Compounds

Abstract

A compound of formula (I), or a pharmaceutically acceptable salt thereof.

##STR00001##

Claims

1. A method of treating cancer, comprising administering to a patient in need thereof a compound of formula (I), or a pharmaceutically acceptable salt thereof: ##STR00218## wherein either: (i) X.sup.0=CR.sup.C, X.sup.1=N, X.sup.2=O; or (ii) X.sup.0=CR.sup.C, X.sup.1=O, X.sup.2=N; or (iii) X.sup.0=S, X.sup.1=N, X.sup.2=N; or (iv) X.sup.0=N, X.sup.1=N, X.sup.2=O; or (v) X.sup.0=O, X.sup.1=N, X.sup.2=N; where R.sup.C is H, CO.sub.2CH.sub.3 or Cl; R.sup.N is H or methyl; X.sup.3 is CR.sup.3 or N; X.sup.4 is CR.sup.4 or N; R.sup.1 to R.sup.5 are independently selected from: (i) H; (ii) halo; (iii) cyano; (iv) C.sub.1-3 alkyl, optionally substituted by one or more fluoro groups; (v) (CH.sub.2).sub.n0C.sub.3-6 cycloalkyl, where n0=0 or 1; (vi) (CH.sub.2).sub.n1C.sub.1-3 alkoxy, where n1=0 or 1, optionally substituted by one or more fluoro groups; (vii) C.sub.1-3 alkylester; (vii) (CH.sub.2).sub.n2-phenyl, where n2=0-2; and (viii) (CH.sub.2).sub.n3C.sub.5 heteroaryl, where n3=0-1, optionally substituted by methyl; and R.sup.Y is selected from: (i) (CH.sub.2).sub.n4-phenyl, where n4=0-2, where phenyl is optionally substituted by: (a) C.sub.1-4 alkyl, optionally substituted by one or more fluoro groups; (b) C.sub.1-4 alkoxy, optionally substituted by phenyl, or one or more fluoro groups; (c) halo; (d) cyano, nitro or amido; (e) phenyl; or (f) (CH.sub.2).sub.n5, where n5 is 3 or 4; (ii) pyridyl; (iii) C.sub.3-4 alkyl; (iv) (CH.sub.2).sub.n6C.sub.3-6 cycloalkyl, where n6=0-2; (v) C.sub.6 heterocyclyl, optionally substituted by C.sub.1-4 alkylester; and (vi) NHR.sup.YN, where R.sup.YN is selected from phenyl or cyclohexyl.

2. The method of claim 1, wherein X.sup.0=CR.sup.C, X.sup.1=N and X.sup.2=O or X.sup.0=CR.sup.C, X.sup.1=O and X.sup.2=N, and R.sup.C is H.

3. The method of claim 1, wherein R.sup.N is H.

4. The method of claim 1, wherein X.sup.3 is CR.sup.3 and X.sup.4 is CR.sup.4.

5. The method of claim 1, wherein R.sup.2 and R.sup.5 are not H, and R.sup.1, R.sup.3 and R.sup.4 are H.

6. The method of claim 5, wherein R.sup.2 is selected from: halo; (CH.sub.2).sub.n0C.sub.3-6 cycloalkyl; (CH.sub.2).sub.n1C.sub.1-3 alkoxy; C.sub.1-3 alkylester; and (CH.sub.2).sub.n3C.sub.5 heteroaryl, optionally substituted by methyl.

7. The method of claim 6, wherein R.sup.2 is selected from Br, Cl, cyclopropyl, methoxy and CO.sub.2CH.sub.3.

8. The method of claim 6, wherein R.sup.2 is selected from: pyrazol-1-yl; pyrazol-3-yl; and pyrazol-4yl; each optionally substituted by methyl.

9. The method of claim 5, wherein R.sup.5 is selected from C.sub.1-3 alkyl and (CH.sub.2).sub.n1C.sub.1-3 alkoxy.

10. The method of claim 9, wherein R.sup.5 is selected from ethyl, methoxy, CH.sub.2OCH.sub.3, isopropoxy, OCH.sub.2CH.sub.3 and OCF.sub.3.

11. The method of claim 1, wherein R.sup.Y is (CH.sub.2).sub.n4-phenyl, where n4=0-2, where phenyl is optionally substituted by: (a) C.sub.1-4 alkyl, optionally substituted by one or more fluoro groups; (b) C.sub.1-4 alkoxy, optionally substituted by phenyl, or one or more fluoro groups; (c) halo; (d) cyano, nitro or amido; (e) phenyl; or (f) (CH.sub.2).sub.n5, where n5 is 3 or 4.

12. The method of claim 11, wherein the phenyl group in R.sup.Y is unsubstituted.

13. The method of claim 11, wherein the phenyl group in R.sup.Y is substituted by one substituent.

14. The method of claim 11, wherein the phenyl group in R.sup.Y is substituted by two substituents.

15. The method of claim 1, wherein R.sup.Y is pyridyl.

16. The method of claim 1, wherein R.sup.Y is C.sub.3-4 alkyl.

17. The method of claim 1, wherein R.sup.Y is (CH.sub.2).sub.n6C.sub.3-6 cycloalkyl, where n6=0-2.

18. The method of claim 1, wherein R.sup.Y is 06 heterocyclyl, optionally substituted by C.sub.1-4 alkylester.

19. The method of claim 1 wherein R.sup.Y is NHR.sup.YN, where R.sup.YN is selected from phenyl or cyclohexyl.

20. The method of claim 1, wherein R.sup.Y is selected from: a) 2,6-dimethoxyphenyl; b) 2,6-dimethoxy or 4-phenylphenyl; c) 2-methoxyphenyl; d) 2-methoxy or 5-ethylphenyl; e) CH.sub.2-phenyl; and f) CH.sub.2CH.sub.2-phenyl.

21. The method of claim 1, with the proviso that when: (a) X.sup.0=CR.sup.C, X.sup.1=O, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, R.sup.1, R.sup.2, R.sup.3 R.sup.4, R.sup.5, R.sup.C and R.sup.N are H, R.sup.Y is not 4-methylphenyl or 3,4-dimethoxyphenyl; (b) X.sup.0=S, X.sup.1=N, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, R.sup.1, R.sup.2, R.sup.3 R.sup.4, R.sup.5 and R.sup.N are H, R.sup.Y is not 4-methylphenyl or 3,4-dimethoxyphenyl; (c) X.sup.0=S, X.sup.1=N, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.N are H, and R.sup.3 is methyl or chloro, R.sup.Y is not 3-chlorophenyl or 3-methylphenyl; (d) X.sup.0=O, X.sup.4=N, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.N are H, and R.sup.3 is CF.sub.3, R.sup.Y is not phenyl; (e) X.sup.0=O, X.sup.1=N, X.sup.2=N, X.sup.3=N, and X.sup.4=CR.sup.4, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.N are H, R.sup.Y is not phenyl, 4-chlorophenyl, 4-bromophenyl or 4-iodophenyl.

22. A pharmaceutical composition comprising the compound or salt as defined in claim 25 and a pharmaceutically acceptable excipient.

23. (canceled)

24. The method of claim 1, wherein the administrating is for simultaneous or sequential administration with radiotherapy and/or chemotherapy.

25. A compound of formula (I), or a pharmaceutically acceptable salt thereof: ##STR00219## wherein X.sup.0, X.sup.1, X.sup.2, X.sup.3, X.sup.4, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.N and R.sup.Y are as defined in claim 1.

26. The compound or salt according to claim 25, wherein at least one of R.sup.1 to R.sup.5 is not H.

27. The compound or salt according to claim 25, wherein R.sup.2 and R.sup.5 are not H.

28. The compound or salt according to claim 25, wherein R.sup.Y is not (CH.sub.2).sub.n3-phenyl, wherein the phenyl is substituted by a single group which is Cl, F or NO.sub.2.

29. The compound or salt according to claim 25, wherein R.sup.Y is not (CH.sub.2).sub.n3-phenyl, wherein the phenyl is substituted by NO.sub.2.

30. The compound or salt according to claim 25, with the proviso that when: (a) X.sup.0=S, X.sup.1=N, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.N are H, and R.sup.3 is H or methyl, R.sup.Y is not phenyl or 4-methylphenyl; (b) X.sup.0=O, X.sup.4=N, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, R.sup.1, R.sup.2, R.sup.3 R.sup.4, R.sup.5 and R.sup.N are H, R.sup.Y is not phenyl or 4-nitrophenyl; (c) X.sup.0=CR.sup.C, X.sup.4=O, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, R.sup.1, R.sup.2, R.sup.3 R.sup.4, R.sup.5, R.sup.C and R.sup.N are H, R.sup.Y is not 4-methylphenyl or 3,4-dimethoxyphenyl; (d) X.sup.0=S, X.sup.1=N, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, R.sup.1, R.sup.2, R.sup.3 R.sup.4, R.sup.5 and R.sup.N are H, R.sup.Y is not 4-methylphenyl or 3,4-dimethoxyphenyl; (e) X.sup.0=S, X.sup.1=N, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.N are H, and R.sup.3 is methyl or chloro, R.sup.Y is not 3-chlorophenyl or 3-methylphenyl; (f) X.sup.0=O, X.sup.1=N, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.N are H, and R.sup.3 is CF.sub.3, R.sup.Y is not phenyl; and (g) X.sup.0=O, X.sup.1=N, X.sup.2=N, X.sup.3=N, and X.sup.4=CR.sup.4, R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.N are H, R.sup.Y is not phenyl, 4-chlorophenyl, 4-bromophenyl or 4-iodophenyl.

Description

EXAMPLES

[0335] The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.

[0336] Acronyms

[0337] 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), phenyl (Ph), benzyl (Bn), methoxy (MeO), ethoxy (EtO), trimethylsilyl (TMS), and acetyl (Ac).

[0338] For convenience, many chemical compounds are represented using well known abbreviations, including but not limited to, d.sup.3-methanol (MeOH), deuterated methanol (d.sub.4-MeOD) ethanol (EtOH), isopropanol (i-PrOH), ether or diethyl ether (Et.sub.2O), ethyl acetate (EtOAc), acetic acid (AcOH), acetonitrile (MeCN), dichloromethane (methylene chloride, DCM), trifluoroacetic acid (TFA), dimethylformamide (DMF), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), deuterated chloroform (CDCl.sub.3), diethylamine (DEA), deuterated dimethylsulfoxide (DMSO-d.sub.6), N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl, EDCl), 1,1-bis(diphenylphosphino)ferrocene (dppf), tert-butyloxycarbonyl (Boc, BOC), 2-(trimethylsilyl)ethoxymethyl (SEM), triethylamine (Et.sub.3N or TEA), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP), N,N-diisopropylethylamine (DIPEA or DIEA), 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (II) (PdCl.sub.2(dppf)), trans-dichlorobis(triphenylphosphine)palladium(II) (PdCl.sub.2(PPh.sub.3).sub.2), tris(dibenzylideneacetone) dipalladium(0) (Pd.sub.2(dba).sub.3), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh.sub.3).sub.4), 1,2-dichloroethane (DCE), benzyl (Bn) and 1-hydroxybenzotriazole (HOBt), N,N,N,N Tetramethylethylenediamine (TMEDA), Lithium bis(trimethylsilyl)amide (LiHMDS), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2,4-dimethoxybenzyl (DMB).

[0339] In addition, TLC refers to thin layer chromatography, prep HPLC refers to preparative high-performance liquid chromatography, Prep. TLC refers to preparative thin layer chromatography, eq refers to equivalents, R.sub.t refers to retention time and con. refers to concentrated.

[0340] General Experimental Details

[0341] Unless otherwise stated the following generalisations apply. .sup.1H NMR spectra were recorded on a Bruker Ultrashield Plus (400 MHz) or a Bruker AVANCE III (400 MHz). The multiplicity of a signal is designated by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; tt, triplet of triplets; br, broad; m, multiplet. All observed coupling constants, J, are reported in Hertz.

[0342] Exchangeable protons are not always observed.

[0343] Analytical LCMS data was generated using methods, including but not limited to, either an Agilent 6100 Series Single Quad LCMS, an Agilent 1260 Infinity Series UPLC/MS or an Agilent 1200 Series G6110A Quadrupole LCMS. Chlorine isotopes are reported as .sup.35Cl, Bromine isotopes are reported as either .sup.79Br or .sup.81Br or both .sup.79Br/.sup.81Br. LC-MS equipment and conditions are as follows:

[0344] LCMS Method a (LCMS-A):

[0345] Equipment Information

[0346] LC model: Agilent 1200 (Pump type: Binary Pump, Detector type: DAD)

[0347] MS model: Agilent G6110A Quadrupole

[0348] Parameters of LCMS

[0349] LC: Column: Xbridge-C18, 2.5 m, 2.130 mm [0350] Column temperature: 30 C. [0351] Acquisition of wavelength: 214 nm, 254 nm [0352] Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH

[0353] MS: Ion source: ES+ (or ES) MS range: 50900 m/z [0354] Fragmentor: 60 Drying gas flow: 10 L/min [0355] Nebulizer pressure: 35 psi Drying gas temperature: 350 C. [0356] Vcap: 3.5 kV

TABLE-US-00002 Gradient Table: Flow (mL/min) T (min) A (%) B (%) 0.5 0.0 70 30 30 0.5 0.2 70 30 0.5 1.8 5 95 0.5 2.4 5 95 0.5 2.6 70 30 0.5 3.5 70 30 35

[0357] Sample Preparation

[0358] The sample was dissolved in methanol, the concentration about 0.111 mg/mL, then filtered through syringe filter with 0.22 m. (Injection volume: 110 L)

[0359] LCMS Method B (LCMS-B):

[0360] Equipment Information

[0361] LC model: Agilent 1200 (Pump type: Binary Pump, Detector type: DAD)

[0362] MS model: Agilent G6110A Quadrupole

[0363] Parameters of LCMS

[0364] LC: Column: Xbridge-C18, 2.5 m, 2.130 mm [0365] Column temperature: 30 C. [0366] Acquisition of wavelength: 214 nm, 254 nm [0367] Mobile phase: A: 0.07% HCOOH aqueous solution, B: MeOH

[0368] MS: Ion source: ES+ (or ES) MS range: 50900 m/z [0369] Fragmentor: 60 Drying gas flow: 10 L/min [0370] Nebulizer pressure: 35 psi Drying gas temperature: 350 C. [0371] Vcap: 3.5 kV

TABLE-US-00003 Gradient Table: Flow (mL/min) T (min) A (%) B (%) 0.5 0.0 70 30 0.5 0.3 70 30 0.5 0.6 50 50 0.5 0.9 40 60 0.5 1.2 30 70 0.5 3.2 5 95 0.5 3.5 5 95 0.5 4.0 70 30 0.5 5.0 70 30

[0372] Sample Preparation

[0373] The sample was dissolved in methanol, the concentration about 0.111 mg/mL, then filtered through the syringe filter with 0.22 m. (Injection volume: 110 L)

[0374] LCMS Method C (LCMS-C):

[0375] Instrument: Agilent 6100 Series Single Quad LC/MS

[0376] Agilent 1200 Series HPLC

[0377] Pump: 1200 Series G1311A Quaternary pump

[0378] Autosampler: 1200 Series G1329A Thermostatted Autosampler

[0379] Detector: 1200 Series G1314B Variable Wavelength Detector

[0380] LC Conditions:

[0381] Reverse Phase HPLC analysis

[0382] Column: Luna C8 (2) 5 m 504.6 mm 100

[0383] Column temperature: 30 C.

[0384] Injection Volume: 5 L

[0385] Solvent A: Water 0.1% Formic Acid

[0386] Solvent B: MeCN 0.1% Formic Acid

[0387] Gradient: 5-100% solvent B over 10 min

[0388] Detection: 254 nm or 214 nm

[0389] MS Conditions:

[0390] Ion Source: Quadrupole

[0391] Ion Mode: Multimode-ES

[0392] Drying gas temp: 300 C.

[0393] Vaporizer temperature: 200 C.

[0394] Capillary voltage (V): 2000 (positive)

[0395] Capillary voltage (V): 4000 (negative)

[0396] Scan Range: 100-1000

[0397] Step size: 0.1 sec

[0398] Acquisition time: 10 min

[0399] LCMS Method D (LCMS-D):

[0400] Instrument: Agilent 1260 Infinity Series UPLC/MS

[0401] Pump: 1260 Infinity G1312B Binary pump

[0402] Autosampler: 1260 Infinity G1367E 1260 HiP ALS

[0403] Detector: 1290 Infinity G4212A 1290 DAD

[0404] LC Conditions:

[0405] Reverse Phase HPLC analysis

[0406] Column: Poroshell 120 EC-C18 2.7 m 503.0 mm

[0407] Column temperature: 35 C.

[0408] Injection Volume: 1 L

[0409] Solvent A: Water 0.1% Formic Acid

[0410] Solvent B: MeCN 0.1% Formic Acid

[0411] Gradient: 5-100% solvent B over 3.8 min

[0412] Detection: monitored at 254 nm and 214 nm

[0413] MS Conditions:

[0414] Ion Source: Quadrupole

[0415] Ion Mode: API-ES

[0416] Drying gas temp: 350 C.

[0417] Capillary voltage (V): 3000 (positive)

[0418] Capillary voltage (V): 3000 (negative)

[0419] Scan Range: 100-1000

[0420] Step size: 0.1 sec

[0421] Acquisition time: 5 min

[0422] LCMS Method E (LCMS-E):

[0423] Instrument: Waters 2695 alliance

[0424] Pump: Quaternary Pump

[0425] Detector: 2996 Photodiode Array Detector

[0426] MS model: Micromass ZQ

[0427] LC Conditions:

[0428] Column: Xbridge-C18, 2.5 m, 2.130 mm

[0429] Column temperature: 30 C.

[0430] Acquisition of wavelength: 214 nm, 254 nm

[0431] Mobile phase: A: 0.05% HCOOH aqueous solution, B: MeOH

[0432] Run time: 5 min

[0433] MS Conditions:

[0434] Ion source: ES+ (or ES) MS range: 50-900 m/z

[0435] Capillary: 3.5 kV Cone: 35 V Extractor: 3 V

[0436] Drying gas flow: 350 L/hr cone: 50 L/hr

[0437] Desolvation temperature: 300 C.

[0438] Source temperature: 120 C.

[0439] Run time: 5 min

TABLE-US-00004 Gradient Table: Flow (mL/min) T (min) A (%) B (%) 0.5 0.0 70 30 0.5 0.3 70 30 0.5 0.6 50 50 0.5 0.9 40 60 0.5 1.2 30 70 0.5 3.2 5 95 0.5 3.5 5 95 0.5 4.0 70 30 0.5 5.0 70 30

[0440] Sample Preparation

[0441] The sample was dissolved in methanol, the concentration about 0.11-1 mg/mL, then filtered through the syringe filter with 0.22 m. (Injection volume: 1-10 L)

[0442] Preparative HPLC

[0443] Instrument type: Varian 940-LC series;

[0444] Pump type: Quaternary Pump;

[0445] Detector type: Diode Array Detector

[0446] HPLC conditions: Waters Sunfire prep C18 OBD, 5 m 19100 mm column, eluting with a gradient of MeOH in water with 0.07% TFA at a flow rate of 15 mL/min. Acquisition wavelength 214 nm, 254 nm

[0447] Analytical thin-layer chromatography was performed on Merck silica gel 60 F254 aluminium-backed plates which were visualised using fluorescence quenching under UV light or a basic KMnQ.sub.4 dip or Ninhydrin dip.

[0448] Preparative thin-layer chromatography was performed using Tklst (China), grand grade: (HPTLC): 82 m>80%; (TLC): 10-40 m. Type: GF254. Compounds were visualised by UV (254 nm).

[0449] Flash chromatography was performed using a Biotage Isolera purification system using either Grace or RediSep silica cartridges.

[0450] Column chromatography was performed using Tklst (China), grand grade, 100-200 meshes silica gel.

[0451] Microwave irradiation was achieved using a CEM Explorer SP Microwave Reactor. Where necessary, anhydrous solvents were purchased from Sigma-Aldrich or dried using conventional methods.

[0452] Preparative Mass-Directed HPLC

[0453] Instrument:

[0454] Waters ZQ 3100Mass Detector

[0455] Waters 2545-Pump

[0456] Waters SFO System Fluidics Organizer

[0457] Waters 2996 Diode Array Detector

[0458] Waters 2767 Sample Manager

[0459] LC Conditions:

[0460] Reverse Phase HPLC analysis

[0461] Column: XBridge C18 5 m 1950 mm

[0462] Injection Volume 500 L

[0463] Solvent A: Water 0.1% Formic Acid

[0464] Solvent B: Acetonitrile 0.1% Formic Acid

[0465] Gradient: 25-100% B over 10 min

[0466] Flow rate: 19 mL/min

[0467] Detection: 100-600 nm

[0468] MS Conditions:

[0469] Ion Source: Single-quadrupole

[0470] Ion Mode: ES positive

[0471] Source Temp: 150 C.

[0472] Desolvation Temp: 350 C.

[0473] Detection: Ion counting

[0474] Capillary (KV)-3.00

[0475] Cone (V): 30

[0476] Extractor (V): 3

[0477] RF Lens (V): 0.1

[0478] can Range: 100-1000 Amu

[0479] Scan Time: 0.5 sec

[0480] Acquisition time: 10 min

[0481] Gas Flow

[0482] Desolvation L/hour-650

[0483] Cone L/hour-100

[0484] Microwave irradiation was achieved using a CEM Explorer SP Microwave Reactor.

[0485] Where necessary, anhydrous solvents were purchased from Sigma-Aldrich or dried using conventional methods.

[0486] Solutions of inorganic acids or bases were made up as aqueous solutions unless stated otherwise.

[0487] Additional sample extraction cartridges used are as follows:

[0488] Phase Separator:

[0489] Manufacturer: Biotage

[0490] Product: ISOLUTE Phase Separator (3 mL unless otherwise stated)

[0491] Si-Amine Cartridges:

[0492] Manufacturer: Silicycle

[0493] Product: Si-amine 500 mg or 1 g

Synthesis of Intermediates

(i) 5-(3-Methoxyphenyl)isoxazol-3-amine I1

[0494] ##STR00041##

[0495] To a stirred solution of 3-(3-methoxyphenyl)-3-oxopropanenitrile (2.0 g, 11.4 mmol) and NaOH (500 mg, 12.5 mmol) in water (15 mL) and ethanol (15 mL) was added hydroxylamine hydrochloride (871 mg, 12.5 mmol) and the mixture was heated at 80 C. overnight. Concentrated HCl (1.4 mL, 12.5 mmol) was then added and the mixture was heated at 80 C. for a further 2 h. The mixture was basified to pH 10 with 2 M NaOH and extracted with EtOAc (50 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=30/1 to 10/1 to 5/1) to give title compound I1 (650 mg, 31%) as a yellow solid. LCMS-B (ES-API): R.sub.t0.71 min; m/z 191.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.41-7.37 (m, 1H), 7.34-7.30 (m, 1H), 7.28-7.25 (m, 1H), 7.04-6.99 (m, 1H), 6.34 (s, 1H), 5.66 (s, 2H), 3.81 (s, 3H).

(ii) 5-(2-Methoxyphenyl)isoxazol-3-amine I2

[0496] ##STR00042##

[0497] To a stirred solution of 3-(2-methoxyphenyl)-3-oxopropanenitrile (1.5 g, 8.56 mmol) and NaOH (377 mg, 9.42 mmol) in water (15 mL) and ethanol (15 mL) was added hydroxylamine hydrochloride (655 mg, 9.42 mmol) and the mixture was heated at 80 C. overnight. Concentrated HCl (0.7 mL, 8.56 mmol) was then added and the mixture was heated at 80 C. for a further 3 h. The mixture was basified to pH 10 with 2 M NaOH and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=500/1 to 200/1 to 100/1) to give title compound I2 (620 mg, 38%) as a yellow solid. LCMS-B (ES-API): R.sub.t0.73 min; m/z 191.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.74 (dd, J=7.8, 1.7 Hz, 1H), 7.48-7.40 (m, 1H), 7.19 (d, J=7.1 Hz, 1H), 7.10-7.03 (m, 1H), 6.29 (s, 1H), 5.60 (s, 2H), 3.92 (s, 3H).

(iii) 5-(2,5-Dimethoxyphenyl)isoxazol-3-amine I5

[0498] ##STR00043##

a) Methyl 2,5-dimethoxybenzoate I3

[0499] To a solution of 2,5-dimethoxybenzoic acid (5.0 g, 27.4 mmol) in MeOH (100 mL) was added H.sub.2SO.sub.4 (2 mL) and the mixture was heated at 70 C. overnight. The mixture was diluted with water (200 mL) and extracted with EtOAc (150 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound I3 (5.0 g, 93%) as a yellow oil. LCMS-A (ES-API): R.sub.t 2.24 min; m/z 197.1 [M+H].sup.+, 219.0 [M+Na].sup.+.

b) 3-(2,5-Dimethoxyphenyl)-3-oxopropanenitrile I4

[0500] To a solution of methyl 2,5-dimethoxybenzoate I3 (4.5 g, 22.9 mmol) and acetonitrile (1.41 g, 16.0 mmol) in toluene (150 mL) at 0 C. was added NaH (60% w/w dispersion in oil, 1.38 g, 34.4 mmol) and the mixture was stirred at 0 C. for 30 min then heated at 110 C. overnight. The reaction was quenched with water (400 mL) and the mixture was extracted with EtOAc (300 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=30/1) to give the title compound I4 (1.9 g 40%) as a yellow solid. LCMS-A (ES-API): R.sub.t 1.15 min; m/z 206.1 [M+H].sup.+.

c) 5-(2,5-Dimethoxyphenyl)isoxazol-3-amine I5

[0501] 3-(2,5-Dimethoxyphenyl)-3-oxopropanenitrile I4 (1.8 g, 8.78 mmol), NaOH (456 mg, 11.4 mmol), and NH.sub.2OH.HCl (793 mg, 11.4 mmol) were dissolved in ethanol (25 mL) and water (25 mL) and the mixture was heated at 80 C. overnight. The mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=5/1) to give the title compound I5 (600 mg 32%) as a yellow solid. LCMS-A (ES-API): R.sub.t 0.88 min; m/z 221.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.25 (d, J=3.1 Hz, 1H), 7.14-7.09 (m, 1H), 7.04-6.99 (m, 1H), 6.30 (s, 1H), 5.63 (s, 2H), 3.86 (s, 3H), 3.76 (s, 3H).

(iv) 5-(2-Ethoxyphenyl)isoxazol-3-amine I7

[0502] ##STR00044##

a) 3-(2-Ethoxyphenyl)-3-oxopropanenitrile I6

[0503] To a solution of ethyl 2-ethoxybenzoate (5.0 g, 25.7 mmol) and acetonitrile (1.06 g, 25.7 mmol) in toluene (30 mL) at 0 C. was added potassium tert-butoxide (2.89 g, 25.7 mol) portion-wise and the mixture was stirred at room temperature for 1 h. Water (30 mL) was slowly added and the layers were separated. The organic layer was extracted with water (30 mL3) and the combined aqueous layers were adjusted to pH 1 with concentrated HCl. The resulting precipitate was collected by filtration and the solid was purified by column chromatography (petroleum ether/EtOAc=50/1 to 20/1) to give the title compound I6 (800 mg, 16%) as a white solid. LCMS-A (ES-API): R.sub.t 1.67 min; m/z 190.1 [M+H].sup.+

b) 5-(2-Ethoxyphenyl)isoxazol-3-amine I7

[0504] To a stirred solution of 3-(2-ethoxyphenyl)-3-oxopropanenitrile I6 (800 mg, 4.23 mmol) and NaOH (186 mg, 4.65 mmol) in water (15 mL) and ethanol (15 mL) was added hydroxylamine hydrochloride (323 mg, 4.65 mmol) and the mixture was heated at 80 C. overnight. The mixture was diluted with water and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=100/0 to 100/1) followed by preparative HPLC to give the title compound I7 (40 mg, 5%) as a white solid. LCMS-A (ES-API): R.sub.t 1.44 min; m/z 205.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.75 (d, J=8.0 Hz, 1H), 7.44-7.37 (m, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.04 (t, J=7.6 Hz, 1H), 6.34 (s, 1H), 5.61 (s, 2H), 4.17 (q, J=6.9 Hz, 2H), 1.44 (t, J=6.9 Hz, 3H). 3-(2-Ethoxyphenyl)isoxazol-5-amine (80 mg, 10%) was also obtained as a white solid. LCMS-A (ES-API): R.sub.t 1.17 min; m/z 205.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.68 (dd, J=7.7, 1.8 Hz, 1H), 7.41-7.34 (m, 1H), 7.13-7.07 (m, 1H), 7.00-6.94 (m, 1H), 6.60 (s, 2H), 5.45 (s, 1H), 4.09 (q, J=6.9 Hz, 2H), 1.37 (t, J=6.9 Hz, 3H).

(v) 5-(2,4-Dimethoxyphenyl)isoxazol-3-amine I8

[0505] ##STR00045##

[0506] To a stirred solution of 3-(2,4-dimethoxyphenyl)-3-oxopropanenitrile (1.0 g, 4.87 mmol) and NaOH (220 mg, 4.53 mmol) in water (7.5 mL) and ethanol (7.5 mL) was added hydroxylamine hydrochloride (350 mg, 5.36 mmol) and the mixture was heated at 80 C. overnight. The mixture was diluted with water and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=5/1 to 2/1 to 1/1) to give the title compound I8 (580 mg, 54%) as a white solid. LCMS-B (ES-API): R.sub.t2.14 min; m/z 221.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.65 (d, J=8.6 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.65 (dd, J=8.7, 2.4 Hz, 1H), 6.14 (s, 1H), 5.53 (s, 2H), 3.90 (s, 3H), 3.82 (s, 3H). 3-(2,4-Dimethoxyphenyl)isoxazol-5-amine (250 mg, 23%) was also obtained as a yellow oil. LCMS-B (ES-API): R.sub.t 1.70 min; m/z 221.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.58 (d, J=8.5 Hz, 1H), 6.65 (d, J=2.4 Hz, 1H), 6.58 (dd, J=8.6, 2.4 Hz, 1H), 6.54 (s, 2H), 5.32 (s, 1H), 3.82 (s, 3H), 3.80 (s, 3H).

(vi) 5-(5-Cyclopropyl-2-methoxyphenyl)isoxazol-3-amine I11

[0507] ##STR00046##

a) Methyl 5-cyclopropyl-2-methoxybenzoate I9

[0508] Methyl 5-bromo-2-methoxybenzoate (4.0 g, 16.3 mmol), cyclopropylboronic acid (2.9 g, 32.6 mmol), Pd(OAc).sub.2 (183 mg, 0.82 mmol), PCy.sub.3 (457 mg, 1.63 mmol) and K.sub.3PO.sub.4 (10.4 g, 48.9 mmol) were dissolved in toluene (60 mL) and water (3 mL) under N.sub.2 and the mixture was heated at 100 C. for 3 h. Water (150 mL) was added and the mixture was extracted with EtOAc (100 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=100/1 to 20/1) to give the title compound I9 (2.3 g, 70%) as a yellow oil. LCMS-A (ES-API): R.sub.t 2.09 min; m/z 207.1 [M+H].sup.+.

b) 3-(5-Cyclopropyl-2-methoxyphenyl)-3-oxopropanenitrile I10

[0509] To a solution of methyl 5-cyclopropyl-2-methoxybenzoate I9 (2.20 g, 10.7 mmol) and acetonitrile (657 mg, 16.0 mmol) in toluene (40 mL) at 0 C. was added NaH (60% w/w dispersion in oil, 640 mg, 16.0 mmol) and the mixture stirred at 0 C. for 30 min then heated at 110 C. overnight. Water (100 mL) was added and the mixture was extracted with EtOAc (100 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=30/1) to give the title compound I10 (1.3 g, 57%) as a yellow oil. LCMS-A (ES-API): R.sub.t 1.14 min; m/z 216.1 [M+H].sup.+.

c) 5-(5-Cyclopropyl-2-methoxyphenyl)isoxazol-3-amine I11

[0510] To a solution of 3-(5-cyclopropyl-2-methoxyphenyl)-3-oxopropanenitrile I10 (1.3 g, 6.04 mmol) and NaOH (314 mg, 7.85 mmol) in water (15 mL) and ethanol (15 mL) was added NH.sub.2OH.HCl (545.6 mg, 7.85 mmol) and the mixture was heated at 80 C. overnight. Water (100 mL) was added and the mixture was extracted with EtOAc (100 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=5/1) to give the title compound I11 (700 mg, 50%) as a yellow oil. LCMS-A (ES-API): R.sub.t2.13 min; m/z 231.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.43 (d, J=2.3 Hz, 1H), 7.16-7.11 (m, 1H), 7.08-7.04 (m, 1H), 6.26 (s, 1H), 5.59 (s, 2H), 3.87 (s, 3H), 1.98-1.90 (m, 1H), 0.95-0.88 (m, 2H), 0.65-0.60 (m, 2H).

(vii) 5-(5-Bromo-2-methoxyphenyl)isoxazol-3-amine I13

[0511] ##STR00047##

a) 3-(5-Bromo-2-methoxyphenyl)-3-oxopropanenitrile I12

[0512] To a solution of diisopropylamine (2.7 g, 26.6 mmol) in THF (100 mL) at 78 C. under N.sub.2 was added n-BuLi (2.5 M solution in hexanes, 10.6 mL, 26.6 mmol) dropwise and the mixture was stirred at 78 C. for 1 h. A solution of acetonitrile (1.1 g, 26.6 mmol) in THF (20 mL) was then added dropwise and stirring was continued for 30 min. A solution of methyl 5-bromo-2-methoxybenzoate (5.0 g, 20.5 mmol) in THF (10 mL) was then added dropwise and the mixture was stirred at 78 C. for 40 min. The reaction was quenched at 78 C. with 1 M HCl and the mixture was diluted with water (400 mL) and extracted with EtOAc (200 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound I12 (5.0 g, 96% yield) as a yellow solid. LCMS-A (ES-API): R.sub.t 2.00 min; m/z 253.9/255.9 [M+H].sup.+.

b) 5-(5-Bromo-2-methoxyphenyl)isoxazol-3-amine I13

[0513] To a solution of 3-(5-bromo-2-methoxyphenyl)-3-oxopropanenitrile I12 (5.0 g, 19.7 mmol) and NaOH (1.02 g, 25.6 mmol) in water (75 mL) and ethanol (75 mL) was added NH.sub.2OH.HCl (1.78 g, 25.6 mmol) and the mixture was heated at 80 C. overnight. Water (400 mL) was added and the mixture was extracted with EtOAc (200 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=10/1) to give the title compound I13 (1.2 g, 22% yield) as a yellow solid. LCMS-A (ES-API): R.sub.t 1.81 min; m/z 268.9/270.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.80 (d, J=2.4 Hz 1H), 7.62-7.59 (m, 1H), 7.17 (d, J=8.8 Hz, 1H), 6.33 (s, 1H), 5.67 (s, 2H), 3.92 (s, 3H). 3-(5-Bromo-2-methoxyphenyl)isoxazol-5-amine (1.4 g, 26% yield) was also obtained as a yellow solid. LCMS-A (ES-API): R.sub.t 2.0 min; m/z 268.9/270.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.75 (d, J=2.8 Hz, 1H), 7.59-7.56 (m, J=2.4 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 6.70 (s, 2H), 5.37 (s, 1H), 3.84 (s, 3H).

