), 0.79 (dd, J = 9.6, 3.8 Hz, 2H), 0.66 (dt, J = 8.0, 3.9 Hz, 2H). LCMS B rt 3.59 min: m/z 191.1 [M H].sup..

(p) Substituted Boronic Acids

(75) The following compounds were made by the Suzuki coupling method E:

(76) TABLE-US-00004 Starting Structure material Product details B1 Faint brown solid (89%). .sup.1H NMR (400 MHz, CDCl.sub.3) 8.57 (s, 1H), 8.19 (ddd, J = 21.9, 11.8, 10.1 Hz, 1H), 8.09-7.98 (m, 1H), 7.57-7.38 (m, 1H), 1.37 (s, 12H). .sup.13C NMR (101 MHz, CDCl.sub.3) 171.66, 139.98, 136.60, 132.84, 128.71, 127.93, 84.21, 24.89. LCMS B rt 3.67 min, m/z 249.2 [M + H].sup.+. B2 Beige solid (93% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 8.36 (s, 1H), 8.01 (s, 1H), 7.86 (s, 1H), 2.42 (s, 3H), 1.36 (s, 12H). LCMS B rt 3.76 min, m/z 263.2 [M + H].sup.+. B3 Faint red solid (76% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 8.50 (d, J = 7.5 Hz, 1H), 8.06-7.93 (m, 1H), 7.22-7.10 (m, 1H), 1.36 (s, 12H). LCMS B rt 3.67 min, m/z 267.1 [M + H].sup.+. B4 0 Faint brown solid (66% yield). 1H NMR (400 MHz, CDCl3) 8.16 (s, 1H), 7.70 (dd, J = 2.5, 1.5 Hz, 1H), 3.88 (s, 3H), 1.36 (s, 12H). LCMS B rt 3.85 min, m/z 281.1 [M + H].sup.+. B5 Faint brown solid (86% yield). 1H NMR (400 MHz, CDCl3) 8.16 (s, 1H), 7.70 (dd, J = 2.5, 1.5 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 1.36 (s, 12H). LCMS B rt 3.69 min, m/z 279.2 [M + H].sup.+. B6 Faint brown solid (86% yield). 1H NMR (400 MHz, CDCl3) 8.16 (s, 1H), 7.70 (dd, J = 2.5, 1.5 Hz, 1H), 7.57 (d, J = 2.3 Hz, 1H), 3.88 (s, 3H), 1.36 (s, 12H). LCMS B rt 3.69 min, m/z 279.2 [M + H].sup.+.

(q) 2-Pyridine Acids

(77) The following compounds were made by Suzuki Coupling F:

(78) TABLE-US-00005 Starting Structure material Product details P1 B1 Off white solid (75% yield). .sup.1H NMR (400 MHz, DMSO) 8.71-8.68 (m, 1H), 8.67 (s, 1H), 8.29 (d, J = 7.8 Hz, 1H), 8.01 (t, J = 8.4 Hz, 2H), 7.91 (td, J = 7.8, 1.8 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.42-7.37 (m, 1H). LCMS B rt 3.17, m/z 200.1 [M + H].sup.+. P2 B2 Colourless solid (70% yield). .sup.1H NMR (400 MHz, DMSO) 8.70-8.67 (m, 1H), 8.46 (s, 1H), 8.14 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.90 (td, J = 7.7, 1.8 Hz, 1H), 7.83 (s, 1H), 7.38 (ddd, J = 7.4, 4.8, 0.9 Hz, 1H), 2.45 (s, 3H). LCMS B rt 3.36 min, m/z 214.1 [M + H].sup.+. P3 B3 Colourless solid (47% yield). .sup.1H NMR (400 MHz, DMSO) 8.69 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.61 (dd, J = 7.2, 2.5 Hz, 1H), 8.33 (ddd, J = 8.7, 4.6, 2.5 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.91 (td, J = 7.8, 1.8 Hz, 1H), 7.48-7.37 (m, 2H). LCMS B rt 3.37 min, m/z 218.1 [M + H].sup.+. P4 B4 Faint yellow solid (80% yield). .sup.1H NMR (400 MHz, DMSO) 8.67 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.39 (dd, J = 6.6, 2.3 Hz, 1H), 8.23 (dd, J = 6.3, 2.2 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.93-7.87 (m, 1H), 7.37 (ddd, J = 7.4, 4.8 , 1.0 Hz, 1H), 2.35 (d, J = 2.1 Hz, 3H). LCMS B rt 3.37 min, m/z 232.2 [M + H].sup.+. P5 0 B5 Beige solid (54% yield). .sup.1H NMR (400 MHz, DMSO) 8.72 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.55 (t, J = 1.5 Hz, 1H), 8.18 (ddd, J = 10.1, 2.5, 1.6 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.95 (td, J = 7.8, 1.8 Hz, 1H), 7.73 (ddd, J = 8.9, 2.5, 1.4 Hz, 1H), 7.45 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H). LCMS B rt 3.41 min, m/z 218.1 [M + H].sup.+. P6 B6 Beige solid (62% yield). .sup.1H NMR (400 MHz, DMSO) 8.70 (d, J = 4.0 Hz, 1H), 8.27 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.92 (td, J = 7.8, 1.7 Hz, 1H), 7.87 (s, 1H), 7.51 (s, 1H), 7.41 (dd, J = 6.8, 4.9 Hz, 1H), 3.90 (s, 3H). LCMS B rt 3.27 min, m/z 230.2 [M + H].sup.+.

(r) 2-Pyrimidine Acids

(79) The following compounds were made by Suzuki Coupling F:

(80) TABLE-US-00006 Starting Structure material Product details P7 B1 Off-white solid (79%) yield). .sup.1H NMR (400 MHz, DMSO) 8.99 (t, J = 1.5 Hz, 1H), 8.95 (d, J = 4.9 Hz, 2H), 8.61 (d, J = 7.9 Hz, 1H), 8.09 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 4.9 Hz, 1H). LCMS B rt 2.96 min, m/z 201.1 [M + H].sup.+. P8 B2 Beige solid (70% yield). .sup.1H NMR (400 MHz, DMSO) 8.93 (d, J = 4.9 Hz, 2H), 8.79 (d, J = 0.4 Hz, 1H), 8.44 (d, J = 0.7 Hz, 1H), 7.91 (d, J = 0.7 Hz, 1H), 7.49 (d, J = 4.9 Hz, 1H), 2.47 (s, 3H). LCMS B rt 215.1 min, m/z 215.1 [M + H].sup.+. P9 B3 Beige solid (78% yield). .sup.1H NMR (400 MHz, DMSO) 8.92 (d, J = 4.8 Hz, 2H), 8.90 (d, J = 2.3 Hz, 1H), 8.59 (ddd, J = 8.6, 4.6, 2.4 Hz, 1H), 7.51-7.42 (m, 2H). LCMS B rt 3.41 min, m/z 219.1 [M + H].sup.+. P10 B4 Beige solid (89% yield). .sup.1H NMR (400 MHz, DMSO) 8.92 (d, J = 4.9 Hz, 2H), 8.72 (dd, J = 6.8, 2.3 Hz, 1H), 8.49 (dd, J = 6.7, 1.7 Hz, 1H), 7.48 (t, J = 4.9 Hz, 1H), 2.37 (d, J = 2.1 Hz, 3H). LCMS B rt 3.49 min, m/z 233.1 [M + H].sup.+. P11 B5 Beige solid (60% yield). .sup.1H NMR (400 MHz, DMSO) 8.95-8.89 (m, 3H), 8.59 (ddd, J = 8.6, 4.7, 2.4 Hz, 1H), 7.52-7.43 (m, 2H). LCMS B rt 3.40 min, m/z 219.1 [M + H].sup.+. P12 B6 Beige solid (65% yield). .sup.1H NMR (400 MHz, DMSO) 8.95 (d, J = 4.9 Hz, 2H), 8.60 (t, J = 1.5 Hz, 1H), 8.14 (dd, J = 2.7, 1.5 Hz, 1H), 7.59 (dd, J = 2.7, 1.4 Hz, 1H), 7.51 (t, J = 4.9 Hz, 1H), 3.90 (s, 3H). LCMS B rt 3.43 min, m/z 231.1 [M + H].sup.+.

(s) 1H-Pyrazole Acids

(81) The following compounds were made by the Ullmann coupling method B:

(82) TABLE-US-00007 Starting Structure material Product details P13 Colourless solid (39% yield). .sup.1H NMR (400 MHz, DMSO) 8.61 (d, J = 2.5 Hz, 1H), 8.40-8.35 (m, 1H), 8.12-8.07 (m, 1H), 7.86 (dd, J = 7.7, 1.1 Hz, 1H), 7.79 (d, J = 1.6 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 6.59-6.55 (m, 1H). LCMS B rt 3.32 min, m/z 189.1 [M + H].sup.+. P14 00 01 Colourless solid (53% yield). .sup.1H NMR (400 MHz, DMSO) 8.17 (s, 1H), 7.94 (d, J = 5.0 Hz, 2H), 7.76 (d, J = 1.4 Hz, 1H), 7.68 (s, 1H), 6.55 (d, J = 1.8 Hz, 1H), 2.44 (s, 3H). LCMS B rt 3.44 min, m/z 203.1 [M + H].sup.+. P15 02 03 Colourless solid (43% yield). .sup.1H NMR (400 MHz, DMSO) 8.56 (d, J = 2.0 Hz, 1H), 8.26 (dd, J = 5.8, 2.5 Hz, 1H), 8.10-8.01 (m, 1H), 7.77 (s, 1H), 7.45 (t, J = 9.6 Hz, 1H), 6.56 (s, 1H). LCMS B rt 3.34 min, m/z 207.1 [M + H].sup.+. P16 04 05 Colourless solid (52% yield). .sup.1H NMR (400 MHz, DMSO) 8.54 (d, J = 2.4 Hz, 1H), 8.09 (s, 1H), 8.02 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 6.58-6.54 (m, 1H), 2.35 (s, 3H). LCMS B rt 3.41 min, m/z 221.2 [M + H].sup.+. P17 06 07 Colourless solid (67% yield). .sup.1H NMR (400 MHz, DMSO) 8.65 (s, 1H), 8.27 (s, 1H), 8.02 (d, J = 9.5 Hz, 1H), 7.80 (s, 1H), 7.57 (s, 1H), 6.59 (s, 1H). LCMS B rt 3.45 min, m/z 207.1 [M + H].sup.+. P18 08 09 Off white solid (59% yield). .sup.1H NMR (400 MHz, DMSO) 8.63 (d, J = 2.3 Hz, 1H), 7.99 (s, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.65 (t, J = 2.0 Hz, 1H), 7.36 (d, J = 1.1 Hz, 1H), 6.56 (dd, J = 2.5, 1.8 Hz, 1H), 3.88 (s, 3H). LCMS B rt 3.41 min, m/z 219.1 [M + H].sup.+.

(t) 3-Methyl-1H-Pyrazole acids

(83) The following compounds were made by the Ullmann coupling method B:

(84) TABLE-US-00008 Starting Structure material Product details P19 0 Colourless solid (49% yield). .sup.1H NMR (400 MHz, DMSO) 8.47 (d, J = 2.4 Hz, 1H), 8.34 (s, 1H), 8.03 (dd, J = 8.0, 1.6 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 2.29 (s, 3H). LCMS B rt 3.45 min, m/z 203.1 [M + H].sup.+. P20 Colourless solid (35% yield). .sup.1H NMR (400 MHz, DMSO) 8.44 (d, J = 2.4 Hz, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.63 (d, J = 0.7 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H), 2.42 (s, 3H), 2.27 (s, 3H). LCMS B rt 3.55 min, m/z 217.1 [M + H].sup.+. P21 Off-white solid (38% yield). .sup.1H NMR (400 MHz, DMSO) 8.43 (d, J = 2.4 Hz, 1H), 8.22 (dd, J = 6.3, 2.9 Hz, 1H), 8.02 (ddd, J = 9.0, 3.9, 3.1 Hz, 1H), 7.43 (dd, J = 10.2, 9.1 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 2.27 (s, 3H). LCMS B rt 3.42, m/z 221.2 [M + H].sup.+. P22 Colourless solid (40% yield). .sup.1H NMR (400 MHz, DMSO) 8.39 (d, J = 2.4 Hz, 1H), 8.02 (dd, J = 5.7, 2.9 Hz, 1H), 7.95 (dd, J = 5.5, 2.8 Hz, 1H), 6.33 (d, J = 2.3 Hz, 1H), 2.32 (d, J = 2.0 Hz, 3H), 2.26 (s, 3H). LCMS B rt 3.53 min, m/z 235.1 [M + H].sup.+. P23 Colourless solid (43%). .sup.1H NMR (400 MHz, DMSO) 8.54 (d, J = 2.4 Hz, 1H), 8.23-8.19 (m, 1H), 7.96 (dt, J = 10.3, 2.3 Hz, 1H), 7.53 (ddd, J = 8.8, 2.4, 1.3 Hz, 1H), 6.39 (s, 1H), 2.28 (s, 3H). LCMS B rt 3.15 min, m/z 221.1 [M + H].sup.+. P24 0 Colourless solid (50% yield). .sup.1H NMR (400 MHz, DMSO) 8.49 (d, J = 2.4 Hz, 1H), 7.95-7.90 (m, 1H), 7.58 (t, J = 2.2 Hz, 1H), 7.31 (dd, J = 2.2, 1.3 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H), 3.87 (s, 3H), 2.27 (s, 3H). LCMS B rt 3.51 min, m/z 233.1 [M + H].sup.+.

(u) 4-Methyl-1H-Pyrazole Acids

(85) The following compounds were made by the Ullmann coupling method B:

(86) TABLE-US-00009 Starting Structure material Product details P25 Off-white solid (49% yield). .sup.1H NMR (400 MHz, DMSO) 8.36 (s, 1H), 8.33-8.30 (m, 1H), 8.02 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 7.84-7.80 (m, 1H), 7.62-7.57 (m, 2H), 2.10 (s, 3H). LCMS B rt 3.45 min, m/z 203.1 [M + H].sup.+. P26 Colourless solid (42% yield). .sup.1H NMR (400 MHz, DMSO) 8.33 (s, 1H), 8.11 (d, J = 1.4 Hz, 1H), 7.86 (s, 1H), 7.64 (d, J = 0.7 Hz, 1H), 7.57 (s, 1H), 2.42 (s, 3H), 2.09 (s, 3H). LCMS B rt 3.53 min, m/z 217.1 [M + H].sup.+. P27 Off-white solid (20% yield?). .sup.1H NMR (400 MHz, DMSO) 8.32 (s, 1H), 8.20 (dd, J = 6.3, 2.9 Hz, 1H), 8.00 (ddd, J = 9.0, 3.9, 3.1 Hz, 1H), 7.58 (s, 1H), 7.43 (dd, J = 10.2, 9.0 Hz, 1H), 2.09 (s, 3H). LCMS B rt 3.44 min, m/z 221.1 [M + H].sup.+. P28 Colourless solid (43% yield). .sup.1H NMR (400 MHz, DMSO) 8.29 (s, 1H), 8.01 (dd, J = 5.8, 2.9 Hz, 1H), 7.94 (dd, J = 5.6, 2.7 Hz, 1H), 7.56 (s, 1H), 2.32 (d, J = 2.2 Hz, 3H), 2.09 (s, 3H). LCMS B rt 3.56 min, m/z 235.1 [M + H].sup.+. P29 0 Colourless solid (45% yield). .sup.1H NMR (400 MHz, DMSO) 8.43 (s, 1H), 8.19 (s, 1H), 7.93 (d, J = 10.1 Hz, 1H), 7.63 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 2.09 (s, 3H). LCMS B rt 3.55 min, m/z 221.1 [M + H].sup.+.

(v) 4-Fluoro-1H-Pyrazole Acids

(87) The following compounds were made by the Ullmann coupling method B:

(88) TABLE-US-00010 Starting Structure material Product details P30 Off-white solid (49% yield). .sup.1H NMR (400 MHz, DMSO) 8.83 (dd, J = 4.5, 0.6 Hz, 1H), 8.34-8.31 (m, 1H), 8.04 (ddd, J = 8.2, 2.4, 1.0 Hz, 1H), 7.90- 7.85 (m, 2H), 7.64 (t, J = 7.9 Hz, 1H). LCMS B rt 3.47 min, m/z 207.1 [M + H].sup.+. P31 Colourless solid (42% yield). .sup.1H NMR (400 MHz, DMSO) 8.75 (dd, J = 4.5, 0.5 Hz, 1H), 8.12 (s, 1H), 7.87-7.783 (m, 2H), 7.69 (d, J = 0.6 Hz, 1H), 2.42 (s, 3H). LCMS B rt 3.52 min, m/z 221.1 [M + H].sup.+. P32 Colourless solid (40% yield). .sup.1H NMR (400 MHz, DMSO) 8.74 (d, J = 4.5 Hz, 1H), 8.03 (dd, J = 5.5, 2.9 Hz, 1H), 7.98-7.93 (m, 1H), 7.86 (d, J = 4.2 Hz, 1H), 2.33 (d, J = 2.2 Hz, 3H). LCMS B rt 3.54 min, m/z 239.1 [M + H].sup.+.

(w) 5-Methyl-1H-Pyrazole Acids

(89) The following compounds were made by the Ullmann coupling method B:

(90) TABLE-US-00011 Starting Structure material Product details P33 Colourless solid (42% yield). .sup.1H NMR (400 MHz, DMSO) 8.43 (d, J = 2.4 Hz, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.63 (s, 1H), 6.34 (d, J = 2.4 Hz, 1H), 2.42 (s, 3H), 2.27 (s, 3H). LCMS B rt 3.51 min, m/z 217.1 [M + H].sup.+. P34 0 Colourless solid (39% yield). .sup.1H NMR (400 MHz, DMSO) 8.39 (d, J = 2.3 Hz, 1H), 8.02 (dd, J = 5.6, 2.9 Hz, 1H), 7.95 (dd, J = 5.5, 2.7 Hz, 1H), 6.34 (d, J = 2.3 Hz, 1H), 2.52-2.47 (m, 2H), 2.33 (d, J = 1.8 Hz, 3H), 2.26 (s, 3H). LCMS B rt 3.51 min, m/z 235.1 [M + H].sup.+. P35 Off-white solid (45% yield). .sup.1H NMR (400 MHz, DMSO) 8.53 (d, J = 2.5 Hz, 1H), 8.21 (s, 1H), 7.95 (d, J = 10.2 Hz, 1H), 7.52 (d, J = 7.4 Hz, 1H), 6.39 (d, J = 2.4 Hz, 1H), 2.28 (s, 3H). LCMS B rt 3.52 min, m/z 221.1 [M + H].sup.+.