(viii) 5-(2-Methoxy-5-(methoxymethyl)phenyl)isoxazol-3-amine I17

[0514] ##STR00048##

2-Bromo-1-methoxy-4-(methoxymethyl)benzene I14

[0515] To a solution of (3-bromo-4-methoxyphenyl)methanol (3.0 g, 13.8 mmol) and iodomethane (9.8 g, 69.1 mmol) in DMF (129 mL) at 0 C. was added NaH (60% w/w dispersion in oil, 1.1 g, 27.6 mmol) and the mixture was stirred at room temperature for 30 min. Water was added and the mixture was extracted with EtOAc (100 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=20/1) to give the title compound I14 (2.3 g, 72% yield) as a yellow oil. LCMS-A (ES-API): R.sub.t2.01 min; m/z 198.9/200.9 [M-CH.sub.3O].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.53 (d, J=2.1 Hz, 1H), 7.23 (dd, J=8.4, 2.1 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 4.35 (s, 2H), 3.88 (s, 3H), 3.35 (s, 3H).

b) Methyl 2-methoxy-5-(methoxymethyl)benzoate I15

[0516] A mixture of 2-bromo-1-methoxy-4-(methoxymethyl)benzene 114 (1.5 g, 6.5 mmol), Pd(dppf)Cl.sub.2.DCM (265 mg, 0.325 mmol) and triethylamine (2.0 g, 19.5 mmol) in methanol (30 mL) was heated at 100 C. under a carbon monoxide atmosphere (0.2 MPa) overnight. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether/EtOAc=20/1 to 10/1) to give the title compound (1.1 g, 84% yield) as yellow oil. LCMS-A (ES-API): R.sub.t0.79 min; m/z 233.0 [M+Na].sup.+.

c) 3-(2-Methoxy-5-(methoxymethyl)phenyl)-3-oxopropanenitrile I16

[0517] To a solution of diisopropylamine (870 mg, 8.6 mmol) in anhydrous THF (40 mL) at 78 C. under N.sub.2 was added n-BuLi (2.5 M solution in hexanes, 3.4 mL, 8.6 mmol) dropwise and the mixture was stirred at 78 C. for 1 h. A solution of acetonitrile (350 mg, 8.6 mmol) in anhydrous THF (10 mL) was then added dropwise and stirring was continued at 78 C. for 30 min. A solution of methyl 2-methoxy-5-(methoxymethyl)benzoate I15 (1.2 g, 5.7 mmol) in anhydrous THF (10 mL) was then added dropwise and the mixture was stirred at 78 C. for 2 h. The reaction was quenched at 78 C. with 1 M HCl and the mixture was extracted with EtOAc (50 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound I16 (1.1 g, 91% yield) as a yellow solid, which was used in the next step without further purification. LCMS-A (ES-API): R.sub.t 0.83 min; m/z 220.0 [M+H].sup.+ 242.0 [M+Na].sup.+.

d) 5-(2-Methoxy-5-(methoxymethyl)phenyl)isoxazol-3-amine I17

[0518] To a solution of 3-(2-methoxy-5-(methoxymethyl)phenyl)-3-oxopropanenitrile I16 (1.5 g, 6.8 mmol) and NaOH (300 mg, 7.5 mmol) in ethanol (20 mL) and water (20 mL) was added NH.sub.2OH.HCl (522 mg, 7.5 mmol) and the mixture was heated at 80 C. overnight. The mixture was concentrated under reduced pressure the residue was purified by column chromatography (DCM/MeOH=200/1) to give an inseparable mixture of 5-(2-methoxy-5-(methoxymethyl)phenyl)isoxazol-3-amine and 3-(2-methoxy-5-(methoxymethyl)phenyl)isoxazol-5-amine, which required further purification. The procedure was repeated using 3-(2-methoxy-5-(methoxymethyl)phenyl)-3-oxopropanenitrile I16 (1.8 g, 8.2 mmol), NH.sub.2OH.HCl (628 mg, 9.0 mmol), NaOH (360 mg, 9.0 mmol) and ethanol/water (20 mL/20 mL) and the crude product was combined with the first batch and purified by column chromatography (DCM/MeOH=300/1 to 200/1) to give a mixture of 5-(2-methoxy-5-(methoxymethyl)phenyl)isoxazol-3-amine and 3-(2-methoxy-5-(methoxymethyl)phenyl)isoxazol-5-amine (3.0 g, 86%) as an orange liquid, which was dissolved in ethanol (40 mL) and water (20 mL). Concentrated aqueous HCl (2.0 mL) was added and the mixture was heated at 80 C. for 3 h, which resulted in decomposition of 3-(2-methoxy-5-(methoxymethyl)phenyl)isoxazol-5-amine. The mixture was neutralized with a saturated aqueous NaHCO.sub.3 solution and extracted with EtOAc (100 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=200/1) to give the title compound I17 (1.1 g, 31%) as an orange solid. LCMS-A (ES-API): R.sub.t 0.78 min, m/z 235.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.69 (d, J=2.0 Hz, 1H), 7.39-7.37 (m, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.29 (s, 1H), 5.61 (s, 2H), 4.39 (s, 2H), 3.92 (s, 3H), 3.27 (s, 3H).

(ix) 2,6-Dimethoxybenzenesulfonyl Chloride I18

[0519] ##STR00049##

[0520] To a solution of 1,3-dimethoxybenzene (5.0 g, 36 mmol) and TMEDA (4.6 g, 39.8 mmol) in n-hexane (100 mL) at 0 C. under N.sub.2 was added n-BuLi (2.5 M solution in hexanes, 16.0 mL, 39.8 mmol) dropwise while keeping the internal reaction temperature below 5 C. The mixture was stirred at 0 C. for 20 min then cooled to 78 C. and SO.sub.2 gas was bubbled through the mixture for 20 min. The mixture was then allowed to warm slowly to 10 C. and the resulting precipitate was collected by filtration and washed with dry ether. The solid was suspended in n-hexane (100 mL), cooled to 0 C. and a solution of SO.sub.2Cl.sub.2 (4.9 g, 36 mmol) in n-hexane (20 mL) was added dropwise while keeping the internal temperature below 3 C. The mixture was then stirred at 0 C. for 1 h and the solids were collected by filtration and washed with cold/7-hexane. The solids were then partitioned between ether and water, the layers were separated and the aqueous layer was further extracted with ether. The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound I18 (4.0 g, 47%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.54 (t, J=8.4 Hz, 1H), 6.66 (d, J=8.4 Hz, 2H), 3.97 (s, 6H).

(x) 5-Ethyl-2-methoxybenzenesulfonyl Chloride I19

[0521] ##STR00050##

[0522] 1-Ethyl-4-methoxybenzene (5.0 g, 37 mmol) was added dropwise to chlorosulfonic acid (20 mL) at 0 C. and the mixture was stirred at room temperature for 2 h then poured onto ice and extracted with EtOAc (50 mL3). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=100/1 to 30/1) to give the title compound I19 (4.6 g, 53%) as a white solid. LCMS-B (ES-API): R.sub.t2.70 min; m/z 256.9 [M+Na].sup.+.

(xi) 2,4-Dimethoxy-[1,1-biphenyl]-3-sulfonyl Chloride I21

[0523] ##STR00051##

a) 2,4-Dimethoxy-1,1-biphenyl I20

[0524] A suspension of 1-bromo-2,4-dimethoxybenzene (5.0 g, 23.0 mmol), phenylboronic acid (3.4 g, 27.6 mmol), Pd(PPh.sub.3).sub.4 (1.3 g, 1.15 mmol) and potassium carbonate (7.3 g, 69.0 mmol) in 1,4-dioxane (30 mL) and water (6 mL) was heated at 90 C. under N.sub.2 for 16 h. The mixture was filtered through a pad of Celite and washed with EtOAc. The filtrate was diluted with water and extracted with EtOAc (30 mL3). The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=100/1 to 10/1) to give the title compound I20 (2.8 g, 57%) as a yellow oil. LCMS-B (ES-API): R.sub.t2.46 min; m/z 215.0 [M+H].sup.+.

b) 2,4-Dimethoxy-[1,1-biphenyl]-3-sulfonyl Chloride I21

[0525] To a solution of 2,4-dimethoxy-1,1-biphenyl I20 (1.0 g, 4.70 mmol) and TMEDA (601 mg, 5.20 mmol) in n-hexane (40 mL) at 0 C. under N.sub.2 was added n-BuLi (2.5 M solution in hexanes, 2.1 mL, 5.20 mmol) dropwise while keeping the internal reaction temperature below 5 C. The mixture was stirred at 0 C. for 20 min then cooled to 70 C. and SO.sub.2 gas was bubbled through the mixture for 20 min. The mixture was then allowed to warm slowly to 10 C. and the resulting precipitate was collected by filtration and washed with dry ether. The solid was suspended in n-hexane (40 mL), cooled to 0 C. and a solution of SO.sub.2Cl.sub.2 (634 mg, 4.7 mmol) in n-hexane (5 mL) was added dropwise while keeping the internal temperature below 3 C. The mixture was then stirred at 0 C. for 1 h and the solids were collected by filtration and washed with cold n-hexane. The solids were then partitioned between ether and water, the layers were separated and the aqueous layer was further extracted with ether. The combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound I21 (590 mg, 40%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.48-7.35 (m, 4H), 7.34-7.21 (m, 2H), 6.89-6.85 (m, 1H), 3.76 (s, 3H), 3.29 (s, 3H).

(xii) 3,5-Dimethoxy-[1,1-biphenyl]-4-sulfonyl Chloride I47

[0526] ##STR00052##

a) 3,5-Dimethoxy-1,1-biphenyl I22

[0527] A suspension of 1-bromo-3,5-dimethoxybenzene (5.0 g, 23.0 mmol), phenylboronic acid (2.8 g, 23.0 mmol), Pd(dppf)Cl.sub.2 (0.57 g, 0.69 mmol) and potassium carbonate (4.8 g, 34.6 mmol) in 1,4-dioxane (80 mL) and water (20 mL) was heated at 90 C. under N2 for 4 h. The mixture was diluted with water, extracted with EtOAc and the combined organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=500/1 to 200/1 to 100/1) to give the title compound 3,5-dimethoxy-1,1-biphenyl I22 (5.2 g, 100%) as a white solid. LCMS-A (ES-API): R.sub.t 2.47 min; m/z 215.0 [M+H].sup.+.

b) 3,5-Dimethoxy-[1,1-biphenyl]-4-sulfonyl Chloride I47

[0528] I47 was prepared from 3,5-dimethoxy-1,1-biphenyl I22 according to the procedure described for 2,4-dimethoxy-[1,1-biphenyl]-3-sulfonyl chloride I21. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.62-7.55 (m, 2H), 7.54-7.44 (m, 3H), 6.81 (s, 2H), 4.04 (s, 6H).

(xiii) 5-(2,5-Dimethoxyphenyl)isoxazol-3-amine I26

[0529] ##STR00053##

a) Ethyl 2-fluoro-5-methoxybenzoate I23

[0530] To a solution of 2-fluoro-5-methoxybenzoic acid (9.0 g, 53 mmol) in EtOH (80 mL) was added concentrated H.sub.2SO.sub.4 (30 drops) and the mixture was heated at 90 C. overnight. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether/EtOAc=20/1) to give the title compound I23 (9.0 g, 86%) as a colourless oil. LCMS-A (ES-API): R.sub.t2.13 min; m/z 199.1 [M+H].sup.+.

b) Ethyl 2-ethoxy-5-methoxybenzoate I24

[0531] To a solution of ethyl 2-fluoro-5-methoxybenzoate I23 (2.0 g, 10 mmol) in THF (30 mL) was added NaOEt (2.0 g, 30 mmol) and the mixture was heated at 80 C. for 2 h. The mixture was diluted with EtOAc, washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=30/1) to give the title compound I24 (0.8 g, 35%) as a pale yellow oil. LCMS-A (ES-API): R.sub.t 2.19 min; m/z 225.1 [M+H].sup.+.

c) 3-(2-Ethoxy-5-methoxyphenyl)-3-oxopropanenitrile I25

[0532] To a solution of diisopropylamine (351 mg, 3.47 mmol) in THF (10 mL) at 78 C. under N.sub.2 was added n-BuLi (2.5 M solution in hexanes, 1.4 mL, 3.47 mmol) dropwise and the mixture was stirred at 78 C. for 1 h. A solution of acetonitrile (142 mg, 3.47 mmol) in THF (1 mL) was then added dropwise and stirring was continued for 30 min. A solution of ethyl 2-ethoxy-5-methoxybenzoate I24 (600 mg, 2.67 mmol) in THF (1 mL) was then added dropwise and the mixture was stirred at 0 C. for 1 h. The reaction was quenched with a saturated aqueous NH.sub.4Cl solution, diluted with EtOAc and the mixture was washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=5/1) to give the title compound I25 (420 mg, 72%) as a yellow solid. LCMS-A (ES-API): R.sub.t 1.96 min; m/z 220.1 [M+H].sup.+.

d) 5-(2-Ethoxy-5-methoxyphenyl)isoxazol-3-amine I26

[0533] To a solution of 3-(2-ethoxy-5-methoxyphenyl)-3-oxopropanenitrile I25 (100 mg, 0.46 mmol) and NH.sub.2OH.HCl (42 mg, 0.6 mmol) in ethanol (3 mL) was added a solution of NaOH (24 mg, 0.6 mmol) in water (3 mL) and the mixture was heated at 90 C. overnight. The reaction was repeated using 3-(2-ethoxy-5-methoxyphenyl)-3-oxopropanenitrile I25 (300 mg, 1.37 mmol), NH.sub.2OH.HCl (123 mg, 1.78 mmol), NaOH (71 mg, 1.78 mmol) and EtOH/water (5 mL/5 mL). The two reaction mixtures were then combined, diluted with EtOAc, washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=3/1) to give the title compound I26 (130 mg, 30%) as a yellow solid. LCMS-A (ES-API): R.sub.t 3.25 min; m/z 235.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.25 (d, J=3.2 Hz, 1H), 7.14-7.09 (m, 1H), 6.98-6.97 (m, 1H), 6.66 (s, 1H), 5.67 (s, 2H), 4.03 (q, J=7.2 Hz, 2H) 3.70 (s, 3H), 1.34 (t, J=6.8 Hz, 3H).

(xiv) 5-(2-Isopropoxy-5-methoxyphenyl)isoxazol-3-amine I29

[0534] ##STR00054##

a) Ethyl 2-isopropoxy-5-methoxybenzoate I27

[0535] To a solution of ethyl 2-fluoro-5-methoxybenzoate I23 (1.0 g, 5.0 mmol) in THF (25 mL) was added sodium propan-2-olate (1.2 g, 15.0 mmol) and the mixture was heated at 80 C. for 1 h. The reaction was repeated on ethyl 2-fluoro-5-methoxybenzoate I23 (1.0 g, 5.0 mmol) and the reaction mixtures were combined, diluted with EtOAc, washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=20/1) to give the title compound I27 (0.6 g, 25%) as a yellow solid. LCMS-A (ES-API): R.sub.t 2.3 min; m/z 239.1 [M+H].sup.+.

3-(2-Isopropoxy-5-methoxyphenyl)-3-oxopropanenitrile I28

[0536] To a solution of diisopropylamine (332 mg, 3.28 mmol) in THF (10 mL) at 78 C. under N.sub.2 was added n-BuLi (2.5 M solution in hexanes, 1.3 mL, 3.28 mmol) dropwise and the mixture was stirred at 78 C. for 1 h. A solution of acetonitrile (135 mg, 3.28 mmol) in THF (1 mL) was then added dropwise and stirring was continued for 30 min. A solution of ethyl 2-isopropoxy-5-methoxybenzoate I27 (600 mg, 2.52 mmol) in THF (1 mL) was then added dropwise and the mixture was stirred at 0 C. for 1 h. The reaction was quenched with a saturated aqueous NH.sub.4Cl solution, diluted with EtOAc and the mixture was washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=5/1) to give the title compound I28 (200 mg, 35%) as a yellow solid. LCMS-A (ES-API): R.sub.t 2.09 min; m/z 234.1 [M+H].sup.+.

c) 5-(2-Isopropoxy-5-methoxyphenyl)isoxazol-3-amine I29

[0537] To a solution of 3-(2-isopropoxy-5-methoxyphenyl)-3-oxopropanenitrile I28 (180 mg, 0.76 mmol) and NH.sub.2OH.HCl (70 mg, 1.0 mmol) in ethanol (5 mL) was added a solution of NaOH (40 mg, 1.0 mmol) in water (5 mL) and the mixture was heated at 80 C. overnight. The mixture was diluted with EtOAc and washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=50/1) to give the title compound I29 (80 mg, 42%) as a yellow solid. LCMS-A (ES-API): R.sub.t 1.99 min; m/z 249.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.25 (d, J=3.2 Hz, 1H), 7.14-7.12 (m, 1H), 7.00-6.97 (m, 1H), 6.38 (s, 1H), 5.62 (s, 2H), 4.72-4.66 (m, 1H) 3.76 (s, 3H), 1.37 (d, J=6.0 Hz, 6H).

(xv) 5-(2-(Trifluoromethoxy)phenyl)isoxazol-3-amine I30

[0538] ##STR00055##

[0539] To a solution of 3-oxo-3-(2-(trifluoromethoxy)phenyl)propanenitrile (500 mg, 2.18 mmol) in ethanol (10 mL) and water (10 mL) was added NaOH (96 mg, 2.40 mmol) and NH.sub.2OH.HCl (167 mg, 2.40 mmol) and the mixture was heated at 70 C. overnight. Concentrated HCl (0.27 mL, 2.40 mmol) was then added and the mixture was heated at 80 C. for 2 h. The mixture was adjusted to pH 10 with 2 NaOH and extracted with EtOAc (30 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=100/0 to 100/1) to give the title compound I30 (205 mg, 38%) as a yellow solid. LCMS-A (ES-API): R.sub.t 2.90 min; m/z 245.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.97-7.90 (m, 1H), 7.65-7.51 (m, 3H), 6.26 (s, 1H), 5.78 (s, 2H).

(xvi) 5-(5-(Cyclohexylmethyl)-2-methoxyphenyl)isoxazol-3-amine I33 and 3-(5-(cyclohexylmethyl)-2-methoxyphenyl)isoxazol-5-amine I34

[0540] ##STR00056##

Methyl 5-(cyclohexylmethyl)-2-methoxybenzoate I31

[0541] To a solution of methyl 5-bromo-2-methoxybenzoate (500 mg, 2.04 mmol), Pd(OAc).sub.2 (9 mg, 0.04 mmol) and SPhos (19 mg, 0.04 mmol) in THF (20 mL) was added (cyclohexylmethyl)zinc(II) bromide (0.5 M solution in THF, 4.9 mL, 2.45 mmol) and the mixture was stirred at room temperature for 2 h. The reaction was quenched with a saturated aqueous NH.sub.4Cl solution (10 mL) then diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=50/1) to give the title compound I31 (284 mg, 53%) as a yellow oil. LCMS-A (ES-API): R.sub.t 2.71 min; m/z 263.0 [M+H].sup.+.

b) 3-(5-(Cyclohexylmethyl)-2-methoxyphenyl)-3-oxopropanenitrile I32

[0542] To a solution of diisopropylamine (732 mg, 7.23 mmol) in anhydrous THF (25 mL) at 78 C. under N.sub.2 was added n-butyllithium (2.5 M solution in hexanes, 3 mL, 7.23 mmol) dropwise and the mixture was stirred at 78 C. for 1 h. A solution of acetonitrile (297 mg, 7.23 mmol) in anhydrous THF (5 mL) was then added dropwise and stirring was continued at 78 C. for 30 min. A solution of methyl 5-(cyclohexylmethyl)-2-methoxybenzoate I31 (1.46 g, 5.56 mmol) in anhydrous THF (5 mL) was then added dropwise and the mixture was stirred at 78 C. for 40 min. The reaction was quenched at 78 C. with 1 M HCl and the mixture was extracted with EtOAc. The organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/EtOAc=40/1) to give the title compound I32 (707 mg, 47%) as a white solid. LCMS-A (ES-API): R.sub.t2.72 min; m/z 272.1 [M+H].sup.+.

c) 5-(5-(Cyclohexylmethyl)-2-methoxyphenyl)isoxazol-3-amine I33 and 3-(5-(cyclohexylmethyl)-2-methoxyphenyl)isoxazol-5-amine I34

[0543] To a solution of 3-(5-(cyclohexylmethyl)-2-methoxyphenyl)-3-oxopropanenitrile I32 (540 mg, 2.0 mmol) and NaOH (88 mg, 2.19 mmol) in water (10 mL) and ethanol (10 mL) was added NH.sub.2OH.HCl (152 mg, 2.19 mmol) and the mixture was heated at 80 C. overnight. The mixture was partitioned between water and EtOAc, the layers were separated and the organic layer was washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=8/1) to give 5-(5-(cyclohexylmethyl)-2-methoxyphenyl)isoxazol-3-amine I33 (85 mg, 12%) as a yellow solid. LCMS-A (ES-API): 2.61 min; m/z 287.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.50 (d, J=2.2 Hz, 1H), 7.20 (dd, J=8.5, 2.3 Hz, 1H), 7.10-7.06 (m, 1H), 6.26 (s, 1H), 5.62 (s, 2H), 3.88 (s, 3H), 2.45 (d, J=7.0 Hz, 2H), 1.68-1.57 (m, 5H), 1.49-1.42 (m, 1H), 1.18-1.08 (m, 3H), 0.96-0.85 (m, 2H). 3-(5-(Cyclohexylmethyl)-2-methoxyphenyl)isoxazol-5-amine I34 (190 mg, 26%) was also obtained as a yellow solid. LCMS-A (ES-API): R.sub.t2.53; m/z 287.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.42 (d, J=2.3 Hz, 1H), 7.17 (dd, J=8.4, 2.3 Hz, 1H), 7.04-7.00 (m, 1H), 6.59 (s, 2H), 5.36 (s, 1H), 3.79 (s, 3H), 2.41 (d, J=7.0 Hz, 2H), 1.68-1.55 (m, 5H), 1.48-1.40 (m, 1H), 1.19-1.08 (m, 3H), 0.96-0.84 (m, 2H).

(xvii) 5-(4-Chloro-2-methoxyphenyl)isoxazol-3-amine I36

[0544] ##STR00057##

a) 3-(4-Chloro-2-methoxyphenyl)-3-oxopropanenitrile I35

[0545] To a solution of diisopropylamine (656 mg, 6.78 mmol) in anhydrous THF (15 mL) at 78 C. under N.sub.2 was added n-butyllithium (2.5 M solution in hexanes, 2.6 mL, 6.78 mmol) dropwise and the mixture was stirred at 78 C. for 1 h. A solution of acetonitrile (266 mg, 6.78 mmol) in anhydrous THF (5 mL) was then added dropwise and stirring was continued at 78 C. for 30 min. A solution of methyl 4-chloro-2-methoxybenzoate (1.0 g, 4.98 mmol) in anhydrous THF (5 mL) was then added and the mixture was stirred at 78 C. for 40 min. The reaction was quenched at 78 C. with 1 M HCl and the mixture was extracted with EtOAc. The organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the title compound I35 (750 mg, 72%) as a yellow solid. LCMS-A (ES-API): R.sub.t1.91 min; m/z 210.0 [M+H].sup.+.

b) 5-(4-Chloro-2-methoxyphenyl)isoxazol-3-amine I36

[0546] To a solution of 3-(4-chloro-2-methoxyphenyl)-3-oxopropanenitrile I35 (350 mg, 1.69 mmol) and NaOH (75 mg, 1.86 mmol) in water (10 mL) and ethanol (10 mL) was added NH.sub.2OH.HCl (130 mg, 1.86 mmol) and the mixture was heated at 80 C. overnight. Concentrated HCl (0.5 mL) was then added and the mixture was stirred at 80 C. for 2.5 h. The mixture was adjusted to pH 10 with 2 M NaOH and extracted with EtOAc. The organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure The residue was purified by column chromatography (petroleum ether/EtOAc=8/1) to give the title compound I36 (130 mg, 35%) as a yellow solid. LCMS-A (ES-API): R.sub.t 1.84 min; m/z 225.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.73 (d, J=8.4 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 7.13 (dd, J=8.4, 2.0 Hz, 1H), 6.28 (s, 1H), 5.64 (s, 2H), 3.95 (s, 3H).

(xviii) 5-(5-Chloro-2-methoxyphenyl)isoxazol-3-amine I38

[0547] ##STR00058##

a) 3-(5-Chloro-2-methoxyphenyl)-3-oxopropanenitrile I37

[0548] To a solution of diisopropylamine (3.29 g, 32.5 mmol) in anhydrous THF (100 mL) at 78 C. under N.sub.2 was added n-butyllithium (2.5 M solution in hexanes, 13.0 mL, 32.5 mmol) dropwise and the mixture was stirred at 78 C. for 1 h. A solution of acetonitrile (1.33 g, 32.5 mmol) in anhydrous THF (20 mL) was then added dropwise and stirring was continued at 78 C. for 30 min. A solution of methyl 5-chloro-2-methoxybenzoate (5.0 g, 25.0 mmol) in anhydrous THF (10 mL) was then added and the mixture was stirred at 78 C. for 40 min. The reaction was quenched at 78 C. with 1 M HCl and the mixture was extracted with EtOAc (100 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the title compound I37 (4.9 g, 94%) as an orange solid, which was used in the next step without further purification. LCMS-A (ES-API): R.sub.t2.10 min; m/z 209.9 [M+H].sup.+, 231.9 [M+Na].sup.+.

b) 5-(5-Chloro-2-methoxyphenyl)isoxazol-3-amine I38

[0549] To a solution of 3-(5-chloro-2-methoxyphenyl)-3-oxopropanenitrile I37 (2.0 g, 9.6 mmol) and NaOH (420 mg, 10.5 mmol) in water (20 mL) and ethanol (20 mL) was added NH.sub.2OH.HCl (730 mg, 10.5 mmol) and the mixture was heated at 80 C. overnight. Water (40 mL) was added and the mixture was extracted with EtOAc (50 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure The residue was purified by column chromatography (DCM/MeOH=400/1) to give the title compound I38 (66 mg, 3%) as a white solid. LCMS-A (ES-API): R.sub.t 1.59 min; m/z 224.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.69 (d, J=2.7 Hz, 1H), 7.53-7.46 (m, 1H), 7.25-7.20 (m, 1H), 6.34 (s, 1H), 5.67 (s, 2H), 3.93 (s, 3H). 3-(5-Chloro-2-methoxyphenyl)isoxazol-5-amine (158 mg, 7%) was also obtained as a white solid. LCMS-A (ES-API): R.sub.t 1.43 min; m/z 224.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.63 (d, J=2.8 Hz, 1H), 7.46 (dd, J=8.9, 2.8 Hz, 1H), 7.17 (d, J=8.9 Hz, 1H), 6.70 (s, 2H), 5.39 (s, 1H), 3.84 (s, 3H).

(xix) 5-(2-Methoxy-5-(oxazol-2-yl)phenyl)isoxazol-3-amine I42

[0550] ##STR00059##

a) 2-(Tributylstannyl)oxazole I39

[0551] To a solution of oxazole (500 mg, 7.25 mmol) in THF (15 mL) at 78 C. under N.sub.2 was added n-BuLi (2.5 M solution in hexanes, 2.9 mL, 7.32 mmol) dropwise and the mixture was stirred at 78 C. for 30 min. Tributylchlorostannane (1.96 mL, 7.25 mmol) was then added and the mixture was allowed to warm to room temperature and stirred for 1 h. The solvent was removed under reduced pressure and residue was taken up in hexanes (50 mL). The resulting precipitate was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound I39 (2.0 g, 77%) as colourless oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.20 (s, 1H), 7.20 (s, 1H), 1.59-1.49 (m, 6H), 1.31-1.26 (m, 6H), 1.16-1.10 (m, 6H), 0.83 (t, J=7.3 Hz, 9H).

b) Methyl 2-methoxy-5-(oxazol-2-yl)benzoate I40

[0552] To a solution of methyl 5-bromo-2-methoxybenzoate (2.0 g, 8.2 mmol) in 1,4-dioxane (25 mL) was added 2-(tributylstannyl)oxazole I39 (4.4 g, 12.3 mmol) and Pd(PPh.sub.3).sub.4 (947 mg, 0.8 mmol) and the mixture was heated at 120 C. for 3 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (petroleum ether/EtOAc=10/1) to give the title compound I40 (550 mg, 29%) as a yellow solid. LCMS-A (ES-API): R.sub.t 0.99 min; m/z 234.0 [M+H].sup.+.

c) 3-(2-Methoxy-5-(oxazol-2-yl)phenyl)-3-oxopropanenitrile I41

[0553] To a solution of diisopropylamine (310 mg, 3.1 mmol) in THF (20 mL) at 78 C. under N.sub.2 was added n-BuLi (2.5 M solution in hexanes, 1.24 mL, 3.1 mmol) dropwise and the mixture was stirred at 78 C. for 1 h. A solution of acetonitrile (126 mg, 3.1 mmol) in THF (5 mL) was then added dropwise and stirring was continued at 78 C. for 30 min. A solution of methyl 2-methoxy-5-(oxazol-2-yl)benzoate I40 (550 mg, 2.4 mmol) in THF (5 mL) was then added and the mixture was stirred at 78 C. for 40 min. The reaction was quenched at 78 C. with 1 M HCl and the mixture was diluted with water and extracted with EtOAc (150 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound I41 (530 mg, 92%) as an orange solid. LCMS-A (ES-API): R.sub.t 0.86 min; m/z 243.0 [M+H].sup.+.

d) 5-(2-Methoxy-5-(oxazol-2-yl)phenyl)isoxazol-3-amine I42

[0554] To a solution of 3-(2-methoxy-5-(oxazol-2-yl)phenyl)-3-oxopropanenitrile I41 (530 mg, 2.19 mmol) and NaOH (114 mg, 2.85 mmol) in ethanol (20 mL) and water (20 mL) was added NH.sub.2OH.HCl (198 mg, 2.85 mmol) and the mixture was heated at 80 C. overnight. Water was added and the mixture was extracted with EtOAc (150 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=5/1) to give the title compound I42 (130 mg, 23%) as a yellow solid. LCMS-A (ES-API): R.sub.t0.74 min; m/z 258.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.32 (d, J=2.2 Hz, 1H), 8.20 (s, 1H), 8.04 (dd, J=8.8, 2.3 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.37 (s, 1H), 6.37 (s, 1H), 5.68 (s, 2H), 4.01 (s, 3H).

(xx) 5-(2-Ethyl-5-methoxyphenyl)isoxazol-3-amine I46

[0555] ##STR00060##

a) Methyl 5-methoxy-2-vinylbenzoate I43

[0556] A mixture of methyl 2-bromo-5-methoxybenzoate (3.0 g, 12.2 mmol), vinylboronic acid (2.26 g, 14.7 mmol), K.sub.2CO.sub.3 (5.08 g, 36.72 mmol) and Pd(dppf)Cl.sub.2.DCM (500 mg, 0.61 mmol) in 1,4-dioxane/H.sub.2O (40 mL/10 mL) was heated at 90 C. under N2 overnight. The mixture was filtered through a pad of Celite and washed with EtOAc. The filtrate was diluted with water, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether) to give the title product I43 (1.9 g, 81%) as a yellow oil. LCMS-A (ES-API): R.sub.t2.28 min; m/z 193.0 [M+H].sup.+.

b) Methyl 2-ethyl-5-methoxybenzoate I44

[0557] To a solution of methyl 5-methoxy-2-vinylbenzoate I43 (1.9 g, 9.89 mmol) in EtOAc (20 mL) was added 10% Pd/C (190 mg) and the mixture was stirred at room temperature under a H.sub.2 atmosphere overnight. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=50/1 to 20/1) to give the title compound I44 (1.31 g, 63%) as a yellow oil. LCMS-A (ES-API): R.sub.t2.45 min; m/z 195.0 [M+H].sup.+.

c) 3-(2-Ethyl-5-methoxyphenyl)-3-oxopropanenitrile I45

[0558] To a solution of diisopropylamine (799 mg, 7.90 mmol) in THF (25 mL) at 78 C. under N2 was added n-BuLi (2.5 M solution in hexanes 3.16 mL, 7.90 mmol) dropwise and the mixture was stirred at 78 C. for 1 h. A solution of acetonitrile (324 mg, 7.90 mmol) in THF (5 mL) was then added dropwise and stirring was continued for 30 min. A solution of methyl 2-ethyl-5-methoxybenzoate I44 (1.18 g, 6.08 mmol) in THF (3 mL) was then added and the mixture was stirred at 78 C. for 40 min. The reaction was diluted with water and the mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=30/1 to 5/1) to give the title compound I45 (829 mg, 67%) as a yellow oil, which was used directly in the next step.

d) 5-(2-Ethyl-5-methoxyphenyl)isoxazol-3-amine I46

[0559] To a solution of 3-(2-ethyl-5-methoxyphenyl)-3-oxopropanenitrile I45 (829 mg, 4.08 mmol) and NaOH (180 mg, 4.49 mmol) in water (10 mL) and ethanol (10 mL) was added NH.sub.2OH.HCl (312 mg, 4.49 mmol) and the mixture was heated at 80 C. overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=20/1 to 5/1) to give the title product I46 (250 mg, 28%) as a white solid. LCMS-A (ES-API): R.sub.t2.13 min; m/z 219.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.29 (d, J=4.2 Hz, 1H), 7.07 (d, J=1.4 Hz, 1H), 7.01-6.98 (m, 1H), 6.08 (s, 1H), 5.64 (s, 2H), 3.78 (s, 3H), 2.72 (q, J=7.4 Hz, 2H), 1.14 (t, J=7.4 Hz, 3H).

(xxi) (3-Methoxyphenyl)methanesulfonyl Chloride I48

[0560] ##STR00061##

a) (3-Methoxyphenyl)methanesulfonic Acid I47a

[0561] A suspension of 1-(bromomethyl)-3-methoxybenzene (2.0 g, 9.95 mmol) and sodium sulfite (1.3 g, 10.6 mmol) in water (40 mL) and acetone (12 mL) was heated at 90 C. for 16 h. The mixture was allowed to cool to room temperature, toluene was added and the mixture was concentrated under reduced pressure to give the title compound (2.0 g, 100%) as a white solid, which was used in the next step without further purification. LCMS-A (ES-API): R.sub.t 0.62 min; m/z 200.9 [MH].sup..

b) (3-Methoxyphenyl)methanesulfonyl Chloride I48

[0562] To a stirred solution of (3-methoxyphenyl)methanesulfonic acid I47a (636 mg, 3.15 mmol) in DCM (25 mL) was added DMF (5 drops) and the mixture was cooled to 20 C. Oxalyl chloride (2.7 mL, 31.4 mmol) was added and the mixture was stirred at 20 C. for 30 min, then allowed to warm to room temperature and stirred for 2 h. DCM (20 mL) was added and the mixture was washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated to give the title compound (450 mg, 65%) as a yellow oil, which was used in the next step without further purification. LCMS-A (ES-API): R.sub.t 0.95 min; m/z 237.8 [M+Na].sup.+ (LCMS sample treated with MeNH.sub.2 to give 1-(3-methoxyphenyl)-N-methylmethanesulfonamide, exact mass: 215.06).

(xxii) Phenylsulfamoyl Chloride I50

[0563] ##STR00062##

a) Phenylsulfamic Acid I49

[0564] To a solution of aniline (2.0 g, 21.5 mmol) and Et.sub.3N (19.6 g, 194 mmol) in chloroform (40 mL) at 0 C. was added chlorosulfonic acid (2.5 g, 21.5 mmol) dropwise and the mixture was stirred at 0 C. for 2 h. The mixture was concentrated under reduced pressure and the residue was dissolved in a 1 M aqueous NaOH solution (75 mL) and concentrated under reduced pressure. The residue was suspended in boiling ethanol, filtered and washed with ethanol. The filter cake was dried under reduced pressure to give the title compound (3.0 g, 81%) as a white solid. LCMS-A (ES-API): R.sub.t 0.30 min; m/z 172.1 [MH].sup..

b) Phenylsulfamoyl Chloride I50

[0565] To a solution of phenylsulfamic acid I49 (2.0 g, 11.5 mmol) in toluene (30 mL) was added PCl.sub.5 (4.8 g, 23.5 mmol) and the mixture was heated at reflux under N.sub.2 for 2 h, then was allowed to cool to room temperature and was filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.3 g, 59%) as a yellow oil, which was used in the next step without further purification. LCMS-A (ES-API): R.sub.t 3.05 min; m/z 188.0 [M+MeOH-Cl].sup.+.

(xxiii) 2-Cyclohexylethane-1-sulfonyl Chloride I52

[0566] ##STR00063##

a) 2-Cyclohexylethane-1-sulfonic Acid I51

[0567] A suspension of (2-bromoethyl)cyclohexane (3.0 g, 16.0 mmol) and sodium sulfite (2.13 g, 17.0 mmol) in water (60 mL) and acetone (18 mL) was heated at 90 C. for 16 h. The mixture was allowed to cool to room temperature, toluene was added and the mixture was concentrated under reduced pressure to give the title compound (3.0 g, 100%) as a white solid, which was used in the next step without further purification.

b) 2-Cyclohexylethane-1-sulfonyl Chloride I52

[0568] To a stirred solution of 2-cyclohexylethane-1-sulfonic acid I51 (605 mg, 3.15 mmol) in DCM (25 mL) was added DMF (5 drops) and the mixture was cooled to 20 C. Oxalyl chloride (2.7 mL, 31.4 mmol) was added and the mixture was stirred at 20 C. for 30 min, then allowed to warm to room temperature and stirred for 2 h. DCM (20 mL) was added and the mixture was washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (270 mg, 45%) as a yellow oil, which was used in the next step without further purification.

(xxiv) Cyclohexylmethanesulfonyl Chloride I54

[0569] ##STR00064##

a) Cyclohexylmethanesulfonic Acid I53

[0570] A suspension of (bromomethyl)cyclohexane (5.0 g, 28.1 mmol) and sodium sulfite (3.8 g, 30.0 mmol) in water (80 mL) and acetone (30 mL) was heated at 90 C. for 16 h. The mixture was allowed to cool to room temperature, toluene was added and the mixture was concentrated under reduced pressure to give the title compound (4.95 g, 99%) as a white solid, which was used in the next step without further purification. LCMS-A (ES-API): R.sub.t 0.36 min; m/z 177.0 [MH].sup..

b) Cyclohexylmethanesulfonyl Chloride I54

[0571] To a stirred solution of cyclohexylmethanesulfonic acid I53 (1.5 g, 8.4 mmol) in DCM (45 mL) was added DMF (12 drops) and the mixture was cooled to 20 C. Oxalyl chloride (10.7 g, 84.2 mmol) was added and the mixture was stirred at 20 C. for 30 min, then allowed to warm to room temperature and stirred for 2 h. DCM (20 mL) was added and the mixture was washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (300 mg, 19%) as a yellow oil, which was used in the next step without further purification.

(xxv) 5-(2-Methoxy-5-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-amine I57

[0572] ##STR00065##

a) tert-Butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate I55

[0573] To a solution of 5-bromo-1,3,4-thiadiazol-2-amine (4.0 g, 22 mmol) in THF (50 mL) was added di-tert-butyl dicarbonate (5.2 g, 24 mmol), Et.sub.3N (4.5 g, 44 mmol) and DMAP (538 mg, 4.4 mmol) and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc (50 mL3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (MeOH/DCM=1/100) to give the title compound (3.4 g, 55%) as a light yellow solid. LCMS-A (ES-API): R.sub.t 1.22 min; m/z 279.9, 281.9 [M+H].sup.+.

b) tert-Butyl (5-(2-methoxy-5-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)carbamate I56

[0574] A mixture of tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate I55 (300 mg, 1.07 mmol), (2-methoxy-5-(trifluoromethyl)phenyl)boronic acid (282 mg, 1.28 mmol), Pd(dppf)Cl.sub.2.DCM (87 mg, 0.107 mmol) and Na.sub.2CO.sub.3 (340 mg, 3.21 mmol) in DME (8 mL) and water (12 mL) was heated at reflux under N.sub.2 for 16 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (MeOH/DCM=1/200 to 1/100) then triturated with MeOH (60 mL) to give the title compound (190 mg, 47%) as a white solid. LCMS-A (ES-API): R.sub.t2.63 min; m/z 376.0 [M+H].sup.+, 319.9 [M-t-Bu+2H].sup.+.

c) 5-(2-Methoxy-5-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-amine I57

[0575] To a stirred solution of tert-butyl (5-(2-methoxy-5-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)carbamate I56 (95 mg, 0.25 mmol) in DCM (3 mL) was added TFA (0.8 mL) and the mixture was stirred at room temperature for 5 h then concentrated under reduced pressure. The residue was diluted with DCM (30 mL), washed with saturated aqueous NaHCO.sub.3 solution (30 mL2) and the organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (60 mg, 86%) as a white solid. LCMS-A (ES-API): R.sub.t1.75 min; m/z 275.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.36 (d, J=2.3 Hz, 1H), 7.81 (dd, J=8.8, 2.4 Hz, 1H), 7.60 (br s, 2H), 7.42 (d, J=8.8 Hz, 1H), 4.03 (s, 3H).

(xxvi) 5-(5-((1H-Pyrazol-1-yl)methyl)-2-methoxyphenyl)isoxazol-3-amine I62

[0576] ##STR00066##

a) Methyl 5-(hydroxymethyl)-2-methoxybenzoate I58

[0577] To a solution of methyl 5-formyl-2-methoxybenzoate (4.6 g, 23.7 mmol) in THF (230 mL) was added NaBH.sub.4 (1.1 g, 28.4 mmol) and the mixture was stirred at room temperature for 2 h. The reaction was quenched with 1 M aqueous HCl then diluted with water and extracted with DCM. The organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/DCM=1/2) to give the title compound (3.2 g, 68%) as a yellow oil. LCMS-E (ES-API): R.sub.t 0.77 min; m/z 197.0 [M+H].sup.+.

b) Methyl 5-(bromomethyl)-2-methoxybenzoate I59

[0578] To a solution of methyl 5-(hydroxymethyl)-2-methoxybenzoate I58 (2.8 g, 14.3 mmol) in DCM (108 mL) was added PPh.sub.3 (5.6 g, 21.4 mmol) and CBr.sub.4 (7.1 g, 21.4 mmol) and the mixture was heated at 40 C. for 90 min. Water was added and the mixture was extracted with DCM. The organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=10/1) to give the title compound (2.2 g, 60%) as a yellow solid. LCMS-A (ES-API): R.sub.t 2.14 min; m/z 258.9/260.9 [M+H].sup.+.

c) Methyl 5-((1H-pyrazol-1-yl)methyl)-2-methoxybenzoate I60

[0579] To a solution of 1H-pyrazole (867 mg, 12.7 mmol) and K.sub.2CO.sub.3 (2.4 g, 17.0 mmol) in DMF (179 mL) was added a solution of methyl 5-(bromomethyl)-2-methoxybenzoate I59 (2.2 g, 8.5 mmol) in DMF (27 mL) and the mixture was heated at 60 C. overnight. Water was added and the mixture was extracted with EtOAc. The organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=8/1) to give the title compound (887 mg, 42%) as a white solid. LCMS-A (ES-API): R.sub.t 0.70 min; m/z 247.0 [M+H].sup.+.

d) 3-(5-((1H-Pyrazol-1-yl)methyl)-2-methoxyphenyl)-3-oxopropanenitrile I61

[0580] To a solution of diisopropylamine (428 mg, 4.2 mmol) in THF (33 mL) at 78 C. under N.sub.2 was added n-BuLi (2.5 M solution in hexanes, 1.7 mL, 4.2 mmol) dropwise and the mixture was stirred at 78 C. for 1 h. A solution of acetonitrile (173 mg, 4.2 mmol) in THF (4 mL) was then added dropwise and stirring was continued at 78 C. for 30 min. A solution of methyl 5-((1H-pyrazol-1-yl)methyl)-2-methoxybenzoate I60 (800 mg, 3.3 mmol) in THF (4 mL) was then added and the mixture was stirred at 78 C. for 40 min. The reaction was quenched at 78 C. with 1 M aqueous HCl and the mixture was diluted with water and extracted with EtOAc (150 mL3). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (690 mg, 86%) as an orange solid. LCMS-A (ES-API): R.sub.t 0.74 min; m/z 256.0 [M+H].sup.+.

e) 5-(5-((1H-Pyrazol-1-yl)methyl)-2-methoxyphenyl)isoxazol-3-amine I62

[0581] To a solution of 3-(5-((1H-pyrazol-1-yl)methyl)-2-methoxyphenyl)-3-oxopropanenitrile I61 (690 mg, 2.7 mmol) and NaOH (120 mg, 3.0 mmol) in ethanol (3.6 mL) and water (3.6 mL) was added NH.sub.2OH.HCl (209 mg, 3.0 mmol) and the mixture was heated at 80 C. overnight. Concentrated aqueous HCl (1.5 mL) was then added and the mixture was heated at 80 C. for a further 2 h. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=6/1) to give the title compound (57 mg, 8%) as a yellow solid. LCMS-A (ES-API): R.sub.t0.62 min; m/z 271.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.83 (d, J=2.3 Hz, 1H), 7.65 (d, J=2.3 Hz, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.33 (dd, J=8.6, 2.3 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 6.27 (s, 1H), 6.26 (t, J=2.0 Hz, 1H), 5.60 (s, 2H), 5.32 (s, 2H), 3.90 (s, 3H).

(xxvii) 5-(2-Methoxy-5-(1H-pyrazol-1-yl)phenyl)isoxazol-3-amine I65

[0582] ##STR00067##

a) Methyl 2-methoxy-5-(1H-pyrazol-1-yl)benzoate I63

[0583] To a solution of methyl 5-bromo-2-methoxybenzoate (500 mg, 2.07 mmol) and 1H-pyrazole (282 mg, 4.14 mmol) in toluene (4 mL) was added CuI (20 mg, 0.104 mmol), K.sub.2CO.sub.3 (602 mg, 4.36 mmol) and (1R,2R)N1,N2-dimethylcyclohexane-1,2-diamine (59 mg, 0.415 mmol) and the mixture was heated at 140 C. for 2 h under microwave irradiation. Water was added and the mixture was extracted with EtOAc (100 mL3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=10/1) to give the title compound (280 mg, 56%) as a yellow oil. LCMS-A (ES-API): R.sub.t 1.07 min; m/z 233.0 [M+H].sup.+.

b) 3-(2-Methoxy-5-(1H-pyrazol-1-yl)phenyl)-3-oxopropanenitrile I64

[0584] To a solution of diisopropylamine (0.68 g, 6.7 mmol) in THF (30 mL) at 78 C. under N.sub.2 was added n-BuLi (2.5 M solution in hexanes, 2.7 mL, 6.7 mmol) dropwise and the mixture was stirred at 78 C. for 1 h. A solution of acetonitrile (0.275 g, 6.7 mmol) in THF (10 mL) was then added dropwise and stirring was continued for 30 min. A solution of methyl 2-methoxy-5-(1H-pyrazol-1-yl)benzoate I63 (1.2 g, 5.2 mmol) in THF (10 mL) was then added dropwise and the mixture was stirred at 78 C. for 40 min. The reaction was quenched at 78 C. with

[0585] 1 M aqueous HCl and the mixture was diluted with water (400 mL) and extracted with EtOAc (200 mL3). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=5/1) to give the title compound (0.96 g, 77%) as a yellow solid. LCMS-E (ES-API): R.sub.t 3.52 min; m/z 242.0 [M+H].sup.+.

c) 5-(2-Methoxy-5-(1H-pyrazol-1-yl)phenyl)isoxazol-3-amine I65

[0586] To a solution of 3-(2-methoxy-5-(1H-pyrazol-1-yl)phenyl)-3-oxopropanenitrile I64 (960 mg, 4.0 mmol) and NaOH (208 mg, 5.2 mmol) in water (25 mL) and ethanol (25 mL) was added NH.sub.2OH.HCl (360 mg, 5.2 mmol) and the mixture was heated at 80 C. overnight. Water (100 mL) was added and the mixture was extracted with EtOAc (200 mL3). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=10/1 to 5/1) to give the title compound (280 mg, 28%) as a yellow solid. LCMS-A (ES-API): R.sub.t 1.60 min; m/z 256.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.53 (d, J=2.4 Hz, 1H), 8.17 (d, J=2.8 Hz, 1H), 7.91-7.88 (m, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 6.53 (t, J=2.0 Hz, 1H), 6.38 (s, 1H), 5.68 (s, 2H), 3.97 (s, 3H).

[0587] 3-(2-Methoxy-5-(1H-pyrazol-1-yl)phenyl)isoxazol-5-amine (230 mg, 25%) was also obtained as a yellow solid. LCMS-B (ES-API): R.sub.t 3.15 min; m/z 257.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.46 (d, J=2.4 Hz, 1H), 8.09 (d, J=2.8 Hz, 1H), 7.86 (dd, J=9.0, 2.9 Hz, 1H), 7.71 (d, J=1.7 Hz, 1H), 7.26 (d, J=9.0 Hz, 1H), 6.71 (s, 2H), 6.51 (t, J=2.5, 1.8

(xxviii) 5-(2-Bromo-6-methoxyphenyl)isoxazol-3-amine I68

[0588] ##STR00068##

a) Methyl 2-bromo-6-methoxybenzoate I66

[0589] To a solution of 2-bromo-6-methoxybenzoic acid (4.7 g, 20.3 mmol) in methanol (100 mL) was added concentrated H.sub.2SO.sub.4 (15 mL) and the mixture was heated at 70 C. for 3 days. The mixture was diluted with water and extracted with EtOAc (300 mL3). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (2.36 g, 48%) as a yellow oil. LCMS-A (ES-API): R.sub.t 2.10 min; m/z 244.9/246.9 [M+H].sup.+.

b) 3-(2-Bromo-6-methoxyphenyl)-3-oxopropanenitrile I67

[0590] To a solution of diisopropylamine (536 mg, 5.3 mmol) in dry THF (40 mL) at 78 C. under N.sub.2 was added n-BuLi (2.5 M solution in hexanes, 2.1 mL, 5.3 mmol) dropwise and the mixture was stirred at 78 C. for 1 h. A solution of acetonitrile (218 mg, 5.30 mmol) in THF (5 mL) was then added dropwise and stirring was continued for 30 min. A solution of methyl 2-bromo-6-methoxybenzoate I66 (1.0 g, 4.08 mmol) in THF (5 mL) was then added rapidly and the mixture was stirred at 78 C. for 40 min. The mixture was adjusted to pH 5 at 78 C. by addition of 1 M aqueous HCl and extracted with EtOAc (40 mL3). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (1.0 g, 99%) as a yellow solid, which was used directly in the next step.

c) 5-(2-Bromo-6-methoxyphenyl)isoxazol-3-amine I68

[0591] To a solution of 3-(2-bromo-6-methoxyphenyl)-3-oxopropanenitrile I67 (1.0 g, 3.95 mmol) and NaOH (174 mg, 4.35 mmol) in water (15 mL) and ethanol (15 mL) was added NH.sub.2OH.HCl (302 mg, 4.35 mmol) and the mixture was heated at 80 C. overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=10/1 to 3/1) to give the title compound (130 mg, 12%) as a yellow oil. LCMS-A (ES-API): R.sub.t 1.35 min; m/z 268.9, 270.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.41 (t, J=8.2 Hz, 1H), 7.34-7.29 (m, 1H), 7.19-7.13 (m, 1H), 5.92 (s, 1H), 5.61 (s, 2H), 3.76 (s, 3H).

(xxix) 5-(3,5-Dimethoxyphenyl)-1,3,4-thiadiazol-2-amine I70

[0592] ##STR00069##

a) tert-Butyl (5-(3,5-dimethoxyphenyl)-1,3,4-thiadiazol-2-yl)carbamate I69

[0593] To a solution of tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate I55 (400 mg, 1.43 mmol) and (3,5-dimethoxyphenyl)boronic acid (520 mg, 2.86 mmol) in 1,4-dioxane (25 mL) and water (5 mL) under N2 was added Pd(PPh.sub.3).sub.4 (166 mg, 0.14 mmol) and Na.sub.2CO.sub.3 (455 mg, 4.29 mmol) and the mixture was heated at 100 C. overnight. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=5/1) to give the title compound (200 mg, 42%) as a white solid. LCMS-E (ES-API): R.sub.t 3.05 min; m/z 338.2 [M+H].sup.+.

b) 5-(3,5-Dimethoxyphenyl)-1,3,4-thiadiazol-2-amine I70

[0594] A mixture of tert-butyl (5-(3,5-dimethoxyphenyl)-1,3,4-thiadiazol-2-yl)carbamate I69 (200 mg, 0.59 mmol) in TFA (201 mg, 1.77 mmol) was stirred at room temperature overnight then concentrated under reduced pressure to give the title compound (100 mg, 72%) as a colourless oil, which was used directly in the next step.

(xxx) 5-(2-(Methoxymethyl)phenyl)-1,3,4-oxadiazol-2-amine I74

[0595] ##STR00070##

a) 2-(Hydroxymethyl)benzoic acid I71

[0596] To a solution of NaOH (2.25 g, 56.0 mmol) in H.sub.2O (50 mL) was added isobenzofuran-1(3H)-one (5.0 g, 37.3 mmol) and the mixture was heated at reflux for 3 h, then allowed to cool to room temperature. Concentrated aqueous HCl was added to the mixture until a precipitate formed, which was collected by filtration to give the title compound (2.7 g, 48%) as a white solid which was used directly in the next step.

b) Methyl 2-(methoxymethyl)benzoate I72

[0597] To a solution of 2-(hydroxymethyl)benzoic acid I71 (2.5 g, 16.4 mmol) and iodomethane (4.7 g, 32.9 mmol) in DMF (100 mL) at 0 C. was added NaH (60% w/w in oil, 984 mg, 24.6 mmol) and the mixture was stirred at room temperature for 30 min. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=20/1) to give the title compound (880 mg, 33%) as a yellow oil. LCMS-A (ES-API): R.sub.t 1.60 min; m/z 181.0 [M+H].sup.+.

c) 2-(Methoxymethyl)benzohydrazide I73

[0598] To a solution of methyl 2-(methoxymethyl)benzoate I72 (850 mg, 4.7 mmol) in MeOH (15 mL) was added hydrazine hydrate (1.5 g, 30 mmol) and the mixture was heated at 120 C. in a sealed tube overnight. Water was added and the mixture was extracted with EtOAc. The organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=5/1) to give the title compound (600 mg, 71%) as a white solid. LCMS-A (ES-API): R.sub.t 0.31 min; m/z 181.0 [M+H].sup.+.

d) 5-(2-(Methoxymethyl)phenyl)-1,3,4-oxadiazol-2-amine I74

[0599] To a solution of 2-(methoxymethyl)benzohydrazide I73 (450 mg, 2.50 mmol) in MeOH (10 mL) was added BrCN (291 mg, 2.75 mmol) and the mixture was heated at 80 C. in a sealed tube overnight. Water was added and the mixture was extracted with EtOAc. The organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=3/1) to give the title compound (100 mg, 20%) as a yellow solid. LCMS-E (ES-API): R.sub.t 0.82 min; m/z 205.96 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.73 (dd, J=7.7, 1.4 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.55-7.48 (m, 1H), 7.47-7.41 (m, 1H), 7.24 (s, 2H), 4.77 (s, 2H), 3.40 (s, 3H).

(xxxi) 5-(5-Chloro-2-isopropoxyphenyl)-1,3,4-thiadiazol-2-amine I76

[0600] ##STR00071##

a) tert-Butyl (5-(5-chloro-2-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)carbamate I75

[0601] A mixture of tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate I55 (500 mg, 1.79 mmol), (5-chloro-2-isopropoxyphenyl)boronic acid (422 mg, 1.97 mmol), Pd(PPh.sub.3).sub.4 (104 mg, 0.09 mmol) and Na.sub.2CO.sub.3 (379 mg, 3.58 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was heated at reflux overnight under N.sub.2. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=3/1) to give the title compound (190 mg, 24%) as a yellow solid. LCMS-A (ES-API): R.sub.t 2.67 min; m/z 370.0 [M+H].sup.+.

b) 5-(5-Chloro-2-isopropoxyphenyl)-1,3,4-thiadiazol-2-amine I76

[0602] To a solution of tert-butyl (5-(5-chloro-2-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)carbamate I75 (100 mg, 0.27 mmol) in DCM (9 mL) was added TFA (3 mL) and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, the residue was diluted with EtOAc and washed with a saturated aqueous NaHCO.sub.3 solution and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (75 mg, 100%) as a white solid. LCMS-A (ES-API): R.sub.t2.19 min; m/z 269.9 [M+H].sup.+.

(xxxii) 5-(5-Methoxy-2-(methoxymethyl)phenyl)-1,3,4-thiadiazol-2-amine I80

[0603] ##STR00072##

a) 2-Bromo-4-methoxy-1-(methoxymethyl)benzene I77

[0604] To a solution of (2-bromo-4-methoxyphenyl)methanol (1.8 g, 8.29 mmol) in THF (25 mL) at 0 C. was added NaH (60% w/w in oil, 398 mg, 9.95 mmol) and the mixture was stirred for 15 min. Iodomethane (1.3 g, 9.12 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water (1 mL) and the mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=10/1) to give the title compound (1.6 g, 84%) as a light yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.37 (d, J=8.4 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 6.58 (dd, J=8.8, 2.4 Hz, 1H), 4.50 (s, 2H), 3.82 (s, 3H), 3.45 (s, 3H).

b) 2-(5-Methoxy-2-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane I78

[0605] To a solution of 2-bromo-4-methoxy-1-(methoxymethyl)benzene I77 (1.6 g, 6.92 mmol) in 1,4-dioxane (25 mL) was added 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (2.6 g, 10.4 mmol), potassium acetate (2.0 g, 20.8 mmol) and Pd(dppf)Cl.sub.2 (260 mg, 0.35 mmol) and the mixture was heated at 100 C. overnight. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=10/1) to give the title compound (1.5 g, 79%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.33-7.29 (m, 2H), 6.94 (dd, J=8.4, 2.9 Hz, 1H), 4.62 (s, 2H), 3.82 (s, 3H), 3.37 (s, 3H), 1.35 (s, 12H).

c) tert-Butyl (5-(5-methoxy-2-(methoxymethyl)phenyl)-1,3,4-thiadiazol-2-yl) carbamate I79

[0606] A mixture of tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate I55 (500 mg, 1.79 mmol), 2-(5-methoxy-2-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane I78 (498 mg, 1.79 mmol), Pd(PPh.sub.3).sub.4 (104 mg, 0.09 mmol) and Na.sub.2CO.sub.3 (379 mg, 3.58 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was heated at 100 C. overnight under N.sub.2. LCMS analysis showed 20% conversion to the title compound.

[0607] A mixture of 2-(5-methoxy-2-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane I78 (120 mg, 0.43 mmol), tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate I55 (100 mg, 0.36 mmol), Pd(dppf)Cl.sub.2.DCM (15 mg, 0.018 mmol) and Na.sub.2CO.sub.3 (76 mg, 0.72 mmol) in 1,2-dimethoxyethane (5 mL) and water (1 mL) was heated at reflux overnight under N.sub.2. LCMS analysis showed 50% conversion to the title compound. This reaction was scaled up accordingly using tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate I55 (300 mg, 1.07 mmol).

[0608] The three reactions were combined, diluted with EtOAc and washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=3/1) to give the title compound (230 mg, 20%) as a yellow solid. LCMS-A (ES-API): R.sub.t2.32 min; m/z 352.0 [M+H].sup.+.

d) 5-(5-Methoxy-2-(methoxymethyl)phenyl)-1,3,4-thiadiazol-2-amine I80

[0609] tert-Butyl (5-(5-methoxy-2-(methoxymethyl)phenyl)-1,3,4-thiadiazol-2-yl)carbamate I79 (120 mg, 0.34 mmol) was dissolved in a 4 M solution of HCl in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 48 h, then concentrated under reduced pressure. The residue was diluted with EtOAc and washed with a saturated aqueous NaHCO.sub.3 solution and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (90 mg, 100%) as a yellow solid. LCMS-A (ES-API): R.sub.t 0.39 min; m/z 274.0 [M+Na].sup.+.

(xxxiii) 5-(2-Chloro-5-methoxyphenyl)-1,3,4-thiadiazol-2-amine I82

[0610] ##STR00073##

a) tert-Butyl (5-(5-chloro-2-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)carbamate I81

[0611] A mixture of tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate I55 (100 mg, 0.36 mmol), (2-chloro-5-methoxyphenyl)boronic acid (75 mg, 0.40 mmol), Pd(PPh.sub.3).sub.4 (21 mg, 0.018 mmol) and Na.sub.2CO.sub.3 (76 mg, 0.72 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was heated at 100 C. overnight under N.sub.2. This reaction was scaled up accordingly with tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate I55 (500 mg, 1.79 mmol) and the two reaction mixtures were combined, diluted with EtOAc and washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=40/1) to give the title compound (260 mg, 35%) as a yellow solid. LCMS-E (ES-API): R.sub.t3.90 min; m/z 341.7 [M+H].sup.+.

[0612] b) 5-(2-Chloro-5-methoxyphenyl)-1,3,4-thiadiazol-2-amine I82 To a solution of tert-butyl (5-(2-chloro-5-methoxyphenyl)-1,3,4-thiadiazol-2-yl)carbamate 181 (150 mg, 0.44 mmol) in DCM (3 mL) was added TFA (1 mL) and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, the residue was diluted with EtOAc and washed with a saturated aqueous NaHCO.sub.3 solution and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (110 mg, 100%) as a yellow solid. LCMS-E (ES-API): R.sub.t0.69 min; m/z 241.9 [M+H].sup.+.

(xxxiv) 5-(5-((1H-Pyrazol-1-yl)methyl)-2-methoxyphenyl)-1,3,4-thiadiazol-2-amine I87

[0613] ##STR00074##

a) 2-Bromo-4-(bromomethyl)-1-methoxybenzene I83

[0614] To a solution of (3-bromo-4-methoxyphenyl)methanol (1.0 g, 4.61 mmol) in DCM (15 mL) was added PPh.sub.3 (1.8 g, 6.92 mmol) and CBr.sub.4 (2.3 g, 6.92 mmol) and the mixture was heated at reflux for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (Pet. Ether/EtOAc=20/1) to give the title compound (0.9 g, 69%) as a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.62 (d, J=1.6 Hz, 1H), 7.34 (dd, J=8.4, 2.4 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 4.46 (s, 2H), 3.92 (s, 3H).

b) 1-(3-Bromo-4-methoxybenzyl)-1H-pyrazole I84

[0615] To a solution of 1H-pyrazole (584 mg, 8.56 mmol) in THF (35 mL) at 0 C. was added NaH (60% w/w in oil, 342 mg, 8.56 mmol) and the mixture was stirred for 10 min. 2-Bromo-4-(bromomethyl)-1-methoxybenzene 183 (800 mg, 2.86 mmol) was then added and the mixture was allowed to warm to room temperature and was stirred for 3 h. The reaction was quenched with water and the mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=5/1) to give the title compound (700 mg, 82%) as a yellow oil. LCMS-E (ES-API): R.sub.t 2.52 min; m/z 267.0 [M+H].sup.+.

c) 1-(4-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-pyrazole I85

[0616] To a solution of 1-(3-bromo-4-methoxybenzyl)-1H-pyrazole I84 (100 mg, 0.37 mmol) in 1,4-dioxane (5 mL) was added 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (142 mg, 0.56 mmol), potassium acetate (73 mg, 0.74 mmol) and Pd(dppf)Cl.sub.2.DCM (16 mg, 0.019 mmol) and the mixture was heated at 100 C. overnight. This reaction was scaled up accordingly using 1-(3-bromo-4-methoxybenzyl)-1H-pyrazole I84 (600 mg, 2.25 mmol) and the two reaction mixtures were combined, diluted with EtOAc and washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=5/1) to give the title compound (400 mg, 49%) as a yellow oil. LCMS-E (ES-API): R.sub.t 2.72 min; m/z 315.2 [M+H].sup.+.

d) tert-Butyl (5-(5-((1H-pyrazol-1-yl)methyl)-2-methoxyphenyl)-1,3,4-thiadiazol-2-yl) carbamate I86

[0617] A mixture of 1-(4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-pyrazole I85 (100 mg, 0.32 mmol), tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate I55 (90 mg, 0.32 mmol), Pd(dppf)Cl.sub.2.DCM (13 mg, 0.016 mmol) and Na.sub.2CO.sub.3 (68 mg, 0.64 mmol) in 1,2-dimethoxyethane (10 mL) and water (2 mL) was heated at 100 C. overnight under N.sub.2. This reaction was scaled up accordingly using 1-(4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-pyrazole I85 (300 mg, 0.95 mmol) and the two reaction mixtures were combined, diluted with EtOAc and washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=1/1) to give the title compound (150 mg, 30%) as an off-white solid. LCMS-A (ES-API): R.sub.t2.34 min; m/z 388.0.

e) 5-(5-((1H-Pyrazol-1-yl)methyl)-2-methoxyphenyl)-1,3,4-thiadiazol-2-amine I87

[0618] tert-Butyl (5-(5-((1H-pyrazol-1-yl)methyl)-2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)carbamate I86 (50 mg, 0.13 mmol) was dissolved in a 4 M solution of HCl in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 4 h then concentrated under reduced pressure. The residue was diluted with EtOAc and washed with a saturated aqueous NaHCO.sub.3 solution and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (45 mg, 100%) as an off-white solid. LCMS-E (ES-API): R.sub.t 0.94 min; m/z 288.1 [M+H].sup.+.

(xxxv) 5-(2-((1H-Pyrazol-1-yl)methyl)phenyl)-1,3,4-thiadiazol-2-amine I90

[0619] ##STR00075##

a) (1-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-pyrazole I88

[0620] To a solution of 1H-pyrazole (550 mg, 8.07 mmol) in THF (20 mL) at 0 C. was added NaH (60% w/w dispersion in oil, 323 mg, 8.07 mmol) and the mixture was stirred for 10 min. 2-(2-(Bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (800 mg, 2.69 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched with water and the mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=10/1) to give the title compound (400 mg, 52%) as a yellow solid. LCMS-E (ES-API): R.sub.t3.25 min; m/z 285.1 [M+H].sup.+.

b) tert-Butyl (5-(2-((1H-pyrazol-1-yl)methyl)phenyl)-1,3,4-thiadiazol-2-yl)carbamate I89

[0621] A mixture of tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate I55 (200 mg, 0.71 mmol), 1-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-pyrazole I88 (202 mg, 0.71 mmol), Pd(PPh.sub.3).sub.4 (46 mg, 0.04 mmol) and Na.sub.2CO.sub.3 (151 mg, 1.42 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was heated at 100 C. overnight under N.sub.2. The mixture was diluted with EtOAc, washed with water and brine and the organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=1/1) to give the title compound (70 mg, 22%) as a yellow solid. LCMS-E (ES-API): R.sub.t2.85 min; m/z 358.0 [M+H].sup.+.

c) 5-(2-((1H-Pyrazol-1-yl)methyl)phenyl)-1,3,4-thiadiazol-2-amine I90

[0622] To a solution of tert-butyl (5-(2-((1H-pyrazol-1-yl)methyl)phenyl)-1,3,4-thiadiazol-2-yl) carbamate I89 (30 mg, 0.08 mmol) in DCM (5 mL) was added TFA (1 mL) and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, the residue was diluted with EtOAc and washed with a saturated aqueous NaHCO.sub.3 solution and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (20 mg, 90%) as a yellow solid. LCMS-E (ES-API): R.sub.t0.85 min; m/z 258.1 [M+H].sup.+.

(xxxvi) 5-(2-Methoxypyridin-3-yl)-1,3,4-thiadiazol-2-amine I92

[0623] ##STR00076##

a) tert-Butyl (5-(2-methoxypyridin-3-yl)-1,3,4-thiadiazol-2-yl)carbamate I91

[0624] A mixture of tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate I55 (100 mg, 0.36 mmol), (2-methoxypyridin-3-yl)boronic acid (61 mg, 1.1 mmol), Pd(PPh.sub.3).sub.4 (21 mg, 0.018 mmol) and K.sub.2CO.sub.3 (99 mg, 0.72 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was heated at reflux under N.sub.2 overnight.

[0625] A mixture of tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate I55 (600 mg, 2.16 mmol), (2-methoxypyridin-3-yl)boronic acid (367 mg, 2.4 mmol), Pd(PPh.sub.3).sub.4 (125 mg, 0.11 mmol) and K.sub.2CO.sub.3 (596 mg, 4.32 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was heated at reflux under N.sub.2 overnight.

[0626] The two mixtures were combined, diluted with EtOAc and washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=4/1) to give the title compound (260 mg, 34%) as a yellow solid. LCMS-A (ES-API): R.sub.t2.23 min; m/z 309.0 [M+H].sup.+.

b) 5-(2-Methoxypyridin-3-yl)-1,3,4-thiadiazol-2-amine I92

[0627] To a solution of tert-butyl (5-(2-methoxypyridin-3-yl)-1,3,4-thiadiazol-2-yl)carbamate I91 (100 mg, 0.32 mmol) in DCM (9 mL) was added TFA (3 mL) and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, the residue was diluted with EtOAc and washed with a saturated aqueous NaHCO.sub.3 solution and brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (70 mg, 100%) as a white solid. LCMS-A (ES-API): R.sub.t 0.36 min; m/z 209.0 [M+H].sup.+.

(xxxvii) 5-(2-Ethoxy-5-methoxyphenyl)-1,2,4-oxadiazol-3-amine I100

[0628] ##STR00077## ##STR00078##

a) Methyl 2-ethoxy-5-methoxybenzoate I93

[0629] To a solution of methyl 2-hydroxy-5-methoxybenzoate (5.0 g, 27.4 mmol) and K.sub.2CO.sub.3 (7.58 g, 54.9 mmol) in DMF (50 mL) was added iodoethane (3.4 g, 24.2 mmol) dropwise and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc (40 mL6). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (4.26 g, 74%) as a yellow oil. LCMS-A (ES-API): R.sub.t 1.79 min; m/z 211.0 [M+H].sup.+.

b) 2-Ethoxy-5-methoxybenzoic Acid I94

[0630] To a solution of methyl 2-ethoxy-5-methoxybenzoate I93 (4.26 g, 20.3 mmol) in THF (50 mL) was added a solution of lithium hydroxide monohydrate (1.77 g, 40.6 mmol) in water (10 mL) dropwise and the mixture was stirred at room temperature overnight. Most of the THF was removed under reduced pressure and the aqueous residue was adjusted to pH 5-6 with aqueous HCl. The resulting precipitate was collected by filtration and dried to give the title compound (3.4 g, 85%) as a white solid. LCMS-A (ES-API): R.sub.t 0.78 min; m/z 197.0 [M+H].sup.+.

c) 2-Ethoxy-5-methoxybenzoyl Chloride I95

[0631] To a solution of 2-ethoxy-5-methoxybenzoic acid I94 (950 mg, 4.8 mmol) and DMF (1 drop) in DCM (20 mL) at 0 C. under N.sub.2 was added a solution of oxalyl chloride (615 mg, 4.8 mmol) in DCM (3 mL) dropwise and the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was concentrated under reduced pressure to give the title compound (995 mg, 97%) as a yellow oil, which was used directly in the next step.

d) N-(5-Methyl-1,2,4-oxadiazol-3-yl)acetamide I96

[0632] A mixture of cyanamide (9.5 g, 0.22 mol) and NH.sub.2OH.HCl (14.7 g, 0.22 mol) in dry EtOH (100 mL) was heated at reflux for 8 h and the solvent was then removed under reduced pressure. Potassium acetate (30 g, 0.31 mol) and Ac.sub.2O (50 mL) were added and the mixture was heated at reflux for 30 min then poured onto ice (300 g). The mixture was made strongly basic with NaOH (45 g) and then heated at 80 C. for 45 min. After cooling to room temperature, the mixture was extracted with EtOAc (100 mL6) and the combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (acetate hydrolysis did not occur) (5.2 g, 17%). LCMS-A (ES-API): R.sub.t 0.274 min; m/z 164.0 [M+Na].sup.+.

e) 5-Methyl-1,2,4-oxadiazol-3-amine I97

[0633] A mixture of N-(5-methyl-1,2,4-oxadiazol-3-yl)acetamide I96 (5.2 g, 31.9 mmol) and NaOH (2.7 g, 63.8 mmol) in EtOH (50 mL) was heated at 80 C. for 45 min then allowed to cool to room temperature and extracted with diethyl ether (50 mL6). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (2.53 g, 80%) as a white solid. LCMS-A (ES-API): R.sub.t 0.36 min; m/z 100.0 [M+H].sup.+.

f) 2-Ethoxy-5-methoxy-N-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide I98

[0634] To a solution of 5-methyl-1,2,4-oxadiazol-3-amine I97 (450 mg, 4.5 mmol) in pyridine (25 mL) at 0 C. under N.sub.2 was slowly added 2-ethoxy-5-methoxybenzoyl chloride I95 (972 mg, 4.5 mmol) and the mixture was stirred at room temperature overnight. Water was added and the mixture was adjusted to pH 4-5 with 1 M aqueous HCl and extracted with EtOAc (150 mL3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=3/1) to give the title compound (400 mg, 30%) as a white solid. LCMS-A (ES-API): R.sub.t 1.56 min; m/z 278.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.9 (s, 1H), 7.27 (d, J=2.8 Hz, 1H), 7.15-7.12 (m, 2H), 4.15 (q, J=6.9 Hz, 2H), 3.76 (s, 3H), 2.56 (s, 3H), 1.37 (t, J=6.9 Hz, 3H).

g) N-(5-(2-Ethoxy-5-methoxyphenyl)-1,2,4-oxadiazol-3-yl)acetamide I99

[0635] A solution of 2-ethoxy-5-methoxy-N-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide I98 (400 mg, 1.4 mmol) in EtOH (20 mL) was heated at reflux overnight. The solvent was removed under reduced pressure and the residue was purified by column chromatography (DCM/MeOH=400/1) to give the title compound (200 mg, 50%) as a white solid. LCMS-A (ES-API): R.sub.t 1.0 min; m/z 278.0 [M+H].sup.+.

h) 5-(2-Ethoxy-5-methoxyphenyl)-1,2,4-oxadiazol-3-amine I100

[0636] A mixture of N-(5-(2-ethoxy-5-methoxyphenyl)-1,2,4-oxadiazol-3-yl)acetamide I99 (170 mg, 0.614 mmol) and concentrated aqueous HCl (2 mL) in EtOH (15 mL) was heated at reflux overnight. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (Pet. Ether/EtOAc=5/1) to give the title compound (70 mg, 49%) as a white solid. LCMS-A (ES-API): R.sub.t 1.05 min; m/z 236.0 [M+H].sup.+.