(x) 3,5-Dimethyl-1H-Pyrazole Acids

(91) The following compound was made by the Ullmann coupling method B:

(92) TABLE-US-00012 Starting Structure material Product details P36 Colourless solid (39% yield). .sup.1H NMR (400 MHz, DMSO) 8.00 (t, J = 1.8 Hz, 1H), 7.94-7.90 (m, 1H), 7.76 (ddd, J = 8.0, 2.2, 1.1 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 6.10 (s, 1H), 2.33 (d, J = 0.4 Hz, 3H), 2.19 (s, 3H). .sup.13C NMR (101 MHz, DMSO) 167.11, 148.83, 140.30, 139.82, 132.30, 129.95, 128.11, 127.88, 124.75, 108.13, 40.60, 40.39, 40.18, 39.97, 39.76, 39.56, 39.35, 13.75, 12.72. LCMS B rt 3.41 min, m/z 217.1 [M + H].sup.+.

(y) 2H-Triazole Acids

(93) The following compounds were made by the Ullmann coupling method B:

(94) TABLE-US-00013 Starting Structure material Product details P37 Colourless solid (32% yield). .sup.1H NMR (400 MHz, DMSO) 8.33 (br s, 1H), 8.13 (br s, 2H), 8.05 (s, 1H), 7.77 (s, 1H), 2.45 (s, 3H). LCMS B rt 3.49 min, m/z 204.2 [M + H].sup.+. P38 Faint yellow solid (46% yield). .sup.1H NMR (400 MHz, DMSO) 8.38-8.35 (m, 1H), 8.20 (s, 2H), 8.05 (dt, J = 9.4, 2.3 Hz, 1H), 7.69 (ddd, J = 8.8, 2.5, 1.3 Hz, 1H). LCMS B rt 3.51 min, m/z 208.2 [M + H].sup.+. P39 0 Colourless solid (35% yield). .sup.1H NMR (400 MHz, DMSO) 8.25 (dd, J = 5.8, 2.8 Hz, 1H), 8.18-8.13 (m, 3H), 2.36 (d, J = 2.3 Hz, 3H). LCMS B rt .348 min, m/z 222.1 [M + H].sup.+.

(z) Ether Acids

(95) The following compounds were made by the Alkylation of Aryl Hydroxyl method:

(96) TABLE-US-00014 Starting Structure material Product details E1 Off white solid (88% yield). .sup.1H NMR (400 MHz, DMSO) 7.53-7.49 (m, 1H), 7.42-7.32 (m, 2H), 7.17 (ddd, J = 8.2, 2.7, 1.0 Hz, 1H), 3.85 (d, J = 7.0 Hz, 2H), 1.22 (dddd, J = 7.9, 5.7, 4.8, 0.8 Hz, 1H), 0.63-0.51 (m, 2H), 0.38-0.29 (m, 2H). LCMS B rt 3.57 min, m/z 191.1 [M H].sup.. E2 Off white solid (75% yield). .sup.1H NMR (400 MHz, DMSO) 7.53 (d, J = 7.7 Hz, 1H), 7.45 (dd, J = 2.4, 1.5 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.22-7.18 (m, 1H), 6.04 (ddt, J = 17.2, 10.4, 5.1 Hz, 1H), 5.40 (ddd, J = 17.3, 3.3, 1.6 Hz, 1H), 5.27 (dd, J= 10.6, 1.5 Hz, 1H), 4.62 (dt, J = 5.1, 1.4 Hz, 2H). LCMS B rt 3.41 min, m/z 177.1 [M H].sup.. E3 A2 Dark beige solid (78% yield). .sup.1H NMR (400 MHz, DMSO) 7.21 (s, 1H), 7.16 (s, 1H), 6.81 (s, 1H), 3.82 (d, J = 6.7 Hz, 2H), 2.27 (s, 3H), 1.20 (s, 1H), 0.56 (d, J = 7.0 Hz, 2H), 0.32 (d, J = 3.7 Hz, 2H). LCMS B rt 3.63 min, m/z 205.1 [M H].sup.. E4 A5 White solid (84% yield). .sup.1H NMR (400 MHz, DMSO) 7.26 (dd, J = 2.2, 1.3 Hz, 1H), 7.22 (ddd, J = 9.0, 2.4, 1.3 Hz, 1H), 7.07 (dt, J = 10.8, 2.4 Hz, 1H), 4.08 (q, J = 7.0 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H). LCMS B rt 3.55 min, m/z 183.1 [M H].sup.. E5 A5 Off white solid (82% yield). .sup.1H NMR (400 MHz, DMSO) 7.24 (d, J = 1.2 Hz, 1H), 7.22-7.17 (m, 1H), 7.08 (dt, J = 10.9, 2.3 Hz, 1H), 4.69 (dt, J = 12.0, 6.0 Hz, 1H), 1.27 (d, J = 6.0 Hz, 6H). LCMS B rt 3.62 min, m/z 197.1 [M H].sup.. E6 A5 Dark beige solid (86% yield). .sup.1H NMR (400 MHz, DMSO) 7.13 (dd, J = 2.2, 1.3 Hz, 1H), 7.08 (ddd, J = 8.9, 2.4, 1.3 Hz, 1H), 6.95 (dt, J = 10.8, 2.4 Hz, 1H), 3.74 (d, J = 7.0 Hz, 2H), 1.16-1.01 (m, 1H), 0.52-0.39 (m, 2H), 0.22-0.14 (m, 2H). LCMS B rt 3.63 min, m/z 209.1 [M H].sup.. E7 0 A5 Off white solid (86% yield). .sup.1H NMR (400 MHz, DMSO) 7.30 (dd, J = 2.1, 1.3 Hz, 1H), 7.24 (ddd, J = 8.9, 2.3, 1.3 Hz, 1H), 7.13 (dt, J = 10.8, 2.4 Hz, 1H), 6.03 (ddt, J = 17.3, 10.5, 5.2 Hz, 1H), 5.41 (dq, J = 17.3, 1.7 Hz, 1H), 5.28 (ddd, J = 10.6, 3.0, 1.4 Hz, 1H), 4.65 (dt, J = 5.2, 1.5 Hz, 2H). LCMS B rt 3.43 min, m/z 195.1 [M H].sup.. E8 A3 Off white solid (82% yield). .sup.1H NMR (400 MHz, DMSO) 7.16-7.08 (m, 2H), 6.02 (ddt, J = 17.3, 10.4, 5.1 Hz, 1H), 5.38 (dq, J = 17.3, 1.7 Hz, 1H), 5.25 (ddd, J = 10.5, 3.1, 1.5 Hz, 1H), 4.56 (dt, J = 5.1, 1.5 Hz, 2H), 2.23 (d, J = 2.3 Hz, 3H). LCMS B rt 3.58 min, m/z 211.2 [M + H].sup.+. E9 A3 Off white solid (80% yield). .sup.1H NMR (400 MHz, DMSO) 7.09 (d, J = 5.5 Hz, 2H), 3.80 (d, J = 7.0 Hz, 2H), 2.22 (d, J = 2.3 Hz, 3H), 1.26-1.11 (m, 1H), 0.58-0.52 (m, 2H), 0.35-0.27 (m, 2H). LCMS B rt 3.42 min, m/z 223.1 [M H].sup..

(aa) 2-Fluoro-5-(furan-2-yl)-3-methylbenzoic acid (I15)

(97) ##STR00163##

(i) 3-(Furan-2-yl)-5-methylbenzoic acid (I14)

(98) To a degassed solution of 9:1 1,4-dioxane:H.sub.2O (4 mL) was added 3-bromo-5-methylbenzoic acid (0.300 g, 1.395 mmol), 2-furanboronic acid (0.187 g, 1.674 mmol), K.sub.2CO.sub.3 (0.289 g, 2.093 mmol) and PdCl.sub.2(PPh.sub.3).sub.2(0.049 g, 0.070 mmol), under an atmosphere of nitrogen. The reaction was irradiated in a CEM microwave reactor at 80 C. for 30 min, then cooled and passed through a pad of Celite. The Celite was washed with a portion of EtOAc (10 mL) and the entire mixture was concentrated to dryness. The residue was taken up in DCM (20 mL) and an aq. soln. of 2 M HCl (20 mL) was added. The two layers were separated, and the aqueous layer was further extracted with DCM (220 mL). The organics were combined, washed with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude material was purified by silica gel chromatography (Isolera Biotage, 24 g Si Cartridge, 0-40% EtOAc in petroleum benzine 40-60 C.) with the fractions containing suspected product collected and concentrated in vacuo to yield 3-(furan-2-yl)-5-methylbenzoic acid (I14)(0.095 g, 34% yield) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.24-8.20 (m, 1H), 7.85-7.81 (m, 1H), 7.77-7.71 (m, 1H), 7.50 (dd, J=1.8, 0.8 Hz, 1H), 6.74 (dd, J=3.4, 0.7 Hz, 1H), 6.50 (dd, J=3.3, 1.8 Hz, 1H), 2.46 (s, 3H).

(ii) 2-Fluoro-5-(furan-2-yl)-3-methylbenzoic acid (I15)

(99) To a degassed solution of 9:1 1,4-dioxane:H.sub.2O (4 mL) was added 5-bromo-2-fluoro-3-methylbenzoic acid (I14) (0.200 g, 0.858 mmol), 2-furanboronic acid (0.106 g, 0.944 mmol), K.sub.2CO.sub.3 (0.178 g, 1.287 mmol) and PdCl.sub.2(PPh.sub.3).sub.2(0.030 g, 0.043 mmol), under an atmosphere of nitrogen. The reaction was irradiated in a CEM microwave reactor at 80 C. for 30 min, then cooled and passed through a pad of Celite. The Celite was washed with EtOAc (20 mL). The mixture was acidified using 2 M HCl (1 mL) and concentrated in vacuo. The crude material was purified by silica gel chromatography (Isolera Biotage, 24 g Si Cartridge, 0-60% EtOAc in petroleum benzine 40-60 C.). Fractions containing the suspected product were concentrated in vacuo to give 2-fluoro-5-(furan-2-yl)-3-methylbenzoic acid (I15) (0.050 g, 26% yield) as a white solid. LCMS B rt. 3.63 min, m/z 221.1 [M+H].sup.+.

(bb) 2,4-Difluoro-5-methyl-[1,1-biphenyl]-3-carboxylic acid (I17)

(100) ##STR00164##

(i) 2,4-Difluoro-5-methyl-1,1-biphenyl (116)

(101) The desired compound was prepared from 1-bromo-2,4-difluoro-5-methylbenzene by general procedure Suzuki Coupling F to obtain a colourless oil (79% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.55-7.35 (m, 5H), 7.29-7.22 (m, 1H), 6.88 (t, J=9.9 Hz, 1H), 2.35-2.26 (m, 3H).

(ii) 2,4-Difluoro-5-methyl-[1,1-biphenyl]-3-carboxylic acid (I17)

(102) The desired compound was prepared from compound I16 by general procedure Carboxylation to obtain a colourless solid (78% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.58-7.37 (m, 6H), 2.41-2.26 (m, 3H).

(cc) 2,6-Difluoro-3-methyl-5-(1H-pyrazol-1-yl)benzoic acid (I19)

(103) ##STR00165##

(i) 1-(2,4-Difluoro-5-methylphenyl)-1H-pyrazole (I18)

(104) The desired compound was prepared from 1-bromo-2,4-difluoro-5-methylbenzene by general procedure Ullmann Coupling Method B to obtain a colourless oil (33% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.94-7.90 (m, 1H), 7.75-7.67 (m, 2H), 6.93 (dd, J=11.2, 9.0 Hz, 1H), 6.47 (dd, J=2.4, 1.9 Hz, 1H), 2.35-2.17 (m, 3H). LCMS B rt 3.61 min, m/z 195.0 [M+H].sup.+.

(ii) 2,6-Difluoro-3-methyl-5-(1H-pyrazol-1-yl)benzoic acid (I19)

(105) The desired compound was prepared from compound I18 by general procedure Carboxylation to obtain a colourless solid (66% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.99 (s, 1H), 7.93 (t, J=7.9 Hz, 1H), 7.79 (s, 1H), 6.54 (s, 1H), 2.36 (d, J=1.7 Hz, 3H). LCMS B rt 3.66 min, m/z 239.1 [M+H].sup.+.

(dd) 3-Ethoxy-2,6-difluoro-5-methylbenzoic acid (I23)

(106) ##STR00166##

(i) 2-(2,4-Difluoro-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (I20)

(107) The desired compound was prepared from 1-bromo-2,4-difluoro-5-methylbenzene by general procedure Suzuki Coupling Method E to obtain a dark brown solid (81% yield) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.48 (dd, J=9.1, 7.1 Hz, 1H), 6.65 (t, J=9.6 Hz, 1H), 2.17-2.14 (m, 3H), 1.28 (d, J=2.5 Hz, 12H).

(ii) 2,4-Difluoro-5-methylphenol (I21)

(108) To a solution of 2-(2,4-difluoro-5-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (I20) (1.0 g, 3.94 mmol, 1.0 eq) in a mixture of NaOH (1 M aqueous solution, 11.8 mL, 11.8 mmol, 3.0 eq) and THF (10 mL) at 0 C. was added H.sub.2O.sub.2(1.34 g, 11.8 mmol, 3 eq). The reaction mixture was stirred at room temperature for 1 h, then the pH of the reaction mixture was adjusted to pH 5 by addition of 1 M HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Mg.sub.2SO.sub.4), filtered and evaporated in vacuo. The crude residue obtained was purified by column chromatography (petroleum ether: EtOAc, 100:1 to 50:1) to give the title compound as a colorless oil, yield (0.38 g, 67% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 6.72 (ddd, J=10.3, 8.3, 5.2 Hz, 2H), 5.03 (s, 1H), 2.12 (d, J=0.9 Hz, 3H).

(iii) 1-Ethoxy-2,4-difluoro-5-methylbenzene (I22)

(109) The desired compound was prepared from 2,4-difluoro-5-methylphenol (I21) by general procedure Alkylation of Aryl Hydroxyl Method to obtain a yellow liquid (55% yield).

(110) .sup.1H NMR (400 MHz, CDCl.sub.3) 6.77 (ddd, J=12.6, 9.9, 8.5 Hz, 2H), 4.05 (q, J=7.0 Hz, 2H), 2.24-2.19 (m, 3H), 1.42 (t, J=7.0 Hz, 3H).

(iv) 3-Ethoxy-2,6-difluoro-5-methylbenzoic acid (I23)

(111) The desired compound was prepared from 1-ethoxy-2,4-difluoro-5-methylbenzene (I22) by general procedure Carboxylation to give a colourless solid (78% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 6.96 (dd, J=8.4, 7.5 Hz, 1H), 4.11 (q, J=7.0 Hz, 2H), 2.34-2.21 (m, 3H), 1.45 (t, J=7.0 Hz, 3H).

(ee) 4-Fluoro-[1,1-biphenyl]-3-carboxylic acid (I24)

(112) ##STR00167##

(113) 4-Fluoro-[1,1-biphenyl]-3-carboxylic acid was made as per general Suzuki Coupling F, from 5-bromo-2-fluorobenzoic acid (1 g, 4.57 mmol) and phenylboronic acid (0.724 g, 5.94 mmol). However after the reaction mixture was cooled down it was passed through a bed of celite, evaporated in-vacuo, acidified with 1 M HCl and the resulting white precipitate was filtered off and dried in an oven at 130 C. (0.988 g, 100%). .sup.1H NMR (400 MHz, DMSO) 13.38 (s, 1H), 8.08 (dd, J=7.0, 2.5 Hz, 1H), 7.93 (ddd, J=8.5, 4.5, 2.6 Hz, 1H), 7.77-7.61 (m, 2H), 7.49 (dd, J=10.3, 4.8 Hz, 2H), 7.41 (ddd, J=7.8, 7.3, 5.9 Hz, 2H).