(xxxviii) 5-(2-Ethylphenyl)-1,3,4-thiadiazol-2-amine I102

[0637] ##STR00079##

a) tert-Butyl (5-(2-ethylphenyl)-1,3,4-thiadiazol-2-yl)carbamate I101

[0638] To a solution of tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate I55 (400 mg, 1.43 mmol), (2-ethylphenyl)boronic acid (429 mg, 2.86 mmol) and Na.sub.2CO.sub.3 (454 mg, 4.28 mmol) in 1,4-dioxane (48 mL) and H.sub.2O (12 mL) was added Pd(PPh.sub.3).sub.4 (83 mg, 0.072 mmol) and the mixture was heated at reflux overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=6/1) to give the title compound (436 mg, 100%) as a yellow oil. LCMS-A (ES-API): R.sub.t2.59 min; m/z 306.2 [M+H].sup.+.

b) 5-(2-Ethylphenyl)-1,3,4-thiadiazol-2-amine I102

[0639] To a solution of tert-butyl (5-(2-ethylphenyl)-1,3,4-thiadiazol-2-yl)carbamate I101 (436 mg, 1.43 mmol) in DCM (30 mL) was added TFA (10 mL) and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (Pet. Ether/EtOAc=8/1) to give the title compound (190 mg, 65%) as a white solid. LCMS-A (ES-API): R.sub.t0.67 min; m/z 206.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.45 (d, J=7.3 Hz, 1H), 7.42-7.35 (m, 2H), 7.32 (s, 2H), 7.31-7.26 (m, 1H), 2.85 (q, J=7.5 Hz, 2H), 1.13 (t, J=7.5 Hz, 3H).

(xxxix) 5-(2-Methoxy-5-(trifluoromethyl)phenyl)isoxazol-3-amine I105

[0640] ##STR00080##

a) Methyl 2-methoxy-5-(trifluoromethyl)benzoate I103

[0641] To a solution of 2-methoxy-5-(trifluoromethyl) benzoic acid (2.0 g, 9.09 mmol) in methanol (100 mL) was added concentrated H.sub.2SO.sub.4 (2 mL) and the mixture was heated at 70 C. overnight. The mixture was then concentrated under reduced pressure to give the title compound (1.3 g, 62%) as a yellow oil. LCMS-A (ES-API): R.sub.t2.26 min; m/z 235.0 [M+H].sup.+. Product was used without further purification.

b) 3-(2-Methoxy-5-(trifluoromethyl)phenyl)-3-oxopropanenitrile I104

[0642] To a solution of diisopropylamine (730 mg, 7.22 mmol) in anhydrous THF (25 mL) at 78 C. under N.sub.2 was added n-butyllithium (2.5 M solution in hexanes, 3.0 mL, 7.22 mmol) dropwise and the mixture was stirred at 78 C. for 1 h. A solution of acetonitrile (300 mg, 7.22 mmol) in anhydrous THF (5 mL) was then added dropwise and the resulting mixture was stirred at 78 C. for 30 min. A solution of methyl 2-methoxy-5-(trifluoromethyl)benzoate I103 (1.3 g, 5.55 mmol) in anhydrous THF (3 mL) was added rapidly and the mixture was stirred at 78 C. for 40 min. The mixture was diluted with water, extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. ether/EtOAc=10/1 to 5/1) to give the title compound (1.3 g, 90%) as a yellow oil, which was used directly in the next step.

c) 5-(2-Methoxy-5-(trifluoromethyl)phenyl)isoxazol-3-amine I105

[0643] To a solution of 3-(2-methoxy-5-(trifluoromethyl)phenyl)-3-oxopropanenitrile I104 (1.3 g, 5.35 mmol) and NaOH (235 mg, 5.88 mmol) in water (15 mL) and ethanol (15 mL) was added hydroxylamine hydrochloride (409 mg, 5.88 mmol) and the mixture was heated at 80 C. overnight. The mixture was diluted with water, extracted with EtOAc and the combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet. Ether/EtOAc=20/1 to 5/1) to give the title compound (250 mg, 18%) as a white solid. LCMS-A (ES-API): R.sub.t2.20 min; m/z 259.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.98 (d, J=2.4 Hz, 1H), 7.82 (dd, J=8.8, 2.4 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 6.39 (s, 1H), 5.71 (s, 2H), 4.02 (s, 3H).

[0644] Additional Intermediates

TABLE-US-00005 I106 Phenylmethanesulfonyl chloride I107 Benzenesulfonyl chloride I108 ((2-Chloroethyl)sulfonyl)benzene I109 5-(2-Methoxyphenyl)-1,3,4-thiadiazol-2-amine

Examples 1-23 (Table A)

[0645] General Method AA:

##STR00081##

[0646] To a solution of the amine (1.0 eq) in anhydrous THF (10 mL) at 78 C. under N.sub.2 was added LiHMDS (1 M solution in THF, 1.8-5.0 eq) dropwise and the mixture was stirred at 78 C. for 2 h unless specified otherwise. A solution of the sulfonyl chloride (1.5 eq, unless specified otherwise) in anhydrous THF (2.0 mL) was then added dropwise and the mixture was allowed to warm to room temperature and stirred overnight. Where specified in Table A, the reaction was quenched with 1 M HCl. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography, preparative TLC, prep HPLC and/or recrystallization to give the desired compound.

[0647] General Method AB:

##STR00082##

[0648] To a solution of the amine (1.0 eq) in pyridine (4 mL) under N.sub.2 was added the sulfonyl chloride (1.5 eq) and DMAP (0.2 eq) and the mixture was heated at 90 C. overnight. The reaction was quenched with 1 M HCl, water was then added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC to give the desired compound.

[0649] The following examples were synthesized according to general method AA or AB using the appropriate amine R.sub.1NH.sub.2 and sulfonyl chloride R.sub.2SO.sub.2Cl intermediate.

TABLE-US-00006 TABLE A Starting Example materials Name and structure Analytical data Method Notes 1 I18 & I13 [00083] LCMS-A (ES-API): R.sub.t 2.34 min; m/z 468.8/470.8 [M + H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.2 (s, 1H), 7.83 (d, J =2.0 Hz, 1H), 7.66-7.63 (m, 1H), 7.49 (t, J = 8.4 Hz, 1H), 7.18 (t, J = 9.2 Hz 1H), 6.77 (d, J = 8.4 Hz, 2H), 6.72 (s, 1H), 3.91 (s, 3H), 3.72 (s, 6H). AA 5.0 eq LiHMDS used; Column chromatog- raphy (petroleum ether/EtOAc 5/1) 2 I106 & I2 [00084] LCMS-A (ES-API): R.sub.t 2.35 min, m/z 345.0 [M + H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.0 (s, 1H), 7.82 (dd, J = 7.8, 1.4 Hz, 1H), 7.56-7.47 (m, 1H), 7.41- 7.30 (m, 5H), 7.23 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.49 (s, 1H), 4.67 (s, 2H), 3.92 (s, 3H). AB Prep. TLC (CHCl.sub.3/ MeOH 100/1) 3 I107 & I2 [00085] LCMS-A (ES-API): R.sub.t 2.20 min, m/z 330.9 [M + H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.6 (s, 1H), 7.90 (d, J = 7.7 Hz, 2H), 7.78- 7.73 (m, 1H), 7.72-7.58 (m, 3H), 7.53-7.46 (m, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.70 (s, 1H), 3.94 (s, 3H). AA 3.0 eq LiHMDS used; Quenched with 1 M HCl before workup; Purified by prep HPLC 4 I108 & I12 [00086] LCMS-A (ES-API): R.sub.t 2.32 min, m/z 380.9 [M + H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.2 (s, 1H), 7.82 (dd, J = 7.8, 1.5 Hz, 1H), 7.54-7.48 (m, 1H), 7.32- 7.17 (m, 6H), 7.11 (t, J = 7.5 Hz, 1H), 6.71 (s, 1H), 3.94 (s, 3H), 3.67-3.58 (m, 2H), 3.08- 2.99 (m, 2H). AA 3.0 eq LiHMDS used; Quenched with 1 M HCl before workup; Prep. TLC (DCM/ MeOH 100/1) 5 I18 & I7 [00087] LCMS-A (ES-API): R.sub.t 2.19 min, m/z 404.9 [M + H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.1 (s, 1H), 7.75 (dd, J = 7.8, 1.7 Hz, 1H), 7.52-7.40 (m, 2H), 7.15 (d, J = 8.4 Hz, 1H), 7.09- 7.02 (m, 1H), 6.78 (s, 1H), 6.75 (s, 2H), 4.14 (q, J = 6.9 Hz, 2H), 3.81 (s, 6H), 1.35 (t, J = 6.9 Hz, 3H). AA 3.0 eq LiHMDS used; Prep.TLC (DCM/ MeOH 100/1) 6 I47 & I5 [00088] LCMS-A (ES-API): R.sub.t 2.41 min, m/z 497.1 [M + H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.2 (s, 1H), 7.77 (d, J = 7.2 Hz, 2H), 7.43- 7.50 (m, 3H), 7.26 (d, J = 2.8 Hz, 1H), 7.15 (d, J = 9.2 Hz, 1H), 7.07 (t, J = 2.8 Hz, 1H), 6.99 (s, 2H), 6.76 (s, 1H), 3.94 (s, 6H), 3.85 (s, 3H), 3.75 (s, 3H). AA 3.0 eq LiHMDS used; Recrystal- lized from petroleum ether 7 I18 & I5 [00089] LCMS-A (ES-API): R.sub.t 2.34 min, m/z 421.1 [M +H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.1 (s, 1H), 7.49 (t, J = 8.5 Hz, 1H), 7.25 (d, J = 3.0 Hz, 1H), 7.14 (d, J = 9.1 Hz, 1H), 7.05 (dd, J = 9.1, 3.1 Hz, 1H), 6.77 (d, J = 8.5 Hz, 2H), 6.70 (s, 1H), 3.84 (s, 3H), 3.83 (s, 6H), 3.75 (s, 3H). AA 3.0 eq LiHMDS used; Recrystal- lized from petroleum ether 8 I18 & I11 [00090] LCMS-A (ES-API): R.sub.t 2.36 min; m/z 431.0 [M +H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.1 (s, 1H), 7.48 (t, J = 8.5 Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), 7.16 (dd, J = 8.7, 2.2 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 8.5 Hz, 2H), 6.66 (s, 1H), 3.85 (s, 3H), 3.82 (s, 6H), 1.97-1.90 (m, 1H), 0.95-0.87 (m, 2H), 0.67-0.58 (m, 2H). AA 3.0 eq LiHMDS used; Recrystal- lized from petroleum ether 9 I18 & I1 [00091] LCMS-A (ES-API): R.sub.t 2.10 min, m/z 391.0 [M + H].sup.+, 413.0 [M + Na].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.1 (s, 1H), 7.48 (t, J = 8.5 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.37-7.33 (m, 1H), 7.31-7.28 (m, 1H), 7.07- 7.02 (m, 1H), 6.77 (s, 1H), 6.76 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 6H). AA 3.0 eq LiHMDS used; Prep. TLC (DCM/ MeOH 100/1) 10 I21 & I2 [00092] LCMS-A (ES-API): R.sub.t 2.48 min, m/z 467.0 [M + H].sup.+, 489.0 [M + Na].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.3 (s, 1H), 7.81- 7.74 (m, 1H), 7.57-7.42 (m, 6H), 7.40-7.34 (m, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.12-7.02 (m, 2H), 6.78 (s, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.38 (s, 3H). AA 3.0 eq LiHMDS used; Prep. TLC (DCM/ MeOH, 100/1) 11 I47 & I2 [00093] LCMS-A (ES-API): R.sub.t 2.42 min, m/z 467.0 [M + H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.2 (s, 1H), 7.82-7.72 (m, 3H), 7.53- 7.38 (m, 4H), 7.20 (d, J = 8.4 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.99 (s, 2H), 6.74 (s, 1H), 3.94 (s, 6H), 3.91 (s, 3H). AA 3.0 eq LiHMDS used; 1.8 eq sulfonyl chloride used; Recrystal- lized from petroleum ether 12 I19 & I8 [00094] LCMS-B (ES-API): R.sub.t 2.82 min, m/z 419.0 [M + H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.2 (s, 1H), 7.69-7.65 (m, 2H), 7.46 (dd, J = 8.5, 2.3 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 6.65 (dd, J = 8.7, 2.4 Hz, 1H), 6.50 (s, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 2.61 (q, J = 7.6 Hz, 2H), 1.15 (t, J = 7.6 Hz, 3H). AA 3.0 eq LiHMDS used; 3.0 eq sulfonyl chloride used; Prep. TLC (DCM/ MeOH, 80/1) 13 I19 & I1 [00095] LCMS-B (ES-API): R.sub.t 2.87 min, m/z 389.0 [M + H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.3 (s, 1H), 7.72 (s, 1H), 7.53-7.28 (m, 4H), 7.12 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 5.6 Hz, 1H), 6.85 (s, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 2.61 (q, J = 7.6 Hz, 2H), 1.15 (t, J = 7.6 Hz, 3H). AA 2.0 eq LiHMDS used and stirred at 78 C. for 30 min before adding sulfonyl chloride; Prep. TLC (DCM/ MeOH, 60/1) 14 I18 & I29 [00096] LCMS-A (ES-API): R.sub.t 2.39 min; m/z 449.0 [M + H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) 7.95 (s, 1H), 7.43-7.33 (m, 2H), 7.10 (s, 1H), 6.93-6.87 (m, 2H), 6.61 (d, J = 8.5 Hz, 2H), 4.60- 4.51 (m, 1H), 3.94 (s, 6H), 3.79 (s, 3H), 1.36 (d, J = 6.0 Hz, 6H). AA 3.0 eq LiHMDS used; Column chromatog- raphy (DCM/ MeOH = 50/1) and recrystal- lization from petroleum ether/ EtOAc = 3/1 15 I18 & I38 [00097] LCMS-A (ES-API): R.sub.t 2.28 min; m/z 424.9 [M + H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.2 (s, 1H), 7.72 (d, J = 2.7 Hz, 1H), 7.56- 7.45 (m, 2H), 7.24 (d, J = 9.0 Hz, 1H), 6.81-6.71 (m, 3H), 3.91 (s, 3H), 3.82 (s, 6H). AA 5 eq LiHMDS used; Prep. TLC (petroleum ether/ EtOAc = 3/1) 16 I18 & I26 [00098] LCMS-A (ES-API): R.sub.t 2.23 min, m/z 435.0 [M + H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 511.1 (s, 1H), 7.48 (t, J = 8.5 Hz, 1H), 7.24 (d, J = 3.1 Hz, 1H), 7.12-7.08 (m, 1H), 7.06-7.00 (m, 1H), 6.79-6.74 (m, 3H), 4.07 (q, J = 6.9 Hz, 2H), 3.80 (s, 6H), 3.75 (s, 3H), 1.31 (t, J = 6.9 Hz, 3H). AA 3.0 eq LiHMDS used; Purified by prep HPLC 17 I18 & I109 [00099] LCMS-A (ES-API): R.sub.t 1.83 min, m/z 407.9 [M + H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 14.1 (s, 1H), 8.03-7.96 (m, 1H), 7.58- 7.50 (m, 1H 7.44 (t, J = 8.4 Hz, 1H), 7.31-7.25 (m, 1H), 7.16-7.09 (m, 1H), 6.74 (d, J = 8.5 Hz, 2H), 3.97 (s, 3H), 3.71 (s, 6H). AB Prep TLC (petroleum ether/ EtOAc = 10/1) 18 I18 & I42 [00100] LCMS-A (ES-API): R.sub.t 2.01 min, m/z 457.9 [M + H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.2 (s, 1H), 8.31 (d, J = 2.2 Hz, 1H), 8.21 (s, 1H), 8.05 (dd, J = 8.8, 2.3 Hz, 1H), 7.47 (t, J = 8.7 Hz, 1H), 7.41-7.34 (m, 2H), 6.82-6.72 (m, 3H), 3.98 (s, 3H), 3.82 (s, 6H). AA 3.0 eq LiHMDS used; Quenched with 1 M HCl before workup; Prep. TLC (CHCl.sub.3/ MeOH = 100/1) 19 I18 & I33 [00101] LCMS-A (ES-API): R.sub.t 2.77 min, m/z 487.0 [M + H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.1 (s, 1H), 7.52-7.44 (m, 2H), 7.24 (dd, J = 8.5, 2.2 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 6.77 (d, J = 8.5 Hz, 2H), 6.67 (s, 1H), 3.86 (s, 3H), 3.83 (s, 6H), 2.44 (d, J = 7.0 Hz, 2H), 1.67- 1.53 (m, 5H), 1.48-1.40 (m, 1H), 1.17-1.08 (m, 3H), 0.95- 0.83 (m, 2H). AA 4 eq LiHMDS used; Prep. TLC (DCM/ MeOH = 75/1) 20 I18 & I34 [00102] LCMS-A (ES-API): R.sub.t 2.71 min, m/z 487.0 [M + H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.8 (s, 1H), 7.52 (t, J = 8.5 Hz, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.24-7.17 (m, 1H), 7.07-7.00 (m, 1H), 6.80 (d, J = 8.5 Hz, 2H), 6.04 (s, 1H), 3.83 (s, 6H), 3.76 (s, 3H), 2.40 (d, J = 7.0 Hz, 2H), 1.70-1.51 (m, 5H), 1.49- 1.36 (m, 1H), 1.19-1.07 (m, 3H), 0.96-0.81 (m, 2H). AA 4 eq LiHMDS used; Prep. TLC (DCM/ MeOH = 75/1) 21 I18 & I36 [00103] LCMS-A (ES-API): R.sub.t 2.29 min, m/z 424.9 [M +H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.1 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.49 (t, J = 8.5 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.14 (dd, J = 8.4, 2.0 Hz, 1H), 6.77 (d, J = 8.5 Hz, 2H), 6.68 (s, 1H), 3.93 (s, 3H), 3.82 (s, 6H). AA 4 eq LiHMDS used; Prep. TLC (DCM/ MeOH = 100/1) 22 I18 & I30 [00104] LCMS-A (ES-API): R.sub.t 2.30 min; m/z 444.9 [M +H].sup.+; .sup.1H NMR (400 MHz, MeOD) 7.91 (dd, J = 7.8, 1.8 Hz, 1H), 7.60-7.54 (m, 1H), 7.51-7.43 (m, 3H), 6.77-6.73 (m, 3H), 3.89 (s, 6H). AA 3.0 eq LiHMDS used; Purified by prep HPLC 23 I18 & I45 [00105] LCMS-A (ES-API): R.sub.t 2.40 min, m/z 419.0 [M + H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.2 (s, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.04- 7.00 (m, 2H), 6.79 (d, J = 8.4 Hz, 2H), 6.46 (s, 1H), 3.81 (s, 6H), 3.76 (s, 3H), 2.59 (q, J = 7.2 Hz, 2H), 1.04 (t, J = 7.2 Hz, 3H) AA 3.0 eq LiHMDS used; Prep. TLC (petroleum ether/ EtOAc = 10/1)

Examples 24-42 (Table B)

[0650] ##STR00106##

[0651] General Procedure BA:

[0652] 5-Phenylisoxazol-3-amine (0.050 g, 0.312 mmol) and the appropriate sulfonyl chloride (1 eq) in pyridine (0.125 L) were irradiated in a microwave reactor at 110 C. for 2 h. The reaction was cooled and concentrated to dryness. The material was partitioned between 1 M HCl (2 mL) and EtOAc (2 mL), then the layers were separated. The organic layer was washed with 1 M HCl (1 mL), brine (1 mL) and dried (Na.sub.2SO.sub.4). The crude material was taken up in minimal EtOAc and allowed to stand for 2 h at 0 C. The resulting precipitate was collected and air-dried to give the desired product.

[0653] General Procedure BB:

[0654] A mixture of 5-phenylisoxazol-3-amine (0.050 g, 0.312 mmol), the appropriate sulfonyl chloride (2 eq) and pyridine (1 mL) was stirred at room temperature for 16 h. The mixtures were diluted with DCM (1 mL) and washed with 1 M HCl (2 mL). The aqueous layer was removed and the organic layer was dried to give the crude residue. The product was purified by HPLC to give the title compound.

[0655] General Method BC:

[0656] Sulfonyl chlorides (0.62 mmol) were added to a solution of 5-phenylisoxazol-3-amine (50 mg, 0.31 mmol) in pyridine (1 mL). The reaction mixture was stirred at room temperature overnight. 2 N HCl (10 mL) and EtOAc were added. The layers were separated and the aqueous layer was extracted with EtOAc (210 mL). The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. Purification via preparative mass-directed HPLC obtained the desired product.

[0657] General Method BD:

[0658] 5-Phenylisoxazol-3-amine (50 mg, 0.312 mmol), the appropriate sulfonyl chloride (0.624 mmol, 2 eq) and pyridine (1 mL) were stirred at room temperature for 3 days. The mixtures were diluted with DCM (1 mL) and washed with 1 M HCl (2 mL). The aqueous layer was removed and the organic layer was dried to give the crude residues. The crude product was purified by HPLC to give the title compound.

[0659] General Method BE:

[0660] 5-Phenylisoxazole-3-amine (50 mg, 0.312 mmol), the appropriate sulfonyl chloride (0.624 mmol, 2 eq) and pyridine (1 mL) were combined. The reaction mixtures were stirred at room temperature for 1 day. The mixtures were diluted with DCM (1 mL) and washed with 1 M HCl (2 mL). The aqueous layer was removed and the organic layer was dried to give the crude residue. The crude material was purified by flash chromatography, gradient eluting with 100% dichloromethane to 30% MeOH/dichloromethane, to give the title compound.

[0661] General Method BF:

[0662] The compounds were prepared as per general method BE and then further purified by HPLC to give the title compound.

[0663] The following examples in Table B were synthesized according to general method BA, BB, BC BD, BE or BF using the appropriate sulfonyl chloride RSO.sub.2Cl intermediate.

TABLE-US-00007 TABLE B Example Structure Name LCMS Method 24 [00107] 3-iodo-N-(5-phenylisoxazol- 3-yl)benzenesulfonamide LCMS: R.sub.t 3.484 min; m/z 426.7 [M + H].sup.+ BA 25 [00108] 4-iodo-N-(5-phenylisoxazol- 3-yl)benzenesulfonamide LCMS: R.sub.t 3.611 min; m/z 426.7 [M + H].sup.+ BA 26 [00109] 4-bromo-N-(5- phenylisoxazol-3- yl)benzenesulfonamide LCMS: R.sub.t 3.594 min; m/z 380.7 [M + H].sup.+ BA 27 [00110] 5-bromo-2-methoxy-N-(5- phenylisoxazol-3- yl)benzenesulfonamide LCMS: R.sub.t 5.57 min, m/z = 409.1 [M + H].sup.+ BB 28 [00111] 4-(tert-butyl)-N-(5- phenylisoxazol-3- yl)benzenesulfonamide LCMS: R.sub.t 5.82 min, m/z 357.4 [M + H].sup.+ BB 29 [00112] N-(5-phenylisoxazol-3- yl)cyclopropanesulfonamide LCMS: R.sub.t 5.06 min, m/z 265.7 [M + H].sup.+. BC 30 [00113] N-(5-phenylisoxazol-3- yl)pyridine-3-sulfonamide LCMS: R.sub.t 5.00 min, m/z 302.5 [M + H].sup.+. BC 31 [00114] N-(5-phenylisoxazol-3- yl)cyclohexanesulfonamide LCMS: R.sub.t 6.47 min, m/z 305.1 [M H]. BC 32 [00115] N-(5-phenylisoxazol-3- yl)propane-1-sulfonamide LCMS: R.sub.t 5.19 min, m/z 267.2 [M + H].sup.+. BC 33 [00116] N-(5-phenylisoxazol-3-yl)- [1,1-biphenyl]-4- sulfonamide LCMS: R.sub.t 6.95 min, m/z 377.28 [M + H].sup.+. BD 34 [00117] N-(5-phenylisoxazol-3-yl)-3- (trifluoromethoxy)benzene- sulfonamide LCMS: R.sub.t 5.64 min, m/z 385.5 [M + H].sup.+. BD 35 [00118] 3-chloro-N-(5- phenylisoxazol-3- yl)benzenesulfonamide LCMS: R.sub.t 5.48 min, m/z 335.4 [M + H].sup.+. BD 36 [00119] 3-methoxy-N-(5- phenylisoxazol-3- yl)benzenesulfonamide LCMS: R.sub.t 5.42 min, m/z 331.5 [M + H].sup.+. BD 37 [00120] 4-methoxy-N-(5- phenylisoxazol-3- yl)benzenesulfonamide LCMS: R.sub.t 5.35 min, m/z 331.3 [M + H].sup.+. BD 38 [00121] 3,4-dichloro-N-(5- phenylisoxazol-3- yl)benzenesulfonamide LCMS: R.sub.t 6.93 min, m/z 369.15 [M + H].sup.+. BF 39 [00122] 2,6-difluoro-N-(5- phenylisoxazol-3- yl)benzenesulfonamide LCMS: R.sub.t 6.15 min, m/z 337.14 [M + H].sup.+. BF 40 [00123] 3,4-dimethyl-N-(5- phenylisoxazol-3- yl)benzenesulfonamide LCMS: R.sub.t 6.60 min, m/z 329.21 [M + H]. BE 41 [00124] 3,4-difluoro-N-(5- phenylisoxazol-3- yl)benzenesulfonamide LCMS: R.sub.t 6.47 min, m/z 337.14 [M + H].sup.+. BE 42 [00125] 5-ethyl-2-methoxy-N-(5- phenylisoxazol-3- yl)benzenesulfonamide LCMS: R.sub.t 5.63 min, m/z 358.8 [M + H].sup.+. BB 76 [00126] N-(5-phenylisoxazol-3-yl)- 5,6,7,8- tetrahydronaphthalene-2- sulfonamide LCMS R.sub.t 5.77 min, m/z = 355.8 [M + H].sup.+ BD

[0664] Compounds in Table C were synthesized following analogous methods to general method BD:

TABLE-US-00008 TABLE C Example Structure Name LCMS 43 [00127] 4-fluoro-N-(5-phenylisoxazol-3- yl)benzenesulfonamide LCMS: R.sub.t 6.28 min, m/z 319.25 [M + H].sup.+. 44 [00128] 3-fluoro-N-(5-phenylisoxazol-3- yl)benzenesulfonamide LCMS: R.sub.t 6.28 min, m/z 319.25 [M + H].sup.+. 45 [00129] 4-cyano-N-(5-phenylisoxazol-3- yl)benzenesulfonamide LCMS: R.sub.t 6.06 min, m/z 326.24 [M + H].sup.+. 46 [00130] 3-cyano-N-(5-phenylisoxazol-3- yl)benzenesulfonamide LCMS: R.sub.t 6.05 min, m/z 326.24 [M + H].sup.+. 47 [00131] N-(5-phenylisoxazol-3-yl)-4- (trifluoromethyl)benzene- sulfonamide LCMS: R.sub.t 6.73 min, m/z 369.15 [M + H].sup.+. 48 [00132] N-(5-phenylisoxazol-3-yl)-2- (trifluoromethyl)benzene- sulfonamide LCMS: R.sub.t 5.56 min, m/z 369.7 [M + H].sup.+. 49 [00133] 4-methyl-N-(5-phenylisoxazol-3- yl)benzenesulfonamide LCMS: R.sub.t 5.52 min, m/z 315.4 [M + H].sup.+. 50 [00134] 3-methyl-N-(5-phenylisoxazol-3- yl)benzenesulfonamide LCMS: R.sub.t 5.51 min, m/z 315.0 [M + H].sup.+. 51 [00135] 2-methyl-N-(5-phenylisoxazol-3- yl)benzenesulfonamide LCMS: R.sub.t 5.46 min, m/z 315.1 [M + H].sup.+.

[0665] General Method D:

##STR00136##

[0666] A suspension of 5-ethyl-2-methoxybenzene-1-sulfonyl chloride I19 (150 mg, 0.639 mmol) and the appropriate amine (0.639 mmol) in pyridine (2 mL) was irradiated in the microwave at 110 C. for 2 hours. Water (20 mL) was added and the resultant solid removed by filtration and air-dried to yield the product.

[0667] Compounds in Table D were synthesized following analogous methods to general method D:

TABLE-US-00009 TABLE D Example Structure Name LCMS 52 [00137] 5-ethyl-2-methoxy-N-(5-phenyl- 1,3,4-thiadiazol-2- yl)benzenesulfonamide LCMS R.sub.t: 6.393 min; m/z 376.0 [M + H].sup.+. 53 [00138] 5-ethyl-2-methoxy-N-(5-phenyl- 1,2,4-oxadiazol-3- yl)benzenesulfonamide LCMS R.sub.t: 6.447 min; m/z 360.0 [M + H].sup.+.

Example 54: 3-Bromo-N-(5-phenylisoxazol-3-yl)benzenesulfonamide, 54

[0668] ##STR00139##

[0669] 5-Phenylisoxazol-3-amine (0.050 g, 0.312 mmol) and 3-bromo-1-sulfonyl chloride (0.080 g, 0.312 mmol) in pyridine (0.125 mL) were irradiated in a microwave reactor at 110 C. for 3 h. The reaction was cooled and concentrated to dryness. The material was partitioned between 1 M HCl (2 mL) and EtOAc (2 mL), then the layers were separated. The organic layer was washed again with 1 M HCl (1 mL), then brine (1 mL), dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The crude material was taken up in minimal EtOAc and hexane was slowly added until precipitation began. The mixture was allowed to stand for 2 h at 0 C. The resulting precipitate was collected and air-dried. Three rounds of precipitation from EtOAc/hexane gave the desired product 54 (0.042 g, 35% yield) as a >98% pure white solid by LCMS. LCMS: R.sub.t 3.585 min; m/z 380.7 [M+H].sup.+.

Example 55: 2,6-Dimethoxy-N-[5-(2-methoxyphenyl)isoxazol-3-yl]-N-methyl-4-phenyl-benzenesulfonamide, 55

[0670] ##STR00140##

[0671] To a solution of 2,6-dimethoxy-N-[5-(2-methoxyphenyl)isoxazol-3-yl]-4-phenyl-benzenesulfonamide 11 (0.0170 g, 0.0364 mmol) in anhydrous DMF (1 mL) was added iodomethane (0.00746 mL, 0.120 mmol) and potassium carbonate (0.020 g, 0.15 mmol). The mixture was stirred at room temperature for 4 h, poured into water and extracted with ethyl acetate (315 mL). The organic phase was washed with brine and evaporated in vacuo to give the desired product (15 mg, 87% yield) as a yellow oil. .sup.1H NMR (400 MHz, Chloroform-d) 7.90 (dd, J=7.8, 1.7 Hz, 1H), 7.57-7.51 (m, 2H), 7.49-7.35 (m, 4H), 7.17 (s, 1H), 7.04 (td, J=7.6, 1.1 Hz, 1H), 6.98 (dd, J=8.4, 1.0 Hz, 1H), 6.75 (s, 2H), 3.92 (s, 3H), 3.88 (s, 6H), 3.46 (s, 3H). Purity 95%. LCMS: R.sub.t 6.417 min, m/z 480.7 [M+H].sup.+, 502.7 [M+Na].sup.+.

Example 56: 2,6-Dimethoxy-N-(5-(2-methoxyphenyl)isoxazol-3-yl)benzenesulfonamide, 56

[0672] ##STR00141##

[0673] A solution of 2,6-dimethoxybenzenesulfonyl chloride I18 (0.0592 g, 0.250 mmol) and 5-(2-methoxyphenyl)-1,2-oxazol-3-amine I2 (0.0476 g, 0.250 mmol) in pyridine (0.500 mL) was irradiated in the microwave at 130 C. for 2 h. The reaction was cooled to room temperature then diluted with EtOAc (10 mL). The organics were washed with 1 M HCl (10 mL) and the aqueous layer back extracted twice with EtOAc (210 mL). The combined organic layers were dried in vacuo and the crude material was purified by solid phase extraction (500 mg, Si-amine cartridge, 3 void volumes of MeOH followed by 3 void volumes of methanolic HCl). The acidic eluate was concentrated in vacuo and the residue wet loaded onto silica gel and purified by column chromatography (4 g, SiO.sub.2 cartridge 0-50% EtOAc in petroleum benzine 40-60 C.) to give the title compound 56 (4.40 mg, 4.5% yield) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.00 (s, 1H), 7.83 (dd, J=1.74, 7.79 Hz, 1H), 7.42-7.34 (m, 2H), 7.05-6.94 (m, 3H), 6.61 (d, J=8.50 Hz, 2H), 3.95 (s, 6H), 3.93 (s, 3H). LCMS: R.sub.t 5.70 min, m/z 390.8 [M+H].sup.+, 412.7 [M+Na].sup.+.

Example 57: 2,4-Dimethoxy-N-(5-(2-methoxyphenyl)isoxazol-3-yl)benzenesulfonamide, 57

[0674] ##STR00142##

[0675] A solution of 2,4-dimethoxybenzene-1-sulfonyl chloride (0.12 g, 0.53 mmol) and 5-(2-methoxyphenyl)isoxazol-3-amine I2 (0.10 g, 0.53 mmol) in pyridine (0.600 mL) was irradiated in the microwave at 130 C. for 2 h. The reaction was cooled to room temperature then diluted with EtOAc (10 mL). The organics were washed with 1 M HCl (10 mL) and the aqueous layer back extracted twice with EtOAc (210 mL). The combined organic layers were dried in vacuo and the residue wet-loaded onto silica gel and the product purified by column chromatography (24 g, SiO.sub.2 cartridge 0-30% EtOAc in petroleum benzine 40-60 C.) to give the desired product 57 (0.192 g, 94% yield) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.85-7.79 (m, 2H), 7.58 (s, 1H), 7.43-7.36 (m, 1H), 7.03-6.96 (m, 2H), 6.89 (s, 1H), 6.51-6.44 (m, 2H), 3.98 (s, 3H), 3.95 (s, 3H), 3.82 (s, 3H). Purity >85% as judged by .sup.1H-NMR. LCMS: R.sub.t 5.86 min, m/z 390.8 [M+H].sup.+.

Example 58: 5-Ethyl-2-methoxy-N-(5-(2-methoxyphenyl)isoxazol-3-yl)benzenesulfonamide, 58

[0676] ##STR00143##

[0677] A solution of 5-(2-methoxyphenyl)isoxazol-3-amine I2 (100 mg, 0.526 mmol) and the 5-ethyl-2-methoxybenzenesulfonyl chloride I19 (123 mg, 0.526 mmol) in pyridine (2 mL) was irradiated in the microwave for 2 h at 100 C. Upon cooling, the reaction mixture was diluted with water (100 mL) and the resultant precipitate removed by filtration. The solid was washed with water (50 mL), petroleum benzine 40-60 C. (50 mL) and air dried to yield the product 58 as a white solid (97 mg, 47%). .sup.1H NMR (400 MHz, DMSO-d.sup.6) =11.32 (s, 1H), 7.76 (dd, J=7.8, 1.7, 1H), 7.70 (d, J=2.3, 1H), 7.53-7.45 (m, 2H), 7.21 (d, J=7.9, 1H), 7.14 (d, J=8.5, 1H), 7.11-7.04 (m, 1H), 6.66 (s, 1H), 3.92 (s, 3H), 3.80 (s, 3H), 2.62 (q, J=7.6, 2H), 1.16 (t, J=7.6, 3H). LCMS: R.sub.t 6.554 min, m/z 389.1 [M+H].sup.+.

Example 59: 5-Ethyl-N-(5-(2-fluorophenyl)isoxazol-3-yl)-2-methoxybenzenesulfonamide, 59

[0678] ##STR00144##

[0679] A solution of 5-ethyl-2-methoxybenzene-1-sulfonyl chloride I19 (263 mg, 1.12 mmol) and 5-(2-fluorophenyl)isoxazol-3-amine (200 mg, 1.12 mmol) in pyridine (2.0 mL) was irradiated in the microwave at 100 C. for 2 hours. Upon cooling the reaction mixture was added to water (50 mL) and the resultant green solid removed by filtration, the solid was dissolved in a minimum amount of acetone (4 mL) before petroleum spirits 40-60 C. (70 mL) was added causing dark blue droplets of oil to form. The mother liquor was decanted off and evaporated to yield a tan solid. The solid was dissolved in acetone (2 mL) then petroleum spirits 40-60 C. (50 mL) was added causing a precipitate to form. The solid was removed by filtration and air dried to yield the product as a tan solid (23 mg, 5%). .sup.1H NMR (400 MHz, DMSO-d.sup.6) =11.46 (s, 1H), 7.87 (td, J=7.7, 1.7, 1H), 7.69 (d, J=2.3, 1H), 7.66-7.55 (m, 1H), 7.52-7.33 (m, 3H), 7.15 (d, J=8.5, 1H), 6.65 (d, J=3.5, 1H), 3.79 (s, 3H), 2.62 (q, J=7.6, 2H), 1.15 (t, J=7.6, 3H). LCMS: R.sub.t 3.787 min, m/z=377.2 [M+H].sup.+.

Example 60: N-(5-(2-Fluorophenyl)isoxazol-3-yl)-5,6,7,8-tetrahydronaphthalene-2-sulfonamide, 60

[0680] ##STR00145##

[0681] A solution of 5-(2-fluorophenyl)isoxazol-3-amine (250 mg, 1.40 mmol) and 5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride (324 mg 1.40 mmol) in pyridine (2 mL) was irradiated in the microwave for 2 hours at 100 C. Upon cooling the reaction mixture was added to water (50 mL) and the resultant precipitate removed by filtration, washed with petroleum benzine 40-60 C. (100 mL) and air dried to yield the title compound as a tan solid (226 mg, 43%). LCMS: R.sub.t 3.978 min; m/z 371.1 [MH].sup.. .sup.1H NMR (400 MHz, DMSO-d.sup.6) =7.93-7.85 (m, 1H), 7.65-7.56 (m, 3H), 7.50-7.35 (m, 2H), 7.28 (d, J=8.0, 1H), 6.70 (d, J=3.3, 1H), 2.87-2.69 (m, 4H), 1.72 (s, 4H).

Example 61: N-(4-Chloro-5-phenylisoxazol-3-yl)-3,4-dimethylbenzenesulfonamide, 61

[0682] ##STR00146##

a) 4-Chloro-5-phenylisoxazol-3-amine, A1

[0683] N-Chlorosuccinimide (0.60 g, 4.5 mmol) was added to a solution of 5-phenyl-1,2-oxazole-3-amine (0.36 g, 2.3 mmol) in DCM (8 mL) at 0 C. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature overnight. Acetonitrile (3 mL) was added to allow remaining solids to dissolve. An additional amount of N-chlorosuccinimide (0.60 g) was added at 0 C. and the reaction mixture was allowed to warm up to room temperature and stirred for 24 h. The reaction mixture was cooled to 0 C. and an extra amount of N-chlorosuccinimide (0.60 g) was added. The reaction mixture was allowed to warm up to room temperature and stirred for 48 h. Water (20 mL) was added followed by DCM (20 mL). The layers were separated and the aqueous layer was extracted with DCM (220 mL). The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. Purification by combiflash (0-100% EtOAc/cyclohexane) obtained the desired product A1 (0.21 g, 48%) as an off-white solid. LCMS: R.sub.t 5.07 min, m/z 195.5 [M+H].sup.+.

b) N-(4-Chloro-5-phenylisoxazol-3-yl)-3,4-dimethylbenzenesulfonamide, 61

[0684] 3,4-Dimethylbenzylsulfonylchloride (0.11 g, 0.53 mmol) was added to a solution of A1 (0.052 g, 0.27 mmol) in pyridine (1 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between 2 N HCl (5 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (210 mL). The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. Purification by combiflash (0-100% EtOAc/cyclohexane) obtained the desired product 61 (15 mg, 15%) as an off-white solid. LCMS: R.sub.t 5.73 min, m/z 363.7 [M+H].sup.+.

Example 62: N-(5-(4-Bromophenyl)isoxazol-3-yl)benzenesulfonamide, 62

[0685] ##STR00147##

[0686] Benzenesulfonyl chloride I107 (0.040 mL, 0.314 mmol), 5-(4-bromophenyl)isoxazol-3-amine (0.050 g, 0.209 mmol) and pyridine (1 mL) were mixed at room temperature and stirred for 16 h. The solvent was removed in vacuo to afford a crude residue. This was dissolved in DCM (2 mL) and 1 M HCl (2 mL) and filtered through a phase separation cartridge. The crude material was purified by flash chromatography gradient eluting with 100% dichloromethane to 20% MeOH/dichloromethane to give the desired product 62 (13 mg, 14% yield). LCMS: R.sub.t 5.66 min, m/z=377.5 [MH].sup..

Example 63: N-(5-phenylisoxazol-3-yl)benzenesulfonamide, 63

[0687] ##STR00148##

[0688] 3-Amino-5-phenylisoxazole (0.051 g, 0.320 mmol), pyridine (1 mL) and benzenesulfonyl chloride I107 (0.094 mL, 0.736 mmol) were mixed at room temperature and stirred for 16 h. The solvent was removed in vacuo to afford a crude residue. This was dissolved in DCM (2 mL) and 1 M HCl (2 mL) and filtered through a phase separation cartridge. All crudes were purified by flash chromatography gradient eluting with 100% dichloromethane to 20% MeOH/dichloromethane to give the title compound 63 (38 mg, 40% yield). LCMS: R.sub.t 5.36 min, m/z=301.5 [M+H].sup.+.

Example 64: 2-Fluoro-N-(5-phenylisoxazol-3-yl)benzenesulfonamide, 64

[0689] ##STR00149##

[0690] 2-Fluorobenzenesulfonyl chloride (0.050 mL, 0.375 mmol), pyridine (1 mL), and 5-phenylisoxazol-3-amine (0.030 g, 0.187 mmol) were mixed at room temperature and stirred for 16 h. Water was added and the precipitate was collected by filtration. The product was recrystallized to give the desired product 64 (58 mg, 97% yield). .sup.1H NMR (300 MHz, Methanol-d.sub.4) 8.02-7.95 (m, 1H), 7.74-7.68 (m, 2H), 7.67-7.59 (m, 1H), 7.47-7.39 (m, 3H), 7.36-7.21 (m, 2H), 6.62 (s, 1H).

Example 65: 2-Phenyl-N-(5-phenylisoxazol-3-yl)ethane-1-sulfonamide, 65

[0691] ##STR00150##

[0692] 2-Phenylethanesulfonylchloride (0.17 g, 0.81 mmol) was added to a solution of 5-phenyl-1,2-oxazole-3-amine (0.065 g, 0.41 mmol) in pyridine (1 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between 2 N HCl (5 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (210 mL). The combined organic layers were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated. Purification by combiflash (0-100% EtOAc/cyclohexane) obtained the desired product 65 (2 mg, 2%) as an off white solid. LCMS: R.sub.t 5.54 min, m/z 329.3 [M+H].sup.+.

Example 66: 2-Fluoro-N-(5-(4-fluoro-[1,1-biphenyl]-3-yl)-1,3,4-thiadiazol-2-yl)benzenesulfonamide, 66

[0693] ##STR00151##

a) 5-(4-fluoro-[1,1-biphenyl]-3-yl)-1,3,4-thiadiazol-2-amine, A2

[0694] A mixture of 2-fluoro-5-phenylbenzoic acid (0.100 g, 0.463 mmol) and thiosemicarbazide (0.46 g, 0.500 mmol) was stirred in POCl.sub.3 (1 mL) and heated to 75 C. for 1 h. Water (2 mL) was slowly added to the reaction and the mixture was heated to reflux for 2 h. After cooling, the reaction was cooled with ice/water and the pH was adjusted to 8 with 15 M KOH. The solid that crashed out was filtered and dried to in vacuo to afford an off-white solid (0.200 g). The solid was recrystallised from hot ethanol affording the desired product A2 as an off white solid (0.125 g, 92% yield). LCMS: R.sub.t 5.21 min, m/z=272.3 [M+H].sup.+.

b) 2-Fluoro-N-(5-(4-fluoro-[1,1-biphenyl]-3-yl)-1,3,4-thiadiazol-2-yl)benzenesulfonamide, 66

[0695] To a solution of A2 (0.035 g, 0.129 mmol) in dry pyridine (1 mL) at 0 C. was added 2-fluorobenzenesulfonyl chloride (0.020 mL, 0.155 mmol). The mixture was stirred at room temperature for 4 days. Another 1.2 eq of 2-fluorobenzenesulfonyl chloride (0.020 mL) was added and the mixture was stirred for a further 16 h while heating to 50 C. The solvent was removed in vacuo. Toluene (1 mL) was added and the solvent was removed in vacuo to afford a crude residue as an orange solid (0.085 g). The crude was purified by preparative TLC eluting with 1% MeOH/dichloromethane affording a clear smear (0.022 g). This was further purified by HPLC collecting the desired product 66 as a pale yellow solid (0.0059 g, 11% yield). LCMS: R.sub.t8.07 min, m/z 430.14 [M+H].sup.+.

Example 67: N-(5-(4-Fluoro-[1,1-biphenyl]-3-yl)-1,3,4-thiadiazol-2-yl)benzenesulfonamide, 67

[0696] ##STR00152##

[0697] To a solution of A2 (0.050 g, 0.184 mmol) in dry pyridine (1 mL) at 0 C. was added benzenesulfonyl chloride I107 (0.028 mL, 0.221 mmol). The mixture was stirred at room temperature for 16 h. Another 1.2 eq of benzenesulfonyl chloride I107 (0.028 mL) was added and the mixture was stirred for a further 16 h. The solvent was removed in vacuo. Toluene (1 mL) was added and the solvent was removed in vacuo to afford a crude residue as an orange solid (0.065 g). This was purified twice by flash chromatography gradient eluting with 100% dichloromethane to 10% MeOH/dichloromethane then gradient eluting with 100% dichloromethane to 5% MeOH/dichloromethane affording the title product 67 as a white paste (0.012 g, 16% yield). LCMS: R.sub.t 5.82 min, m/z 412.0 [M+H].sup.+.

Example 68: 2-Fluoro-N-(5-phenyl-1,2,4-oxadiazol-3-yl)benzenesulfonamide, 68

[0698] ##STR00153##

[0699] 2-Fluorobenzenesulfonyl chloride (0.045 mL, 0.340 mmol), (0.030 g, 0.170 mmol) and pyridine (1 mL) were mixed at room temperature and stirred for 16 h. Water was added and the precipitate filtered. The solid was further purified by HPLC to give the title compound 68 (9.0 mg, 15% yield). LCMS R.sub.t 6.73 min, m/z=320.20 [M+H].sup.+.

Example 69: Methyl 3-(3-((2,6-dimethoxyphenyl)sulfonamido)isoxazol-5-yl)-4-methoxybenzoate, 69

[0700] ##STR00154##

[0701] A mixture of N-(5-(5-bromo-2-methoxyphenyl)isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 1 (100 mg, 0.212 mmol), Pd(OAc).sub.2 (1.4 mg, 3.9 umol), Xantphos (11 mg, 0.19 mmol) and Et.sub.3N (107 mg, 1.2 mmol) in MeOH (15 mL) was heated at 100 C. under a CO atmosphere (1 atm) overnight. The catalyst was removed by filtration, washed with MeOH and the filtrate was concentrated under reduced pressure. The residue was purified by prep. TLC (DCM/MeOH=50/1) to give the title compound 69 (20 mg, 21%) as a white solid. LCMS-A (ES-API): R.sub.t2.08 min; m/z 448.9 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.53 (d, J=2.2 Hz, 1H), 8.08 (dd, J=8.8, 2.2 Hz, 1H), 7.94 (s, 1H), 7.40 (t, J=8.5 Hz, 1H), 7.05-6.98 (m, 2H), 6.62 (d, J=8.6 Hz, 2H), 4.00 (s, 3H), 3.96 (s, 6H), 3.90 (s, 3H).

Example 70: N-(5-(2,5-Dimethoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,6-dimethoxybenzenesulfonamide, 70

[0702] ##STR00155##

a) tert-Butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate, A3

[0703] To a solution of 5-bromo-1,3,4-thiadiazol-2-amine (1.0 g, 5.56 mmol) in THF (15 mL) was added di-tert-butyl dicarbonate (1.3 g, 6.12 mmol), Et.sub.3N (1.1 g, 11.1 mmol) and DMAP (136 mg, 1.11 mmol) and mixture was stirred at room temperature overnight. The mixture was partitioned between water and EtOAc, the layers were separated and the organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=100/1) to give the title compound A3 (0.8 g, 50%) as a yellow solid. LCMS (ES-API): R.sub.t 2.10 min; m/z 279.9/281.8 [M+H].sup.+.

b) tert-Butyl (5-(2,5-dimethoxyphenyl)-1,3,4-thiadiazol-2-yl)carbamate, A4

[0704] To a solution of tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate A3 (100 mg, 0.36 mmol) in 1,4-dioxane (5 mL) was added (2,5-dimethoxyphenyl)boronic acid (73 mg, 0.40 mmol), Pd(PPh.sub.3).sub.4 and a solution of K.sub.2CO.sub.3 (100 mg, 0.72 mmol) in water (1 mL) and the mixture was heated at 100 C. overnight. To a second solution of tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate A3 (600 mg, 2.14 mmol) in 1,4-dioxane (10 mL) was added (2,5-dimethoxyphenyl)boronic acid (428 mg, 2.35 mmol), Pd(PPh.sub.3).sub.4 (124 mg, 0.107 mmol) and a solution of K.sub.2CO.sub.3 (590 mg, 4.28 mmol) in water (2 mL) and the mixture was heated at 100 C. overnight. The two reaction mixtures were combined and partitioned between water and EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=40/1) to give the title compound A4 (350 mg, 42%) as a yellow solid. LCMS (ES-API): R.sub.t2.39 min; m/z 338.0 [M+H].sup.+.

c) 5-(2,5-Dimethoxyphenyl)-1,3,4-thiadiazol-2-amine, A5

[0705] To a solution of tert-butyl (5-(2,5-dimethoxyphenyl)-1,3,4-thiadiazol-2-yl)carbamate A4 (100 mg, 0.3 mmol) in DCM (5 mL) was added TFA (1.5 mL) and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was diluted with a saturated aqueous NaHCO.sub.3 solution and extracted with EtOAc. The organic extract was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound A5 (80 mg, >100%) as a yellow solid, which was used directly in the next step without further purification. LCMS (ES-API): R.sub.t 0.54 min; m/z 238.0 [M+H].sup.+.

d) N-(5-(2,5-Dimethoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,6-dimethoxybenzenesulfonamide, 70

[0706] To a solution of 5-(2,5-dimethoxyphenyl)-1,3,4-thiadiazol-2-amine A5 (80 mg, assumed 0.3 mmol) in pyridine (3 mL) was added 2,6-dimethoxybenzenesulfonyl chloride I18 (107 mg, 0.45 mmol) and the mixture was heated at 120 C. under microwave irradiation for 2 h. The mixture was concentrated under reduced pressure and the residue was partitioned between water and EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=20/1) to give the title compound 70 (20 mg, 15% over two steps) as a yellow solid. R.sub.t 2.02 min; m/z 437.9 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.64 (d, J=3.2 Hz, 1H), 7.35 (t, J=8.4 Hz, 1H), 7.03-7.01 (m, 1H), 6.96-6.94 (m, 1H), 6.60 (d, J=8.4 Hz, 2H), 3.93 (s, 3H), 3.85 (s, 6H), 3.83 (s, 3H).

Example 71: 2,6-Dimethoxy-N-(5-(5-methoxy-2-(methoxymethyl)phenyl)isoxazol-3-yl)benzenesulfonamide, 71

[0707] ##STR00156## ##STR00157##

a) (2-Bromo-4-methoxyphenyl)methanol, A6

[0708] To a solution of 2-bromo-4-methoxybenzaldehyde (5.0 g, 23 mmol) in MeOH (30 mL) was added NaBH.sub.4 (1.1 g, 28 mmol) and the mixture was stirred at room temperature for 2 h. The reaction was quenched with water (1 mL) and the mixture was partitioned between water and EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=5/1) to give the title compound A6 (4.2 g, 84%) as a colourless oil. LCMS-A (ES-API): R.sub.t 0.85 min; m/z 238.9 [M+Na].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.38 (d, J=8.4 Hz, 1H), 7.13 (d, J=2.8 Hz, 1H), 6.89-6.87 (m, 1H), 4.70 (s, 2H), 3.82 (s, 3H).

b) 2-Bromo-4-methoxy-1-(methoxymethyl)benzene, A7

[0709] To a solution of (2-bromo-4-methoxyphenyl)methanol A6 (200 mg, 0.92 mmol) in DMF (5 mL) at 0 C. was added NaH (60% dispersion in oil, 40 mg, 1.01 mmol) and the mixture was stirred for 15 min. Methyl iodide (143 mg, 1.01 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with water (1 mL). The following procedure was performed twice: To a solution of (2-bromo-4-methoxyphenyl)methanol A6 (2.0 g, 9.21 mmol) in DMF (20 mL) at 0 C. was added NaH (60% dispersion in oil, 400 mg, 10.1 mmol) and the mixture was stirred for 15 min. Methyl iodide (1.4 g, 10.1 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 1 h. The three reaction mixtures were combined and partitioned between water and EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=10/1) to give the title compound A7 (1.8 g, 43% yield) as a light yellow oil. LCMS-A (ES-API): R.sub.t 2.18 min; m/z 231.1 [M+H].sup.+.

c) Methyl 5-methoxy-2-(methoxymethyl)benzoate, A8

[0710] To a solution of 2-bromo-4-methoxy-1-(methoxymethyl)benzene A7 (600 mg, 2.6 mmol) in MeOH (15 mL) was added Pd(OAc).sub.2 (58 mg, 0.26 mmol), Et.sub.3N (789 g, 7.8 mmol) and Xantphos (150 mg, 0.26 mmol) and the mixture was heated at 90 C. under a CO atmosphere (1 atm) for 48 h. The reaction was performed two more times as follows:

[0711] 1. To a solution of 2-bromo-4-methoxy-1-(methoxymethyl)benzene A7 (1.1 g, 4.76 mmol) in MeOH (15 mL) was added Pd(OAc).sub.2 (108 mg, 0.48 mmol), Et.sub.3N (1.4 g, 14.3 mmol) and Xantphos (278 mg, 0.48 mmol) and the mixture was heated at 90 C. under a CO atmosphere (1 atm) overnight.

[0712] 2. To a solution of 2-bromo-4-methoxy-1-(methoxymethyl)benzene A7 (1.3 g, 5.63 mmol) in MeOH (20 mL) was added Pd(OAc).sub.2 (126 mg, 0.56 mmol), Et.sub.3N (1.7 g, 16.9 mmol) and Xantphos (307 mg, 0.56 mmol) and the mixture was heated at 90 C. under a CO atmosphere (1 atm) for 48 h. The three reaction mixtures were combined and partitioned between water and EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=20/1) to give the title compound A8 (600 mg, 22%) as a yellow oil. LCMS-A (ES-API): R.sub.t 2.18 min; m/z 233.0 [M+Na].sup.+.

d) 3-(5-Methoxy-2-(methoxymethyl)phenyl)-3-oxopropanenitrile, A9

[0713] To a solution of diisopropylamine (63 mg, 0.62 mmol) in THF (10 mL) at 78 C. under N2 was added n-BuLi (2.5 M solution in hexanes, 0.25 mL, 0.62 mmol) dropwise and the mixture was stirred at 78 C. for 0.5 h. A solution of acetonitrile (25 mg, 0.62 mmol) in THF (1 mL) was added dropwise and stirring was continued for 30 min. A solution of methyl 5-methoxy-2-(methoxymethyl)benzoate A8 (100 mg, 0.48 mmol) in THF (1 mL) was then added dropwise and the mixture was stirred at 78 C. for 1 h. The reaction was quenched with a saturated aqueous NH.sub.4Cl solution. The procedure was repeated using methyl 5-methoxy-2-(methoxymethyl)benzoate A8 (500 mg, 2.38 mmol) and the two reaction mixtures were combined and partitioned between water and EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=4/1) to give the title compound A9 (480 mg, 77%) as a yellow solid. LCMS-A (ES-API): R.sub.t 1.04 min; m/z 220.1 [M+H].sup.+.

e) 5-(5-Methoxy-2-(methoxymethyl)phenyl)isoxazol-3-amine, A10

[0714] To a solution of 3-(5-methoxy-2-(methoxymethyl)phenyl)-3-oxopropanenitrile A9 (100 mg, 0.46 mmol) in ethanol (5 mL) was added a solution of NaOH (24 mg, 0.60 mmol) in H.sub.2O (5 mL) followed by NH.sub.2OH.HCl (42 mg, 0.6 mmol) and the mixture was heated at 80 C. overnight. The procedure was repeated as follows: To a solution of 3-(5-methoxy-2-(methoxymethyl)phenyl)-3-oxopropanenitrile A9 (300 mg, 1.37 mmol) in ethanol (5 mL) was added a solution of NaOH (71 mg, 1.78 mmol) in H.sub.2O (5 mL) followed by NH.sub.2OH.HCl (124 mg, 1.78 mmol) and the mixture was heated at 80 C. overnight. The two reaction mixtures were combined and partitioned between water and EtOAc. The layers were separated and the organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=20/1) to give the title compound A10 (60 mg, 14%) as a yellow solid. LCMS-A (ES-API): R.sub.t 0.70 min; m/z 235.0 [M+H].sup.+.

f) 2,6-Dimethoxy-N-(5-(5-methoxy-2-(methoxymethyl)phenyl)isoxazol-3-yl)benzenesulfonamide, 71

[0715] To a solution of 5-(5-methoxy-2-(methoxymethyl)phenyl)isoxazol-3-amine A10 (60 mg, 0.26 mmol) in pyridine (3 mL) was added 2,6-dimethoxybenzenesulfonyl chloride I18 (92 mg, 0.39 mmol) and the mixture was heated at 120 C. for 2 h under microwave irradiation. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (DCM/MeOH=50/1) to give the title compound 71 (15 mg, 14%) as a yellow solid. LCMS-A (ES-API): R.sub.t 2.19 min; m/z 435.0 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.96 (s, 1H), 7.43-7.39 (m, 2H), 7.20 (d, J=2.8 Hz, 1H), 6.98 (dd, J=8.4, 2.4 Hz, 1H), 6.81 (s, 1H), 6.62 (d, J=8.8 Hz, 2H), 4.40 (s, 2H), 3.96 (s, 6H), 3.82 (s, 3H), 3.39 (s, 3H).

Example 72: 2,6-Dimethoxy-N-(5-(2-methoxy-5-(1H-pyrazol-5-yl)phenyl)isoxazol-3-yl)benzenesulfonamide, 72

[0716] ##STR00158##

a) N-(5-(5-Bromo-2-methoxyphenyl)isoxazol-3-yl)-N-(2,4-dimethoxybenzyl)-2,6-dimethoxybenzenesulfonamide, A11

[0717] To a solution of N-(5-(5-bromo-2-methoxyphenyl)isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 1 (300 mg, 639 mmol), (2,4-dimethoxyphenyl)methanol (430 mg, 2.6 mmol) and PPh.sub.3 (502 mg, 1.9 mmol) in THF (15 mL) at 0 C. was added a solution of DIAD (258 mg, 1.3 mmol) in THF (5 mL) dropwise and the mixture was allowed to warm to room temperature and stirred overnight. Water was added and the mixture was extracted with EtOAc (200 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=3/1) then rinsed with MeOH to give the title compound A11 (70 mg, 18%) as a white solid. LCMS-A (ES-API): R.sub.t 2.53 min; m/z 619.0 [M+H].sup.+.

b) N-(2,4-Dimethoxybenzyl)-2,6-dimethoxy-N-(5-(2-methoxy-5-(1H-pyrazol-5-yl)phenyl)isoxazol-3-yl)benzenesulfonamide, A12

[0718] A mixture of N-(5-(5-bromo-2-methoxyphenyl)isoxazol-3-yl)-N-(2,4-dimethoxybenzyl)-2,6-dimethoxybenzenesulfonamide A11 (65 mg, 0.105 mmol), (1H-pyrazol-5-yl)boronic acid (17.7 mg, 0.158 mmol), Pd(dppf)Cl.sub.2 (3.9 mg, 0.005 mmol) and Cs.sub.2CO.sub.3 (103 mg, 0.103 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was heated at 100 C. under N.sub.2 overnight. Water was added and the mixture was extracted with EtOAc (200 mL3). The combined organic extracts were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/EtOAc=1/1) to give the title compound A12 (35 mg, 55% yield) as a white solid. LCMS-A (ES-API): R.sub.t 2.43 min; m/z 607.0 [M+H].sup.+.

c) 2,6-Dimethoxy-N-(5-(2-methoxy-5-(1H-pyrazol-5-yl)phenyl)isoxazol-3-yl)benzenesulfonamide, 72

[0719] A solution of N-(2,4-dimethoxybenzyl)-2,6-dimethoxy-N-(5-(2-methoxy-5-(1H-pyrazol-5-yl)phenyl)isoxazol-3-yl)benzenesulfonamide A12 (35 mg, 0.16 mmol) in TFA (5 mL) was stirred at room temperature overnight then concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=100/1) to give the title compound 72 (8 mg, 31%) as a white solid. LCMS-A (ES-API): R.sub.t 1.63 min; m/z 457.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.9 (br s, 1H), 11.0 (brs, 1H), 8.17 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.76 (br s, 1H), 7.50 (t, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.78 (d, J=8.4 Hz, 2H), 6.72 (d, J=6.4 Hz, 2H), 3.93 (s, 3H), 3.83 (s, 6H).

Example 73: 2,6-Dimethoxy-N-(5-(2-methoxy-5-(methoxymethyl)phenyl)isoxazol-3-yl)benzenesulfonamide, 73

[0720] ##STR00159##

[0721] To a solution of 5-(2-methoxy-5-(methoxymethyl)phenyl)isoxazol-3-amine I17 (1.0 g, 4.27 mmol) in dry THF (40 mL) at 78 C. under N.sub.2 was added LiHMDS (1.0 M solution in THF, 12.8 mL, 12.8 mmol) dropwise and the mixture was stirred at 78 C. for 1 h. A solution of 2,6-dimethoxybenzenesulfonyl chloride I18 (1.52 g, 6.41 mmol) in anhydrous THF (2 mL) was then added dropwise and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was acidified to pH 4-5 with 1 M aqueous HCl and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=200/1) to give the title compound 73 (800 mg, 43% yield) as a white solid. LCMS-A (ES-API): R.sub.t 2.15 min; m/z, 435.0 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.1 (s, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.49 (t, J=8.5 Hz, 1H), 7.41 (dd, J=8.6, 2.2 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 6.77 (d, J=8.5 Hz, 2H), 6.69 (s, 1H), 4.38 (s, 2H), 3.90 (s, 3H), 3.83 (s, 6H), 3.26 (s, 3H).

Example 74: N-(3-(2-bromophenyl)isoxazol-5-yl)-5-ethyl-2-methoxybenzenesulfonamide, 74

[0722] ##STR00160##

[0723] A mixture of 5-ethyl-2-methoxylbenzenesulfonyl chloride I19 (0.098 g, 0.418 mmol), pyridine (1 mL) and 3-(2-bromophenyl)-1,2-oxazol-5-amine (0.050 g, 0.209 mmol) was stirred at room temperature for 16 h. The mixtures were diluted with DCM (1 mL) and washed with 1 M HCl (2 mL). The aqueous layer was removed and the organic layer was dried to give the crude residue. The product was purified by HPLC to give the title compound 74 (12 mg, 13% yield). LCMS R.sub.t 5.75 min, m/z=436.9/438.8 [M+H].sup.+.

Example 75: N-(3-(3-bromophenyl)isoxazol-5-yl)-5-ethyl-2-methoxybenzenesulfonamide, 75

[0724] ##STR00161##

[0725] A mixture of 5-ethyl-2-methoxylbenzenesulfonyl chloride I19 (0.098 g, 0.418 mmol), pyridine (1 mL) and 3-(3-bromophenyl)isoxazol-5-amine (0.050 g, 0.209 mmol) was stirred at room temperature for 16 h. The mixtures were diluted with DCM (1 mL) and washed with 1 M HCl (2 mL). The aqueous layer was removed and the organic layer was dried to give the crude residue. The product was purified by HPLC to give the title compound (12 mg, 13% yield). LCMS R.sub.t 5.91 min, m/z=438.8 [M+H].sup.+.

Example 77: N-(3-(3-benzylphenyl)isoxazol-5-yl)-3,4-dimethylbenzenesulfonamide, 77

[0726] ##STR00162##

a) 3-(3-Benzylphenyl)isoxazol-5-amine, A13

[0727] Benzylzinc bromide (0.502 mL, 0.5 M in THF, 0.251 mmol) was added to a solution of 3-(3-bromo-phenyl)-isoxazol-5-ylamine (0.050 g, 0.209 mmol), Pd(OAc).sub.2 (0.001 g, 0.004 mmol), S-Phos (0.002 g, 0.004 mmol) in THF (2 mL). The mixture was stirred for 16 h at room temperature. Additional benzylzinc bromide (0.502 mL, 0.5 M in THF, 0.251 mmol), Pd(OAc).sub.2 (0.003 g, 0.012 mmol) and S-Phos (0.009 g, 0.024 mmol) were added and the mixture continued stirring for 16 h. The mixture was quenched with saturated NH.sub.4Cl (3 mL) and diluted in EtOAc (5 mL). The organic layer was isolated and washed with water (25 mL). The organic layer was dried (magnesium sulfate), filtered and reduced in vacuo to afford A13 as a brown oil (0.052 g, 99% crude yield). The product was used without further purification. LCMS R.sub.t5.42 min, m/z=251.5 [M+H].sup.+.

b) N-(3-(3-benzylphenyl)isoxazol-5-yl)-3,4-dimethylbenzenesulfonamide, 77

[0728] A mixture of 3-(3-benzylphenyl)isoxazol-5-amine A13 (0.169 g, 0.675 mmol), 3,4-dimethylbenzenesulfonyl chloride (0.104 g, 0.506 mmol) and pyridine (1 mL) was stirred at room temperature for 16 h. The mixtures were diluted with DCM (1 mL) and washed with 1M HCl (2 mL). The aqueous layer was removed and the organic layer was dried to give the crude residue. The product was purified by HPLC to give the title compound 77 (1.3 mg, 1%). LCMS R.sub.t 6.36 min, m/z=419.8 [M+H].sup.+.

Example 78: 3,4-dimethyl-N-(3-(3-phenethylphenyl)isoxazol-5-yl)benzenesulfonamide, 78

[0729] ##STR00163##

a) 3-(3-Phenethylphenyl)isoxazol-5-amine, A14

[0730] Phenethylzinc bromide (0.502 mL, 0.5 M in THF, 0.251 mmol) was added to a solution of 3-(3-bromophenyl)-isoxazol-5-ylamine (0.050 g, 0.209 mmol), Pd(OAc).sub.2 (0.001 g, 0.004 mmol), S-Phos (0.002 g, 0.008 mmol) in THF (2 mL). The mixture was stirred for 16 h at room temperature. Phenethylzinc bromide (0.502 mL, 0.5 M in THF, 0.251 mmol), Pd(OAc).sub.2 (0.003 g, 0.012 mmol) and S-Phos (0.009 g, 0.024 mmol) were added and the reaction continued stirring for another 16 h. The mixture was quenched with saturated NH.sub.4Cl (3 mL) and diluted in EtOAc (5 mL). The organic layer was isolated and washed with water (25 mL). The organic layer was dried (magnesium sulfate), filtered and reduced in vacuo to afford A14 as a brown oil (0.046 g, 83% crude yield). A14 was used without further purification. LCMS R.sub.t 5.60 min, m/z=265.7 [M+H].sup.+.

b) 3,4-Dimethyl-N-(3-(3-phenethylphenyl)isoxazol-5-yl)benzenesulfonamide, 78

[0731] A mixture of 3-(3-benzylphenyl)isoxazol-5-amine A14 (0.092 g, 0.348 mmol) (0.050 g, 0.312 mmol), 3,4-dimethylbenzenesulfonyl chloride (0.096 g, 0.47 mmol) and pyridine (1 mL) was stirred at room temperature for 16 h. The mixture was diluted with DCM (1 mL) and washed with 1M HCl (2 mL). The aqueous layer was removed and the organic layer was dried to give the crude residue. The product was purified by HPLC to give the title compound 78 (17 mg, 11% yield).) LCMS R.sub.t 6.51 min, m/z=433.4 [M+H].sup.+.

Example 79: N-(3-(2-bromophenyl)isoxazol-5-yl)benzenesulfonamide, 79

[0732] ##STR00164##

[0733] A mixture of 3-(2-bromophenyl)isoxazol-5-amine (0.050 g, 0.209 mmol), benzenesulfonyl chloride I107 (0.040 mL, 0.314 mmol) and pyridine (1 mL) was stirred at room temperature for 16 h. The solvent was removed in vacuo to afford the crude residue. This was dissolved in DCM (2 mL) and 1M HCl (2 mL) and filtered through a phase separation cartridge. The crude was purified by flash chromatography gradient eluting with 100% dichloromethane to 20% MeOH/dichloromethane to give the title compound 79 (21 mg, 27% yield) LCMS R.sub.t 5.85 min, m/z=378.9 [M+H].sup.+.