Example 1

(114) The following compounds were synthesised according to the Amide Coupling method B from commercially available starting materials:

(115) TABLE-US-00015 Structure Product details 1 Yellow solid (54% yield). .sup.1H NMR (Acetone-d6) 8.55 (s, 1H), 7.98-7.95 (m, 5H), 7.82-7.79 (m, 1H), 7.70-7.58 (m, 5H, H), 7.51-7.35 (m, 4H). LCMS C rt 7.73 min, m/z 403.2 [M + H].sup.+. 2 White solid (13% yield). .sup.1H NMR (DMSO) 10.78 (s, 1H), 10.01 (s, 1H), 7.96 (s, 1H), 7.85-7.81 (m, 3H), 7.71-7.68 (m, 2H), 7.64-7.59 (m, 2H), 7.54-7.51 (m, 5H), 7.39-7.46 (m, 1H). LCMS C rt 7.03 min, m/z 353.1 [M + H].sup.+. 3 0 White solid (8% yield). .sup.1H NMR (Acetone-d6) 10.03 (s, 1H), 8.52 (s, 1H), 8.08-7.94 (m, 4H), 7.67-7.59 (m, 3H), 7.52-7.49 (m, 1H), 7.41-7.38 (m, 1H), 7.32-7.29 (m, 1H), 2.88 (sept, 1H J = 6.93 Hz), 1.18 (d, 6H, J = 6.93 Hz). LCMS C rt 7.53 min, m/z 369.1 [M + H].sup.+. 4 White solid (23% yield) as a white solid; .sup.1H NMR (DMSO): 10.53 (s, 1H), 10.17 (s, 1H), 8.49 (s, 1H), 8.15-8.00 (m, 3H), 7.89-7.86 (m, 1H), 7.71-7.63 (m, 2H), 7.37-7.35 (m, 1H), 7.15-7.08 (m, 2H), 2.19 (s, 3H), LCMS C rt 6.92 min, m/z 359.1 [M + H]. 5 Faint yellow solid (64% yield). .sup.1H NMR (400 MHz, DMSO) 10.8 (s, 1H), 10.3 (s, 1H), 8.0 (s, 1H), 7.90 (d, 1H), 7.80 (t, 1H), 7.70 (d, 2H), 7.40 (t, 1H), 7.32-7.20 (m, 2H). 6 Colourless solid (66% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.75 (s, 1H), 10.0 (s, 1H), 8.0 (s, 1H), 7.9 (d, 1H), 7.82 (d, 2H), 7.7-7.6 (m, 2H), 7.52 (t, 2H), 7.25 (t, 1H). 7 Colourless sticky solid (15.9 mg, 18% yield). .sup.1H NMR (400 MHz, DMSO) 12.98 (s, 1H), 10.76 (s, 1H), 10.04 (d, J = 2.4 Hz, 1H), 8.13 (s, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.86-7.79 (m, 3H), 7.65-7.47 (m, 5H), 6.74 (d, J = 2.0 Hz, 1H). LCMS A rt 5.39 min, m/z 343.1 [M + H].sup.+. 8 Colourless solid (13.1 mg, 7% yield). .sup.1H NMR (400 MHz, DMSO) 10.74 (s, 1H), 10.05 (s, 1H), 8.02 (s, 1H), 7.93 (dd, J = 2.9, 1.3 Hz, 1H), 7.88-7.84 (m, 3H), 7.68 (dd, J = 5.0, 2.9 Hz, 1H), 7.66-7.42 (m, 6H). LCMS A rt 6.21 min, m/z 359.1 [M + H].sup.+. 9 Colourless solid (30.7 mg, 13% yield). .sup.1H NMR (400 MHz, DMSO) 10.66 (s, 1H), 10.02 (s, 1H), 7.83 (d, J = 7.4 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.9 Hz, 1H), 7.28-7.15 (m, 2H), 7.09 (dd, J= 8.1, 1.8 Hz, 1H), 3.93 (t, J = 6.5 Hz, 2H), 1.85- 1.60 (sex. J = 7.1 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H). LCMS A rt 6.21, m/z 335.1 [M + H].sup.+. 10 HOBt was used instead of HOAt Colourless solid (0.254 g, 91% yield). .sup.1H NMR (400 MHz, DMSO) 10.64 (s, 1H), 9.98 (s, 1H), 7.93-7.71 (m, 2H), 7.70-7.58 (m, 1H), 7.55-7.51 (m, 3H), 7.48 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 2.90 (hept, J = 6.8 Hz, 1H), 1.19 (d, J = 6.9 Hz, 6H). LCMS A rt 6.27, m/z 319.1 [M + H].sup.+. 11 Colourless solid (70 mg, 15% yield). .sup.1H NMR (400 MHz, DMSO) 10.61 (br s, 1H), 9.99 (br s, 1H), 7.83 (d, J = 7.5 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.9 Hz, 1H), 7.25-7.12 (m, 2H), 7.07 (dd, J = 8.1, 2.0 Hz, 1H), 4.62 (sept., 6.0 Hz, 1H), 1.26 (d, J = 6.0 Hz, 6H). LCMS A rt 6.12, m/z 335.1 [M + H].sup.+. 12 Colourless solid (9.5 mg, 10% yield). .sup.1H NMR (400 MHz, DMSO) 13.84 (s, 1H), 10.83 (d, J = 3.4 Hz, 1H), 10.14 (d, J = 3.4 Hz, 1H), 9.19 (s, 2H), 8.12 (s, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 7.3 Hz, 2H), 7.74 (d, J = 7.8 Hz, 1H), 7.63 (q, J = 7.3 Hz, 2H), 7.58-7.43 (m, 2H). LCMS A rt 5.32 min, m/z 355.1 [M + H].sup.+. 13 0 Colourless solid (42.7 mg, 34% yield). .sup.1H NMR (400 MHz, DMSO) 10.93 (s, 1H), 10.13 (s, 1H), 8.24 (s, 1H), 8.11 (dd, J = 5.3, 4.0 Hz, 1H), 7.97 (d, J = 3.2 Hz, 1H), 7.91-7.81 (m, 3H), 7.77 (d, J= 7.9 Hz, 1H), 7.69- 7.41 (m, 4H). LCMS A rt 5.80 min, m/z 360.1 [M + H].sup.+. 14 HOBt was used instead of HOAt Colourless solid (87 mg, 40% yield). .sup.1H NMR (400 MHz, DMSO) 10.83 (d, J = 3.3 Hz, 1H), 10.09 (d, J = 3.3 Hz, 1H), 7.93 (s, 1H), 7.86-7.82 (m, 3H), 7.71-7.43 (m, 7H), 7.17 (dd, J = 5.1, 3.6 Hz, 1H). LCMS A rt 6.27, m/z 359.1 [M + H].sup.+. 15 Colourless solid (70 mg, 39% yield). .sup.1H NMR (400 MHz, DMSO) 10.66 (br s, 1H), 10.01 (br s, 1H), 7.89-7.73 (m, 2H), 7.69-7.58 (m, 1H), 7.55-7.51 (m, 2H), 7.33 (t, J = 7.9 Hz, 1H), 7.24-7.20 (m, 2H), 7.08 (dd, J = 8.1, 1.8 Hz, 1H), 3.97 (t, J = 6.5 Hz, 2H), 1.75-1.62 (pent. J = 6.6 Hz, 2H), 1.51-1.33 (sex., J = 7.5 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H). LCMS A rt 6.46 min, m/z 349.1 [M + H].sup.+. 16 Colourless solid (52 mg, 29% yield). .sup.1H NMR (400 MHz, DMSO) 10.66 (br s, 1H), 10.03 (br s, 1H), 7.93-7.75 (m, 2H), 7.68-7.58 (m, 1H), 7.55-7.51 (m, 2H), 7.33 (t, J = 7.9 Hz, 1H), 7.24-7.21 (m, 2H), 7.09 (ddd, J = 8.2, 2.5, 0.8 Hz, 1H), 3.75 (d, J = 6.5 Hz, 2H), 2.05-1.94 (m, 1H), 0.98 (d, J = 6.7 Hz, 6H). LCMS A rt 6.15 min, m/z 349.1 [M + H].sup.+. 17 HOBt was used instead of HOAt Colourless solid (45 mg, 25% yeld). .sup.1H NMR (400 MHz, DMSO) 10.64 (br s. 1H), 10.01 (br s, 1H), 7.88-7.79 (m, 2H), 7.62 (ddd, J= 8.7, 2.4, 1.2 Hz, 1H), 7.55-7.47 (m, 4H), 7.39-7.33 (m, 2H), 2.62 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H). LCMS A rt 6.15 min, m/z 305.1 [M + H].sup.+. 18 Colourless solid (57 mg, 16% yield). .sup.1H NMR (400 MHz, DMSO) 10.65 (s, 1H), 10.01 (s, 1H), 7.91-7.72 (m, 2H), 7.70-7.58 (m, 1H), 7.58-7.43 (m, 2H), 7.33 (t, J = 7.9 Hz, 1H), 7.21 (dd, J = 15.2, 5.0 Hz, 2H), 7.08 (ddd, J = 8.2, 2.5, 0.7 Hz, 1H), 4.03 (q, J = 7.0 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H). LCMS A rt 6.00 min m/z 321.1 [M + H].sup.+. 19 Colourless solid (153 mg, 36% yield). .sup.1H NMR (400 MHz, DMSO) 10.63 (d, J = 2.6 Hz, 1H), 10.01 (d, J = 3.0 Hz, 1H), 7.91-7.75 (m, 2H), 7.68-7.57 (m, 1H), 7.57-7.42 (m, 4H), 7.42-7.23 (m, 2H), 2.32 (s, 3H). LCMS A rt 5.94 min, m/z 291.1 [M + H].sup.+. 20 Colourless solid (267 mg, 41% yield). .sup.1H NMR (400 MHz, DMSO) 10.66 (d, J = 2.5 Hz, 1H), 10.25 (d, J = 2.6 Hz, 1H), 7.78 (td, J = 7.6, 1.6 Hz, 1H), 7.74-7.59 (m, 1H), 7.50-7.47 (m, 2H), 7.43-7.20 (m, 4H), 2.31 (s, 3H). LCMS A rt 5.96 min, m/z 309.0 [M + H].sup.+. 21 Colourless solid (38 mg, 37% yield). .sup.1H NMR (400 MHz, DMSO) 10.63 (s, 1H), 9.98 (s, 1H), 8.00-7.73 (m, 2H), 7.71-7.55 (m, 1H), 7.55-7.43 (m, 4H), 7.42-7.19 (m, 2H), 2.62-2.51 (t, J = 7.8 Hz, 2H), 1.67-1.48 (sex, J = 7.5 Hz, 2H), 0.88 (t, J = 7.3 Hz, 3H). LCMS A rt 6.14 min, m/z 319.0 [M + H].sup.+. 22 Colourless solid (42 mg, 29% yield). .sup.1H NMR (400 MHz, DMSO) 10.86 (br s, 1H), 10.12 (br s, 1H), 7.84 (d, J = 7.4 Hz, 2H), 7.73 (d, J = 7.3 Hz, 1H), 7.67-7.50 (m, 6H). LCMS A rt 6.22 min, m/z 361.1 [M + H].sup.+. 23 0 Colourless solid (41 mg, 36% yield). .sup.1H NMR (400 MHz, DMSO) 10.63 (s, 1H), 9.98 (s, 1H), 8.00-7.73 (m, 2H), 7.72-7.57 (m, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.9 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 7.16 (s, 1H), 7.06 (dd, J = 8.1, 1.8 Hz, 1H), 4.85-4.81 (m, 1H), 1.98-1.77 (m, 2H), 1.70-1.65 (m, 4H), 1.61-1.58 (m, 2H). LCMS A rt 6.45 min, m/z 361.1 [M + H].sup.+.

Example 2

(116) The following compounds were synthesised according to the Sulfonamide coupling method from commercially available starting materials:

(117) TABLE-US-00016 Structure Product details 24 Colourless solid (59% yield). .sup.1HNMR (400 MHz, CDCl.sub.3) 10.7 (s, 1H), 10.4 (s, 1H), 7.87-7.80 (m, 2H), 7.73 (m, 3H), 7.45-7.30 (m, 5H), 730-7.22 (m, 2H) 25 Colourless solid (61% yield). .sup.1H-NMR (400 MHz, CDCl.sub.3): 10.8 (s, 1H), 10.08 (s, 1H), 7.90 (s, 1H), 7.80 (m, 5H), 7.60 (d, 6H), 7.35 (t, 2H). 26 Colourless solid (56% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) 10.80 (s, 1H), 10.08 (s, 1H), 7.85 (d, 2H), 7.78 (d, 1H), 7.68-7.60 (m, 3H), 7.60-7.48 (m, 4H), 7.06 (d, 2H), 3.80 (s, 3H). 27 Colourless solid (59% yield). .sup.1H NMR (400 MHz, CDCl.sub.3): 10.8 (s, 1H), 10.08 (s, 1H), 7.78 (d, 3H), 7.60 (d, 4H), 7.51-7.27 (m, 3H), 7.10 (d, 2H), 3.77 (s, 3H). 28 Colourless solid (57% yield). .sup.1H NMR (400 MHz, CDCl.sub.3): 10.8 (s, 1H), 10.08 (s, 1H), 7.98 (s, 1H), 7.86 (d, 4H), 7.65 (t, 4H), 7.53 (m, 4H), 7.41 (t, 1H), 7.25 (d, 2H), 7.0 (d, 1H), 3.77 (s, 3H). 29 Colourless solid (61% yield). .sup.1H NMR (400 MHz, DMSO) 10.7 (s, 1H), 10.08 (s, 1H), 7.95 (s, 1H), 7.85 (d, 3H), 7.65-7.45 (m, 8H), 7.17 (t, 1H). 30 Colourless solid (62% yield). .sup.1H NMR (400 MHz, DMSO) 10.7 (s, 1H), 10.08 (s, 1H), 7.80 (d, 3H), 7.65 (t, 2H), 7.60-7.45 (m, 5H), 7.40 (m, 1H), 7.30-7.25 (m, 2H). 31 Colourless solid (65% yield). .sup.1H NMR (400 MHz, DMSO) 10.7 (s, 1H), 10.08 (s, 1H), 8.20 (s, 1H), 8.05 (d, 2H), 7.93 (d, 1H), 7.85 (t, 3H), 7.7 (m, 2H), 7.62 (t, 1H), 7.55 (m, 3H) 32 Colourless solid (60% yield). .sup.1H NMR (400 MHz, DMSO): 10.7 (s, 1H), 10.08 (s, 1H), 8.00 (s, 1H), 7.93 (d, 1H), 7.82 (d, 3H), 7.75 (d, 2H), 7.62 (m, 2H), 7.50 (m, 5H). 33 00 Colourless solid (62% yield). .sup.1H NMR (400 MHz, DMSO) 710.7 (s, 1H), 10.08 (s, 1H), 7.88 (d, 2H), 7.68-7.60 (m, 2H), 7.60-7.48 (m, 6H), 7.46-7.41 (m, 1H), 7.38-7.30 (m, 2H). 34 01 Colourless solid (63% yield). .sup.1H NMR (400 MHz, DMSO) 10.75 (s, 1H), 10.05 (s, 1H), 7.84 (d, 2H), 7.72 (d, 2H), 7.65-7.50 (m, 6H), 7.45 (s, 3H).

Example 3

(118) The following compounds were synthesised according to the specified Amide coupling (M) from the named intermediates (Int):

(119) TABLE-US-00017 Structure M Int 35 02 C I1 Colourless solid (18% yield). .sup.1H NMR (400 MHz, DMSO) 10.82 (s, 1H), 10.26 (s, 1H), 8.02 (d, J = 4.2 Hz, 1H), 7.90 (d, J = 7.0 Hz, 2H), 7.78-7.30 (m, 9H). LCMS A rt 6.52 min, m/z 405.0 [M + H].sup.+. 36 03 B I2 Off-white solid (35% yield). .sup.1H NMR (400 MHz, DMSO) 10.64 (s, 1H), 10.16 (s, 1H), 7.89 (d, J = 7.3 Hz, 2H), 7.72 (dd, J = 6.6, 1.7 Hz, 1H), 7.69-7.60 (m, 3H), 7.57 (t, J = 7.5 Hz, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.44-7.35 (m, 2H), 2.30 (s, 3H). LCMS A rt 6.48 min, m/z 385.1 [M + H].sup.+. 37 04 B I3 Colourless solid (60 mg, 61% yield). .sup.1H NMR (400 MHz, DMSO) 10.78 (s, 1H), 10.12 (s, 1H), 7.94 (dd, J = 6.9, 2.1 Hz, 1H), 7.84 (d, J = 7.5 Hz, 2H), 7.78 (d, J = 3.7 Hz, 1H), 7.72-7.61 (m, 2H), 7.61-7.51 (m, 3H), 7.47 (t, J = 8.9 Hz, 1H). LCMS A rt 6.55 min, m/z 411.0 [M + H].sup.+. 38 05 B P7 Off-white solid (25 mg, 17% yield). .sup.1H NMR (400 MHz, DMSO) 10.88 (s, 1H), 10.08 (s, 1H), 8.95 (d, J = 4.8 Hz, 2H), 8.71 (s, 1H), 8.54 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 7.3 Hz, 3H), 7.74-7.30 (m, 5H). LCMS A rt 5.63 min, m/z 355.1 [M + H].sup.+. 39 06 B P1 Colourless solid (75 mg, 48% yield). .sup.1H NMR (400 MHz, DMSO) 10.84 (s, 1H), 10.08 (s, 1H), 8.70 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.40 (s, 1H), 8.24 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.98-7.89 (m, 1H), 7.89-7.80 (m, 2H), 7.74 (d, J = 7.8 Hz, 1H), 7.67-7.60 (m, 1H), 7.60- 7.48 (m, 3H), 7.40 (ddd, J = 7.4, 4.8, 1.0 Hz, 1H). LCMS B rt 5.40 min, m/z 354.1 [M + H].sup.+. 40 07 B P13 Colourless solid (30 mg, 28% yield). .sup.1H NMR (400 MHz, DMSO) 10.83 (s, 1H), 10.10 (s, 1H), 8.53 (s, 1H), 8.30-7.41 (m, 10H), 6.58 (s, 1H). LCMS B rt 5.73 min, m/z 343.1 [M + H].sup.+. 41 08 A P1 Colourless solid (60% yield). .sup.1H NMR (400 MHz, DMSO) 10.88 (d, J = 2.0 Hz, 1H), 10.35 (d, J = 2.3 Hz, 1H), 8.70 (d, J = 4.7 Hz, 1H), 8.42 (s, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.93 (td, J = 7.7, 1.8 Hz, 1H), 7.82 (t, J = 7.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.69 (dd, J = 13.6, 7.0 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.41 (dd, J = 11.5, 6.7 Hz, 2H), 7.30 (t, J = 8.0 Hz, 1H). LCMS B rt 3.44 min, m/z 372.1 [M + H].sup.+. 42 09 A P2 Colourless solid (72% yield). .sup.1H NMR (400 MHz, DMSO) 10.82 (d, J = 2.4 Hz, 1H), 10.32 (d, J = 2.5 Hz, 1H), 8.68 (d, J = 4.7 Hz, 1H), 8.21 (s, 1H), 8.07 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.92 (td, J = 7.7, 1.7 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.72-7.64 (m, 1H), 7.57 (s, 1H), 7.40 (t, J = 8.7 Hz, 2H), 7.30 (t, J = 8.0 Hz, 1H), 2.41 (s, 3H). LCMS B rt 3.49 min, m/z 386.1 [M + H].sup.+. 43 0 A P3 Colourless solid (65% yield). .sup.1H NMR (400 MHz, DMSO) 10.68 (s, 1H), 10.18 (s, 1H), 8.68 (d, J = 4.8 Hz, 1H), 8.26-8.18 (m, 1H), 8.14-8.09 (m, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.94-7.86 (m, 3H), 7.65 (t, J = 7.4 Hz, 1H), 7.58 (t, J = 7.5 Hz, 2H), 7.43-7.35 (m, 2H). LCMS B rt 3.44 min, m/z 372.1 [M + H].sup.+. 44 A P4 Colourless solid (67% yield). .sup.1H NMR (400 MHz, DMSO) 10.66 (d, J = 3.3 Hz, 1H), 10.18 (d, J = 3.3 Hz, 1H), 8.67 (d, J = 4.4 Hz, 1H), 8.16-8.08 (m, 1H), 7.92 (ddd, J = 13.1, 12.7, 4.6 Hz, 5H), 7.65 (t, J = 7.4 Hz, 1H), 7.58 (t, J = 7.5 Hz, 2H), 7.38 (ddd, J = 7.1, 4.8, 1.1 Hz, 1H), 2.32 (s, 3H). LCMS B rt 3.50 min, m/z 386.1 [M + M].sup.+. 45 A P5 Colourless solid (69% yield). .sup.1H NMR (400 MHz, DMSO) 10.94 (d, J = 2.9 Hz, 1H), 10.17 (d, J = 3.1 Hz, 1H), 8.71 (d, J = 4.6 Hz, 1H), 8.30 (s, 1H), 8.08 (t, J = 8.6 Hz, 2H), 7.95 (t, J = 8.1 Hz, 1H), 7.86 (d, J = 7.7 Hz, 2H), 7.64 (t, J = 7.3 Hz, 1H), 7.55 (t, J = 7.8 Hz, 3H), 7.44 (dd, J = 7.3, 4.9 Hz, 1H). LCMS B rt 3.55 min, m/z 372.1 [M + H].sup.+. 46 A P5 Colourless solid (66% yield). .sup.1H NMR (400 MHz, DMSO) 10.98 (br s, 1H), 10.43 (br s, 1H), 8.71 (d, J = 4.4 Hz, 1H), 8.31 (s, 1H), 8.13-8.02 (m, 2H), 7.96 (t, J = 7.7 Hz, 1H), 7.82 (t, J = 7.3 Hz, 1H), 7.70 (dd, J = 12.7, 7.3 Hz, 1H), 7.54 (d, J = 9.8 Hz, 1H), 7.43 (dd, J = 17.4, 7.9 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H). LCMS B rt 3.49 min, m/z 390.1 [M + H].sup.+. 47 A P6 Colourless solid (65% yield). .sup.1H NMR (400 MHz, DMSO) 10.83 (br s, 1H), 10.10 (br s, 1H), 8.70 (d, J = 3.6 Hz, 1H), 8.02 (d, J = 9.6 Hz, 2H), 7.93 (t, J = 7.5 Hz, 1H), 7.86 (d, J = 7.4 Hz, 2H), 7.80 (s, 1H), 7.69- 7.60 (m, 1H), 7.55 (t, J = 7.4 Hz, 2H), 7.45-7.36 (m, 1H), 7.29 (s, 1H), 3.87 (s, 3H). LCMS B rt 3.48 min, m/z 384.1 [M + H].sup.+. 48 A P6 Colourless solid (70% yield). .sup.1H NMR (400 MHz, DMSO) 10.86 (d, J = 2.6 Hz, 1H), 10.34 (d, J = 2.6 Hz, 1H), 8.69 (dd, J = 6.0, 1.2 Hz, 1H), 8.04-7.98 (m, 2H), 7.92 (td, J = 7.7, 1.8 Hz, 1H), 7.84-7.77 (m, 2H), 7.73-7.65 (m, 1H), 7.41 (td, J = 8.0, 6.2 Hz, 2H), 7.33-7.26 (m, 2H), 3.86 (s, 3H). LCMS B rt 3.48 min, m/z 402.2 [M + M].sup.+. 49 A P8 Colourless solid (67% yield). .sup.1H NMR (400 MHz, DMSO) 10.86 (d, J = 2.5 Hz, 1H), 10.31 (d, J = 2.5 Hz, 1H), 8.93 (d, J = 4.9 Hz, 2H), 8.53 (s, 1H), 8.37 (s, 1H), 7.81 (td, J = 7.7, 1.6 Hz, 1H), 7.72-7.64 (m, 2H), 7.49 (t, J = 4.9 Hz, 1H), 7.44-7.36 (m, 1H), 7.30 (t, J = 7.7 Hz, 1H), 2.43 (s, 3H). LCMS B rt 3.69 min, m/z 387.1 [M + H].sup.+. 50 A P8 Colourless solid (58% yield). .sup.1H NMR (400 MHz, DMSO) 10.83 (br s, 1H), 10.08 (br s, 1H), 8.93 (d, J = 4.8 Hz, 2H), 8.52 (s, 1H), 8.37 (s, 1H), 7.86 (d, J = 7.5 Hz, 2H), 7.68 (s, 1H), 7.63 (t, J = 7.3 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.48 (t, J = 4.8 Hz, 1H), 2.43 (s, 3H). LCMS B rt 3.54 min, m/z 369.1 [M + H].sup.+. 51 A P11 Colourless solid (69% yield). .sup.1H NMR (400 MHz, DMSO) 11.00 (d, J = 2.4 Hz, 1H), 10.18 (d, J = 2.7 Hz, 1H), 8.98 (d, J = 4.8 Hz, 2H), 8.59 (s, 1H), 8.26 (d, J = 9.4 Hz, 1H), 7.87 (d, J = 7.7 Hz, 2H), 7.66 (dd, J = 19.9, 8.1 Hz, 2H), 7.56 (t, J = 6.5 Hz, 3H). LCMS B rt 3.55 min, m/z 373.2 [M + H].sup.+. 52 A P11 Colourless solid (66% yield). .sup.1H NMR (400 MHz, DMSO) 11.03 (d, J = 2.5 Hz, 1H), 10.43 (d, J = 2.5 Hz, 1H), 8.97 (d, J = 4.9 Hz, 2H), 8.60 (s, 1H), 8.26 (d, J = 11.1 Hz, 1H), 7.82 (t, J = 7.5 Hz, 1H), 7.70 (dd, J = 15.1, 9.0 Hz, 2H), 7.54 (t, J = 4.9 Hz, 1H), 7.45-7.38 (m, 1H), 7.31 (t, J = 7.6 Hz, 1H). LCMS B rt 3.61 min, m/z 391.1 [M + H].sup.+. 53 0 A P10 Colourless solid (67% yield). .sup.1H NMR (400 MHz, DMSO) 10.69 (d, J = 3.0 Hz, 1H), 10.20 (d, J = 3.1 Hz, 1H), 8.92 (d, J = 4.9 Hz, 2H), 8.41 (d, J = 6.7 Hz, 1H), 8.24 (dd, J = 6.0, 1.6 Hz, 1H), 7.93-7.85 (m, 2H), 7.65 (t, J = 7.3 Hz, 1H), 7.58 (t, J = 7.4 Hz, 2H), 7.48 (t, J = 4.9 Hz, 1H), 2.34 (s, 3H). LCMS B rt 3.51 min, m/z 387.1 [M + H].sup.+. 54 A P9 Colourless solid (65% yield). .sup.1H NMR (400 MHz, DMSO) 10.71 (br s, 1H), 10.21 (br s, 1H), 8.93 (d, J = 4.9 Hz, 2H), 8.51 (ddd, J = 8.6, 5.0, 2.3 Hz, 1H), 8.43 (dd, J = 6.8, 2.3 Hz, 1H), 7.92-7.84 (m, 2H), 7.65 (ddd, J = 6.5, 2.4, 1.2 Hz, 1H), 7.58 (t, J = 7.5 Hz, 2H), 7.46 (dt, J = 18.5, 6.9 Hz, 2H). LCMS B rt 3.50 min, m/z 373.1 [M + H].sup.+. 55 A P12 Colourless solid (54% yield). .sup.1H NMR (400 MHz, DMSO) 10.90 (br s, 1H), 10.34 (br s, 1H), 8.94 (d, J = 4.9 Hz, 2H), 8.33 (d, J = 1.4 Hz, 1H), 8.07-8.02 (m, 1H), 7.82 (dd, J = 11.2, 3.7 Hz, 1H), 7.69 (dd, J = 12.4, 6.5 Hz, 1H), 7.50 (t, J = 4.9 Hz, 1H), 7.45-7.36 (m, 2H), 7.33-7.25 (m, 1H), 3.87 (s, 3H). LCMS B rt 3.46 min, m/z 403.1 [M + H].sup.+. 56 A P12 Colorless solid (65% yield). .sup.1H NMR (400 MHz, DMSO) 10.87 (br s, 1H), 10.10 (br s, 1H), 8.95 (d, J = 4.9 Hz, 2H), 8.33 (s, 1H), 8.07 (s, 1H), 7.86 (d, J = 7.8 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.53 (dt, J = 9.7, 6.4 Hz, 3H), 7.42 (s, 1H), 3.88 (s, 3H). LCMS B rt 3.45 min, m/z 385.1 [M + H].sup.+. 57 A P7 Colourless solid (66% yield). .sup.1H NMR (400 MHz, DMSO) 10.92 (d, J = 2.5 Hz, 1H), 10.34 (d, J = 2.5 Hz, 1H), 8.94 (d, J = 4.9 Hz, 2H), 8.73 (d, J = 1.5 Hz, 1H), 8.54 (d, J = 5.1 Hz, 1H), 7.88-7.78 (m, 2H), 7.73- 7.65 (m, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.50 (t, J = 4.9 Hz, 1H), 7.44-7.37 (m, 1H), 7.30 (td, J = 7.7, 1.0 Hz, 1H). LCMS B rt 3.44 min, m/z 373.1 [M + H].sup.+. 58 A P13 Colourless solid (68% yield). .sup.1H NMR (400 MHz, DMSO) 10.88 (d, J = 2.1 Hz, 1H), 10.37 (d, J = 2.3 Hz, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.15 (s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.87-7.76 (m, 2H), 7.69 (dd, J = 13.7, 8.7 Hz, 1H), 7.59 (dt, J = 15.5, 7.7 Hz, 2H), 7.46-7.35 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 6.61-6.50 (m, 1H). LCMS B rt 3.47 min, m/z 361.1 [M + H].sup.+. 59 A P14 Colourless solid (71% yield). .sup.1H NMR (400 MHz, DMSO) 10.81 (s, 1H), 10.36 (s, 1H), 8.48 (d, J = 2.5 Hz, 1H), 7.95 (s, 1H), 7.87-7.75 (m, 3H), 7.73-7.63 (m, 1H), 7.41 (dd, J = 17.2, 7.3 Hz, 2H), 7.30 (t, J = 7.6 Hz, 1H), 6.60-6.48 (m, 1H), 2.39 (s, 3H). LCMS B rt 3.52 min. m/z 374.1 [M + H].sup.+. 60 A P16 Colourless solid (67% yield). .sup.1H NMR (400 MHz, DMSO) 10.67 (br s, 1H), 10.22 (br s, 1H), 8.49 (d, J = 2.5 Hz, 1H), 7.95-7.86 (m, 3H), 7.77 (d, J = 1.6 Hz, 1H), 7.68- 7.61 (m, 2H), 7.58 (t, J = 7.5 Hz, 2H), 6.58-6.53 (m, 1H), 2.32 (d, J = 1.4 Hz, 3H). LCMS B rt 3.57 min, m/z 375.2 [M + H].sup.+. 61 A P15 Colourless solid (78% yield). .sup.1H NMR (400 MHz, DMSO) 10.71 (s, 1H), 10.21 (s, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.04-7.95 (m, 1H), 7.89 (d, J = 7.5 Hz, 2H), 7.83 (dd, J = 5.7, 2.7 Hz, 1H), 7.77 (s, 1H), 7.65 (t, J = 7.3 Hz, 1H), 7.58 (t, J = 7.5 Hz, 2H), 7.43 (t, J = 9.2 Hz, 1H), 6.56 (s, 1H). LCMS B rt 3.46 min, m/z 361.1 [M + H].sup.+. 62 A P18 Colourless solid (63% yield). .sup.1H NMR (400 MHz, DMSO) 10.82 (s, 1H), 10.11 (s, 1H), 8.54 (d, J = 2.3 Hz, 1H), 7.89-7.82 (m, 2H), 7.79-7.72 (m, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.55 (dd, J = 10.8, 4.1 Hz, 3H), 7.16 (s, 1H), 6.59-6.53 (m, 1H), 3.85 (s, 3H). LCMS B rt 3.56 min, m/z 372.1 [M + H].sup.+. 