Example 80: N-(3-(3-bromophenyl)isoxazol-5-yl)benzenesulfonamide, 80

[0734] ##STR00165##

[0735] A mixture of 3-(3-bromophenyl)isoxazol-5-amine (0.050 g, 0.209 mmol), benzenesulfonyl chloride I107 (0.040 mL, 0.314 mmol) and pyridine (1 mL) was stirred at room temperature for 16 h. The solvent was removed in vacuo to afford a crude residue. This was dissolved in DCM (2 mL) and 1M HCl (2 mL) and filtered through a phase separation cartridge. The crude product was purified by flash chromatography gradient eluting with 100% dichloromethane to 20% MeOH/dichloromethane to give the title compound (66 mg, 84% yield) LCMS R.sub.t6.13 min, m/z=381.4 [M+H].sup.+.

Example 81: 1-phenyl-N-(5-phenylisoxazol-3-yl)methanesulfonamide, 81

[0736] ##STR00166##

[0737] 3-Amino-5-phenylisoxazole (0.051 g, 0.320 mmol), pyridine (1 mL) and phenylmethanesulfonyl chloride I106 (0.140 g, 0.736 mmol) were mixed at room temperature and stirred for 16 h. The solvent was removed in vacuo to afford a crude residue. The residue was dissolved in DCM (2 mL) and 1M HCl (2 mL) and filtered through a phase separation cartridge. The crude was purified by flash chromatography, gradient eluting with 100% dichloromethane to 20% MeOH/dichloromethane, to give the title compound 81 (86 mg, 86% yield). LCMS: R.sub.t 5.38 min, m/z=315.4 [M+H].sup.+.

Example 82: 2-fluoro-N-(3-phenylisoxazol-5-yl)benzenesulfonamide, 82

[0738] ##STR00167##

[0739] 2-Fluorobenzenesulfonyl chloride (0.050 mL, 0.375 mmol), 3-phenylisoxazol-5-amine (0.030 g, 0.187 mmol) and pyridine (1 mL) were mixed at room temperature and stirred for 16 h. Water was added and the resultant precipitate was filtered to give the title compound 82 (32 mg, 53% yield). LCMS: R.sub.t 6.88 min, m/z=318.0 [M+H].sup.+.

Example 83: methyl 5-((3,4-dimethylphenyl)sulfonamido)-3-(4-methoxyphenyl)isoxazole-4-carboxylate, 83

[0740] ##STR00168##

[0741] To a solution of methyl 5-amino-3-(4-methoxyphenyl)isoxazole-4-carboxylate (0.057 g, 0.230 mmol) in dry THF (2 mL) at 0 C. was added NaH (0.011 g, 0.459 mmol) and the mixture was stirred for 10 min while warming to room temperature. The temperature was again cooled to 0 C. and 3,4-dimethylbenzenesulfonyl chloride (0.094 g, 0.459 mmol) was added and the reaction was stirred for 16 h while warming to room temperature. The solvent was removed and the residue suspended in MeOH, filtered and reduced to give an orange/white solid (0.201 g). A fraction of the solid was purified by HPLC to give the title compound 83 as a clear oil (0.004 g, 4% yield). LCMS: R.sub.t 6.60 min, m/z=417.22 [M+H].sup.+.

Example 84: 2,6-Dimethoxy-N-(5-(4-methoxy-[1,1-biphenyl]-3-yl)isoxazol-3-yl)benzenesulfonamide, 84

[0742] ##STR00169##

[0743] To a solution of N-(5-(5-bromo-2-methoxyphenyl)isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 1 (50 mg, 0.106 mmol) and phenylboronic acid (20 mg, 0.160 mmol) in 1,4-dioxane (5 mL) and H.sub.2O (1 mL) was added CS.sub.2CO.sub.3 (104 mg, 0.319 mmol) and Pd(dppf)Cl.sub.2 (4 mg, 0.005 mmol) and the mixture was heated at 100 C. overnight. The mixture was diluted with water and washed with EtOAc (30 mL2). The aqueous layer was then adjusted to pH 4-5 with 1 M aqueous HCl and extracted with EtOAc (50 mL2). The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether/EtOAc=5/1) to give the title compound (40 mg, 81%) as a white solid. LCMS (ES-API): R.sub.t2.41 min; m/z 467.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.1 (s, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.79-7.76 (m, 1H), 7.67 (d, J=7.2 Hz, 2H), 7.51-7.47 (m, 3H), 7.36-7.29 (m, 2H), 6.79-6.74 (m, 3H), 3.95 (s, 3H), 3.84 (s, 6H).

Example 85: 5-Ethyl-2-methoxy-N-(3-(pyridin-4-yl)isoxazol-5-yl)benzenesulfonamide, 85

[0744] ##STR00170##

a) 3-(Pyridin-4-yl)isoxazol-5-amine, A15

[0745] To a solution of 3-oxo-3-(pyridin-4-yl)propanenitrile (1.5 g, 10.3 mmol) and NaOH (452 mg, 11.3 mmol) in water (15 mL) and ethanol (15 mL) was added hydroxylamine hydrochloride (787 mg, 11.3 mmol) and the mixture was heated at 80 C. overnight. Concentrated aqueous HCl (1.3 mL, 11.3 mmol) was then added and the mixture was heated at 80 C. for a further 2 h. The mixture was adjusted to pH 10 with 2 M aqueous NaOH and extracted with EtOAc (50 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=100/1 to 60/1) to give the title compound (200 mg, 13%) as a white solid. LCMS-B (ES-API): R.sub.t 0.26 min; m/z 162.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.68-8.63 (m, 2H), 7.72-7.67 (m, 2H), 6.94 (s, 2H), 5.52 (s, 1H).

b) 5-Ethyl-2-methoxy-N-(3-(pyridin-4-yl)isoxazol-5-yl)benzenesulfonamide, 85

[0746] To a solution of 3-(pyridin-4-yl)isoxazol-5-amine A15 (50 mg, 0.31 mmol) in pyridine (2 mL) was added 5-ethyl-2-methoxybenzenesulfonyl chloride I19 (109 mg, 0.46 mmol) and DMAP (4 mg, 0.031 mmol) and the mixture was heated at 90 C. overnight. Water (20 mL) was added and the mixture and adjusted to pH 5-6 with 2 M aqueous HCl and extracted with EtOAc (30 mL3). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep. TLC (DCM/MeOH=80/1) to give the title compound (15 mg, 13%) as a yellow solid. LCMS-B (ES-API): R.sub.t2.11 min; m/z 360.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.69 (d, J=6.0 Hz, 2H), 7.78 (d, J=6.4 Hz, 2H), 7.71 (d, J=2.3 Hz, 1H), 7.47 (dd, J=8.5, 2.3 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 6.35 (s, 1H), 3.79 (s, 3H), 2.60 (q, J=7.6 Hz, 2H), 1.14 (t, J=7.6 Hz, 3H).

Example 86: 5-Ethyl-2-methoxy-N-(3-(3-methoxyphenyl)isoxazol-5-yl)benzenesulfonamide, 86

[0747] ##STR00171##

a) 2-Bromo-1-(3-methoxyphenyl)ethan-1-one oxime, A16

[0748] To a suspension of 2-bromo-1-(3-methoxyphenyl)ethan-1-one (5.0 g, 21.8 mmol) in MeOH (40 mL) and water (6 mL) at 0 C. was added hydroxylamine hydrochloride (4.5 g, 65.4 mmol) and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc (60 mL3). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give the title compound (5.2 g, 98%) as grey solid. .sup.1H NMR analysis showed an unassigned 3:7 mixture of oxime isomers. LCMS-B (ES-API): R.sub.t2.41 min; m/z 243.9/245.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.1 (br s, 0.3H), 12.0 (br s, 0.7H), 7.35 (t, J=7.9 Hz, 1H), 7.31-7.23 (m, 2H), 7.03-6.97 (m, 1H), 4.71 (s, 1.4H), 4.55 (s, 0.6H), 3.79 (s, 3H).

b) 3-(3-Methoxyphenyl)isoxazol-5-amine, A17

[0749] To a stirred suspension of KCN (960 mg, 14.7 mmol) in MeOH (60 mL) was added a solution of oxime A16 (3.0 g, 12.3 mmol) in MeOH (15 mL) and the mixture was stirred at room temperature for 20 min. The mixture was diluted with water, extracted with EtOAc (40 mL3) and the combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether/EtOAc=20/1 to 10/1 to 6/1) to give the title compound (1.2 g, 47%) as a yellow solid. LCMS-B (ES-API): R.sub.t 1.78 min; m/z 191.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.36 (t, J=7.9 Hz, 1H), 7.30-7.27 (m, 1H), 7.25-7.23 (m, 1H), 7.02-6.98 (m, 1H), 6.75 (s, 2H), 5.40 (s, 1H), 3.80 (s, 3H).

c) 5-Ethyl-2-methoxy-N-(3-(3-methoxyphenyl)isoxazol-5-yl)benzenesulfonamide, 86

[0750] To a solution of 3-(3-methoxyphenyl)isoxazol-5-amine A17 (250 mg, 1.31 mmol) in pyridine (20 mL) was added 5-ethyl-2-methoxybenzenesulfonyl chloride I19 (461 mg, 1.97 mmol) and DMAP (16 mg, 0.131 mmol) and the mixture was heated at 90 C. overnight. The mixture was diluted with water, adjusted to pH 5 with 1 M aqueous HCl and extracted with EtOAc (40 mL3). The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether/EtOAc=10/1 to 6/1 to 3/1) to give the title compound (90 mg, 17%) as a white solid. LCMS-B (ES-API): R.sub.t 2.82 min; m/z 389.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.72 (d, J=2.3 Hz, 1H), 7.49 (dd, J=8.5, 2.3 Hz, 1H), 7.40-7.31 (m, 2H), 7.30-7.27 (m, 1H), 7.16 (d, J=8.6 Hz, 1H), 7.06-7.01 (m, 1H), 6.28 (s, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 2.60 (q, J=7.5 Hz, 2H), 1.14 (t, J=7.5 Hz, 3H).

Example 87: N-(5-(5-Cyano-2-methoxyphenyl)isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide, 87

[0751] ##STR00172##

[0752] To a solution of N-(5-(5-bromo-2-methoxyphenyl)isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 1 (50 mg, 0.106 mmol) in DMF (3 mL) was added Zn(CN).sub.2 (13.5 mg, 0.128 mmol) and Pd(PPh.sub.3).sub.4 (6.2 mg, 0.005 mmol) and the mixture was heated at 130 C. for 2 h under microwave irradiation. The mixture was diluted with water, extracted with EtOAc (50 mL3) and the combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep. TLC (DCM/MeOH=70/1) to give the title compound (15 mg, 34%) as a white solid. LCMS-B (ES-API): R.sub.t 1.90 min; m/z 416.0 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.12 (d, J=2.0 Hz, 1H), 7.68 (dd, J=8.8, 2.0 Hz, 1H), 7.41 (t, J=8.4 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 7.04 (s, 1H), 6.63 (d, J=8.8 Hz, 2H), 4.02 (s, 3H), 3.96 (s, 6H).

Example 88: 2,6-Dimethoxy-N-(5-(2-(trifluoromethyl)phenyl)isoxazol-3-yl)benzenesulfonamide, 88

[0753] ##STR00173##

a) 5-(2-(Trifluoromethyl)phenyl)isoxazol-3-amine, A18

[0754] To a solution of 3-oxo-3-(2-(trifluoromethyl)phenyl)propanenitrile (500 mg, 2.35 mmol) and NaOH (103 mg, 2.58 mmol) in H.sub.2O (8 mL) and EtOH (8 mL) was added hydroxylamine hydrochloride (179 mg, 2.58 mmol) and the mixture was heated at 80 C. overnight. Concentrated aqueous HCl (0.5 mL, 3 mmol) was then added and the mixture was heated at 80 C. for a further 2.5 h. The mixture was adjusted to pH 10 with 2 M aqueous NaOH and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH=200/1) to give the title compound (170 mg, 32%) as a yellow oil. LCMS-A (ES-API): R.sub.t1.33 min; m/z 229.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.91 (d, J=7.6 Hz, 1H), 7.80-7.72 (m, 3H), 6.14 (s, 1H), 5.72 (s, 2H).

b) 2,6-Dimethoxy-N-(5-(2-(trifluoromethyl)phenyl)isoxazol-3-yl)benzenesulfonamide, 88

[0755] To a solution of 5-(2-(trifluoromethyl)phenyl)isoxazol-3-amine A18 (60 mg, 0.263 mmol) in anhydrous THF (12 mL) at 78 C. under N.sub.2 was added LiHMDS (1 M solution in THF, 1.1 mL, 1.05 mmol) dropwise and the mixture was stirred at 78 C. for 2 h. A solution of 2,6-dimethoxybenzenesulfonyl chloride I18 (94 mg, 0.394 mmol) in anhydrous THF (2 mL) was then added dropwise and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with water, extracted with EtOAc and the combined organic extracts were washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep. TLC (DCM/MeOH=20/1) to give the title compound (31 mg, 28%) as a white solid. LCMS-A (ES-API): R.sub.t2.27 min; m/z 428.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.93 (d, J=8.0 Hz, 1H), 7.80-7.77 (m, 3H), 7.50 (t, J=8.6 Hz, 1H), 7.03 (s, 1H), 6.78 (d, J=8.4 Hz, 2H), 6.56 (s, 1H), 3.79 (s, 6H).

[0756] Other Compounds

[0757] The following compounds were obtained commercially:

TABLE-US-00010 Example Structure 89 [00174] 90 [00175] 91 [00176] 92 [00177]

Examples 93-115 (Table E)

[0758] General Method EA

##STR00178##

[0759] To a solution of the amine (1.0 eq) in anhydrous THF (10 mL) at 78 C. under N.sub.2 was added LiHMDS (1 M solution in THF, 3.0 eq) dropwise and the mixture was stirred at 78 C. for 2 h. A solution of the sulfonyl chloride (1.5 eq) in anhydrous THF (2.0 mL) was then added dropwise and the mixture was allowed to warm to room temperature and was stirred overnight. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography, prep. TLC or recrystallisation to give the desired compound.

[0760] General Method EB:

##STR00179##

[0761] To a solution of the amine (1.0 eq) in pyridine (4 mL) under N.sub.2 was added the sulfonyl chloride (1.5 eq) and DMAP (0.2 eq) and the mixture was heated at 90 C. overnight. The reaction was quenched with 1 M aqueous HCl, water was then added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC to give the desired compound.

[0762] General Method EC:

##STR00180##

[0763] To a solution of the amine (1.0 eq) in pyridine (2 mL) was added the sulfonyl chloride (2.0 eq) and the mixture was heated at 120 C. under microwave irradiation for 2 h. The reaction was quenched with 1 M aqueous HCl, water was then added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC to give the desired compound.

[0764] The following examples were synthesised according to general method EA, EB or EC using the appropriate amine R.sub.1NH.sub.2 and sulfonyl chloride R.sub.2SO.sub.2Cl intermediate.

TABLE-US-00011 Starting Example materials Name and structure Analytical data Method Notes 93 I18 & 5-phenyl isoxazol-3- amine [00181] LCMS-E (ES-API): R.sub.t 2.60 min; m/z 361.0 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.1 (br s, 1H), 7.73- 7.71 (m, 2H), 7.52-7.38 (m, 4H), 6.72 (d, J = 8.4 Hz, 2H), 6.70 (s, 1H), 3.78 (s, 6H). EC Prep. TLC (EtOAc/ DCM = 1/3) 94 I18 & I87 [00182] LCMS-E (ES-API): R.sub.t 1.57 min; m/z 488.1 [M + H].sup.+, .sup.1H NMR (400 MHz, d.sub.4- MeOD) 7.98 (d, J = 2.3 Hz, 1H), 7.73 (s, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.44 (t, J = 8.5 Hz, 1H), 7.39 (dd, J = 8.7, 2.3 Hz, 1H), 7.18 (d, J = 8.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 6.33 (t, J = 2.2 Hz, 1H), 5.36 (s, 2H), 4.00 (s, 3H), 3.79 (s, 6H). EC 1.5 eq sulfonyl chloride used; Prep. TLC (DCM/ MeOH = 20/1) 95 I18 & I74 [00183] LCMS-A (ES-API): R.sub.t 3.35 min; m/z 406.0 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.75 (d, J = 7.8 Hz, 1H), 7.68-7.59 (m, 2H), 7.51- 7.42 (m, 2H), 6.76 (d, J = 8.4 Hz, 2H), 4.69 (s, 2H), 3.73 (s, 6H), 3.33 (s, 3H). EA Prep. TLC (DCM/ MeOH = 20/1) 96 I18 & I80 [00184] LCMS-A (ES-API): R.sub.t 2.03 min; m/z 451.9 [M + H].sup.+, .sup.1H NMR (400 MHz, d.sub.4- MeOD) 7.49-7.43 (m, 2H), 7.19 (d, J = 2.7 Hz, 1H), 7.10 (dd, J = 8.5, 2.7 Hz, 1H), 6.76 (d, J = 8.80 Hz, 2H), 4.59 (s, 2H), 3.86 (s, 3H), 3.82 (s, 6H), 3.34 (s, 3H). EC 1.5 eq sulfonyl chloride used; Prep. TLC (DCM/ MeOH = 15/1) 97 2,6- Difluoro benzene sulfonyl chloride & I2 [00185] LCMS-E (ES-API): R.sub.t 2.84 min; m/z 366.8 [M +H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.6 (br s, 1H), 7.82-7.72 (m, 2H), 7.53-7.46 (m, 1H), 7.33 (t, J = 9.3 Hz, 2H), 7.21 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.69 (s, 1H), 3.92 (s, 3H). EC 1.2 eq sulfonyl chloride used; Column chromatog- raphy (Pet. Ether/ EtOAc = 10/1 to 5/1) 98 I18 & I62 [00186] LCMS-A (ES-API): R.sub.t 2.14 min; m/z 471.0 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.81 (d, J = 2.2 Hz, 1H), 7.64 (s, 1H), 7.47-7.42 (m, 2H), 7.34 (d, J = 8.9 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.74 (d, J = 8.5 Hz, 2H), 6.67 (s, 1H), 6.24 (t, J = 2.1 Hz, 1H), 5.31 (s, 2H), EC 3.5 eq sulfonyl chloride used; Prep. TLC (Pet. Ether/ EtOAc = 1/1) 3.87 (s, 3H), 3.79 (s, 6H). 99 I18 & I70 [00187] LCMS-A (ES-API): R.sub.t 2.23 min; m/z 437.9 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 14.1 (br s, 1H), 7.45 (t, J = 8.4 Hz, 1H), 6.94 (d, J = 2.3 Hz, 2H), 6.75 (d, J = 8.5 Hz, 2H), 6.68 (t, J = 2.3 Hz, 1H), 3.82 (s, 6H), 3.71 (s, 6H). EC Prep. TLC (DCM/ MeOH = 30/1) 100 I18 & I57 [00188] LCMS-A (ES-API): R.sub.t 2.37 min; m/z 475.9 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 14.2 (br s, 1H), 8.25 (d, J = 2.4 Hz, 1H), 7.90 (dd, J = 9.0, 2.4 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.44 (t, J = 8.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 4.06 (s, 3H), 3.71 (s, 6H). EC 1.0 mL pyridine used; Prep. TLC (Pet. Ether/ EtOAc = 1/1) 101 I18 & I90 [00189] LCMS-A (ES-API): R.sub.t 1.90 min; m/z 458.0 [M + H].sup.+, .sup.1H NMR (400 MHz, d.sub.4- MeOD) 7.72-7.68 (m, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.53 (d, J = 1.9 Hz, 1H), 7.52-7.45 (m, 3H), 7.00-6.95 (m, 1H), 6.77 (d, J = 8.4 Hz, 2H), 6.33 (t, J = 2.1 Hz, 1H), 5.73 (s, 2H), 3.82 (s, 6H). EC 1.5 eq sulfonyl chloride used; Purified by prep. HPLC 102 Cyclohexane- sulfonyl chloride & I2 [00190] LCMS-A (ES-API): R.sub.t 2.41 min; m/z 337.0 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.9 (br s, 1H), 7.82 (dd, J = 7.8, 1.8 Hz, 1H), 7.55-7.47 (m, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.72 (s, 1H), 3.94 (s, 3H), 3.28-3.20 (m, 1H), 2.08-2.05 (m, 2H), 1.84- 1.73 (m, 2H), 1.62- EA Purified by prep. HPLC 1.59 (m, 1H), 1.49-1.36 (m, 2H), 1.33-1.24 (m, 2H), 1.19-1.08 (m, 1H). 103 I48 & I2 [00191] LCMS-A (ES-API): R.sub.t 2.34 min; m/z 375.0 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.0 (br s, 1H), 7.82 (dd, J = 7.7, 1.7 Hz, 1H), 7.55-7.48 (m, 1H), 7.31-7.25 (m, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.11 (t, J = 7.6, 1.0 Hz, 1H), 6.94-6.88 (m, 2H), 6.88 (s, 1H), 6.50 (s, 1H), EC 1.5 eq sulfonyl chloride used; 1.0 mL pyridine used; Prep. TLC (Pet. Ether/ EtOAc = 4.63 (s, 2H), 3.92 (s, 3H), 2/1) 3.69 (s, 3H). 104 I18 & I102 [00192] LCMS-B (ES-API): R.sub.t 2.61 min; m/z 406.0 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 14.2 (br s, 1H), 7.56 (dd, J = 7.6, 1.3 Hz, 1H), 7.52-7.42 (m, 3H), 7.39-7.34 (m, 1H), 6.76 (d, J = 8.4 Hz, 2H), 3.73 (s, 6H), 2.85 (q, J = 7.5 Hz, 2H), 1.16 (t, J = 7.5 Hz, 3H). EC 1.0 mL pyridine used; Prep. TLC (DCM/ MeOH = 50/1) 105 I18 & I65 [00193] LCMS-B (ES-API): R.sub.t 2.47 min; m/z 457.0 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.2 (br s, 1H), 8.53 (d, J = 2.6 Hz, 1H), 8.18 (d, J = 2.8 Hz, 1H), 7.93 (dd, J = 9.1, 2.8 Hz, 1H), 7.73 (s, 1H), 7.49 (t, J = 8.5 Hz, 1H), 7.33 (d, J = 9.1 Hz, 1H), 6.79-6.77 (m, 3H), 6.52 (t, J = 2.1 Hz, 1H), 3.95 (s, 3H), 3.84 (s, 6H). EC Prep. TLC (DCM/ MeOH = 50/1) 106 I18 & I105 [00194] LCMS-A (ES-API): R.sub.t 2.43 min; m/z 458.9 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.2 (br s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.85 (dd, J = 9.0, 2.4 Hz, 1H), 7.49 (t, J = 8.5 Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H), 6.77 (d, J = 8.4 Hz, 2H), 6.78 (s, 1H), 4.00 (s, 3H), 3.82 (s, 6H). EC 1.5 eq sulfonyl chloride used; 1.0 mL pyridine used; No HCl used in workup; Prep. TLC (Pet. Ether/ EtOAc = 3/1) 107 2-Phenylethane- 1-sulfonyl chloride & I17 [00195] LCMS-A (ES-API): R.sub.t 2.46 min; m/z 403.0 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.69 (d, J = 2.2 Hz, 1H), 7.37 (dd, J = 8.5, 2.3 Hz, 1H), 7.29- 7.24 (m, 2H), 7.22-7.13 (m, 4H), 6.56 (s, 1H), 4.39 (s, 2H), 3.90 (s, 3H), 3.27 (s, 3H), 3.25 -3.21 (m, 2H), 2.98-2.91 (m, 2H). EC 1.0 mL pyridine used; Prep. TLC (Pet. Ether/ EtOAc = 3/1) 108 I18 & I68 [00196] LCMS-A (ES-API): R.sub.t 2.32 min; m/z 468.8/470.8 [M + H].sup.+, 1H NMR (400 MHz, DMSO-d.sub.6) 11.2 (br s, 1H), 7.41 (t, J = 8.2 Hz, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 8.4 Hz, 2H), 6.31 (s, 1H), 3.76 (s, 6H), 3.72 (s, 3H). EC 1.2 eq sulfonyl chloride used; 3.0 mL pyridine used; No HCl used in workup; Prep. TLC (Pet. Ether/ EtOAc = 1/1) 109 I18 & I100 [00197] LCMS-A (ES-API): R.sub.t 2.24 min; m/z 436.0 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.7 (s, 1H), 7.50 (t, J = 8.5 Hz, 1H), 7.29 (dd, J = 2.6, 1.0 Hz, 1H), 7.23-7.16 (m, 2H), 6.78 (d, J = 8.4 Hz, 2H), 4.08 (q, J = 6.9 Hz, 2H), 3.79 (s, 6H), 3.75 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H). EC 1.2 eq sulfonyl chloride and 0.2 eq DMAP used; 1.5 mL pyridine used; Prep. TLC (DCM/ MeOH = 30/1) 110 I18 & I182 [00198] LCMS-A (ES-API): R.sub.t 2.27 min; m/z 441.9 [M + H].sup.+, .sup.1H NMR (400 MHz, CDCl.sub.3) 7.49 (d, J = 3.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.99 (dd, J = 8.9, 2.8 Hz, 1H), 6.61 (d, J = 8.4 Hz, 2H), 3.89 (s, 6H), 3.85 (s, 3H). EC 1.5 eq sulfonyl chloride used; Concen- trated and purified by Prep. TLC (DCM/ MeOH = 15/1) 111 I18 & I76 [00199] LCMS-A (ES-API): R.sub.t 2.42 min; m/z 469.9 [M + H].sup.+, .sup.1H NMR (400 MHz, CDCl.sub.3) 8.11 (d, J = 2.6 Hz, 1H), 7.40-7.35 (m, 2H), 6.94 (d, J = 8.9 Hz, 1H), 6.62 (d, J = 8.1 Hz, 2H), 4.79- 4.70 (m, 1H), 3.88 (s, 6H), 1.46 (d, J = 5.9 Hz, 6H). EC 1.5 eq sulfonyl chloride used; 3.0 mL pyridine used; No HCl used in workup; Prep. TLC (DCM/ MeOH = 15/1) 112 I106 & I17 [00200] LCMS-A (ES-API): R.sub.t 2.33 min; m/z 389.0 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.1 (br s, 1H), 7.76 (d, J = 2.2 Hz, 1H), 7.45 (dd, J = 8.6, 2.2 Hz, 1H), 7.41-7.30 (m, 5H), 7.21 (d, J = 8.5 Hz, 1H), 6.49 (s, 1H), 4.66 (s, 2H), 4.42 (s, 2H), 3.93 (s, 3H), 3.29 (s, 3H). EB Prep. TLC (Pet. Ether/ EtOAc = 2/1) 113 I18 & I92 [00201] LCMS-A (ES-API): R.sub.t 1.51 min; m/z 408.9 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 14.2 (br s, 1H), 8.38 (d, J = 6.2 Hz, 2H), 7.45 (t, J = 8.4 Hz, 1H), 7.25-7.19 (m, 1H), 6.76 (d, J = 8.4 Hz, 2H), 4.06 (s, 3H), 3.71 (s, 6H). EC 1.5 eq sulfonyl chloride used; 3.0 mL pyridine used; No HCl used in workup; Column chromatog- raphy (DCM/ MeOH = 50/1) 114 I52 & I2 [00202] LCMS-E (ES-API): R.sub.t 3.40 min; m/z 365.1 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.75-7.73 (m, 1H), 7.47-7.38 (m, 1H), 7.17 (d, J = 8.5 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.54-6.53 (m, 1H), 3.90 (s, 3H), 3.01-2.89 (m, 2H), 1.67-1.50 (m, 7H), 1.34-1.05 (m, 4H), 0.89-0.77 (m, 2H). EA 4.2 eq sulfonyl chloride used; Column chromatog- raphy (Pet. Ether/ EtOAc = 3/1) 115 I54 & I2 [00203] LCMS-E (ES-API): R.sub.t 3.24 min; m/z 351.9 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.78 (dd, J = 7.8, 1.7 Hz, 1H), 7.50- 7.43 (m, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.61 (s, 1H), 3.92 (s, 3H), 3.02 (d, J = 5.5 Hz, 2H), 2.05-1.94 (m, 1H), 1.91-1.80 (m, 3H), 1.68- 1.52 (m, 3H), 1.37-1.27 (m, 1H), 1.15-0.99 (m, 3H). EA Prep. TLC (Pet. Ether/ EtOA = 3/1)

Example 116: N-Phenyl((5-(2-methoxyphenyl)-1,2-oxazol-3-yl)amino)sulfonamide, I16

[0765] ##STR00204##

[0766] A mixture of 5-(2-methoxyphenyl)isoxazol-3-amine I2 (40 mg, 0.21 mmol) and phenylsulfamoyl chloride I50 (200 mg, 1.05 mmol) in toluene (6 mL) was heated at 60 C. for 2 h. The mixture was adjusted to pH 5 with 1 M aqueous HCl and extracted with EtOAc (20 mL3). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep. TLC (DCM/MeOH=30/1) to give the title compound (18 mg, 25%) as a white solid. LCMS-A (ES-API): R.sub.t3.79 min; m/z 346.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.4 (br s, 1H), 10.5 (br s, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H), 7.35-7.14 (m, 5H), 7.15-6.93 (m, 2H), 6.77 (s, 1H), 3.94 (s, 3H).

Example 117: N-Cyclohexyl((5-(2-methoxyphenyl)-1,2-oxazol-3-yl)amino)sulfonamide, 117

[0767] ##STR00205##

[0768] A mixture of 5-(2-methoxyphenyl)isoxazol-3-amine I2 (40 mg, 0.21 mmol) and cyclohexylsulfamoyl chloride (50 mg, 0.25 mmol) in pyridine (1 mL) was stirred at room temperature until LCMS analysis showed the starting material was consumed. The mixture was concentrated under reduced pressure and the residue was purified by prep. TLC (DCM/MeOH=20/1) to give the title compound (20 mg, 27%) as a white solid. LCMS-E (ES-API): R.sub.t3.04 min; m/z 351.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.7 (s, 1H), 7.81 (dd, J=7.8, 1.7 Hz, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.54-7.47 (m, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.14-7.07 (m, 1H), 6.79 (s, 1H), 3.94 (s, 3H), 3.12-3.04 (m, 1H), 1.82-1.73 (m, 2H), 1.70-1.60 (m, 2H), 1.54-1.45 (m, 1H), 1.22-1.14 (m, 4H), 1.09-0.99 (m, 1H).

Example 118: 2,6-Dimethoxy-N-(5-(2-methoxy-5-(1-methyl-1H-pyrazol-3-yl)phenyl)isoxazol-3-yl)benzenesulfonamide, 118

[0769] ##STR00206##

[0770] A mixture of N-(5-(5-bromo-2-methoxyphenyl)isoxazol-3-yl)-2,6-dimethoxybenzene sulfonamide 1 (50 mg, 0.11 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (55.6 mg, 0.27 mmol), Pd(dppf)Cl.sub.2.DCM (8.0 mg, 0.01 mmol) and Na.sub.2CO.sub.3 (34 mg, 0.32 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was heated at 100 C. under N.sub.2 overnight. The mixture was adjusted to pH 5 with 1 M aqueous HCl and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep. TLC (Pet. Ether/EtOAc=2/1) to give the title compound (42 mg, 83%) as a white solid. LCMS-A (ES-API): R.sub.t 2.19 min; m/z 471.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.1 (brs, 1H), 8.13 (d, J=2.3 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.71 (d, J=2.2 Hz, 1H), 7.47-7.40 (m, 1H), 7.20 (d, J=8.7 Hz, 1H), 6.74 (d, J=8.5 Hz, 2H), 6.70 (s, 1H), 6.67 (d, J=2.3 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.80 (s, 6H).

[0771] The following Examples (119-121) were synthesised from N-(5-(5-bromo-2-methoxyphenyl)isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 1 and the appropriate boronic acid or ester according to the procedure described for Example 118.

TABLE-US-00012 Starting Example material Name and structure Analytical data Notes 119 1-Methyl- 5-(4,4,5,5- tetramethyl- 1,3,2- dioxaborolan- 2-yl)-1H- pyrazole [00207] LCMS-A (ES-API): R.sub.t 2.15 min; m/z 471.0 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.1 (br s, 1H), 7.77 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.45 (s, 1H), 7.43- 7.36 (m, 1H), 7.30 (d, J = 8.7 Hz, 1H), 6.73- 6.71 (m, 3H), 6.39 (s, 1H), 3.95 (s, 3H), 3.82 (s, 3H), 3.79 (s, 6H). Prep. TLC (Pet. Ether/EtOAc = 1/1) 120 (1H- Pyrazol-4- yl)boronic acid [00208] LC-MS-A (ES-API): R.sub.t 1.90 min; m/z 457.0 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.9 (br s, 1H), 11.1 (br s, 1H), 8.16-9.96 (m, 2H), 7.92 (d, J = 2.3 Hz, 1H), 7.70 (dd, J = 8.7, 2.3 Hz, 1H), 7.49 (t, J = 8.5 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 8.5 Hz, 2H), 6.70 (s, 1H), 3.90 (s, 3H), 3.83 (s, 6H). Prep. TLC (DCM/MeOH = 30/1) followed by prep. HPLC 121 1-Methyl- 4-(4,4,5,5- tetramethyl- 1,3,2- dioxaborolan- 2-yl)-1H- pyrazole [00209] LCMS-A (ES-API): R.sub.t 2.12 min; m/z 471.0 [M + H].sup.+, .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.1 (br s, 1H), 8.15 (s, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.84 (s, 1H), 7.65 (dd, J = 8.7, 2.3 Hz, 1H), 7.49 (t, J = 8.5 Hz, 1H), 7.20 (d, J= 8.7 Hz, 1H), 6.78 (d, J = 8.5 Hz, 2H), 6.71 (s, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.83 (s, 6H). Prep. TLC (DCM/MeOH = 70/1)

Example 122: 2,6-Dimethoxy-N-(5-(3-methoxy-[1,1-biphenyl]-2-yl)isoxazol-3-yl)benzenesulfonamide, 122

[0772] ##STR00210##

[0773] To a solution of N-(5-(2-bromo-6-methoxyphenyl)isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide 108 (30 mg, 0.06 mmol) in 1,4-dioxane (2.5 mL) and water (0.5 mL) was added phenylboronic acid (12 mg, 0.09 mmol), Pd(PPh.sub.3).sub.4 (8 mg, 0.006 mmol) and Na.sub.2CO.sub.3 (27 mg, 0.26 mmol) and the mixture was heated at 100 C. under N.sub.2 overnight. Water was added and the mixture was extracted with EtOAc (10 mL3). The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep. TLC (Pet. Ether/EtOAc=1/1) to give the title compound (10 mg, 36%) as a white solid. LCMS-A (ES-API): R.sub.t2.41 min; m/z 467.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.9 (br s, 1H), 7.60-7.40 (m, 2H), 7.28-7.09 (m, 4H), 7.00-6.97 (m, 3H), 6.74 (d, J=8.4 Hz, 2H), 6.08 (s, 1H), 3.76 (s, 3H), 3.72 (s, 6H).

Example 123: 2-Fluoro-6-methoxy-N-(5-(2-methoxyphenyl)isoxazol-3-yl)benzenesulfonamide, 123

[0774] ##STR00211##

[0775] To a solution of 2,6-difluoro-N-(5-(2-methoxyphenyl)isoxazol-3-yl)benzenesulfonamide 97 (50 mg, 0.14 mmol) in MeOH (3 mL) was added MeONa (54 mg, 0.84 mmol) and the mixture was heated at 120 C. in a sealed tube overnight. The mixture was adjusted to pH 5 with 1 M aqueous HCl and extracted with EtOAc. The organic extract was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep. TLC (DCM/MeOH=50/1) to give the title compound (15 mg, 28%) as a white solid. LCMS-A (ES-API): R.sub.t 2.84 min; m/z 366.8 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.6 (br s, 1H), 7.82-7.70 (m, 1H), 7.62-7.52 (m, 1H), 7.51-7.43 (m, 1H), 7.23-7.15 (m, 1H), 7.12-6.89 (m, 3H), 6.68 (s, 1H), 3.92 (s, 3H), 3.84 (s, 3H).