63 0 A P18 Colourless solid (72% yield). .sup.1H NMR (400 MHz, DMSO) 10.85 (d, J = 2.2 Hz, 1H), 10.37 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 2.4 Hz, 1H), 7.81 (t, J = 6.9 Hz, 1H), 7.76 (d, J = 6.0 Hz, 2H), 7.70 (dd, J = 13.2, 7.4 Hz, 1H), 7.57 (s, 1H), 7.46-7.37 (m, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.17 (s, 1H), 6.64- 6.47 (m, 1H), 3.85 (s, 3H). LCMS B rt 3.53 min, m/z 391.1 [M + H].sup.+. 64 A P17 Colourless solid (67% yield). .sup.1H NMR (400 MHz, DMSO) 10.97 (s, 1H), 10.45 (s, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.06 (s, 1H), 7.95 (dt, J = 10.1, 2.1 Hz, 1H), 7.84-7.78 (m, 2H), 7.70 (ddd, J = 8.2, 7.4, 1.7 Hz, 1H), 7.45-7.38 (m, 2H), 7.34-7.28 (m, 1H), 6.61 (dd, J = 2.5, 1.8 Hz, 1H). LCMS B rt 3.57 min, m/z 379.1 [M + H].sup.+. 65 A P17 Colourless solid (60% yield). .sup.1H NMR (400 MHz, DMSO) 10.93 (d, J = 1.9 Hz, 1H), 10.19 (d, J = 2.6 Hz, 1H), 8.59 (d, J = 2.5 Hz, 1H), 8.05 (s, 1H), 7.94 (d, J = 10.0 Hz, 1H), 7.84 (dd, J = 18.2, 4.4 Hz, 3H), 7.64 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.41 (d, J = 8.7 Hz, 1H), 6.63-6.58 (m, 1H), 2.25 (s, 3H). LCMS B rt 3.52 min, m/z 360.1 [M + H].sup.+. 66 A P19 Colourless solid (68% yield). .sup.1H NMR (400 MHz, DMSO) 10.87 (d, J = 1.8 Hz, 1H), 10.36 (d, J = 2.1 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.10 (s, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.81 (t, J = 6.9 Hz, 1H), 7.69 (dd, J = 12.3, 6.8 Hz, 1H), 7.55 (dt, J = 15.5, 7.6 Hz, 2H), 7.45-7.37 (m, 1H), 7.30 (t, J = 7.6 Hz, 1H), 6.36 (d, J = 2.2 Hz, 1H), 2.28 (s, 3H). LCMS B rt 3.51 min, m/z 375.1 [M + H].sup.+. 67 A P20 Colourless solid (71% yield). .sup.1H NMR (400 MHz, DMSO) 10.79 (s, 1H), 10.34 (s, 1H), 8.35 (d, J = 2.1 Hz, 1H), 7.90 (s, 1H), 7.86-7.79 (m, 2H), 7.69 (dd, J = 12.4, 6.7 Hz, 1H), 7.40 (t, J = 9.2 Hz, 2H), 7.30 (t, J = 7.6 Hz, 1H), 6.35 (d, J = 2.2 Hz, 1H), 2.37 (s, 3H), 2.27 (s, 3H). LCMS B rt 3.66 min, m/z 389.1 [M + H].sup.+. 68 A P21 Colourless solid (78% yield). .sup.1H NMR (400 MHz, DMSO) 10.67 (s, 1H), 10.20 (s, 1H), 8.38 (d, J = 2.4 Hz, 1H), 7.95-7.85 (m, 3H), 7.81-7.75 (m, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.61-7.53 (m, 2H), 7.39 (t, J = 9.3 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 2.27 (s, 3H). LCMS B rt 3.57 min, m/z 375.1 [M + H].sup.+. 69 A P22 Colourless solid (60% yield). .sup.1H NMR (400 MHz, DMSO) 10.65 (s, 1H), 10.19 (s, 1H), 8.34 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 7.8 Hz, 2H), 7.85 (d, J = 5.5 Hz, 1H), 7.66 (t, J = 7.3 Hz, 1H), 7.58 (t, J = 7.5 Hz, 3H), 6.34 (d, J = 2.0 Hz, 1H), 2.30 (s, 3H), 2.27 (s, 3H). LCMS B rt 3.62 min m/z 389.1 [M + H].sup.+. 70 A P24 Colourless solid (69% yield). .sup.1H NMR (400 MHz, DMSO) 10.84 (d, J = 2.3 Hz, 1H), 10.36 (d, J = 2.4 Hz, 1H), 8.40 (d, J = 2.3 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.74- 7.67 (m, 2H), 7.50 (s, 1H), 7.45-7.37 (m, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.13 (s, 1H), 6.36 (d, J = 2.3 Hz, 1H), 3.85 (s, 3H), 2.27 (s, 3H). LCMS B rt 3.60 min, m/z 405.1 [M + H].sup.+. 71 A P23 Colourless solid (59% yield). .sup.1H NMR (400 MHz, DMSO) 10.96 (s, 1H), 10.44 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.01 (s, 1H), 7.88 (d, J = 10.2 Hz, 1H), 7.82 (t, J = 7.5 Hz, 1H), 7.75-7.66 (m, 1H), 7.37 (ddd, J = 23.2, 17.1, 8.9 Hz, 3H), 6.40 (d, J = 2.4 Hz, 1H), 2.29 (s, 3H). LCMS B rt 3.25 min, m/z 393.1 [M + H].sup.+. 72 A P23 Colourless solid (54% yield). .sup.1H NMR (400 MHz, DMSO) 10.92 (s, 1H), 10.20 (s, 1H), 8.45 (d, J = 2.5 Hz, 1H), 7.99 (s, 1H), 7.86 (dd, J = 10.3, 3.1 Hz, 3H), 7.64 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 2.4 Hz, 1H), 2.28 (s, 3H). LCMS B rt 3.23 min, m/z 375.1 [M + H].sup.+. 73 0 A P30 Colourless solid (67% yield). .sup.1H NMR (400 MHz, DMSO) 10.88 (d, J = 2.0 Hz, 1H), 10.38 (d, J = 2.2 Hz, 1H), 8.72 (d, J = 4.5 Hz, 1H), 8.11 (s, 1H), 7.98-7.91 (m, 1H), 7.88 (d, J = 4.2 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.69 (tt, J = 4.9, 4.3 Hz, 1H), 7.60 (dt, J = 15.6, 7.8 Hz, 2H), 7.44-7.35 (m, 1H), 7.33-7.25 (m, 1H). LCMS B rt 3.58 min, m/z 379.1 [M + H].sup.+. 74 A P31 Colourless solid (55% yield). .sup.1H NMR (400 MHz, DMSO) 10.75 (s, 1H), 10.18 (s, 1H), 8.68 (d, J = 4.5 Hz, 1H), 7.87 (dd, J = 12.7, 8.8 Hz, 4H), 7.79 (s, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.45 (s, 1H), 2.39 (s, 3H). LCMS B rt 3.65 min, m/z 375.2 [M + H].sup.+. 75 A P31 Colourless solid (67% yield). .sup.1H NMR (400 MHz, DMSO) 10.75 (s, 1H), 10.29 (s, 1H), 8.61 (d, J = 4.4 Hz, 1H), 7.85 (s, 1H), 7.80 (d, J = 4.2 Hz, 1H), 7.77-7.70 (m, 2H), 7.62 (dd, J = 13.3, 7.2 Hz, 1H), 7.40 (s, 1H), 7.37-7.30 (m, 1H), 7.27-7.20 (m, 1H), 2.32 (s, 3H). LCMS B rt 3.67 min, m/z 393.1 [M + H].sup.+. 76 A P32 Colourless solid (69% yield). .sup.1H NMR (400 MHz, DMSO) 10.66 (s, 1H), 10.21 (s, 1H), 8.69 (d, J = 4.2 Hz, 1H), 7.91-7.82 (m, 4H), 7.68-7.61 (m, 1H), 7.61-7.54 (m, 3H), 2.30 (d, J = 1.5 Hz, 3H). LCMS B rt 3.65 min, m/z 391.1 [M H].sup.. 77 A P25 Colourless solid (65% yield). .sup.1H NMR (400 MHz, DMSO) 10.89 (s, 1H), 10.37 (s, 1H), 8.31 (s, 1H), 8.11 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.82 (t, J = 7.4 Hz, 1H), 7.75- 7.64 (m, 1H), 7.62-7.51 (m, 3H), 7.47- 7.35 (m, 1H), 7.30 (t, J = 7.6 Hz, 1H), 2.11 (s, 3H). LCMS B rt 3.55 min, m/z 375.1 [M + H].sup.+. 78 A P26 Colourless solid (70% yield). .sup.1H NMR (400 MHz, DMSO) 10.79 (s, 1H), 10.34 (s, 1H), 8.26 (s, 1H), 7.90 (s, 1H), 7.82 (d, J = 7.5 Hz, 2H), 7.74-7.64 (m, 1H), 7.58 (s, 1H), 7.44-7.35 (m, 2H), 7.30 (t, J = 7.6 Hz, 1H), 2.38 (s, 3H), 2.10 (s, 3H). LCMS B rt 3.61 min, m/z 389.1 [M + H].sup.+. 79 A P28 Colourless solid (69% yield). .sup.1H NMR (400 MHz, DMSO) 10.65 (s, 1H), 10.19 (s, 1H), 8.24 (s, 1H), 7.88 (d, J = 7.5 Hz, 2H), 7.83 (s, 1H), 7.67-7.61 (m, 1H), 7.58 (d, J = 7.3 Hz, 4H), 2.29 (s, 3H), 2.09 (s, 3H). LCMS B rt 3.58 min, m/z 389.1 [M + H].sup.+. 80 A P29 Colourless solid (60% yield). .sup.1H NMR (400 MHz, DMSO) 10.95 (s, 1H), 10.44 (s, 1H), 8.34 (s, 1H), 8.01-7.98 (m, 1H), 7.88-7.77 (m, 2H), 7.70 (ddd, J = 13.3, 7.3, 1.7 Hz, 1H), 7.63 (s, 1H), 7.45-7.27 (m, 3H), 2.10 (s, 3H). LCMS B rt 3.61 min, m/z 393.1 [M + H].sup.+. 81 A P29 Colourless solid (55% yield). .sup.1H NMR (400 MHz, DMSO) 10.91 (s, 1H), 10.17 (s, 1H), 8.35 (s, 1H), 7.99 (s, 1H), 7.85 (d, J = 7.4 Hz, 3H), 7.67-7.60 (m, 2H), 7.55 (t, J = 7.6 Hz, 2H), 7.36 (d, J = 8.9 Hz, 1H), 2.10 (s, 3H). LCMS B rt 3.59 min, m/z 375.2 [M + H].sup.+. 82 A P27 Colourless solid (63% yield). .sup.1H NMR (400 MHz, DMSO) 10.67 (s, 1H), 10.21 (s, 1H), 8.29 (s, 1H), 7.89 (d, J = 7.2 Hz, 3H), 7.77 (dd, J = 5.8, 2.8 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.61-7.53 (m, 3H), 7.40 (t, J = 9.3 Hz, 1H), 2.10 (s, 3H). LCMS B rt 3.56 min, m/z 375.1 [M + H].sup.+. 83 0 A P36 Colourless solid (62% yield). .sup.1H NMR (400 MHz, DMSO) 10.87 (d, J = 2.5 Hz, 1H), 10.35 (d, J = 2.6 Hz, 1H), 7.83-7.77 (m, 2H), 7.73-7.65 (m, 2H), 7.56 (t, J = 7.9 Hz, 1H), 7.40 (dd, J = 13.1, 5.6 Hz, 2H), 7.34-7.26 (m, 1H), 6.09 (s, 1H), 2.29 (s, 3H), 2.18 (s, 3H). LCMS B rt 3.49 min, m/z 389.2 [M + H].sup.+. 84 A P33 Colourless solid (63% yield). .sup.1H NMR (400 MHz, DMSO) 10.79 (s, 1H), 10.33 (s, 1H), 8.35 (d, J = 2.4 Hz, 1H), 7.90 (s, 1H), 7.81 (dd, J = 10.7, 3.2 Hz, 2H), 7.69 (dd, J = 14.2, 8.1 Hz, 1H), 7.40 (t, J = 9.2 Hz, 2H), 7.30 (td, J = 7.8, 0.9 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 2.38 (s, 3H), 2.27 (s, 3H). LCMS B rt 3.58 min, m/z 389.1 [M + H].sup.+. 85 A P34 Colourless solid (69% yield). .sup.1H NMR (400 MHz, DMSO) 10.63 (s, 1H), 10.18 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 7.4 Hz, 2H), 7.84 (dd, J = 6.0, 2.6 Hz, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.61-7.54 (m, 3H), 6.34 (d, J = 2.4 Hz, 1H), 2.29 (d, J = 1.5 Hz, 3H), 2.26 (s, 3H). LCMS B rt 3.58 min, m/z 389.2 [M + H].sup.+. 86 A P35 Colourless solid (60% yield). .sup.1H NMR (400 MHz, DMSO) 10.95 (s, 1H), 10.43 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.00 (s, 1H), 7.87 (dt, J = 10.2, 2.1 Hz, 1H), 7.81 (td, J = 7.7, 1.6 Hz, 1H), 7.70 (ddd, J = 8.1, 4.9, 1.6 Hz, 1H), 7.47-7.27 (m, 3H), 6.39 (d, J = 2.4 Hz, 1H), 2.28 (s, 3H). LCMS B rt 3.60 min, m/z 393.1 [M + H].sup.+. 87 A P39 Colourless solid (52% yield). .sup.1H NMR (400 MHz, DMSO) 10.76 (s, 1H), 10.25 (s, 1H), 8.15 (s, 2H), 8.08 (dd, J = 5.9, 2.4 Hz, 1H), 7.92-7.86 (m, 2H), 7.79 (dd, J = 5.2, 2.7 Hz, 1H), 7.66 (t, J = 7.9 Hz, 1H), 7.58 (t, J = 7.5 Hz, 2H), 2.35 (d, J = 1.5 Hz, 3H). LCMS B rt 3.56 min, m/z 376.1 [M + H].sup.+. 88 A P37 Colourless solid (62% yield). .sup.1H NMR (400 MHz, DMSO) 10.93 (s, 1H), 10.37 (s, 1H), 8.15 (s, 2H), 8.14 (s, 1H), 8.03 (s, 1H), 7.81 (td, J = 7.6, 1.6 Hz, 1H), 7.69 (ddd, J = 8.1, 5.0, 1.7 Hz, 1H), 7.57 (s, 1H), 7.45-7.35 (m, 1H), 7.30 (td, J = 7.7, 0.9 Hz, 1H), 2.43 (s, 3H). LCMS B rt 3.58 min, m/z 376.2 [M + H].sup.+. 89 A P38 Colourless solid (60% yield). .sup.1H NMR (400 MHz, DMSO) 11.10 (s, 1H), 10.48 (s, 1H), 8.21 (s, 3H), 8.01 (dt, J = 9.4, 1.9 Hz, 1H), 7.81 (dd, J = 10.6, 4.4 Hz, 1H), 7.70 (dd, J = 13.2, 7.3 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.45-7.38 (m, 1H), 7.31 (t, J = 7.6 Hz, 1H). LCMS B rt 3.60 min, m/z 380.1 [M + H].sup.+. 90 B E1 Colourless solid (67% yield). .sup.1H NMR (400 MHz, DMSO) 10.67 (s, 1H), 10.25 (s, 1H), 7.78 (td, J = 7.7, 1.6 Hz, 1H), 7.72- 7.65 (m, 1H), 7.42-7.36 (m, 1H), 7.35- 7.27 (m, 2H), 7.22 (dd, J = 11.4, 4.9 Hz, 2H), 7.09 (dd, J = 7.8, 2.1 Hz, 1H), 3.82 (d, J = 7.0 Hz, 2H), 1.29-1.14 (m, 1H), 0.60- 0.49 (m, 2H), 0.39-0.24 (m, 2H). LCMS B rt 3.63, m/z 365.1 [M + H].sup.+. 91 B E7 Colourless solid (61% yield). .sup.1H NMR (400 MHz, DMSO) 10.79 (s, 1H), 10.36 (s, 1H), 7.79 (td, J = 7.7, 1.6 Hz, 1H), 7.75- 7.63 (m, 1H), 7.47-7.36 (m, 1H), 7.30 (td, J = 7.8, 0.9 Hz, 1H), 7.12 (s, 1H), 7.10- 7.00 (m, 2H), 6.02 (ddt, J = 17.2, 10.5, 5.2 Hz, 1H), 5.39 (dd, J = 17.3, 1.7 Hz, 1H), 5.28 (dd, J = 10.5, 1.5 Hz, 1H), 4.61 (d, J = 5.2 Hz, 2H). LCMS B rt 3.64 min, m/z 369.1 [M + H].sup.+. 