Example 124: 2-(Benzyloxy)-N-(5-(2-ethylphenyl)isoxazol-3-yl)-6-methoxybenzenesulfonamide, 124

[0776] ##STR00212##

[0777] To a solution of 2-fluoro-6-methoxy-N-(5-(2-methoxyphenyl)isoxazol-3-yl)benzenesulfonamide 123 (50 mg, 0.13 mmol) in THF (50 mL) was added benzyl alcohol (29 mg, 0.26 mmol) and f-BuOK (30 mg, 0.26 mmol) and the mixture was heated at 50 C. under N.sub.2 overnight. The mixture was acidified to pH 5 with 1 M aqueous HCl and extracted with EtOAc. The organic extract was dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by prep. TLC (DCM/MeOH=50/1) to give the title compound (20 mg, 33%) as a white solid. LCMS-B (ES-API): R.sub.t 4.19 min; m/z 467.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.2 (br s, 1H), 7.74 (dd, J=7.9, 1.8 Hz, 1H), 7.53 (d, J=7.5 Hz, 2H), 7.51-7.39 (m, 2H), 7.33-7.25 (m, 3H), 7.17 (d, J=8.4 Hz, 1H), 7.06 (t, J=7.6 Hz, 1H), 6.81-6.74 (m, 3H), 5.28 (s, 2H), 3.82 (s, 3H), 3.76 (s, 3H).

Example 125: N-(5-(3,4-Dimethoxyphenyl)-1,3,4-oxadiazol-2-yl)-5-ethyl-2-methoxybenzenesulfonamide, 125

[0778] ##STR00213##

[0779] A suspension of 5-ethyl-2-methoxybenzene-1-sulfonyl chloride I19 (150 mg, 0.639 mmol) and 5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazol-2-amine (141 mg, 0.639 mmol) in pyridine (2 mL) was irradiated in the microwave at 110 C. for 2 hours. The product was purified by column chromatography (0-100% EtOAc in petroleum benzine 40-60 C.) to give the title compound as a white solid (109 mg, 40%). LCMS-C: R.sub.t 6.167 min; m/z 420.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.70 (d, J=2.3 Hz, 1H), 7.46-7.38 (m, 2H), 7.31 (d, J=2.0 Hz, 1H), 7.18-7.06 (m, 2H), 3.91-3.78 (m, 6H), 3.72 (s, 3H), 2.63 (q, J=7.6 Hz, 2H), 1.18 (t, J=7.5 Hz, 3H).

Example 126:5-Ethyl-2-methoxy-N-(5-phenyl-1,3,4-oxadiazol-2-yl)benzenesulfonamide, 126

[0780] ##STR00214##

[0781] A suspension of 5-ethyl-2-methoxybenzene-1-sulfonyl chloride I19 (150 mg, 0.639 mmol) and 5-phenyl-1,3,4-oxadiazol-2-amine (103 mg, 0.639 mmol) in pyridine (2 mL) was irradiated in the microwave at 110 C. for 2 hours. The product was purified by column chromatography (0-100% EtOAc in petroleum benzine 40-60 C.) to give the title compound as a white solid (142 mg, 62%). LCMS-C: R.sub.t 6.308 min; m/z 360.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.88-7.80 (m, 2H), 7.71 (d, J=2.3 Hz, 1H), 7.68-7.55 (m, 3H), 7.42 (dd, J=8.4, 2.3 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 3.72 (s, 2H), 2.63 (q, J=7.6 Hz, 2H), 1.18 (t, J=7.6 Hz, 3H).

Example 127: N-(5-(2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)tetrahydro-2H-pyran-4-sulfonamide, 127

[0782] ##STR00215##

[0783] Lithium bis(trimethylsilyl)amide solution 1.0 M in THF (0.386 mL, 0.386 mmol) was added to a solution of 5-(2-methoxyphenyl)-1,3,4-thiadiazol-2-amine I109 (0.040 g, 0.193 mmol) in THF (0.965 mL) at 0 C. and the reaction was stirred for 15 min. A solution of tetrahydropyran-4-sulfonyl chloride (0.029 mL, 0.232 mmol) in THF (0.5 mL) was added dropwise, the resulting mixture was warmed to room temperature and stirred for 4 h. The reaction was quenched with 1 M HCl and extracted with EtOAc (3). The combined organics were washed with brine, dried (MgSO.sub.4) and concentrated. Purification by column chromatography (4 g silica cartridge, 20-60% ethyl acetate in petroleum benzine 40-60 C.) gave the title compound as a pale yellow solid. LCMS-D: rt 3.15 min, m/z 355.9 [M+H].sup.+

Example 128 and 129: tert-Butyl 4-(N-(5-(2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)sulfamoyl)piperidine-1-carboxylate, 128 and N-(5-(2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)piperidine-4-sulfonamide hydrochloride, 129

[0784] ##STR00216##

a) tert-butyl 4-(N-(5-(2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)sulfamoyl)piperidine-1-carboxylate I28

[0785] Lithium bis(trimethylsilyl)amide solution 1.0 M in THF (0.386 mL, 0.386 mmol) was added to a solution of 5-(2-methoxyphenyl)-1,3,4-thiadiazol-2-amine I109 (0.040 g, 0.193 mmol) in tetrahydrofuran (1.93 mL) at 10 C. and the reaction was stirred for 10 min. A solution of tert-butyl 4-chlorosulfonylpiperidine-1-carboxylate (0.066 g, 0.232 mmol) in THF (0.5 mL) was added dropwise, the resulting mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water (5 mL), acidified with 1 M HCl and extracted with EtOAc (310 mL). The combined organics were washed with brine, dried (MgSO.sub.4) and concentrated. Purification by column chromatography (4 g silica cartridge, 50-90% ethyl acetate in petroleum benzine 40-60 C.) gave the title compound (0.013 g, 15% yield) as a pale yellow oil. LCMS-C: rt 6.14 min, m/z 453.2 [MH].sup., .sup.1H NMR (400 MHz, CDCl.sub.3) 8.07 (dd, J=7.9, 1.7 Hz, 1H), 7.47 (ddd, J=8.4, 7.4, 1.7 Hz, 1H), 7.07 (td, J=7.6, 1.0 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 4.34-4.18 (m, 2H), 3.98 (s, 3H), 3.16 (tt, J=11.9, 3.6 Hz, 1H), 2.80-2.69 (m, 2H), 2.17 (dd, J=13.6, 3.6 Hz, 2H), 1.77 (qd, J=12.5, 4.5 Hz, 2H), 1.46 (s, 9H).

b) N-(5-(2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)piperidine-4-sulfonamide hydrochloride I29

[0786] HCl (4 M in 1,4-dioxane, 0.055 mL) was added to a solution of tert-butyl 4-(N-(5-(2-methoxyphenyl)-1,3,4-thiadiazol-2-yl)sulfamoyl)piperidine-1-carboxylate I28 (0.010 g 0.022 mmol) in DCM (0.06 mL). The reaction was stirred for 18 h and the solvent was removed to give title compound (6.0 mg, 70% yield) as a white solid. LCMS-D: rt 2.83 min, m/z 354.9 [M-Cl].sup.+.

Assays

[0787] Protein Preparation

[0788] KAT5

[0789] Molecular Biology: A codon optimized DNA sequence (for expression in Escherichia coli) encoding amino acid residues 2 to 461 (Uniprot Q92993-2) of human KAT5 isoform was synthesised by GenScript USA Inc (Piscataway, N.J., USA). This was ligated into a modified pET43a E. coli expression vector designed to encode an N-terminal hexahistidine tag followed by a tobacco etch virus protease (TEV) cleavage site and by the KAT5 sequence. The resulting protein sequence is listed below.

TABLE-US-00013 MGHHHHHHGTENLYFQGSAEVGEIIEGCRLPVLRRNQDNEDEWPLAEIL SVKDISGRKLFYVHYIDFNKRLDEWVTHERLDLKKIQFPKKEAKTPTKN GLPGSRPGSPEREVKRKVEVVSPATPVPSETAPASVFPQNGAARRAVAA QPGRKRKSNCLGTDEDSQDSSDGIPSAPRMTGSLVSDRSHDDIVTRMKN IECIELGRHRLKPWYFSPYPQELTTLPVLYLCEFCLKYGRSLKCLQRHL TKCDLRHPPGNEIYRKGTISFFEIDGRKNKSYSQNLCLLAKCFLDHKTL YYDTDPFLFYVMTEYDCKGFHIVGYFSKEKESTEDYNVACILTLPPYQR RGYGKLLIEFSYELSKVEGKTGTPEKPLSDLGLLSYRSYWSQTILEILM GLKSESGERPQITINEISEITSIKKEDVISTLQYLNLINYYKGQYILTL SEDIVDGHERAMLKRLLRIDSKCLHFTPKDWSKRGKWAS*

[0790] Protein Expression: To produce recombinant KAT5 protein, expression plasmid was transformed into E. coli BL21 DE3 strain and grown with shaking at 37 C. in 1 L volumes of Terrific broth (TB) supplemented with 100 g/mL Ampicillin and 50 M zinc until an OD600 of 0.8 was reached. Cultures were transferred to 18 C. and protein expression induced by the addition of Isopropyl -D-1-thiogalactopyranoside to a final concentration of 0.5 mM and the cultures shaken overnight for further 16 hours. Following expression, cell cultures were centrifuged at 5000g for 20 min and cell pellet stored frozen at 20 C.

[0791] Protein Purification: Protein purification was initiated by thawing the cell pellet (25 g wet weight) in Lysis buffer (50 mM Hepes pH 7.4, 500 mM NaCl, 5 mM imidazole, 5% [v/v]glycerol, 0.1% [w/v] CHAPS, 2 mM 2-mercaptoethanol, 3 mM MgCl.sub.2 0.5 mg/mL lysozyme, benzonase endonuclease [EMD Millipore], 1 mM PMSF, complete protease inhibitor tablets EDTA-free [Roche]) using a ratio of 6 mL of buffer per 1 g of cells. Cells were further lysed by sonication using a Misonix Liquid Processor (630 second pulses, amplitude 60 [70 watts]) and then centrifuged at 48,000g at 4 C. Supernatant (cell lysate) was mixed with 20 mL of Q-Sepharose FF resin (GE Healthcare) pre-equilibrated with Q buffer (20 mM Hepes pH 7.4.1 M NaCl). The unbound fraction from Q-Sepharose FF was then incubated with 5 mL of complete His-Tag Purification Resin (Roche), pre-equilibrated with IMAC Wash Buffer (20 mM hepes pH 7.4, 500 mM NaCl, 35 mM imidazole). The resin was washed with IMAC Wash Buffer, and bound KAT5 eluted with IMAC Elution buffer (20 mM hepes pH 7.4, 500 mM NaCl, 300 mM imidazole). IMAC-eluted protein was immediately desalted into Storage buffer (50 mM Na citrate pH 6.5, 500 mM NaCl, 5% [v/v] glycerol) using 2 HiPrep 26/10 desalting columns (GE Healthcare) in series. Desalted protein was further purified by passing through a HiLoad 26/60 Superdex 75 column pre-equilibrated in Storage buffer. Finally, KAT5 protein was concentrated to 1.5 mg/mL using Amicon Ultra centrifugal filter unit (Utra-15 MWCO 10 kDa), flash-frozen in liquid nitrogen and stored in 70 C. freezer.

[0792] KAT6A

[0793] Molecular Biology: The DNA sequence encoding amino acid residues 507 to 778 (Uniprot Q92794-1) of human KAT6A was amplified by PCR and was ligated into a modified pET E. coli expression vector designed to encode a NusA solubility tag followed by a hexahistidine tag and a tobacco etch virus protease (TEV) cleavage site and by the KAT6A sequence. The resulting protein sequence is listed below.

TABLE-US-00014 MNKEILAVVEAVSNEKALPREKIFEALESALATATKKKYEQEIDVRVQI DRKSGDFDTFRRWLVVDEVTQPTKEITLEAARYEDESLNLGDYVEDQIE SVTFDRITTQTAKQVIVQKVREAERAMVVDQFREHEGEIITGVVKKVNR DNISLDLGNNAEAVILREDMLPRENFRPGDRVRGVLYSVRPEARGAQLF VTRSKPEMLIELFRIEVPEIGEEVIEIKAAARDPGSRAKIAVKTNDKRI DPVGACVGMRGARVQAVSTELGGERIDIVLWDDNPAQFVINAMAPADVA SIVVDEDKHTMDIAVEAGNLAQAIGRNGQNVRLASQLSGWELNVMTVDD LQAKHQAEAHAAIDTFTKYLDIDEDFATVLVEEGFSTLEELAYVPMKEL LEIEGLDEPTVEALRERAKNALATIAQAQEESLGDNKPADDLLNLEGVD RDLAFKLAARGVCTLEDLAEQGIDDLADIEGLTDEKAGALIMAARNICW FGDEATSGSGHHHHHHSAGENLYFQGAMGRCPSVIEFGKYEIHTWYSSP YPQEYSRLPKLYLCEFCLKYMKSRTILQQHMKKCGWFHPPVNEIYRKNN ISVFEVDGNVSTIYCQNLCLLAKLFLDHKTLYYDVEPFLFYVLTQNDVK GCHLVGYFSKEKHCQQKYNVSCIMILPQYQRKGYGRFLIDFSYLLSKRE GQAGSPEKPLSDLGRLSYMAYWKSVILECLYHQNDKQISIKKLSKLTGI CPQDITSTLHHLRMLDFRSDQFVIIRREKLIQDHMAKLQLNLRPVDVDP ECLRWTP

[0794] Protein Expression: To produce recombinant KAT6A protein, expression plasmid was transformed into E. coli BL21 DE3 strain and grown with shaking at 37 C. in 1 L volumes of Terrific broth (TB) supplemented with 100 g/mL Ampicillin until an OD600 of 0.8 was reached. Cultures were transferred to 18 C. and protein expression induced by the addition of Isopropyl 3-D-1-thiogalactopyranoside to a final concentration of 0.5 mM and the cultures shaken overnight for further 16 hours. Following expression, cell cultures were centrifuged at 5000g for 20 min and cell pellet stored frozen at 20 C.

[0795] Protein Purification: Protein purification was initiated by thawing the cell pellet (40 g wet weight) in Lysis buffer (25 mM Tris-HCl pH 7.8, 500 mM NaCl, 5 mM DTT, 0.01% [v/v] Triton-X 100, 5% [v/v] glycerol, 2 mM MgCl.sub.2, 10 mM Imidazole, 0.5 mg/mL lysozyme, benzonase endonuclease [EMD Millipore], 1 mM PMSF, complete protease inhibitor tablets EDTA-free [Roche]) using a ratio of 5 mL of buffer per 1 g of cells. Cells were further lysed by 3 passes (at 15000 psi) through an ice cooled Avestin C5 cell crusher and then centrifuged at 48,000g at 4 C. Supernatant (cell lysate) was filtered through a 5 m filter and applied onto 5 mL HiTrap IMAC Sepharose FF column (GE Healthcare) pre-equilibrated with IMAC wash buffer (25 mM Tris-HCl pH 7.8, 500 mM NaCl, 5 mM DTT, 0.01% [v/v] Triton-X 100, 5% [v/v] glycerol, 20 mM Imidazole) using a Profinia Affinity chromatography purification system (Bio-Rad). The IMAC column was then washed with IMAC Wash buffer and bound KAT6A protein eluted with IMAC Elution buffer (25 mM Tris-HCl pH 7.8, 500 mM NaCl, 5% [v/v] glycerol, 5 mM DTT, 250 mM Imidazole). IMAC-eluted protein was further purified by passing through a HiLoad 26/60 Superdex 200 column pre-equilibrated in Storage buffer (25 mM Tris-HCl pH 7.8, 500 mM NaCl, 5 mM DTT, 5% [v/v]glycerol). Finally, KAT6A protein was concentrated to 1 mg/mL using Amicon Ultra centrifugal filter unit (Utra-15 MWCO 10 kDa), flash-frozen in liquid nitrogen and stored in 70 C. freezer.

[0796] KAT6B was obtained from SignalChem, catalog ID: K315-381BG

[0797] KAT7

[0798] Molecular Biology: A codon optimized DNA sequence encoding amino acid residues 325 to 611 (Uniprot 095251-1) of human KAT7 was synthesised by GenScript USA Inc (Piscataway, N.J., USA). This was ligated into a modified pET43a E. coli expression vector designed to encode an N-terminal hexahistidine tag followed by a tobacco etch virus protease (TEV) cleavage site and by the KAT7 sequence. The resulting protein sequence is listed below.

TABLE-US-00015 MGHHHHHHGTENLYFQGSRLQGQITEGSNMIKTIAFGRYELDTWYHSPY PEEYARLGRLYMCEFCLKYMKSQTILRRHMAKCVWKHPPGDEIYRKGSI SVFEVDGKKNKIYCQNLCLLAKLFLDHKTLYYDVEPFLFYVMTEADNTG CHLIGYFSKEKNSFLNYNVSCILTMPQYMRQGYGKMLIDFSYLLSKVEE KVGSPERPLSDLGLISYRSYWKEVLLRYLHNFQGKEISIKEISQETAVN PVDIVSTLQALQMLKYWKGKHLVLKRQDLIDEWIAKEAKRSNSNKTMDP SCLKWTPPKGTAS

[0799] Protein Expression: To produce recombinant KAT7 protein, expression plasmid was transformed into E. coli BL21 DE3 RIL strain and grown with shaking at 37 C. in 1 L volumes of Terrific broth (TB) supplemented with 100 g/mL Ampicillin and 50 M zinc until an OD600 of 0.8 was reached. Cultures were transferred to 18 C. and protein expression induced by the addition of Isopropyl -D-1-thiogalactopyranoside to a final concentration of 0.5 mM and the cultures shaken overnight for further 16 hours. Following expression, cell cultures were centrifuged at 5000g for 20 min and cell pellet stored frozen at 20 C. Protein Purification: Protein purification was initiated by thawing the cell pellet (10 g wet weight) in Lysis buffer (50 mM Hepes pH 7.5, 300 mM NaCl, 5 mM DTT, 5 mM Imidazole, 0.05% [v/v] Brij 35, 10% [v/v] glycerol, 3 mM MgCl.sub.2 0.5 mg/mL lysozyme, benzonase endonuclease [EMD Millipore], 1 mM PMSF, complete protease inhibitor tablets EDTA-free [Roche]) using a ratio of 10 mL of buffer per 1 g of cells. Cells were further lysed by sonication using a Misonix Liquid Processor (630 second pulses, amplitude 60 [70 watts]) and then centrifuged at 48,000g at 4 C. Supernatant (cell lysate) was incubated with 1 mL of complete His-Tag Purification Resin (Roche), pre-equilibrated with IMAC Wash Buffer 1 (25 mM Hepes pH 7.5, 800 mM NaCl, 5 mM imidazole, 10% [v/v] glycerol, 5 mM DTT, 0.01% [v/v] Brij 35, 50 mM arginine, 50 mM glutamic acid). The resin was sequentially washed with IMAC Wash buffer 1 and IMAC Wash buffer 2 (25 mM hepes pH 7.5, 300 mM NaCl, 20 mM imidazole, 10% [v/v] glycerol, 5 mM DTT, 0.01% [v/v] Brij 35, 50 mM arginine, 50 mM glutamic acid). Bound KAT7 protein was eluted with IMAC Elution buffer (25 mM hepes pH 7.5, 200 mM NaCl, 500 mM imidazole, 10% [v/v] glycerol, 5 mM DTT 0.01% [v/v] Brij 35, 50 mM arginine, 50 mM glutamic acid). The eluting protein was collected directly into 4 volumes of Desalt Buffer (50 mM Na citrate pH 6.5, 200 mM NaCl, 0.01% [v/v] Brij 35, 10% [v/v] glycerol, 5 mM DTT) to bring the final imidazole concentration to 100 mM. IMAC-eluted protein was immediately desalted into Desalt buffer using 2 HiPrep 26/10 desalting columns (GE Healthcare) in series. Desalted protein was further purified by passing through a HiLoad 26/60 Superdex 75 column pre-equilibrated in Storage Buffer (50 mM Na citrate pH 6.5, 200 mM NaCl, 10% [v/v] glycerol, 5 mM DTT). Finally, KAT7 protein was concentrated to 3.5 mg/mL using Amicon Ultra centrifugal filter unit (Utra-15 MWCO 10 kDa), flash-frozen in liquid nitrogen and stored in 70 C. freezer.

[0800] KAT8

[0801] Molecular Biology: A codon optimized DNA sequence (for expression in E. coli) encoding amino acid residues 177 to 447 (Uniprot Q9H7Z6-1) of human KAT8 was synthesised by Thermo Fisher Scientific GENEART GmbH (Regensberg, Germany). This was ligated into pPROEX Hta E. coli expression vector designed to encode an N-terminal hexahistidine tag followed by a tobacco etch virus protease (TEV) cleavage site and by the KAT8 sequence. The resulting protein sequence is listed below.

TABLE-US-00016 MSYYHHHHHHDYDIPTTENLYFQGAKYVDKIHIGNYEIDAWYFSPFPED YGKQPKLWLCEYCLKYMKYEKSYRFHLGQCQWRQPPGKEIYRKSNISVY EVDGKDHKIYCQNLCLLAKLFLDHKTLYFDVEPFVFYILTEVDRQGAHI VGYFSKEKESPDGNNVACILTLPPYQRRGYGKFLIAFSYELSKLESTVG SPEKPLSDLGKLSYRSYWSWVLLEILRDFRGTLSIKDLSQMTSITQNDI ISTLQSLNMVKYWKGQHVICVTPKLVEEHLKSAQYKKPPITVDSVCLKW AP*

[0802] Protein Expression: To produce recombinant KAT8 protein, expression plasmid was transformed into E. coli BL21 DE3 strain and grown with shaking at 37 C. in 1 L volumes of Terrific broth (TB) supplemented with 100 g/mL Ampicillin until an OD600 of 0.8 was reached. Cultures were transferred to 18 C. and protein expression induced by the addition of Isopropyl -D-1-thiogalactopyranoside to a final concentration of 0.5 mM and the cultures shaken overnight for further 16 hours. Following expression, cell cultures were centrifuged at 5000g for 20 min and cell pellet stored frozen at 20 C.

[0803] Protein Purification: Protein purification was initiated by thawing the cell pellet (34 g wet weight) in Lysis buffer (20 mM Hepes pH 7.5, 500 mM NaCl, 5 mM Imidazole, 5% [v/v]glycerol, 0.01% [v/v] Triton-X 100, 5 mM 2-mercaptoethanol, 2 mM MgCl.sub.2 0.5 mg/mL lysozyme, benzonase endonuclease [EMD Millipore], 1 mM PMSF, complete protease inhibitor tablets EDTA-free [Roche]) using a ratio of 3 mL of buffer per 1 g of cells. Cells were further lysed by 3 passes (at 15000 psi) through an ice cooled Avestin C5 cell crusher and then centrifuged at 48,000g at 4 C. Supernatant (cell lysate) was filtered through a 0.2 m filter and applied onto 5 mL HiTrap IMAC Sepharose FF column (GE Healthcare) pre-equilibrated with IMAC wash buffer 1 (20 mM Hepes pH 7.5, 500 mM NaCl, 0.5 mM TCEP, 5 mM Imidazole) using a Profinia Affinity chromatography purification system (Bio-Rad). The IMAC column was then sequentially washed with IMAC Wash buffer 1 and IMAC Wash buffer 2 (20 mM Hepes pH 7.5, 500 mM NaCl, 0.5 mM TCEP, 10 mM Imidazole) and bound KAT8 protein eluted with IMAC Elution buffer (20 mM Hepes pH 7.5, 500 mM NaCl, 0.5 mM TCEP, 500 mM Imidazole). IMAC-eluted protein was further purified by passing through a HiLoad 26/60 Superdex 200 column pre-equilibrated in Storage buffer (20 mM Hepes pH 7.5, 500 mM NaCl, 1 mM TCEP). Finally, KAT8 protein was concentrated to 0.2 mg/mL using Amicon Ultra centrifugal filter unit (Utra-15 MWCO 10 kDa), flash-frozen in liquid nitrogen and stored in 70 C. freezer.

[0804] Acetyltransferase Biochemical Assay

[0805] To determine the inhibition of KAT enzymatic activity by 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 0.01% m/v chicken egg white albumin).

[0806] Reactions were set up with 1 M Acetyl coenzyme A, 100 nM of full-length recombinant histone labelled by limited biotinylation (KAT6A, KAT6B, KAT7: H3.1, KAT5, KAT8: H4), 10/5/8/40/20 nM of KAT5/KAT6A/KAT6B/KAT7/KAT8 enzyme respectively, and an acetyl-lysine specific antibody (H3.1: Cell Signaling Technology, H4: Abeam). 11-point dilution series of the test compounds 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, DMSO only) 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 min 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 8 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 (% I) 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.

[0807] The results are shown in tables 1 to 5 below:

TABLE-US-00017 TABLE 1 (TIP60-KAT5) Example IC50 (M) 1 =0.2132 2 =23.995 3 =20.547 4 =11.995 5 =1.0012 6 =0.1639 7 =0.5856 8 =0.4157 9 =2.4311 10 =5.2472 11 =0.8673 12 =3.0962 13 =12.193 14 =0.1421 15 =0.315 16 =0.2189 17 =2.066 18 =0.4446 19 =2.6329 20 =6.02 21 =23.967 22 =1.3355 23 =0.1402 24 =19.462 25 =31.296 26 =33.849 27 =23.748 28 =21.253 29 >125 30 >125 31 =87.893 32 =116.16 34 =50.713 35 >125 36 >125 37 =113.95 38 =36.993 39 =58.497 40 =28.962 41 =64.168 42 =55.488 43 =86.4 44 =82.907 45 >125 46 >125 47 >125 48 =71.151 49 =42.835 50 =41.352 51 =75.275 52 =56.669 53 =54.783 54 =38.286 55 >125 56 =1.6636 57 =10.409 58 =19.008 59 =26.102 60 =12.439 61 =69.613 62 =68.322 63 =65.242 64 =88.353 65 =57.525 66 =12.308 67 =8.1757 68 >125 69 =0.8447 70 =0.6959 71 =0.4159 72 =0.1063 73 =1.1547 74 =12.995 75 =13.782 76 >125 77 =3.2648 78 =2.5063 79 =21.468 80 =26.616 81 =121.01 82 =27.072 83 =108.63 84 =1.8407 85 >125 86 =25.909 87 =19.221 88 =27.863 89 =21.206 90 =21.184 92 =61.856 93 =81.2054 94 =62.2136 95 =22.1163 96 =2.2549 97 =31.9712 98 =45.4491 99 =19.0089 100 =11.2055 101 >125.0000 102 =7.3324 103 =64.7593 104 =58.7659 105 =1.0976 106 =2.8637 107 =26.3454 108 =67.7482 109 =16.4566 110 =4.2450 111 =0.2384 112 =14.4120 113 =60.1489 114 =19.8700 115 =57.4577 116 =34.0304 117 =5.2586 118 =41.8736 119 =0.7878 120 =1.4454 121 =7.8697 122 =68.8714 123 =34.2996 124 =12.9392 125 >125.0000 126 =14.5937 127 >125.0000 128 =97.3157 129 >125.0000

TABLE-US-00018 TABLE 2 (MOZ-KAT6A) Example IC50 (M) 1 =0.0403 2 =2.2179 3 =2.1385 4 =3.539 5 =0.2765 6 =0.0412 7 =0.1888 8 =0.0252 9 =0.4228 10 =1.6461 11 =0.2826 12 =0.6147 13 =0.6818 14 =0.1514 15 =0.1642 16 =0.1325 17 =2.1009 18 =0.9502 19 =1.0903 20 =8.1888 21 =9.0707 22 =0.3626 23 =0.0464 24 =7.5264 25 =5.3321 26 =10.536 27 =7.6321 28 =8.8399 29 =95.979 30 =81.289 31 =25.061 32 =37.747 34 =14.26 35 =109.99 36 =30.644 37 =32.484 38 =9.2962 39 =25.168 40 =3.967 41 =23.685 42 =4.209 43 =36.651 44 =63.074 45 =48.673 46 =59.399 47 =39.061 48 =18.214 49 =14.327 50 =18.217 51 =42.301 52 =27.966 53 =12.708 54 =11.403 55 =89.616 56 =0.9422 57 =4.1786 58 =9.6181 59 =2.4298 60 =1.5219 61 =23.847 62 =52.623 63 =20.08 64 =28.968 65 =17.886 66 =10.855 67 =8.3855 68 =92.403 69 =0.6479 70 =0.2898 71 =1.5592 72 =0.0449 73 =0.0273 74 =5.6231 75 =5.3545 76 =91.183 77 =2.1968 78 =1.3038 79 =28.351 80 =14.84 81 =22.581 82 =9.3499 83 =80.816 84 =0.236 85 =51.784 86 =7.4115 87 =2.1888 88 =4.9095 89 =9.8455 90 =16.353 91 =30.055 92 =14.94 93 =21.6029 94 =7.2928 95 =0.8699 96 =4.8561 97 =13.3500 98 =0.6931 99 =2.8105 100 =0.9310 101 >125.0000 102 =21.0661 103 =14.1291 104 =38.3881 105 =0.0760 106 =0.7315 107 =0.5002 108 =20.0693 109 =10.5520 110 =0.9847 111 =0.0691 112 =0.1706 113 =30.0982 114 =2.5004 115 =20.4316 116 =31.4091 117 =6.9326 118 =10.8306 119 =0.2265 120 =0.1945 121 =3.1157 122 =15.4242 123 =25.4151 124 =1.2518 125 =54.1379 126 =9.4041 127 >125.0000 128 =23.0152 129 =20.8982

TABLE-US-00019 TABLE 3 (HBO-KAT7) Example IC50 (M) 1 =0.0876 2 =3.0005 3 =3.2552 4 =6.3614 5 =0.1109 6 =0.0422 7 =0.1057 8 =0.102 9 =1.22 10 =0.9356 11 =0.4758 12 =4.4653 13 =1.5196 14 =0.0256 15 =0.1058 16 =0.062 17 =0.5652 18 =0.8678 19 =0.5014 20 =3.7859 21 =3.8705 22 =0.0796 23 =0.0102 24 =10.876 25 =16.267 26 =29.326 27 =16.652 28 =16.816 29 >125 30 >125 31 =22.412 32 =34.805 34 =10.192 35 >125 36 =49.835 37 =43.085 38 =33.199 39 =22.237 40 =15.577 41 =47.961 42 =9.9191 43 =25.23 44 =59.083 45 =123.23 46 =93.596 47 =66.172 48 =25.528 49 =24.549 50 =21.139 51 =54.965 52 =37.759 53 =19.191 54 =17.61 55 =63.571 56 =0.4731 57 =3.4541 58 =3.9555 59 =5.9579 60 =6.1869 61 =45.521 62 =53.147 63 =33.046 64 =32.457 65 =46.869 66 =13.639 67 =9.7499 68 >125 69 =0.2615 70 =0.1288 71 =0.0354 72 =0.0388 73 =0.3688 74 =9.1331 75 =9.5078 77 =0.4338 78 =1.0779 79 =10.099 80 =27.003 81 =47.292 82 =27.683 83 >125 84 =0.3289 85 =97.312 86 =14.265 87 =5.4145 88 =5.4379 89 =20.904 90 =23.509 91 =20.885 92 =37.341 93 =4.5750 94 =4.7667 95 =1.2967 96 =0.0924 97 =3.4862 98 =3.1485 99 =3.0790 100 =2.8451 101 =107.4056 102 =0.9936 103 =3.0305 104 =18.5367 105 =0.1321 106 =1.5310 107 =4.0861 108 =20.3222 109 =0.6718 110 =0.3717 111 =0.1376 112 =1.4029 113 =11.2556 114 =3.4529 115 =6.8021 116 =3.3319 117 =0.4537 118 =3.0847 119 =0.3216 120 =0.2150 121 =0.4527 122 =75.5323 123 =5.6804 124 =1.0896 125 =86.2109 126 =7.4482 127 =25.3925 128 =9.6780 129 =85.2041

TABLE-US-00020 TABLE 4 (MOF-KAT8) Example IC50 (M) 1 =1.2049 2 =42.857 3 =40.082 4 =32.524 5 =3.9631 6 =0.7462 7 =5.1154 8 =4.034 9 =12.561 10 =20.628 11 =8.8423 12 =10.322 13 =25.534 22 =1.0461 31 =50.349 40 =26.272 42 =43.575 45 >125 55 >125 56 =35.954 57 =78.111 58 =39.034 59 =31.02 62 =16.153 63 >125 73 =5.7769 77 =2.0273 78 =0.7684 84 =5.5111 87 =76.623 88 =21.759

TABLE-US-00021 TABLE 5 (QKF-KAT6B) Example IC50 (M) 2 =7.7689 4 =23.731 14 =0.1232 15 =0.0854 16 =0.3098 17 =3.7189 18 =1.0003 19 =2.1125 56 =3.1417 73 =0.1174 84 =1.5532

[0808] Histone H3 Lysine 23 Acetylation Biomarker Assay

[0809] Compounds may be tested for their ability to inhibit acetylation of the histone H3K23 marker in the following assay:

[0810] The cell line U2OS was seeded at a density of 9,000 cells per well in 96 well optical quality tissue culture plates in RPMI medium and 10% foetal bovine serum, and allowed to adhere for 24 hours under standard culture conditions (37 degree Celsius, 5% CO2). At the end of this period the medium was aspirated. Compound dilutions prepared in DMSO were added to medium, with negative control wells reserved for treatment with DMSO only and 100% inhibition positive controls receiving a potent inhibitor compound (e.g. cas 2055397-28-7, benzoic acid, 3-fluoro-5-(2-pyridinyl)-, 2-[(2-fluorophenyl)sulfonyl]hydrazide) (Baell, J., Nguyen, H. N., Leaver, D. J., Cleary, B. L., Lagiakos, H. R., Sheikh, B. N., Thomas. T. J., Aryl sulfonohydrazides, WO2016198507A1, 2016) at 10 M concentration and 200 L transferred to the cells. After incubation for 24 hours, the cells were fixed with 3.7% formaldehyde in PBS for 20 minutes at room temperature, washed (55 minutes) with phosphate buffer saline containing 0.1% Tween 20 and blocked with Odyssey blocking buffer (LI-COR, Lincoln, Nebr.) containing 0.1% TritonX100. Anti-H3K23ac specific antibody (Abeam ab177275) in Odyssey blocking buffer containing 0.1% Tween 20 was added and incubated for 16 hours at 4 degree Celsius. After washing (as above), a secondary antibody labelled with Alexa647 dye (LifeTechnologies) and Hoechst 33342 (1 g/mL, SigmaAldrich) were added for 1 hour incubation. Plates were washed as previously and read on a PerkinElmer Phenix high content imaging platform. Using a Columbus image analysis pipeline, individual nuclei were located by Hoechst 33342 stain and the acetylation level was calculated from the Alexa647-related intensity in the same area. The resulting mean intensity per cell was directly converted to percent inhibition relative to controls on the same plate and the data fitted against a four-parameter logistic model to determine the 50% inhibitory concentration (IC.sub.50).