92 B E4 Colourless solid (65% yield). .sup.1H NMR (400 MHz, DMSO) 10.78 (s, 1H), 10.34 (s, 1H), 7.86-7.61 (m, 2H), 7.40 (t, J = 8.6 Hz, 1H), 7.37-7.22 (m, 1H), 7.18-6.91 (m, 3H), 4.05 (dt, J = 6.7, 4.1 Hz, 2H), 1.32 (td, J = 6.9, 2.8 Hz, 3H). LCMS B rt 3.61 min, m/z 357.1 [M + H].sup.+. 93 0 B E3 Colourless solid (55% yield). .sup.1H NMR (400 MHz, DMSO) 10.49 (s, 1H), 10.09 (s, 1H), 7.92-7.77 (m, 2H), 7.68-7.61 (m, 1H), 7.55 (t, J = 7.5 Hz, 2H), 6.97 (dd, J = 5.6, 3.1 Hz, 1H), 6.63 (dd, J = 4.7, 3.3 Hz, 1H), 3.76 (d, J = 7.0 Hz, 2H), 3.36 (m, 1H, underneath H.sub.2O peak) 2.19 (d, J = 1.7 Hz, 3H), 0.60-0.51 (m, 2H), 0.34-0.26 (m, 2H). LCMS B rt 3.69 min, m/z 379.1 [M + H].sup.+. 94 B E9 Colourless solid (70% yield). .sup.1H NMR (400 MHz, DMSO) 10.61 (d, J = 2.2 Hz, 1H), 10.23 (d, J = 2.4 Hz, 1H), 7.78 (td, J = 7.6, 1.7 Hz, 1H), 7.73-7.62 (m, 1H), 7.39 (dd, J = 9.7, 8.6 Hz, 1H), 7.32-7.26 (m, 1H), 7.04 (d, J = 18.0 Hz, 2H), 6.91 (s, 1H), 3.80 (d, J = 7.0 Hz, 2H), 3.36 (m, 1H, underneath H.sub.2O peak), 2.26 (s, 3H). 0.64- 0.46 (m, 2H), 0.37-0.22 (m, 2H). LCMS B rt 3.69 min, m/z 379.1 [M + H].sup.+. 95 B E8 Colourless solid (62% yield). .sup.1H NMR (400 MHz, DMSO) 10.50 (s, 1H), 10.10 (s, 1H), 7.88-7.83 (m, 2H), 7.64 (ddd, J = 6.6, 3.8, 1.2 Hz, 1H), 7.55 (dd, J = 10.4, 4.7 Hz, 2H), 7.01 (dd, J = 5.4, 3.2 Hz, 1H), 6.67 (dd, J = 4.7, 3.4 Hz, 1H), 6.01 (ddt, J = 17.2, 10.4, 5.2 Hz, 1H), 5.37 (ddd, J = 17.3, 3.4, 1.6 Hz, 1H), 5.26 (dd, J = 10.5, 1.6 Hz, 1H), 4.53 (dt, J = 5.1, 1.4 Hz, 2H), 2.19 (d, J = 1.8 Hz, 3H). LCMS B rt 3.68 min m/z 365.2 [M + H].sup.+. 96 B E5 Colourless solid (63% yield). .sup.1H NMR (400 MHz, DMSO) 10.77 (s, 1H), 10.33 (s, 1H), 7.78 (t, J = 7.4 Hz, 1H), 7.69 (dd, J = 12.4, 6.6 Hz, 1H), 7.44-7.36 (m, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.06 (s, 1H), 7.00 (dd, J = 8.8, 6.4 Hz, 2H), 4.66 (dt, J = 12.0, 6.0 Hz, 1H), 1.26 (d, J = 6.0 Hz, 6H). LCMS B rt 3.68 min, m/z 371.2 [M + H].sup.+. 97 B E6 Colourless solid (72% yield). .sup.1H NMR (400 MHz, DMSO) 10.77 (s, 1H), 10.35 (s, 1H), 7.79 (dd, J = 10.5, 4.4 Hz, 1H), 7.73- 7.66 (m, 1H), 7.45-7.37 (m, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.10 (s, 1H), 7.02 (dd, J = 9.9, 1.5 Hz, 2H), 3.86 (d, J = 7.1 Hz, 2H), 1.22 (qd, J = 7.7, 3.8 Hz, 1H), 0.62-0.54 (m, 2H), 0.36-0.27 (m, 2H). LCMS B rt 3.69, m/z 383.1 [M + H].sup.+. 99 A I4 Pale brown solid (62% yield). .sup.1H NMR (400 MHz, DMSO): 10.90 (s, 1H), 10.40 (s, 1H), 9.67 (dd, J = 2.5, 1.2 Hz, 1H), 9.33 (dd, J = 5.5, 1.2 Hz, 1H), 8.22 (t, J = 1.5, 1.5 Hz, 1H), 8.13-8.09 (m, 1H), 8.05 (dd, J = 5.4, 2.5 Hz, 1H), 7.84-7.78 (m, 2H), 7.75-7.64 (m, 1H), 7.65 (t, J = 7.7, 7.7 Hz, 1H), 7.44-7.37 (m, 1H), 7.30 (td, J = 7.6, 7.6, 1.1 Hz, 1H). LCMS B rt 3.30 min, m/z 373.1 [M + H].sup.+. 100 A I5 Off-white solid (34% yield). .sup.1H NMR (400 MHz, DMSO): 10.88 (d, J = 3.4 Hz, 1H), 10.15 (d, J = 3.3 Hz, 1H), 7.88-7.83 (m, 4H), 7.75-7.70 (m, 1H), 7.67-7.61 (m, 1H), 7.58-7.52 (m, 2H), 7.39-7.34 (m, 1H), 7.13 (dd, J = 3.4, 0.8 Hz, 1H), 6.65 (dd, J = 3.4, 1.8 Hz, 1H). LCMS B rt 3.69 min, m/z 361.1 [M + H].sup.+. 101 A I5 Off-white solid (25% yield). .sup.1H NMR (400 MHz, DMSO): 10.92 (s, 1H), 10.41 (s, 1H), 7.89-7.78 (m, 3H), 7.75-7.66 (m, 2H), 7.44-7.35 (m, 2H), 7.31 (td, J = 7.7, 7.6, 1.1 Hz, 1H), 7.14-7.10 (m, 1H), 6.65 (dd, J = 3.5, 1.8 Hz, 1H). LCMS B rt 3.63 min, m/z 379.1 [M + H].sup.+. 102 A I6 Off-white solid (24% yield). .sup.1H NMR (400 MHz, DMSO) 10.77 (d, J = 3.4 Hz, 1H), 10.07 (d, J = 3.3 Hz, 1H), 7.87-7.82 (m, 2H), 7.79 (dd, J = 1.7, 0.7 Hz, 1H), 7.66- 7.58 (m, 2H), 7.57-7.52 (m, 2H), 7.38 (dd, J = 2.4, 1.4 Hz, 1H), 7.14 (dd, J = 2.4, 1.4 Hz, 1H), 7.03 (dd, J = 3.4, 0.8 Hz, 1H), 6.62 (dd, J = 3.4, 1.8 Hz, 1H). 3.83 (s, 3H). LCMS B rt 3.61 min, m/z 371.1 [M H].sup.. 103 A I6 Off-white solid (46% yield). .sup.1H NMR (400 MHz, DMSO): 10.80 (d, J = 2.7 Hz, 1H), 10.33 (d, J = 2.7 Hz, 1H), 7.83-7.77 (m, 2H), 7.73-7.66 (m, 1H), 7.61 (t, J = 1.5, 1.5 Hz, 1H), 7.44-7.37 (m, 2H), 7.30 (td, J = 7.6, 7.6, 1.1 Hz, 1H), 7.16-7.13 (m, 1H), 7.03 (dd, J = 3.4, 0.8 Hz, 1H), 6.62 (dd, J = 3.4, 1.8 Hz, 1H), 3.82 (s, 3H). LCMS B rt 3.61 min, m/z 391.1 [M + H].sup.+. 104 0 A I7 White solid (35% yield). .sup.1H NMR (400 MHz, DMSO) 10.91 (d, J = 3.4 Hz, 1H), 10.16 (d, J = 3.3 Hz, 1H), 7.96-7.93 (m, 2H), 7.89-7.82 (m, 3H), 7.68-7.62 (m, 1H), 7.60-7.51 (m, 3H), 7.16 (d, J = 3.4 Hz, 1H), 6.65 (dd, J = 3.4, 1.8 Hz, 1H). LCMS B rt 3.71 min, m/z 377.1 [M + H].sup.+. 105 B I7 White solid (63% yield). .sup.1H NMR (400 MHz, DMSO) 10.95 (d, J = 2.7 Hz, 1H), 10.43 (d, J = 2.6 Hz, 1H), 7.98-7.93 (m, 2H), 7.85-7.78 (m, 2H), 7.74-7.66 (m, 1H), 7.59 (t, J = 1.6 Hz, 1H), 7.46-7.37 (m, 1H), 7.31 (td, J = 7.6, 7.6, 1.1 Hz, 1H), 7.15 (d, J = 3.4 Hz, 1H), 6.65 (dd, J = 3.4, 1.8 Hz, 1H). LCMS B rt 3.38 min, m/z 395.1 [M + H].sup.+. 106 B I8 White solid (56% yield). .sup.1H NMR (400 MHz, DMSO): 11.09 (s, 1H), 10.25 (s, 1H), 8.78 (dd, J = 5.0, 0.8 Hz, 1H), 8.16 (dd, J = 1.5, 0.9 Hz, 1H), 8.12-8.08 (m, 2H), 7.88-7.84 (m, 2H), 7.68-7.62 (m, 1H), 7.59-7.46 (m, 6H). LCMS B rt 3.61 min, m/z 354.1 [M + H].sup.+. 107 B I8 White solid (59% yield). .sup.1H NMR (400 MHz, DMSO): 11.13 (s, 1H), 10.53 (s, 1H), 8.78 (dd, J = 5.0, 0.8 Hz, 1H), 8.16 (dd, J = 1.5, 0.9 Hz, 1H), 8.12-8.07 (m, 2H), 7.82 (td, J = 7.6, 7.4, 1.7 Hz, 1H), 7.75-7.68 (m, 1H), 7.57-7.46 (m, 4H), 7.42 (ddd, J = 10.6, 8.3, 1.1 Hz, 1H), 7.32 (td, J = 7.7, 7.6, 1.1 Hz, 1H). LCMS B rt 3.59 min, m/z 372.1 [M + H].sup.+. 108 B I9 Pale brown solid (43% yield). .sup.1H NMR (400 MHz, DMSO) 10.72 (s, 1H), 10.20 (s, 1H), 9.69 (dd, J = 2.5, 1.2 Hz, 1H), 9.34 (dd, J = 5.5, 1.2 Hz, 1H), 8.08 (dd, J = 5.5, 2.5 Hz, 1H), 7.94 (dd, J = 11.2, 1.7 Hz, 1H), 7.91-7.87 (m, 2H), 7.84 (dd, J = 8.1, 1.7 Hz, 1H), 7.68-7.63 (m, 1H), 7.61- 7.54 (m, 3H). LCMS B rt 3.31 min, m/z 373.2 [M + H].sup.+. 109 B I10 White solid (29% yield). .sup.1H NMR (400 MHz, DMSO): 11.00 (d, J = 3.4 Hz, 1H), 10.22 (d, J = 3.4 Hz, 1H), 9.04 (d, J = 2.3 Hz, 1H), 8.78 (d, J = 2.1 Hz, 1H), 8.31 (t, J = 2.2, 2.2 Hz, 1H), 7.90-7.85 (m, 2H), 7.80-7.75 (m, 2H), 7.67-7.62 (m, 1H), 7.59-7.51 (m, 4H), 7.49-7.44 (m, 1H). LCMS B rt 3.49 min, m/z 354.1 [M + H].sup.+. 110 B I10 White solid (60% yield). .sup.1H NMR (400 MHz, DMSO): 11.05 (d, J = 2.8 Hz, 1H), 10.50 (d, J = 2.8 Hz, 1H), 9.05 (d, J = 2.2 Hz, 1H), 8.80 (d, J = 2.1 Hz, 1H), 8.32 (t, J = 2.2, 2.2 Hz, 1H), 7.84 (td, J = 7.5, 7.5, 1.8 Hz, 1H), 7.79-7.76 (m, 2H), 7.74- 7.67 (m, 1H), 7.56-7.51 (m, 2H), 7.48- 7.40 (m, 2H), 7.32 (td, J = 7.7, 7.7, 1.1 Hz, 1H). LCMS B rt 3.53 min, m/z 372.1 [M + H].sup.+. 111 B I11 White solid (59% yield). .sup.1H NMR (400 MHz, DMSO) 10.78 (s, 1H), 10.35 (s, 1H), 7.79 (td, J = 7.6, 7.6, 1.8 Hz, 1H), 7.74-7.65 (m, 1H), 7.40 (ddd, J = 10.6, 8.4, 1.2 Hz, 1H), 7.30 (td, J = 7.6, 7.6, 1.1 Hz, 1H), 7.09 (d, J = 1.5 Hz, 1H), 7.02 (dd, J = 9.8, 1.8 Hz, 2H), 3.95 (t, J = 6.5, 6.5 Hz, 2H), 1.72 (h, J = 7.5, 7.5, 7.5, 7.4, 7.4 Hz, 2H), 0.96 (t, J = 7.4, 7.4 Hz, 3H). LCMS B rt 3.68 min, m/z 371.1 [M + H].sup.+. 112 B I11 White solid (53% yield). .sup.1H NMR (400 MHz, DMSO) 10.74 (s, 1H), 10.08 (s, 1H), 7.84-7.80 (m, 2H), 7.67-7.61 (m, 1H), 7.58-7.51 (m, 2H), 7.11-7.08 (m, 1H), 7.01 (dd, J = 10.2, 2.0 Hz, 2H), 3.96 (t, J = 6.5, 6.5 Hz, 2H), 1.72 (h, J = 7.3, 7.3, 7.2, 7.2, 7.2 Hz, 2H), 0.97 (t, J = 7.4, 7.4 Hz, 3H). LCMS B rt 3.69 min, m/z 353.1 [M + H].sup.+. 113 B I12 White solid (55% yield). .sup.1H NMR (400 MHz, DMSO) 10.52 (s, 1H), 10.11 (s, 1H), 7.89-7.84 (m, 2H), 7.69-7.62 (m, 1H), 7.60-7.53 (m, 2H), 7.03-6.96 (m, 1H), 6.64 (dd, J = 5.0, 3.1 Hz, 1H), 3.88 (t, J = 6.5, 6.5 Hz, 2H), 1.70 (h, J = 7.4, 7.4, 7.3, 7.3, 7.3 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H). LCMS A rt 6.6 min, m/z 367.1 [M + H].sup.+. 114 0 B I13 White solid (56% yield). .sup.1H NMR (400 MHz, DMSO) 10.51 (d, J = 3.3 Hz, 1H), 10.10 (d, J = 3.3 Hz, 1H), 7.88-7.84 (m, 2H), 7.67-7.61 (m, 1H), 7.56 (dd, J = 8.3, 6.8 Hz, 2H), 6.96 (dd, J = 5.7, 3.1 Hz, 1H), 6.60 (dd, J = 5.0, 3.1 Hz, 1H), 4.51 (hept, J = 6.0 Hz, 1H), 2.18 (d, J = 2.1 Hz, 3H), 1.23 (d, J = 6.0 Hz, 6H). LCMS A rt 6.57 min, m/z 367.1 [M + H].sup.+. 150 A A14 Colourless solid (51% yield). .sup.1H NMR (400 MHz, DMSO) 10.68 (s, 1H), 10.26 (s, 1H), 7.79 (td, J = 7.7, 1.7 Hz, 1H), 7.69 (ddd, J = 7.3, 5.0, 1.7 Hz, 1H), 7.46-7.16 (m, 5H), 7.12 (dd, J = 8.2, 1.7 Hz, 1H), 6.04 (ddt, J = 17.2, 10.5, 5.2 Hz, 1H), 5.42- 5.36 (m, 1H), 5.27 (ddd, J = 10.5, 3.0, 1.4 Hz, 1H), 4.59 (dt, J = 5.2, 1.5 Hz, 2H). LCMS B rt 3.57 min, m/z 351.1 [M + H].sup.+. 151 B A15 Colourless solid (38% yield). .sup.1H NMR (400 MHz, DMSO) 10.61 (s, 1H), 10.21 (s, 1H), 7.79 (t, J = 7.4 Hz, 1H), 7.68 (d, J = 5.0 Hz, 1H), 7.45-7.35 (m, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.12 (d, J = 15.8 Hz, 2H), 7.02 (s, 1H), 4.38 (d, J = 3.5 Hz, 1H), 2.29 (s, 3H), 0.78 (d, J = 6.1 Hz, 2H), 0.63 (s, 2H). LCMS B rt 3.66 min, m/z 365.1 [M + H].sup.+. 154 A I17 Colourless solid (54% yield). .sup.1H NMR (400 MHz, DMSO) 10.84 (s, 1H), 10.36 (s, 1H), 7.94-7.80 (m, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.61-7.46 (m, 7H), 7.43 (dd, J = 8.9, 4.6 Hz, 1H), 2.25 (d, J = 7.0 Hz, 3H). LCMS B rt 3.41 min, m/z 402.8 [M + H].sup.+. 155 A I19 Colourless solid (47% yield). .sup.1H NMR (400 MHz, DMSO) 10.89 (s, 1H), 10.39 (s, 1H), 8.14 (t, J = 2.5 Hz, 1H), 7.95-7.85 (m, 2H), 7.82-7.77 (m, 2H), 7.66 (d, J = 7.5 Hz, 1H), 7.59 (t, J = 7.6 Hz, 2H), 6.59- 6.56 (m, 1H), 2.27 (s, 3H). LCMS B rt 3.20 min, m/z 393.4 [M + H].sup.+. 156 A I23 Colourless solid (61% yield). .sup.1H NMR (400 MHz, DMSO) 10.75 (s, 1H), 10.30 (s, 1H), 7.88-7.81 (m, 2H), 7.70-7.63 (m, 1H), 7.58 (d, J = 7.8 Hz, 2H), 7.23-7.12 (m, 1H), 4.07 (q, J = 7.0 Hz, 2H), 2.18 (s, 3H), 1.32 (t, J = 7.0 Hz, 3H). LCMS B rt 3.27 min, m/z 371.4 [M + H].sup.+. 157 A I24 Colourless solid (5.5 mg, 3% yield). .sup.1H NMR (400 MHz, DMSO) 10.69 (s, 1H), 10.18 (s, 1H), 7.89 (d, J = 7.4 Hz, 2H), 7.81 (s, 1H), 7.71-7.53 (m, 6H), 7.49 (t, J = 7.3 Hz, 2H), 7.44-7.26 (m, 2H). LCMS A rt 6.31 min, m/z 371.1 [M + H].sup.+.