[0811] The results are shown in table 6 below:

TABLE-US-00022 Example IC50 (M) 1 =0.0284 2 >10 3 >10 4 >10 5 =0.8951 6 =0.4709 7 =0.0491 8 =0.0518 14 =0.1325 15 =0.141 16 =0.1169 17 =2.2578 18 =1.5344 19 >10 22 =2.131 23 =0.1776 56 =2.0667 70 =0.2753 71 =0.0693 72 =0.2042 73 =0.0171 84 =0.6452 96 =3.9408 105 =0.1730 111 =0.4745 112 =0.1868 116 >20.0000 117 =5.5641 119 =0.6337

[0812] Histone H3 Lysine 14 Acetylation Biomarker Assay

[0813] Compounds may be tested for their ability to inhibit acetylation of the histone H3 Lysine 14 marker in the following assay:

[0814] The cell line U2OS was seeded at a density of 3,000 cells per well in 384-well optical quality tissue culture plates in RPMI medium supplemented with 10% foetal bovine serum and 10 mM Hepes. The cells were allowed to adhere for 24 hours under standard culture conditions (37 degree Celsius, 5% CO2). At the end of this period the cells were washed with serum free medium. Compound dilutions prepared in DMSO were added to the serum free medium, with negative control wells reserved for treatment with DMSO only and 100% inhibition positive controls receiving a potent inhibitor compound (e.g. (Z)-4-fluoro-N-((3-hydroxyphenyl)sulfonyl)-5-methyl-[1,1-biphenyl]-3-carbohydrazonic acid) at 10 M concentration. After incubation for 24 hours, the cells were fixed with 4% formaldehyde in PBS for 15 minutes at room temperature, washed with phosphate buffer saline and blocked with blocking buffer containing 0.2% TritonX100 and 2% BSA. Anti-H3K14ac specific antibody (Cell Signalling Technologies) in blocking buffer was added and incubated overnight at 4 degree Celsius. After washing, a secondary antibody labelled with AlexaFluor 488 dye (ThermoFisher) and Hoechst 33342 (1 g/mL, Life Technologies) were added for 2 hours incubation at room temperature. Plates were washed and read on a PerkinElmer Opera HCS high content imaging platform. Using a Columbus image analysis pipeline, individual nuclei were located by Hoechst 33342 stain and the acetylation level was calculated from the AlexaFluor 488-related intensity in the same area. The resulting mean intensity per cell was converted to percent inhibition relative to controls on the same plate and the data fitted against a four-parameter logistic model to determine the 50% inhibitory concentration (IC.sub.50).

[0815] The results are shown in table 7 below

TABLE-US-00023 Example IC50 (M) 1 =0.1245 3 =39.233 5 =2.328 6 =0.5256 7 =0.4958 8 =0.3446 10 =4.1416 11 =2.7388 12 >40 13 =22.384 14 =0.2197 15 =0.4495 16 =0.1926 17 =3.1957 18 =3.8432 21 >40 22 =0.762 23 =0.2157 56 =2.6426 57 >40 58 =22.414 72 =0.5749 73 =1.2902 84 =0.8783 96 =7.3834 102 =25.6297 105 =3.0025 116 >40.0000

[0816] H2A.Z Lysine 7 Acetylation Biomarker Assay

[0817] Compounds may be tested for their ability to inhibit the histone H2A.Z Lysine 7 acetylation marker in the following assay:

[0818] The cell line U2OS was seeded at a density of 3,000 cells per well in 384-well optical quality tissue culture plates in RPMI medium supplemented with 10% foetal bovine serum and 10 mM Hepes. The cells were allowed to adhere for 24 hours under standard culture conditions (37 degree Celsius, 5% CO.sub.2). At the end of this period the cells were washed with serum free medium. Compound dilutions prepared in DMSO were added to the serum free medium, with negative control wells reserved for treatment with DMSO only and 100% inhibition positive controls receiving a potent inhibitor compound enantiomer 1 of 7-iodo-N-(2-(oxazol-2-yl)-2-phenylethyl)-2H-benzo[e][1,2,4]thiadiazine-3-carboxamide 1,1-dioxide, which is compound 146 of co-pending application GB1713962.7, filed on 31 Aug. 2018, at 30 M concentration. After incubation for 24 hours, the cells were fixed with 4% formaldehyde in PBS for 15 minutes at room temperature, washed with phosphate buffer saline and blocked with blocking buffer containing 0.2% TritonX100 and 2% BSA. Anti-H2A.ZK7ac specific antibody (Abeam) in blocking buffer was added and incubated overnight at 4 degree Celsius. After washing, a secondary antibody labelled with AlexaFluor 488 dye (ThermoFisher) and Hoechst 33342 (1 g/mL, Life Technologies) were added for 2 hours incubation at room temperature. Plates were washed and read on a PerkinElmer Opera HCS high content imaging platform. Using a Columbus image analysis pipeline, individual nuclei were located by Hoechst 33342 stain and the acetylation level was calculated from the AlexaFluor 488-related intensity in the same area. The resulting mean intensity per cell was converted to percent inhibition relative to controls on the same plate and the data fitted against a four-parameter logistic model to determine the 50% inhibitory concentration (IC.sub.50).

[0819] The results are shown in table 8 below:

TABLE-US-00024 Example IC50 (M) 1 =2.2314 3 >40 5 =5.6448 6 =1.3537 7 =2.1859 8 =3.2736 10 >40 11 =5.3163 12 >40 14 =2.5007 15 =12.111 16 =1.7681 17 =29.343 18 =19.891 19 =5.4231 21 >40 22 =4.7723 23 =9.9897 56 =24.141 58 >40 72 =4.7343 73 =35.244 84 =3.1481 96 =27.2425 102 >40.0000 105 =17.0797 116 >40.0000

STATEMENTS OF INVENTION

[0820] 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of therapy:

##STR00217##

[0821] wherein either:

[0822] (i) X.sup.0=CR.sup.C, X.sup.1=N, X.sup.2=O; or

[0823] (ii) X.sup.0=CR.sup.C, X.sup.1=O, X.sup.2=N; or

[0824] (iii) X.sup.0=S, X.sup.1=N, X.sup.2=N; or

[0825] (iv) X.sup.0=N, X.sup.1=N, X.sup.2=O; or

[0826] (v) X.sup.0=O, X.sup.1=N, X.sup.2=N;

[0827] where R.sup.C is H, CO.sub.2CH.sub.3 or Cl;

[0828] R.sup.N is H or methyl;

[0829] X.sup.3 is CR.sup.3 or N;

[0830] X.sup.4 is CR.sup.4 or N;

[0831] R.sup.1 to R.sup.5 are independently selected from: [0832] (i) H; [0833] (ii) halo; [0834] (iii) cyano; [0835] (iv) C.sub.1-3 alkyl, optionally substituted by one or more fluoro groups; [0836] (v) (CH.sub.2).sub.n0C.sub.3-6 cycloalkyl, where n0=0 or 1; [0837] (vi) (CH.sub.2).sub.n1C.sub.1-3 alkoxy, where n1=0 or 1, optionally substituted by one or more fluoro groups; [0838] (vii) C.sub.1-3 alkylester; [0839] (vii) (CH.sub.2).sub.n2-phenyl, where n2=0-2; and [0840] (viii) (CH.sub.2).sub.n3C.sub.5 heteroaryl, wherein n3=0-1, optionally substituted by methyl; and

[0841] R.sup.Y is selected from: [0842] (i) (CH.sub.2).sub.n4-phenyl, where n4=0-2, where phenyl is optionally substituted by [0843] (a) C.sub.1-4 alkyl, optionally substituted by one or more fluoro groups; [0844] (b) C.sub.1-4 alkoxy, optionally substituted by phenyl, or one or more fluoro groups; [0845] (c) halo; [0846] (d) cyano, nitro or amido; [0847] (e) phenyl; or [0848] (f) (CH.sub.2).sub.n5, where n5 is 3 or 4; [0849] (ii) pyridyl; [0850] (iii) C.sub.3-4 alkyl; [0851] (iv) (CH.sub.2).sub.n6C.sub.3-6 cycloalkyl, where n6=0-2; [0852] (v) C.sub.6 heterocyclyl, optionally substituted by C.sub.1-4alkylester; and [0853] (vi) NHR.sup.YN, where R.sup.YN is selected from phenyl or cyclohexyl.

[0854] 2. A compound for use according to statement 1, wherein X.sup.0=CR.sup.C, X.sup.1=N and X.sup.2=O.

[0855] 3. A compound for use according to statement 1, wherein X.sup.0=CR.sup.C, X.sup.1=O and X.sup.2=N.

[0856] 4. A compound for use according to any one of statements 1 to 3, wherein R.sup.C is H.

[0857] 5. A compound for use according to any one of statements 1 to 3, wherein R.sup.C is CO.sub.2CH.sub.3.

[0858] 6. A compound for use according to any one of statements 1 to 3, wherein R.sup.C is Cl.

[0859] 7. A compound for use according to statement 1, wherein X.sup.0=S, X.sup.1=N and X.sup.2=N.

[0860] 8. A compound for use according to statement 1, wherein X.sup.0=N, X.sup.1=N and X.sup.2=O.

[0861] 9. A compound for use according to statement 1, wherein X.sup.0=O, X.sup.1=N, and X.sup.2=N.

[0862] 10. A compound for use according to any one of statements 1 to 9, wherein R.sup.N is H.

[0863] 11. A compound for use according to any one of statements 1 to 9, wherein R.sup.N is methyl.

[0864] 12. A compound for use according to any one of statements 1 to 11, wherein X.sup.3 is CR.sup.3 and X.sup.4 is CR.sup.4.

[0865] 13. A compound for use according to any one of statements 1 to 12, wherein when R.sup.1 to R.sup.5 is halo, it is selected from F, Cl and Br.

[0866] 14. A compound for use according to any one of statements 1 to 13, wherein when R.sup.1 to R.sup.5 is C.sub.1-3 alkyl, optionally substituted by one or more fluoro groups, it is selected from methyl, ethyl and propyl.

[0867] 15. A compound for use according to any one of statements 1 to 13, wherein when R.sup.1 to R.sup.5 is C.sub.1-3 alkyl, optionally substituted by one or more fluoro groups, the C.sub.1-3 alkyl is perfluorinated.

[0868] 16. A compound for use according to any one of statements 1 to 15, wherein when R.sup.1 to R.sup.5 is (CH.sub.2).sub.n0C.sub.3-6 cycloalkyl, n0 is 0.

[0869] 17. A compound for use according to any one of statements 1 to 15, wherein when R.sup.1 to R.sup.5 is (CH.sub.2).sub.n0C.sub.3-6 cycloalkyl, n0 is 1.

[0870] 18. A compound for use according to any one of statements 1 to 17, wherein when R.sup.1 to R.sup.5 is (CH.sub.2).sub.n1C.sub.1-3 alkoxy, n1 is 0.

[0871] 19. A compound for use according to any one of statements 1 to 17, wherein when R.sup.1 to R.sup.5 is (CH.sub.2).sub.n1C.sub.1-3 alkoxy, n1 is 1.

[0872] 20. A compound for use according to any one of statements 1 to 19, wherein when R.sup.1 to R.sup.5 is C.sub.1-3 alkylester, it is selected from CO.sub.2CH.sub.3, CO.sub.2CH.sub.2CH.sub.3 and CO.sub.2CH.sub.2CH.sub.2CH.sub.3.

[0873] 21. A compound for use according to any one of statements 1 to 20, wherein when R.sup.1 to R.sup.5 is (CH.sub.2).sub.n2-phenyl, it is phenyl.

[0874] 22. A compound for use according to any one of statements 1 to 20, wherein when R.sup.1 to R.sup.5 is (CH.sub.2).sub.n2-phenyl, it is CH.sub.2-phenyl.

[0875] 23. A compound for use according to any one of statements 1 to 20, wherein when R.sup.1 to R.sup.5 is (CH.sub.2).sub.n2-phenyl, it is C.sub.2H.sub.5-phenyl.

[0876] 24. A compound for use according to any one of statements 1 to 23, wherein when R.sup.1 to R.sup.5 is (CH.sub.2).sub.n3C.sub.5 heteroaryl, where n3=0-1, optionally substituted by methyl; n3 is 0.

[0877] 25. A compound for use according to any one of statements 1 to 23, wherein when R.sup.1 to R.sup.5 is (CH.sub.2).sub.n3C.sub.5 heteroaryl, where n3=0-1, optionally substituted by methyl; n3 is 1.

[0878] 26. A compound for use according to any one of statements 1 to 25, wherein when R.sup.1 to R.sup.5 is (CH.sub.2).sub.n3C.sub.5 heteroaryl, it is selected from (CH.sub.2).sub.n3-oxazolyl, (CH.sub.2).sub.n3-isoxazolyl, (CH.sub.2).sub.n3-thiazolyl, (CH.sub.2).sub.n3-isothiazolyl, (CH.sub.2).sub.n3-imidazolyl and (CH.sub.2).sub.n3-pyrazolyl.

[0879] 27. A compound for use according to statement 26, wherein when R.sup.1 to R.sup.5 is (CH.sub.2).sub.n3C.sub.5 heteroaryl, it is selected from (CH.sub.2).sub.n3-oxazolyl and (CH.sub.2).sub.n3-pyrazolyl.

[0880] 28. A compound for use according to any one of statements 1 to 11, wherein R.sup.2 and R.sup.5 are not H, and R.sup.1, R.sup.3 and R.sup.4 are H.

[0881] 29. A compound for use according to statement 28, wherein R.sup.2 is selected from: halo; [0882] (CH.sub.2).sub.n0C.sub.3-6 cycloalkyl; [0883] (CH.sub.2).sub.n1C.sub.1-3 alkoxy; [0884] C.sub.1-3 alkylester; and [0885] (CH.sub.2).sub.n3C.sub.5 heteroaryl, optionally substituted by methyl.

[0886] 30. A compound for use according to statement 29, wherein R.sup.2 is selected from Br, Cl, cyclopropyl, methoxy and CO.sub.2CH.sub.3.

[0887] 31. A compound for use according to statement 29, wherein R.sup.2 is selected from: [0888] pyrazol-1-yl; [0889] pyrazol-3-yl; and [0890] pyrazol-4yl; each optionally substituted by methyl.

[0891] 32. A compound for use according to any one of statements 28 to 30, wherein R.sup.5 is selected from C.sub.1-3 alkyl and (CH.sub.2).sub.n1C.sub.1-3 alkoxy.

[0892] 33. A compound for use according to statement 32, wherein R.sup.5 is selected from ethyl, methoxy, CH.sub.2OCH.sub.3, isopropoxy, OCH.sub.2CH.sub.3 and OCF.sub.3.

[0893] 34. A compound for use according to any one of statements 1 to 33, wherein R.sup.Y is (CH.sub.2).sub.n4-phenyl, where n4=0-2, where phenyl is optionally substituted by: [0894] (a) C.sub.1-4 alkyl, optionally substituted by one or more fluoro groups; [0895] (b) C.sub.1-4 alkoxy, optionally substituted by phenyl, or one or more fluoro groups; [0896] (c) halo; [0897] (d) cyano, nitro or amido; [0898] (e) phenyl; or [0899] (f) (CH.sub.2).sub.n5, where n5 is 3 or 4.

[0900] 35. A compound for use according to claim 34, wherein n4 is 0.

[0901] 36. A compound for use according to claim 34, wherein n4 is 1.

[0902] 37. A compound for use according to claim 34, wherein n4 is 2.

[0903] 38. A compound for use according to any one of claims 34 to 37, wherein the phenyl group in R.sup.Y is unsubstituted.

[0904] 39. A compound for use according to any one of claims 34 to 37, wherein the phenyl group in R.sup.Y is substituted by one substituent.

[0905] 40. A compound for use according to any one of claims 34 to 37, wherein the phenyl group in R.sup.Y is substituted by two substituents.

[0906] 41. A compound for use according to any one of claims 34 to 37 and 39 to 40, wherein when R.sup.Y is substituted by C.sub.1-4 alkyl, optionally substituted by one or more fluoro groups, the C.sub.1-4 alkyl is unsubstituted by fluoro.

[0907] 42. A compound for use according to any one of claims 34 to 37 and 39 to 40, wherein when R.sup.Y is substituted by C.sub.1-4 alkyl, optionally substituted by one or more fluoro groups, the C.sub.1-4 alkyl is perfluorinated.

[0908] 43. A compound for use according to any one of claims 34 to 37 and 39 to 42, wherein when the phenyl group in R.sup.Y is substituted by C.sub.1-4 alkoxy, optionally substituted by one or more fluoro groups, the C.sub.1-4 alkyloxy is unsubstituted by fluoro.

[0909] 44. A compound for use according to any one of claims 34 to 37 and 39 to 42, wherein when the phenyl group in R.sup.Y is substituted by C.sub.1-4 alkoxy, optionally substituted by one or more fluoro groups, the C.sub.1-4 alkyloxy is perfluorinated.

[0910] 45. A compound for use according to any one of claims 34 to 37 and 39 to 44, wherein when the phenyl group in R.sup.Y is substituted by halo, the halo group is selected from F, Cl, Br and I.

[0911] 46. A compound for use according to claim 45, wherein the halo group is F.

[0912] 47. A compound for use according to claim 45, wherein the halo group is Cl.

[0913] 48. A compound for use according to claim 45, wherein the halo group is Br.

[0914] 49. A compound for use according to claim 45, wherein the halo group is I.

[0915] 50. A compound for use according to any one of claims 34 to 37 and 39 to 49, wherein when the phenyl group in R.sup.Y is substituted by cyano.

[0916] 51. A compound for use according to any one of claims 34 to 37 and 39 to 50, wherein when the phenyl group in R.sup.Y is substituted by nitro.

[0917] 52. A compound for use according to any one of claims 34 to 37 and 39 to 51, wherein when the phenyl group in R.sup.Y is substituted by amido.

[0918] 53. A compound for use according to any one of claims 34 to 37 and 39 to 52, wherein when the phenyl group in R.sup.Y is substituted by phenyl.

[0919] 54. A compound for use according to any one of claims 34 to 37 and 39 to 53, wherein when the phenyl group in R.sup.Y is substituted by (CH.sub.2).sub.n5, n5 is 3.

[0920] 55. A compound for use according to any one of claims 34 to 37 and 39 to 53, wherein when the phenyl group in R.sup.Y is substituted by (CH.sub.2).sub.n5, n5 is 4.

[0921] 56. A compound for use according to any one of statements 1 to 33, wherein R.sup.Y is pyridyl.

[0922] 57. A compound for use according to any one of statements 1 to 33, wherein R.sup.Y is C.sub.3-4 alkyl.

[0923] 58. A compound for use according to statement 57, wherein R.sup.Y is propyl.

[0924] 59. A compound for use according to statement 57, wherein R.sup.Y is butyl.

[0925] 60. A compound for use according to any one of statements 1 to 33, wherein R.sup.Y is (CH.sub.2).sub.n6C.sub.3-6 cycloalkyl, where n6=0-2.

[0926] 61. A compound for use according to statement 60, wherein R.sup.Y is cyclopropyl.

[0927] 62. A compound for use according to statement 60, wherein R.sup.Y is cyclobutyl.

[0928] 63. A compound for use according to statement 60, wherein R.sup.Y is cyclopentyl.

[0929] 64. A compound for use according to statement 60, wherein R.sup.Y is cyclohexyl.

[0930] 65. A compound for use according to any one of statements 1 to 33, wherein R.sup.Y is C.sub.6 heterocyclyl, optionally substituted by C.sub.1-4 alkylester.

[0931] 66. A compound for use according to statement 65, wherein R.sup.Y is tetrahydropyran-4-yl.

[0932] 67. A compound for use according to statement 65, wherein R.sup.Y is 4-piperidyl.

[0933] 68. A compound for use according to any one of statements 1 to 33, wherein R.sup.Y is NHR.sup.YN where R.sup.YN is selected from phenyl or cyclohexyl.

[0934] 69. A compound for use according to statement 68, wherein R.sup.Y is NH-phenyl.

[0935] 70. A compound for use according to statement 68, wherein R.sup.Y is NH-cyclohexyl.

[0936] 71. A compound for use according to any one of statements 1 to 33, wherein R.sup.Y is 2,6-dimethoxyphenyl.

[0937] 72. A compound for use according to any one of statements 1 to 33, wherein R.sup.Y is 2,6-dimethoxy or 4-phenylphenyl.

[0938] 73. A compound for use according to any one of statements 1 to 33, wherein R.sup.Y is 2-methoxyphenyl.

[0939] 74. A compound for use according to any one of statements 1 to 33, wherein R.sup.Y is 2-methoxy or 5-ethylphenyl.

[0940] 75. A compound for use according to any one of statements 1 to 33, wherein R.sup.Y is CH.sub.2phenyl.

[0941] 76. A compound for use according to any one of statements 1 to 33, wherein R.sup.Y is CH.sub.2CH.sub.2phenyl.

[0942] 77. A compound for use according to statement 1, with the proviso that when: [0943] X.sup.0=CR.sup.C, X.sup.1=O, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, [0944] R.sup.1, R.sup.2, R.sup.3 R.sup.4, R.sup.5, R.sup.C and R.sup.N are H, [0945] R.sup.Y is not 4-methylphenyl or 3,4-dimethoxyphenyl.

[0946] 78. A compound for use according to statement 1, with the proviso that when: [0947] X.sup.0=S, X.sup.1=N, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, [0948] R.sup.1, R.sup.2, R.sup.3 R.sup.4, R.sup.5 and R.sup.N are H, [0949] R.sup.Y is not 4-methylphenyl or 3,4-dimethoxyphenyl.

[0950] 79. A compound for use according to statement 1, with the proviso that when: [0951] X.sup.0=S, X.sup.1=N, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, [0952] R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.N are H, and R.sup.3 is methyl or chloro, [0953] R.sup.Y is not 3-chlorophenyl or 3-methylphenyl.

[0954] 80. A compound for use according to statement 1, with the proviso that when: [0955] X.sup.0=O, X.sup.1=N, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, [0956] R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.N are H, and R.sup.3 is CF.sub.3, [0957] R.sup.Y is not phenyl.

[0958] 81. A compound for use according to statement 1, with the proviso that when: [0959] X.sup.0=O, X.sup.1=N, X.sup.2=N, X.sup.3=N, and X.sup.4=CR.sup.4, [0960] R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.N are H, [0961] R.sup.Y is not phenyl, 4-chlorophenyl, 4-bromophenyl or 4-iodophenyl.

[0962] 82. A pharmaceutical composition comprising a compound as defined in any one of statements 1 to 81 and a pharmaceutically acceptable excipient.

[0963] 83. A method of treatment of cancer, comprising administering to a patient in need of treatment, a compound as defined in any one of statements 1 to 81 or a pharmaceutical composition according to statement 82.

[0964] 84. A method according to statement 83, wherein the compound is administered simultaneously or sequentially with radiotherapy and/or chemotherapy

[0965] 85. The use of a compound as defined in any one of statements 1 to 81 in the manufacture of a medicament for treating cancer.

[0966] 86. A compound as defined in any one of statements 1 to 81 or a pharmaceutical composition according to statement 82 for use in the treatment of cancer.

[0967] 87. A compound or pharmaceutical composition according to statement 86, wherein the treatment is for simultaneous or sequential administration with radiotherapy and/or chemotherapy.

[0968] 88. A compound as defined in any one of statements 1 to 81 or a pharmaceutically acceptable salt thereof.

[0969] 89. A compound according to statement 88, wherein at least one of R.sup.1 to R.sup.5 is not H.

[0970] 90. A compound according to either statement 88 or statement 89, wherein R.sup.2 and R.sup.5 are not H.

[0971] 91. A compound according to any one of statements 88 to 90, wherein R.sup.Y is not (CH.sub.2).sub.n4-phenyl, wherein the phenyl is substituted by a single group which is Cl, F or NO.sub.2.

[0972] 92. A compound according to any one of statements 88 to 91, wherein R.sup.Y is not (CH.sub.2).sub.n4-phenyl, wherein the phenyl is substituted by NO.sub.2.

[0973] 93. A compound according to statement 88, with the proviso that when: [0974] X.sup.0=S, X.sup.1=N, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, [0975] R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.N are H, and R.sup.3 is H or methyl, [0976] R.sup.Y is not phenyl or 4-methylphenyl.

[0977] 94. A compound according to statement 88, with the proviso that when: [0978] X.sup.0=O, X.sup.1=N, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, [0979] R.sup.1, R.sup.2, R.sup.3 R.sup.4, R.sup.5 and R.sup.N are H, [0980] R.sup.Y is not phenyl or 4-nitrophenyl.

[0981] 95. A compound according to statement 88, with the proviso that when: [0982] X.sup.0=CR.sup.C, X.sup.1=O, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, [0983] R.sup.1, R.sup.2, R.sup.3 R.sup.4, R.sup.5, R.sup.C and R.sup.N are H, [0984] R.sup.Y is not 4-methylphenyl or 3,4-dimethoxyphenyl.

[0985] 96. A compound according to statement 88, with the proviso that when: [0986] X.sup.0=S, X.sup.1=N, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, [0987] R.sup.1, R.sup.2, R.sup.3 R.sup.4, R.sup.5 and R.sup.N are H, [0988] R.sup.Y is not 4-methylphenyl or 3,4-dimethoxyphenyl.

[0989] 97. A compound according to statement 88, with the proviso that when: [0990] X.sup.0=S, X.sup.1=N, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, [0991] R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.N are H, and R.sup.3 is methyl or chloro, [0992] R.sup.Y is not 3-chlorophenyl or 3-methylphenyl.

[0993] 98. A compound according to statement 88, with the proviso that when: [0994] X.sup.0=O, X.sup.1=N, X.sup.2=N, X.sup.3=CR.sup.3, and X.sup.4=CR.sup.4, [0995] R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.N are H, and R.sup.3 is CF.sub.3, [0996] R.sup.Y is not phenyl.

[0997] 99. A compound according to statement 88, with the proviso that when: [0998] X.sup.0=O, X.sup.1=N, X.sup.2=N, X.sup.3=N, and X.sup.4=CR.sup.4, [0999] R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.N are H, [1000] R.sup.Y is not phenyl, 4-chlorophenyl, 4-bromophenyl or 4-iodophenyl.

[1001] 100. A compound for use according to statement 1,

[1002] wherein either:

[1003] (i) X.sup.0=CR.sup.C, X.sup.1=N, X.sup.2=O; or

[1004] (ii) X.sup.0=CR.sup.C, X.sup.1=O, X.sup.2=N; or

[1005] (iii) X.sup.0=S, X.sup.1=N, X.sup.2=N; or

[1006] (iv) X.sup.0=N, X.sup.1=N, X.sup.2=O; or

[1007] (v) X.sup.0=O, X.sup.1=N, X.sup.2=N;

[1008] where R.sup.C is H, CO.sub.2Me or Cl;

[1009] R.sup.N is H or Me;

[1010] X.sup.3 is CR.sup.3 or N;

[1011] X.sup.4 is CR.sup.4 or N;

[1012] R.sup.1 to R.sup.5 are independently selected from: [1013] (i) H; [1014] (ii) halo; [1015] (iii) cyano; [1016] (iv) C.sub.1-3 alkyl, optionally substituted by one or more F;

[1017] (v) (CH.sub.2).sub.n0C.sub.3-6 cycloalkyl, where n0=0 or 1;

[1018] (vi) (CH.sub.2).sub.n1C.sub.1-3 alkoxy, where n1=0 or 1, optionally substituted by one or more F;

[1019] (vii) C.sub.1-3 alkylester;

[1020] (vii) (CH.sub.2).sub.n2-Ph, where n2=0-2;

[1021] (viii) C.sub.5 heteroaryl

[1022] R.sup.Y is selected from: [1023] (i) (CH.sub.2).sub.n4Ph, where n4=0-2, where Ph is optionally substituted by [1024] (a) C.sub.1-4 alkyl, optionally substituted by one or more F; [1025] (b) C.sub.1-4 alkoxy, optionally substituted by one or more F; [1026] (c) halo; [1027] (d) cyano, nitro or amido; [1028] (e) phenyl; or [1029] (f) (CH.sub.2).sub.n5, where n5 is 3 or 4; [1030] (ii) pyridyl; [1031] (iii) C.sub.3-4 alkyl; [1032] (iv) C.sub.3-6 cycloalkyl

[1033] 101. A compound for use according to statement 100, wherein X.sup.0=CR.sup.C, X.sup.1=N and X.sup.2=O or

[1034] X.sup.0=CR.sup.C, X.sup.1=O and X.sup.2=N, and R.sup.C is H.

[1035] 102. A compound for use according to any either statement 100 or statement 101, wherein R.sup.N is H.

[1036] 103. A compound for use according to any one of statements 100 to 102, wherein X.sup.3 is CR.sup.3 and X.sup.4 is CR.sup.4.

[1037] 104. A compound for use according to any one of statements 100 to 103, wherein R.sup.2 and R.sup.5 are not H, and R.sup.1, R.sup.3 and R.sup.4 are H.

[1038] 105. A compound for use according to statement 104, wherein R.sup.2 is selected from halo, (CH.sub.2).sub.n0C.sub.3-6 cycloalkyl, (CH.sub.2).sub.n1C.sub.1-3 alkoxy and C.sub.1-3 alkylester.

[1039] 106. A compound for use according to statement 105, wherein R.sup.2 is selected from Br, Cl, cyclopropyl, OMe and CO.sub.2Me.

[1040] 107. A compound for use according to any one of statements 104 to 106, wherein R.sup.5 is selected from C.sub.1-3 alkyl and (CH.sub.2).sub.n1C.sub.1-3 alkoxy.

[1041] 108. A compound for use according to statement 107, wherein R.sup.5 is selected from Et, OMe, CH.sub.2OMe, O-iPr, O-Et and OCF.sub.3.

[1042] 109. A compound for use according to any one of statements 100 to 108, wherein R.sup.Y is (CH.sub.2).sub.n4Ph, where n4=0-2, where Ph is optionally substituted by: [1043] (a) C.sub.1-4 alkyl, optionally substituted by one or more F; [1044] (b) C.sub.1-4 alkoxy, optionally substituted by one or more F; [1045] (c) halo; [1046] (d) cyano, nitro or amido; [1047] (e) phenyl; or [1048] (f) (CH.sub.2).sub.n5, where n5 is 3 or 4.

[1049] 110. A compound for use according to statement 109, wherein the Ph group in R.sup.Y is unsubstituted.

[1050] 111. A compound for use according to statement 109, wherein the Ph group in R.sup.Y bears a single substituent.

[1051] 112. A compound for use according to statement 109, wherein the Ph group in R.sup.Y bears two substituents.

[1052] 113. A compound for use according to any one of statements 100 to 108, wherein R.sup.Y is pyridyl.

[1053] 114. A compound for use according to any one of statements 100 to 108, wherein R.sup.Y is C.sub.3-4 alkyl.

[1054] 115. A compound for use according to any one of statements 100 to 108, wherein R.sup.Y is C.sub.3-6 cycloalkyl.

[1055] 116. A compound for use according to any one of statements 100 to 108, wherein R.sup.Y is selected from:

[1056] a) 2,6-dimethoxyphenyl;

[1057] b) 2,6-dimethoxy, 4-phenylphenyl;

[1058] c) 2-methoxyphenyl;

[1059] d) 2-methoxy, 5-ethylphenyl;

[1060] e) CH.sub.2Ph; and

[1061] f) CH.sub.2CH.sub.2Ph.

[1062] 117. A pharmaceutical composition comprising a compound as defined in any one of statements 100 to 116 and a pharmaceutically acceptable excipient.

[1063] 118. A compound as defined in any one of statements 100 to 116 or a pharmaceutical composition according to statement 117 for use in the treatment of cancer.

[1064] 119. A compound or pharmaceutical composition according to statement 118, wherein the treatment is for simultaneous or sequential administration with radiotherapy and/or chemotherapy.

[1065] 120. A compound as defined in any one of statements 100 to 116 or a pharmaceutical salt thereof.

[1066] 121. A compound according to statement 120, wherein at least one of R.sup.1 to R.sup.5 is not H.

[1067] 122. A compound according to either statement 120 or statement 121, wherein R.sup.2 and R.sup.5 are not H.

[1068] 123. A compound according to any one of statements 120 to 122, wherein R.sup.Y is not (CH.sub.2).sub.n4Ph, wherein the Ph is substituted by a single group which is Cl, F or NO.sub.2.

[1069] 124. A compound according to any one of statements 120 to 123, wherein R.sup.Y is not (CH.sub.2).sub.n4Ph, wherein the Ph is substituted by NO.sub.2.

REFERENCES

[1070] Aggarwal and Calvi, Nature, 2004, 430, 372-376 doi:10.1038/nature02694 [1071] Avvakumov et al., Oncogene, 2007, 26, 5395-5407 doi: 10.1038/sj.one. 1210608 [1072] Berge et al., J. Pharm. Sci., 1977, 66, 1-19 doi: 10.1002/jps.2600660104 [1073] Borrow et al., Nat. Genet., 1996, 14, 33-41 doi:10.1038/ng0996-33 [1074] Dekker et al., Drug, Discov. Today, 2014, 19, 654-660 doi: 10.1016/j.drudis.2013.11.012 [1075] Doyon et al., Mol. Cell., 2006, 27, 51-64 doi:10.1016/j.molcel.2005.12.007 [1076] Dhuban et al., Sci. Immunol., 2017, 2, 9297 doi: 10.1126/sciimmunol.aai9297 [1077] Duong et al., Cancer Res., 2013, 73, 5556-5568 doi:10.1158/0008-5472.CAN-13-0013 [1078] Ghizzoni et al., Eur. J. Med. Chem., 2012, 47, 337-344 doi:10.1016/j.ejmech.2011.11.001 [1079] Gil et al., J. Proteomics, 2017, 150, 297-309 doi:10.1016/j.jprot.2016.10.003 [1080] Gobert, M. et al., Cancer Research, 2009, 69, 2000-2009 doi: 10.1158/0008-5472.CAN-08-2360 [1081] Holbert et al., J. Biol. Chem., 2007, 282, 36603-36613 doi:10.1074/jbc.M705812200 [1082] Iizuka et al., Mol. Cell. Biol., 2006, 26, 1098-1108 doi:10.1128/MCB.26.3.1098-1108.2006 [1083] Iizuka et al., Cancer Sci., 2013, 104, 1647-1655 doi: 10.1111/cas. 12303 [1084] Jeong, et al., Blood Res 2016 51(3), 152-154 doi:10.5045/br.2016.51.3.152 [1085] Joshi, et al., Immunity 2015, 43, 579-590 doi:10.1016/j.immuni.2015.08.006 [1086] Li, B. et al., PNAS, 2007, 104, 4571-4576 doi:10.1073/pnas.0700298104 [1087] Melero, et al. Nature Reviews Cancer, 2015, 15, 457-472 doi:10.1038/nrc3973 [1088] Merson et al., J. Neurosci., 2006, 26, 11359-11370 doi:10.1523/JNEUROSCI.2247-06.2006 [1089] Miller, A. M. et al. J. Immunol., 2006, 177, 7398-7405 doi:10.4049/jimmunol.177.10.7398 [1090] Persa, E. et al. Cancer Letters, 2015 368(2), 252-261 doi:10.1016/j.canlet.2015.03.003 [1091] Sheikh et al., Blood, 2015, 125(12), 1910-21 doi:10.1182/blood-2014-08-594655 [1092] Shi et al, Nature Biotech, 2015, 33, 661-667 doi:10.1038/nbt.3235 [1093] Su et al., Int. J. Mol. Sci., 2016, 17, 1-18 doi:10.3390/ijms17101594 [1094] Stern et al., Crit. Rev. Oncol. Hematol., 2005, 54, 11-29 doi:10.1016/j.critrevonc.2004.10.011 [1095] Thomas et al., Development, 2000, 127, 2537-2548 PMID:10821753 [1096] Tao, H. et al., Lung Cancer, 2012, 75, 95-101 doi:10.1016/j.lungcan.2011.06.002 [1097] Turner-Ivey et al., Neoplasia, 2014, 16(8): 644-655 doi:10.1016/j.neo.2014.07.007 [1098] Valerio et al., Cancer Research, 2017, 77(7), 1753-62 doi:10.1158/0008-5472.CAN-16-2374 [1099] Vizmanos et al., Genes Chromosomes Cancer, 2003, 36(4), 402-405 doi:10.1002/gcc.10174 [1100] Voss et al., BioEssays, 2009, 31(10), 1050-1061 doi:10.1002/bies.200900051 [1101] Wang, L., et al. EBioMedicine, 2016, 13, 99-112 doi:10.1016/j.ebiom.2016.10.018 [1102] Wang, X. et al., Oncogene, 2017, 36, 3048-3058 doi:10.1038/onc.2016.458 [1103] Xiao, Y. et al., Cell reports, 2014, 7, 1471-1480 doi:10.1016/j.celrep.2014.04.021 [1104] Yan, M. et al., Breast Cancer Research, 2011, 13, R.sup.47 doi: 10.1186/bcr2869 [1105] Zack et al., Nature Genetics 2013 45, 1134-1140 doi:10.1038/ng.2760 [1106] Zhang et al., Mini. Rev. Med. Chem., 2017, 17, 1-8 doi: 10.2174/1389557516666160923125031