Example 4

(120) The following compound was synthesised according to the specified Amide coupling (M) from commercially available starting materials:

(121) TABLE-US-00018 Structure M Product details 98 C Colourless solid (11% yield). .sup.1H NMR (400 MHz, DMSO) 10.85 (s, 1H), 10.12 (s, 1H), 8.95 (s, 1H), 8.61 (s, 1H), 8.29-7.98 (m, 2H), 7.89 (dd, J = 22.7, 6.5 Hz, 3H), 7.74-7.44 (m, 6H). LCMS B rt 4.67, m/z 354.1 [M + H].sup.+. 115 B White solid (25% yield). .sup.1H NMR (400 MHz, DMSO) 11.03 (s, 1H), 10.41 (s, 1H), 9.40 (s, 1H), 8.34 (t, J = 1.7, 1.7 Hz, 1H), 8.21-8.15 (m, 1H), 7.96-7.91 (m, 1H), 7.81 (td, J = 7.5, 7.5, 1.8 Hz, 1H), 7.73-7.66 (m, 2H), 7.48-7.37 (m, 1H), 7.30 (td, J = 7.6, 7.6, 1.1 Hz, 1H). LCMS B rt 3.35 min, m/z 363.1 [M + H].sup.+. 116 B White solid (68% yield). .sup.1H NMR (400 MHz, DMSO) 10.76 (d, J = 3.1 Hz, 1H), 10.11 (d, J = 3.1 Hz, 1H), 8.31 (dd, J = 8.0, 1.6 Hz, 2H). 8.20- 8.16 (m, 1H), 8.01 (t, J = 7.8, 7.8 Hz, 1H), 7.89- 7.86 (m, 2H), 7.76 (dd, J = 7.7, 0.8 Hz, 1H), 7.69- 7.63 (m, 1H), 7.59-7.48 (m, 5H). LCMS B rt 3.68 min, m/z 354.1 [M + H].sup.+. 117 0 B White solid (70% yield). .sup.1H NMR (400 MHz, DMSO) 10.92 (d, J = 3.1 Hz, 1H), 10.37 (d, J = 2.9 Hz, 1H), 8.34 (d, J = 7.2 Hz, 2H), 8.18 (d, J = 7.9 Hz, 1H), 8.01 (t, J = 7.7, 7.7 Hz, 1H), 7.86- 7.74 (m, 2H), 7.70 (dd, J = 11.9, 6.0 Hz, 1H), 7.57-7.38 (m, 4H), 7.29 (t, J = 7.6, 7.6 Hz, 1H). LCMS B rt 3.69 min, m/z 372.1 [M + H].sup.+. 118 B Colourless solid (56% yield). .sup.1H NMR (400 MHz, DMSO) .sup.1H NMR (400 MHz, DMSO) 5 11.00 (s, 1H), 10.39 (s, 1H), 9.77 (s, 1H), 8.36 (d, J = 1.5 Hz, 1H), 8.21 (d, J = 7.9 Hz, 1H), 7.92 (dd, J = 6.6, 1.5 Hz, 1H), 7.82 (td, J = 7.6, 1.6 Hz, 1H), 7.68 (dd, J = 9.1, 6.5 Hz, 2H), 7.49-7.38 (m, 1H), 7.30 (dd, J = 7.6, 1.0 Hz, 1H). LCMS B rt 3.11 min, m/z 363.1 [M + H].sup.+. 119 B White solid (0.059 g, 33% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.96 (d, J = 2.1 Hz, 1H), 10.16 (d, J = 2.7 Hz, 1H), 8.04-7.96 (m, 2H), 7.93 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 7.5 Hz, 2H), 7.71 (t, J = 7.7 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.54 (t, J = 7.5 Hz, 2H). LCMS A rt 6.77 min, m/z 344.1 [M + H].sup.+. 120 B White solid (0.104 g, 34% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.27 (s, 1H), 7.79 (td, J = 7.7, 1.5 Hz, 2H), 7.72-7.64 (m, 1H), 7.43-7.22 (m, 3H), 7.20 (s, 1H), 7.08 (dd, J = 8.1, 1.8 Hz, 1H), 4.03 (q, J = 6.9 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H). LCMS A rt 6.00 min, m/z 337.0 [M H].sup.. 121 B White solid (0.101 g, 52% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.68 (s, 1H), 10.25 (s, 1H), 7.79 (td, J = 7.7, 1.7 Hz, 1H), 7.69 (ddd, J = 8.3, 5.0, 1.7 Hz, 1H), 7.44-7.20 (m, 5H), 7.10 (dd, J = 8.2, 1.7 Hz, 1H), 3.94 (t, J = 6.5 Hz, 2H), 1.79-1.50 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). LCMS B rt 3.41 min, m/z 353.2 [M + H].sup.+. 122 B White solid (0.105 g, 51% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.68 (s, 1H), 10.24 (s, 1H), 7.8 (td, J = 7.6, 1.7 Hz, 1H), 7.73-7.65 (m, 1H), 7.57 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.45-7.32 (m, 3H), 7.30 (td, J = 7.7, 1.0 Hz, 1H), 2.9 (m, 1H), 1.21 (s, 3H), 1.19 (s, 3H). LCMS B rt 3.41, m/z 337.1 [M + H].sup.+. 123 B White solid (0.191 g, 99% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.69 (s, 1H), 10.27 (s, 1H), 7.79 (t, J = 6.9 Hz, 1H), 7.68 (d, J = 4.6 Hz, 1H), 7.44-7.35 (m, 1H), 7.31 (dt, J = 10.8, 7.8 Hz, 2H), 7.25-7.15 (m, 2H), 7.07 (d, J = 7.5 Hz, 1H), 4.77-4.50 (m, 1H), 1.25 (d, J = 5.8 Hz, 6H). LCMS A rt 6.87 min, m/z 353.1 [M + H].sup.+. 124 B White solid (0.191 g, 99% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.82 (s, 1H), 10.35 (s, 1H), 8.03 (s, 1H), 7.93 (d, J = 1.6 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.81 (t, J = 6.8 Hz, 1H), 7.73-7.65 (m, 2H), 7.58 (d, J = 6.2 Hz, 2H), 7.48 (t, J = 7.7 Hz, 1H), 7.44-7.37 (m, 1H), 7.30 (t, J = 7.6 Hz, 1H). LCMS A rt 6.90 min, m/z 377.1 [M + H].sup.+. 125 B White solid (0.129 g, 70% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.70 (d, J = 2.3 Hz, 1H), 10.27 (d, J = 2.5 Hz, 1H), 7.82-7.75 (m, 1H), 7.72-7.64 (m, 1H), 7.44-7.19 (m, 5H), 7.09 (dd, J = 8.1, 1.7 Hz, 1H), 3.97 (t, J = 6.5 Hz, 2H), 1.75-1.62 (m, 2H), 1.42 (dd, J = 14.9, 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H). LCMS A rt 7.45 min, m/z 367.1 [M + H].sup.+. 126 B White solid (0.145 g, 78% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.70 (s, 1H), 10.28 (s, 1H), 7.79 (td, J = 7.7, 1.6 Hz, 1H), 7.68 (ddd, J = 8.1, 5.0, 1.7 Hz, 1H), 7.44-7.21 (m, 5H), 7.09 (dd, J = 8.1, 1.7 Hz, 1H), 3.74 (d, J = 6.5 Hz, 2H), 2.00 (dt, J = 13.3, 6.6 Hz, 1H), 0.97 (d, J = 6.7 Hz, 6H). LCMS B rt 3.74, m/z 367.2 [M + H].sup.+. 127 00 B White solid (0.081 g, 38% yield). .sup.1H NMR (400 MHz, DMSO-D6) 10.67 (s, 1H), 10.24 (s, 1H), 7.79 (t, J = 7.5 Hz, 1H), 7.68 (dd, J = 12.5, 6.5 Hz, 1H), 7.53 (s, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.43- 7.24 (m, 4H), 2.61 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H). LCMS A rt 6.90 min, m/z 323.1 [M + H].sup.+. 128 01 B White solid (0.218 g, 79% yield). .sup.1H NMR (400 MHz, DMSO) 10.94 (d, J = 2.4 Hz, 1H), 10.40 (d, J = 2.5 Hz, 1H), 7.80 (td, J = 7.7, 1.7 Hz, 1H), 7.76-7.66 (m, 2H), 7.65-7.56 (m, 3H), 7.45- 7.38 (m, 1H), 7.31 (td, J = 7.7, 1.0 Hz, 1H). LCMS B rt 3.73 min, m/z 379.2 [M + H].sup.+. 129 02 B White solid (0.122 g, 65% yield). .sup.1H NMR (400 MHz, DMSO) 10.86 (s, 1H), 10.34 (s, 1H), 7.95 (s, 1H), 7.82 (dd, J = 12.9, 7.0 Hz, 2H), 7.70 (dd, J = 12.4, 6.7 Hz, 1H), 7.64-7.56 (m, 3H), 7.49 (t, J = 7.7 Hz, 1H), 7.45-7.38 (m, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.18 (dd, J = 5.0, 3.7 Hz, 1H). LCMS B rt 3.59, m/z 377.1 [M + H].sup.+. 130 03 B White solid (0.058 g, 48% yield). .sup.1H NMR (400 MHz, DMSO) 10.66 (s, 1H), 10.25 (s, 1H), 7.80 (td, J = 7.7, 1.7 Hz, 1H), 7.72-7.65 (m, 1H), 7.53- 7.47 (m, 2H), 7.43-7.33 (m, 3H), 7.29 (td, J = 7.7, 1.0 Hz, 1H), 2.57 (t, J = 7.6, 2H), 1.70-1.48 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H). LCMS B rt 3.66 min, m/z 337.2 [M + H].sup.+. 131 04 B White solid (0.127 g, 69% yield). .sup.1H NMR (400 MHz, DMSO) 10.64 (s, 1H), 10.26 (s, 1H), 7.79 (t, J = 6.7 Hz, 1H), 7.72-7.65 (m, 1H), 7.43- 7.36 (m, 1H), 7.31 (dt, J = 10.3, 7.7 Hz, 2H), 7.22 (d, J = 7.8 Hz, 1H), 7.17 (s, 1H), 7.07 (d, J = 8.2 Hz, 1H), 4.92-4.74 (m, 1H), 1.98-1.86 (m, 2H), 1.76-1.64 (m, 4H), 1.63-1.53 (m, 2H). LCMS B rt 3.37 min, m/z 379.2 [M + H].sup.+. 132 05 B White solid (0.04 g, 94% yield). .sup.1H NMR (400 MHz, DMSO) 7.93 (s, 1H), 7.87 (s, 1H), 7.81 (t, J = 6.7 Hz, 1H), 7.73-7.64 (m, 3H), 7.59 (s, 1H), 7.45-7.37 (m, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.18 (dd, J = 5.0, 3.7 Hz, 1H). LCMS B rt 3.76 min, m/z 411.1 [M + H].sup.+. 133 06 B White solid (0.198 g, 60% yield). LCMS A rt 6.38 min, m/z 389.0 [M + H].sup.+. 134 07 B White solid (0.108 g, 81% yield). .sup.1H NMR (400 MHz, DMSO) 10.55 (d, J = 3.3 Hz, 1H), 10.11 (d, J = 3.4 Hz, 1H), 7.90-7.82 (m, 2H), 7.70- 7.61 (m, 1H), 7.56 (t, J = 7.5 Hz, 2H), 7.16 (t, J = 9.3 Hz, 1H), 7.08-7.01 (m, 1H), 6.80 (dd, J = 5.5, 3.1 Hz, 1H), 4.64-4.42 (m, 1H), 1.24 (d, J = 6.0 Hz, 6H). LCMS B rt 3.61 min, m/z 353.1 [M + H].sup.+. 135 08 B White solid (0.111 g, 91% yield). .sup.1H NMR (400 MHz, DMSO) 10.86 (s, 1H), 10.34 (s, 1H), 7.95 (s, 1H), 7.82 (dd, J = 12.9, 7.0 Hz, 2H), 7.70 (dd, J = 12.4, 6.7 Hz, 1H), 7.64-7.56 (m, 3H), 7.49 (t, J = 7.7 Hz, 1H), 7.45-7.38 (m, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.18 (dd, J = 5.0, 3.7 Hz, 1H). LCMS B rt 3.61 min, m/z 361.1 [M + H].sup.+. 136 09 B White solid (0.111 g, 61% yield). .sup.1H NMR (400 MHz, DMSO) 10.55 (s, 1H), 10.12 (s, 1H), 7.86 (d, J = 7.3 Hz, 2H), 7.65 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.5 Hz, 2H), 7.19 (t, J = 9.3 Hz, 1H), 7.13- 7.04 (m, 1H), 6.86 (dd, J = 5.3, 3.2 Hz, 1H), 6.02 (ddd, J = 22.4, 10.4, 5.2 Hz, 1H), 5.38 (dd, J = 17.3, 1.6 Hz, 1H), 5.27 (d, J = 10.6 Hz, 1H), 4.56 (d, J = 5.1 Hz, 2H). LCMS B rt 3.57 min, m/z 351.1 [M + H].sup.+. 137 0 B White solid (0.072 g, 73% yield). .sup.1H NMR (400 MHz, DMSO) 10.62 (s, 1H), 10.23 (s, 1H), 7.78 (td, J = 7.7, 1.5 Hz, 1H), 7.68 (ddd, J = 8.1, 5.0, 1.7 Hz, 1H), 7.43-7.35 (m, 1H), 7.32-7.26 (m, 1H), 7.07 (s, 1H), 7.02 (s, 1H), 6.91 (s, 1H), 4.01 (q, J = 6.9 Hz, 2H), 2.27 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H). LCMS A rt 6.19 min, m/z 353.1 [M + H].sup.+. 138 B White solid (0.078 g, 88% yield). .sup.1H NMR (400 MHz, DMSO) 10.51 (s, 1H), 10.10 (s, 1H), 7.86 (d, J = 7.5 Hz, 2H), 7.64 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.5 Hz, 2H), 6.97 (dd, J = 5.3, 2.9 Hz, 1H), 6.78-6.48 (m, 1H), 3.98 (q, J = 6.9 Hz, 2H), 2.19 (s, 3H), 1.30 (t, J = 6.9 Hz, 3H). LCMS A rt 6.22 min, m/z 353.1 [M + H].sup.+. 139 B White solid (0.085 g, 35% yield). .sup.1H NMR (400 MHz, DMSO) 10.62 (s, 1H), 10.23 (s, 1H), 7.78 (dd, J = 10.6, 4.3 Hz, 1H), 7.69 (dd, J = 12.3, 6.7 Hz, 1H), 7.44-7.36 (m, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.05 (s, 1H), 7.01 (s, 1H), 6.90 (s, 1H), 4.68- 4.49 (m, 1H), 2.27 (s, 3H), 1.25 (d, J = 6.0 Hz, 6H). LCMS A rt 6.35 min, m/z 367.2 [M + H].sup.+. 140 B White solid (0.069 g, 77% yield). .sup.1H NMR (400 MHz, MeOD) 8.00-7.94 (m, 2H), 7.68-7.60 (m, 1H), 7.59-7.51 (m, 2H), 7.12 (dd, J = 6.0, 2.1 Hz, 2H), 7.06-7.01 (m, 1H), 4.72 (d, J = 2.4 Hz, 3H), 2.99 (t, J = 2.4 Hz, 1H). LCMS B rt 3.51 min, m/z 349.1 [M + H].sup.+. 141 B White solid (0.102 g, 75% yield). .sup.1H NMR (400 MHz, DMSO) 10.63 (s, 1H), 10.24 (s, 1H), 7.78 (t, J = 6.8 Hz, 1H), 7.68 (dd, J = 12.3, 6.5 Hz, 1H), 7.44-7.35 (m, 2H), 7.30 (t, J = 7.6 Hz, 1H), 6.79 (s, 1H), 6.61 (s, 1H), 4.60 (dt, J = 12.0, 6.0 Hz, 1H), 3.73 (s, 3H), 1.24 (d, J = 6.0 Hz, 6H). LCMS B rt 3.62 min, m/z 383.1 [M + H].sup.+. 142 B White solid (0.093 g, 65% yield). .sup.1H NMR (400 MHz, DMSO) 7.82-7.75 (m, 1H), 7.72-7.64 (m, 1H), 7.39 (dd, J = 9.9, 8.8 Hz, 1H), 7.29 (td, J = 7.7, 1.0 Hz, 1H), 6.80 (d, J = 2.3 Hz, 2H), 6.63 (t, J = 2.2 Hz, 1H), 4.01 (q, J = 7.0 Hz, 2H), 3.74 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H). LCMS B rt 3.57 min, m/z 369.1 [M + H].sup.+. 143 B White solid (0.025 g, 29% yield). .sup.1H NMR (400 MHz, DMSO) 7.82-7.75 (m, 1H), 7.72-7.64 (m, 1H), 7.39 (dd, J = 9.9, 8.8 Hz, 1H), 7.29 (td, J = 7.7, 1.0 Hz, 1H), 6.80 (d, J = 2.3 Hz, 1H), 6.63 (t, J = 2.2 Hz, 1H), 4.01 (q, J = 7.0 Hz, 2H), 3.74 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H). LCMS B rt 3.62 min, m/z 371.1 [M + H].sup.+. 144 B White solid (0.069 g, 75% yield). .sup.1H NMR (400 MHz, Acetone) 8.04-7.88 (m, 2H), 7.65 (dd, J = 10.5, 4.3 Hz, 1H), 7.56 (dd, J = 10.4, 4.7 Hz, 2H), 7.10 (ddd, J = 14.0, 13.1, 6.6 Hz, 2H), 7.01 (dd, J = 5.5, 3.1 Hz, 1H), 4.03 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). LCMS A rt 6.03 min, m/z 339.1 [M + H].sup.+. 145 B White solid (0.106 g, 37% yield). .sup.1H NMR (400 MHz, DMSO) 10.51 (s, 1H), 10.10 (s, 1H), 7.86 (d, J = 7.4 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.6 Hz, 2H), 7.01 (dd, J = 5.6, 3.1 Hz, 1H), 6.75-6.57 (m, 1H), 6.01 (ddd, J = 22.4, 10.4, 5.2 Hz, 1H), 5.37 (dd, J = 17.3, 1.6 Hz, 1H), 5.26 (dd, J = 10.5, 1.4 Hz, 1H), 4.53 (d, J = 5.1 Hz, 2H), 2.19 (s, 3H). LCMS B rt 3.66 min, m/z 365.2 [M + H].sup.+. 146 B White solid (0.021 g, 68% yield). .sup.1H NMR (400 MHz, DMSO) 10.51 (d, J = 3.0 Hz, 1H), 10.10 (d, J = 3.0 Hz, 1H), 7.86 (d, J = 7.4 Hz, 2H), 7.64 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.5 Hz, 2H), 7.01 (d, J = 1.9 Hz, 1H), 6.77-6.56 (m, 1H), 4.99 (d, J = 28.4 Hz, 2H), 4.43 (s, 2H), 2.19 (s, 3H), 1.75 (s, 3H). LCMS B rt 3.72 min, m/z 379.2 [M + H].sup.+.

(122) Compound 147 was made by analogous methods:

(123) ##STR00320##

(124) Commercial Compounds

(125) TABLE-US-00019 Structure Supplier 148 Princeton BioMolecular Research 149 Chembridge

Example 5

(a) N-(2-Fluoro-5-(furan-2-yl)-3-methylbenzoyl)benzenesulfonohydrazide (152)

(126) ##STR00323##

(127) 2-Fluoro-5-(furan-2-yl)-3-methylbenzoic acid (I15) (0.045 g, 0.204 mmol), benzenesulfonyl hydrazide (0.044 g, 0.255 mmol), HOAt (0.035 g, 0.255 mmol) and EDCI.HCl (0.049 g, 0.255 mmol) were dissolved in MeCN (3 mL), under an atmosphere of nitrogen. The solution was heated to 40 C. and allowed to stir for 17 h, upon which the reaction was cooled, concentrated in vacuo, then loaded directly onto silica for purification. The crude material was purified by silica gel chromatography (Isolera Biotage, 12 g Si Cartridge, 0-60% EtOAc in petroleum benzine 40-60 C.) with the fractions containing suspected product collected and concentrated in vacuo, to yield the title compound (0.018 g, 24% yield) as a white solid.

(128) .sup.1H NMR (400 MHz, DMSO) 10.63 (d, J=3.3 Hz, 1H), 10.17 (d, J=3.3 Hz, 1H), 7.90-7.86 (m, 2H), 7.77 (dd, J=1.7, 0.7 Hz, 1H), 7.75 (dd, J=6.4, 2.0 Hz, 1H), 7.66 (tt, J=6.6, 6.6, 1.3, 1.3 Hz, 1H), 7.61-7.54 (m, 2H), 7.45 (dd, J=6.0, 2.2 Hz, 1H), 6.95 (dd, J=3.4, 0.8 Hz, 1H), 6.60 (dd, J=3.4, 1.8 Hz, 1H), 2.27 (d, J=2.0 Hz, 3H). LCMS B rt. 3.692 min, m/z 375.1 [M+H]+.

(b) 2-Fluoro-N-(3-(furan-2-yl)-5-methylbenzoyl)benzenesulfonohydrazide (153)

(129) ##STR00324##

(130) 3-(Furan-2-yl)-5-methylbenzoic acid (I14) (0.045 g, 0.223 mmol), 2 fluorobenzenesulfonyl hydrazide (0.053 g, 0.278 mmol), HOAt (0.038 g, 0.278 mmol) and EDCI.HCl (0.053 g, 0.278 mmol) were dissolved in MeCN (3 mL) under an atmosphere of nitrogen. The solution was heated to 40 C. and allowed to stir for 17 h, upon which the reaction was cooled, concentrated in vacuo, then loaded directly onto silica for purification. The crude material was purified by silica gel chromatography (Isolera Biotage, 12 g Si Cartridge, 0-60% EtOAc in petroleum benzine 40-60 C.) with the fractions containing suspected product collected and concentrated in vacuo, to yield the title compound (0.020 g, 24% yield) as a white solid.

(131) .sup.1H NMR (400 MHz, DMSO): 10.77 (d, J=2.7 Hz, 1H), 10.30 (d, J=2.7 Hz, 1H), 7.84-7.76 (m, 3H), 7.72-7.65 (m, 2H), 7.43-7.37 (m, 2H), 7.30 (td, J=7.6, 7.6, 1.1 Hz, 1H), 6.98-6.96 (m, 1H), 6.61 (dd, J=3.4, 1.8 Hz, 1H), 2.35 (s, 3H). LCMS B rt 3.70 min, m/z 373.0 [MH].sup..

Example 6Moz Biochemical Assay

(132) Compounds of the invention may be tested for in vitro activity in the following assay: Active Moz protein was expressed as N-terminal fusion protein with a His.sub.6 tag in BL21 E. coli cells. Protein purification was performed via nickel-immobilized metal ion affinity chromatography followed by gel filtration. To determine the inhibition of Moz activity by the test compounds, assay reactions were conducted in a volume of 8 L in 384-well low volume assay plates. The reactions were performed in assay buffer (100 mM Tris-HCl, pH 7.8, 15 mM NaCl, 1 mM EDTA, 0.01% Tween-20, 1 mM Dithiothreitol, and 0.02% m/v chicken egg white albumin). Reactions were set up with 0.4 M Acetyl coenzyme A (AcCoA), 50 nM N-terminal histone H4 peptide (sequence SGRGKGGKGLGKGGAKRHRKV-GGK-biotin), 10 nM MOZ enzyme, and an acetyl-lysine specific antibody (final dilution 1:10000). 11-point dilution series of the compounds of the invention were prepared in DMSO; a volume of 100 nL was transferred using a pin tool into assay plates containing substrates, before adding enzyme to start the reaction. Positive (no compound) and negative (AcCoA omitted) control reactions were included on the same plates and received the same amount of DMSO as the compound treated wells. After adding all reagents, the plates were sealed with adhesive seals and incubated for 90 minutes at room temperature. An additional 4 L of assay buffer containing AlphaScreen Protein A acceptor beads and Streptavidin donor beads (PerkinElmer, Waltham, Mass.) to a final concentration of 4 g/mL was then added. After incubation for 2 hours the plates were read using an EnVision 2103 multi label plate reader (PerkinElmer) in HTS AlphaScreen mode. IC.sub.50 values were obtained from the raw readings by calculating percent inhibition (%1) for each reaction relative to controls on the same plate (% I=(ICN)/(CPCN) where CN/CP are the averages of the negative/positive reactions, respectively), then fitting the % I data vs. compound concentration [I] to % I=(A+((BA)/(1+((C/[I]){circumflex over ()}D)))) where A is the lower asymptote, B is the upper asymptote, C is the IC.sub.50 value, and D is the slope.

(133) Results

(134) TABLE-US-00020 IC.sub.50 (M) 1 2.951 2 0.287 3 7.795 4 0.195 5 0.123 6 2.044 7 7.438 8 0.162 9 0.449 10 6.865 11 0.475 12 125.000 13 0.998 14 0.470 15 3.173 16 1.672 17 3.789 18 0.432 19 2.436 20 0.378 21 2.353 22 8.465 23 0.406 24 0.139 25 3.834 26 40.034 27 11.242 28 3.215 29 0.548 30 0.721 31 8.549 32 25.807 33 0.270 34 8.016 35 0.082 36 0.055 37 85.376 38 0.674 39 0.181 40 0.635 41 0.142 42 0.077 43 0.100 44 0.075 45 0.097 46 0.051 47 0.393 48 0.085 49 0.089 50 0.231 51 0.449 52 0.073 53 0.065 54 0.137 55 0.150 56 1.253 57 0.126 58 0.123 59 0.047 60 0.062 61 0.097 62 1.174 63 0.097 64 0.070 65 0.440 66 0.120 67 0.060 68 0.153 69 0.068 70 0.203 71 0.078 72 0.426 73 0.411 74 0.552 75 0.094 76 0.119 77 0.303 78 0.122 79 0.084 80 0.126 81 0.748 82 0.221 83 0.331 84 0.058 85 0.087 86 0.091 87 0.041 88 0.054 89 0.140 90 0.116 91 0.060 92 0.106 93 0.084 94 0.061 95 0.050 96 0.093 97 0.091 98 13.148 99 63.672 100 0.144 101 0.066 102 0.478 103 0.109 104 0.106 105 0.093 106 18.961 107 1.915 108 125.000 109 21.345 110 2.592 111 0.072 112 0.422 113 0.052 114 0.064 115 4.623 116 16.622 117 4.550 118 0.488 119 10.491 120 0.126 121 0.117 122 0.966 123 0.093 124 0.066 125 0.437 126 0.176 127 0.675 128 0.558 129 0.077 130 0.120 131 0.244 132 0.096 133 0.839 134 0.060 135 0.098 136 0.053 137 0.062 138 0.062 139 0.043 140 0.151 141 0.133 142 0.167 143 0.074 144 0.185 145 0.100 146 0.055 147 90.950 148 1.774 149 7.067 150 0.043 151 0.145 152 0.008 153 0.010 154 0.010 155 0.071 157 0.017

Example 7Bioassays for Development of MOZ Specific Inhibitors

(135) Mouse embryonic fibroblasts are isolated from wild type or Moz heterozygous animals and cultured at 3% oxygen/5% carbon dioxide/92% nitrogen. Cells are plated at a density of 1,020 cells/cm.sup.2 or 2,040 cells/cm.sup.2 or 10,204 cells/cm.sup.2. A reference value for MOZ inhibition is generated through comparison with cells with a complete null mutation of MOZ. The absence of a functional Moz gene leads to senescence in 7-14 days at 3% oxygen.

(136) Bioassay 1

(137) Cells are plated in triplicate cultures at 10,204 cells/cm.sup.2 in the presence of a test compound. Compounds are tested at 500 nM, 1 M, 2 M, 5 M, 10 M and 20 M. Control compounds include those that have a similar structure but show no activity in biochemical assays. After 48 hours, cells are passaged and counted, then replated at 10,204/cm.sup.2. This procedure is continued for 336 hours. The total number of cells produced at each passage is then calculated and compared between treatment groups. Cellular senescence is determined by cell cycle arrest, i.e. reduced incorporation of BrdU, reduced level of Ki67 staining and flow cytometric analysis of DNA content, combined with increased expression of -galactosidase (determined after 384 hours), likewise determined by flow cytometry. Cells are analysed by flow cytometry for the absence of markers of apoptosis by staining with propidium iodide and FITC-conjugated annexin V. The level of DNA damaged is assessed by H2A.X staining, a marker of DNA strand breaks. Moz heterozygous cells are used to demonstrate that the primary effect of the active compounds is on-target by demonstrating that Moz heterozygous cells have an increased sensitivity to active inhibitors.

(138) Bioassay 2

(139) Cells are plated in triplicate at 2,040 cells/cm.sup.2 in the presence of a test compound. Compounds are tested at 500 nM, 1 M, 2 M, 5 M, 10 M and 20 M. Control compounds include those that have a similar structure but show no activity in biochemical assays. Cells are grown for 144 hours then harvested for RNA purification or chromatin immunoprecipitation assays. RT-qPCR is used to assay the levels of MOZ target genes Ink4a, ink4b, Arf, Cdc6, Cdca8, Cdca2, E2f2, Ezh2, Skp2 and Melk. Chromatin immunoprecipitation is used to demonstrate that the target of MOZ acetyltransferase activity, histone 3 lysine 9 acetylation, is reduced, but that histone 3 lysine 14 acetylation, which is not a MOZ target, is not affected.

(140) Bioassay 3

(141) Cells are plated in triplicate at 1,020 cells/cm2 in the presence of a test compound. Compounds are tested at 500 nM, 1 M, 2 M, 5 M, 10 M and 20 M. Control compounds include those that have a similar structure but show no activity in biochemical assays. Cells are grown for 144 hours then harvested for assessment of population doublings and percentage of dead cells.

(142) Bioassay 4

(143) To test if cells expressing mutant forms of RAS sensitized to senescence induction, MOZ inhibitors were combined with the ectopic expression of KRASG12V. Cells are plated in triplicate cultures at 10,204 cells/cm2 then transfected with control retroviral vectors pBABE or pBABE containing a mutant KrasG12V expression cassette. Cultures were maintained at 3% O2. Selection for transfected cells is achieved using puromycin. Compounds are tested at 0 M 1 M, 2.5 M, and 5 M. After 48 hours, cells are passaged and counted, then replated at 10,204/cm2. This procedure is continued for 336 hours. The total number of cells produced at each passage is then calculated and compared between treatment groups. Cellular senescence is determined by cell cycle arrest. Comparisons are between cells treated with vehicle only expressing the control vector, cells treated with 5 M expressing the control vector (concentration shown in bioassay 1 to produce cellular senescence) and cells treated with 0 uM 1 M, 2.5 M, and 5 M expressing the KrasV12 expressing vector vector

(144) Bioassay 5

(145) Using a loss of function mutation in MOZ (KAT6a) we have demonstrated that MOZ is required for proliferation of B cells and that even heterozygous loss of MOZ delays onset of lymphoma 3.9 fold. (Sheikh et al 2015b). Therefore the agents disclosed herein may be useful in preventing relapse of patients in remission after standard treatments or in combination with standard treatments, since inhibition of proliferation of the target progenitor or stem cell may reduce the probability of acquiring additional mutations that would otherwise enhance the cancer phenotype.

(146) Pro-B cells are purified by positive selection using antiCD19-magnetic beads and fluorescence activated cell sorting using the criterion: cell surface expression of B220, CD19 and cKit but not IgM. After purification, 25,000 pro-B cells are seeded onto 3.5 cm culture dishes plate containing methylcellulose (MethoCult M3630, STEM CELL technologies) for 7 days. After 7 days culture, colonies in which there were more than 50 cells are counted. Subsequently, 190,000 pro-B cells are replated into methylcellulose for another 7 days of culture, followed by enumeration. Wild type or E-Myc pre-leukemia pre B cells are treated with vehicle (DMSO), compound 108 or compound 36 at various concentrations

(147) Bioassay 6

(148) Pre B cells are isolated from bone marrow according to the criterion: cell surface expression of B220, CD19, but not cKit or IgM. Proliferation curves of wild type pre-B cells and Ep-Myc pre-leukemia pre B cells are generated by counting cells cultured on OP9 cell feeder layer in the presence of the growth factor IL-7. Media is changed every two days and cells are passaged every 4 days. Wild type or Ep-Myc pre-leukemia pre B cells are treated with vehicle (DMSO), inactive compound or active compounds at various concentrations

(149) Bioassay 7

(150) Pre B cells are isolated from bone marrow according to the criterion: cell surface expression of B220, CD19, but not cKit or IgM. Pre-B cells are cultured on OP9 cells with IL7 in the presence of compounds at concentrations from 0.01 M to 20 M in vitro for 4 days. Cell number is then enumerated and an IC50 is calculated.

(151) Bioassay 8

(152) Pre B cells are isolated from bone marrow according to the criterion: cell surface expression of B220, CD19, but not cKit or IgM. Pre-B cells are cultured on OP9 cells with IL7 in the presence of compounds at various concentrations. The stages of the cell cycle in cultured pre-B cells with and without treatment is analysed by flow cytometry using a stain for DNA content combined with the cell cycle marker Ki67 to enumerate the proportion of cells in different phases of the cell cycle.

(153) Bioassay 9

(154) Pre B cells are isolated from bone marrow according to the criterion: cell surface expression of B220, CD19, but not cKit or IgM. Pre-B cells are cultured on OP9 cells with IL7 in the presence of compounds at various concentrations. The stages of the cell cycle in pre-B cells with and without treatment is analysed using flow cytometry to assay, using a stain for DNA content combined with BrdU to determine the proportion of cells in S phase.

(155) Bioassay 10

(156) Mice were treated with compounds at the dosage of 50 mg/kg by I.P injection. Compounds are prepared for injection as a slurry in 50% PEG400/H2O. The effect on the B cell lineage is determined by fluorescent cytometry using characteristic cell surface markers expressed at different stages of B cell development.

(157) Results

(158) Bioassay 1

(159) Testing compound 36 in Bioassay 1 allows calculation of a dose at which 50% senescence occur (IC50).

(160) TABLE-US-00021 IC50 (M) R.sup.2 36 1.600 0.965

(161) An end point of cellular senescence was confirmed at doses of 5 M, 10 M and 20 M by the absence of proliferation, cellular morphology and up regulation of -galactosidase by 186% (5 M) 195% (10 M) and 185% (20 M) at 384 hours after plating, which is equivalent to the effect of genetic deletion of MOZ. The mechanism of action of these compounds, i.e. causing cell cycle arrest and senescence, was confirmed by repeating this assay using cells in which the INK4a/ARF pathways was inactivated by genetic deletion of a key exon common to both INK4a and the alternative splice product of the CDKN2a locus ARF. In the absence of INK4a and ARF cells cannot undergo senescence and no inhibition of cell proliferation was detected when INK4a and ARF null cells were treated with compound 37 at 1 M, 2 M, 5 M, 10 M, or the control compound.

(162) Bioassay 2

(163) Four active compounds tested using Bioassay 2. Treatment of cells at a does of 5 M showed a reduction of mRNA coding for the MOZ regulated gene Cdc6. The reduction in gene expression, compared to vehicle, is similar to that observed in the genetic knock out of MOZ function.

(164) TABLE-US-00022 CDC6 mRNA % control [5 M] 36 65.1% 137 67.5% 64 60.9% 53 62.8%

(165) Bioassay 3

(166) Testing compounds in Bioassay 3 allows calculation of a dose at which cell proliferation is inhibited 50% (IC50).

(167) TABLE-US-00023 IC.sub.50 (M) R.sup.2 36 0.551 0.995 137 1.168 0.870 120 0.651 0.984 58 0.481 0.995 64 0.992 0.985 53 0.635 0.958 88 1.257 0.706 87 0.614 0.941

(168) Bioassay 4

(169) Compound 36 treatment of mouse embryonic fibroblasts shows a dose dependent decrease in cell number in the presence of mutant KRas (KrasG12).

(170) TABLE-US-00024 Cumulative Cell Counts Treatment 0 h 96 h 168 h 264 h 336 h pBABE vehicle 100000 216666.7 362666.7 681866.7 1033253 5 m 100000 198333.3 233500 300666.7 226600 KrasG12V vehicle 100000 136666.7 157166.7 266316.7 180760 KrasG12V 1 m 100000 128333.3 129833.3 145100 132000 KrasG12V 2.5 m 100000 141666.7 121666.7 101433.3 94133.33 KrasG12V 5 m 100000 126666.7 106166.7 81641.67 50940 S.E.M pBABE vehicle 0 11155.47 26831.16 60355.8 284707.7 S.E.M 5 m 0 12224.75 14430.87 40846.96 38168.57 KrasG12V vehicle 0 4944.132 11816.42 44086.33 14682.29 S.E.M 1 m 0 6009.252 5393.927 9436.631 7937.254 2.5 m 0 9098.229 7666.667 11683.2 20231.06 5 m 0 9189.366 11417.58 10548.07 7294.628

(171) Bioassay 5

(172) Enumeration of FACs-purified pro-B cell colonies in methylcellulose culture subjected to inhibitor treatment. The active compound 36 greatly inhibits colony formation as compared to vehicle or inactive compound 108. Compound 36 is equally effective in inhibiting proliferation and secondary colony formation of cells expressing the oncogene cMyc.

(173) TABLE-US-00025 colony number S.E.M Treatment wild type pro-B cells DMSO(n = 4) 247.125 4.7 1 M Compound 108 (n = 4) 245.125 6.4 1 M Compound 36 (n = 4) 161.25 7.2 Treatment E-Myc pre- leukemia pro-B cells DMSO(n = 4) 177.5 5.0 1 M Compound 108 (n = 4) 180.5 7.0 1 M Compound 36 (n = 4) 104.625 2.4 Treatment wild type pro-B cells secondary colony formation DMSO vehicle (n = 4) 76.375 2.9 1 M Compound 108 (n = 4) 77 1.9 1 M Compound 36 (n = 4) 12.25 1.7 Treatment E-Myc pre- leukemia pro-B cells secondary colony formation DMSO vehicle (n = 4) 78.375 2.3 1 M Compound 108 (n = 4) 78 1.7 1 M Compound 36 (n = 4) 9.75 0.9

(174) Bioassay 6

(175) The proliferation wild type and pre-leukaemic B cell progenitors is inhibited with active compound 36 compared to vehicle. Results are presented as cumulative average cell number with the S.E.M tabulated below.

(176) TABLE-US-00026 Treatment Day 0 Day 4 Day 8 Day 12 Wild type pre B cells- cell count Vehicle (n = 3) 15000 65777 2212281 8768019 10 M Compound 36 (n = 3) 15000 26111 8192 0.000 5 M Compound 36 (n = 3) 15000 32555 19925 0.000 1 M Compound 36 (n = 3) 15000 54333 73474 15097 Wild type pre B cells S.E.M Vehicle (n = 3) 0 3045 245283 1710161 10 M Compound 36 (n = 3) 0 3045 440 0.000 5 M Compound 36 (n = 3) 0 1637 739 0.000 1 M Compound 36 (n = 3) 0 1953 10515 12912 Treatment Day 0 Day 4 Day 8 Day 12 Day 16 E-Myc pre-leukemia pre-B cells- cell count Vehicle (n = 3) 100000 449444 4859277 20013531 526508291 5 M Compound 36 (n = 3) 100000 79444 33236 0 0 1 M Compound 36 (n = 3) 100000 172777 135815 29983 0 0.2 M Compound 36 (n = 3) 100000 373055 1110631 464403 81501 E-Myc pre-leukemia pre-B cells- SEM Vehicle (n = 3) 0 15880 221940 2045775 7840593 5 M Compound 36 (n = 3) 0 4747 2866 0 0 1 M Compound 36 (n = 3) 0 17148 4295 2614 0 0.2 M Compound 36 (n = 3) 0 11142 63477 99859 46278

(177) Bioassay 7

(178) Dose response wild type and pre B cells treated with different concentrations of active compound 36 and inactive but structurally similar compound 108. Note that compound 36 is effective in suppression of pre B cell proliferation even when these cells express the cMyc oncogene at high levels, whereas inactive compound 108 has no effect.

(179) TABLE-US-00027 Cells Compound IC50 M wild type Pre B cells Compound 36 0.364 E-Myc pre-leukemia pre B cells Compound 36 0.421 wild type Pre B cells Compound 108 2.45e{circumflex over ()}10

(180) Bioassay 8

(181) Cell cycle analysis of wild type pre-B cells treated with compound 36 or inactive compound compound 108. The number of cells in S phase was down-regulated by 40 percent in wild type pre-B cells after compound 36 treatment. Four biological replicates for each treatment were performed.

(182) Data are presented as means.e.m.

(183) TABLE-US-00028 G2/ S.E.M. S.E.M. S.E.M. Treatment G0 G1 S M G0 S.E.M.G1 S G2/M Cell cycle analysis of wild type pre B cells cultured for 4 days Vehicle (n = 4) 10.5% 52.3% 25.0% 11.6% 0.007 0.009 0.008 0.003 1 M Compound 108 (n = 4) 10.8% 53.7% 23.6% 12.1% 0.014 0.014 0.006 0.005 1 M Compound 36 (n = 4) 14.5% 55.9% 15.6% 12.7% 0.013 0.006 0.005 0.003 Cell cycle analysis of wild type pre B cells cultured for 6 days Vehicle (n = 4) 7.8% 62.9% 15.0% 7.5% 1.1% 1.3% 0.6% 0.2% 1 M Compound 108 (n = 4) 8.6% 62.0% 14.7% 8.5% 0.9% 0.9% 0.7% 0.4% 1 M compound 36 (n = 4) 11.0% 66.6% 8.3% 9.0% 1.5% 1.2% 0.8% 0.3%

(184) Bioassay 9

(185) Cell cycle analysis of wild type pre-B cells treated with compound 36 or inactive compound compound 108 using the S-phase marker BrdU. Note that treatment with the active compound 36 treatment leads to a reduction of cells in S-phase and a corresponding increase in cells in G0/G1. Three biological replicates for each treatment were performed.

(186) TABLE-US-00029 Treatment G0/G1 S G2/M vehicle (n = 3) 42.7 44.0 6.8 1 M Compound 108 (n = 3) 44.2 46.2 5.2 1 M Compound 36 (n = 3) 54.9 32.7 5.5

(187) Bioassay 10.

(188) Treatment of mice with active compounds 46 and 137 displayed markedly reduced numbers of pre B cells in the bone marrow after daily I.P. injection. This result is similar to the suppression of pre B cell numbers seen after ablation of the Moz gene providing evidence of an on-target effect in vivo.

(189) TABLE-US-00030 Wild type mice treated with compound daily, data are percentage of WBC per femur pro-B pre-B immature B mature B Treatment cells cells cells cells vehicle 1.66% 21.66% 4.40% 2.82% (n = 3) Compound 1.14% 10.59% 3.33% 3.65% 46 (n = 3) Compound 1.01% 12.71% 3.92% 3.16% 137 (n = 3)

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